Journal articles: 'Mitochondrial oxidative folding'

1

Morgan, Bruce, and Hui Lu. "Oxidative folding competes with mitochondrial import of the small Tim proteins." Biochemical Journal 411, no. 1 (March 13, 2008): 115–22. http://dx.doi.org/10.1042/bj20071476.

Full text

Abstract:

All small Tim proteins of the mitochondrial intermembrane space contain two conserved CX3C motifs, which form two intramolecular disulfide bonds essential for function, but only the cysteine-reduced, but not oxidized, proteins can be imported into mitochondria. We have shown that Tim10 can be oxidized by glutathione under cytosolic concentrations. However, it was unknown whether oxidative folding of other small Tims can occur under similar conditions and whether oxidative folding competes kinetically with mitochondrial import. In the present study, the effect of glutathione on the cysteine-redox state of Tim9 was investigated, and the standard redox potential of Tim9 was determined to be approx. −0.31 V at pH 7.4 and 25 °C with both the wild-type and Tim9F43W mutant proteins, using reverse-phase HPLC and fluorescence approaches. The results show that reduced Tim9 can be oxidized by glutathione under cytosolic concentrations. Next, we studied the rate of mitochondrial import and oxidative folding of Tim9 under identical conditions. The rate of import was approx. 3-fold slower than that of oxidative folding of Tim9, resulting in approx. 20% of the precursor protein being imported into an excess amount of mitochondria. A similar correlation between import and oxidative folding was obtained for Tim10. Therefore we conclude that oxidative folding and mitochondrial import are kinetically competitive processes. The efficiency of mitochondrial import of the small Tim proteins is controlled, at least partially in vitro, by the rate of oxidative folding, suggesting that a cofactor is required to stabilize the cysteine residues of the precursors from oxidation in vivo.

APA, Harvard, Vancouver, ISO, and other styles

2

Wrobel, Lidia, Agata Trojanowska, Malgorzata E. Sztolsztener, and Agnieszka Chacinska. "Mitochondrial protein import: Mia40 facilitates Tim22 translocation into the inner membrane of mitochondria." Molecular Biology of the Cell 24, no. 5 (March 2013): 543–54. http://dx.doi.org/10.1091/mbc.e12-09-0649.

Full text

Abstract:

The mitochondrial intermembrane space assembly (MIA) pathway is generally considered to be dedicated to the redox-dependent import and biogenesis of proteins localized to the intermembrane space of mitochondria. The oxidoreductase Mia40 is a central component of the pathway responsible for the transfer of disulfide bonds to intermembrane space precursor proteins, causing their oxidative folding. Here we present the first evidence that the function of Mia40 is not restricted to the transport and oxidative folding of intermembrane space proteins. We identify Tim22, a multispanning membrane protein and core component of the TIM22 translocase of inner membrane, as a protein with cysteine residues undergoing oxidation during Tim22 biogenesis. We show that Mia40 is involved in the biogenesis and complex assembly of Tim22. Tim22 forms a disulfide-bonded intermediate with Mia40 upon import into mitochondria. Of interest, Mia40 binds the Tim22 precursor also via noncovalent interactions. We propose that Mia40 not only is responsible for disulfide bond formation, but also assists the Tim22 protein in its integration into the inner membrane of mitochondria.

APA, Harvard, Vancouver, ISO, and other styles

3

Böttinger, Lena, Agnieszka Gornicka, Tomasz Czerwik, Piotr Bragoszewski, Adrianna Loniewska-Lwowska, Agnes Schulze-Specking, Kaye N. Truscott, Bernard Guiard, Dusanka Milenkovic, and Agnieszka Chacinska. "In vivo evidence for cooperation of Mia40 and Erv1 in the oxidation of mitochondrial proteins." Molecular Biology of the Cell 23, no. 20 (October 15, 2012): 3957–69. http://dx.doi.org/10.1091/mbc.e12-05-0358.

Full text

Abstract:

The intermembrane space of mitochondria accommodates the essential mitochondrial intermembrane space assembly (MIA) machinery that catalyzes oxidative folding of proteins. The disulfide bond formation pathway is based on a relay of reactions involving disulfide transfer from the sulfhydryl oxidase Erv1 to Mia40 and from Mia40 to substrate proteins. However, the substrates of the MIA typically contain two disulfide bonds. It was unclear what the mechanisms are that ensure that proteins are released from Mia40 in a fully oxidized form. In this work, we dissect the stage of the oxidative folding relay, in which Mia40 binds to its substrate. We identify dynamics of the Mia40–substrate intermediate complex. Our experiments performed in a native environment, both in organello and in vivo, show that Erv1 directly participates in Mia40–substrate complex dynamics by forming a ternary complex. Thus Mia40 in cooperation with Erv1 promotes the formation of two disulfide bonds in the substrate protein, ensuring the efficiency of oxidative folding in the intermembrane space of mitochondria.

APA, Harvard, Vancouver, ISO, and other styles

4

Fischer, Manuel, Sebastian Horn, Anouar Belkacemi, Kerstin Kojer, Carmelina Petrungaro, Markus Habich, Muna Ali, et al. "Protein import and oxidative folding in the mitochondrial intermembrane space of intact mammalian cells." Molecular Biology of the Cell 24, no. 14 (July 15, 2013): 2160–70. http://dx.doi.org/10.1091/mbc.e12-12-0862.

Full text

Abstract:

Oxidation of cysteine residues to disulfides drives import of many proteins into the intermembrane space of mitochondria. Recent studies in yeast unraveled the basic principles of mitochondrial protein oxidation, but the kinetics under physiological conditions is unknown. We developed assays to follow protein oxidation in living mammalian cells, which reveal that import and oxidative folding of proteins are kinetically and functionally coupled and depend on the oxidoreductase Mia40, the sulfhydryl oxidase augmenter of liver regeneration (ALR), and the intracellular glutathione pool. Kinetics of substrate oxidation depends on the amount of Mia40 and requires tightly balanced amounts of ALR. Mia40-dependent import of Cox19 in human cells depends on the inner membrane potential. Our observations reveal considerable differences in the velocities of mitochondrial import pathways: whereas preproteins with bipartite targeting sequences are imported within seconds, substrates of Mia40 remain in the cytosol for several minutes and apparently escape premature degradation and oxidation.

APA, Harvard, Vancouver, ISO, and other styles

5

Szarka, András, and Gábor Bánhegyi. "Oxidative folding: recent developments." BioMolecular Concepts 2, no. 5 (October 1, 2011): 379–90. http://dx.doi.org/10.1515/bmc.2011.038.

Full text

Abstract:

AbstractDisulfide bond formation in proteins is an effective tool of both structure stabilization and redox regulation. The prokaryotic periplasm and the endoplasmic reticulum of eukaryotes were long considered as the only compartments for enzyme mediated formation of stable disulfide bonds. Recently, the mitochondrial intermembrane space has emerged as the third protein-oxidizing compartment. The classic view on the mechanism of oxidative folding in the endoplasmic reticulum has also been reshaped by new observations. Moreover, besides the structure stabilizing function, reversible disulfide bridge formation in some proteins of the endoplasmic reticulum, seems to play a regulatory role. This review briefly summarizes the present knowledge of the redox systems supporting oxidative folding, emphasizing recent developments.

APA, Harvard, Vancouver, ISO, and other styles

6

Bragoszewski, Piotr, Michal Wasilewski, Paulina Sakowska, Agnieszka Gornicka, Lena Böttinger, Jian Qiu, Nils Wiedemann, and Agnieszka Chacinska. "Retro-translocation of mitochondrial intermembrane space proteins." Proceedings of the National Academy of Sciences 112, no. 25 (June 8, 2015): 7713–18. http://dx.doi.org/10.1073/pnas.1504615112.

Full text

Abstract:

The content of mitochondrial proteome is maintained through two highly dynamic processes, the influx of newly synthesized proteins from the cytosol and the protein degradation. Mitochondrial proteins are targeted to the intermembrane space by the mitochondrial intermembrane space assembly pathway that couples their import and oxidative folding. The folding trap was proposed to be a driving mechanism for the mitochondrial accumulation of these proteins. Whether the reverse movement of unfolded proteins to the cytosol occurs across the intact outer membrane is unknown. We found that reduced, conformationally destabilized proteins are released from mitochondria in a size-limited manner. We identified the general import pore protein Tom40 as an escape gate. We propose that the mitochondrial proteome is not only regulated by the import and degradation of proteins but also by their retro-translocation to the external cytosolic location. Thus, protein release is a mechanism that contributes to the mitochondrial proteome surveillance.

APA, Harvard, Vancouver, ISO, and other styles

7

Tang, Xiaofan, Lynda K. Harris, and Hui Lu. "Effects of Liposome and Cardiolipin on Folding and Function of Mitochondrial Erv1." International Journal of Molecular Sciences 21, no. 24 (December 10, 2020): 9402. http://dx.doi.org/10.3390/ijms21249402.

Full text

Abstract:

Erv1 (EC number 1.8.3.2) is an essential mitochondrial enzyme catalyzing protein import and oxidative folding in the mitochondrial intermembrane space. Erv1 has both oxidase and cytochrome c reductase activities. While both Erv1 and cytochrome c were reported to be membrane associated in mitochondria, it is unknown how the mitochondrial membrane environment may affect the function of Erv1. Here, in this study, we used liposomes to mimic the mitochondrial membrane and investigated the effect of liposomes and cardiolipin on the folding and function of yeast Erv1. Enzyme kinetics of both the oxidase and cytochrome c reductase activity of Erv1 were studied using oxygen consumption analysis and spectroscopic methods. Our results showed that the presence of liposomes has mild impacts on Erv1 oxidase activity, but significantly inhibited the catalytic efficiency of Erv1 cytochrome c reductase activity in a cardiolipin-dependent manner. Taken together, the results of this study provide important insights into the function of Erv1 in the mitochondria, suggesting that molecular oxygen is a better substrate than cytochrome c for Erv1 in the yeast mitochondria.

APA, Harvard, Vancouver, ISO, and other styles

8

Clarke, Benjamin E., Bernadett Kalmar, and Linda Greensmith. "Enhanced Expression of TRAP1 Protects Mitochondrial Function in Motor Neurons under Conditions of Oxidative Stress." International Journal of Molecular Sciences 23, no. 3 (February 4, 2022): 1789. http://dx.doi.org/10.3390/ijms23031789.

Full text

Abstract:

TNF-receptor associated protein (TRAP1) is a cytoprotective mitochondrial-specific member of the Hsp90 heat shock protein family of protein chaperones that has been shown to antagonise mitochondrial apoptosis and oxidative stress, regulate the mitochondrial permeability transition pore and control protein folding in mitochondria. Here we show that overexpression of TRAP1 protects motor neurons from mitochondrial dysfunction and death induced by exposure to oxidative stress conditions modelling amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease in which motor neurons degenerate, leading to muscle weakness and atrophy and death, typically within 3 years of diagnosis. In primary murine motor neurons, shRNA-mediated knockdown of TRAP1 expression results in mitochondrial dysfunction but does not further exacerbate damage induced by oxidative stress alone. Together, these results show that TRAP1 may be a potential therapeutic target for neurodegenerative diseases such as ALS, where mitochondrial dysfunction has been shown to be an early marker of pathogenesis.

APA, Harvard, Vancouver, ISO, and other styles

9

Sideris, Dionisia P., and Kostas Tokatlidis. "Oxidative Protein Folding in the Mitochondrial Intermembrane Space." Antioxidants & Redox Signaling 13, no. 8 (October 15, 2010): 1189–204. http://dx.doi.org/10.1089/ars.2010.3157.

Full text

APA, Harvard, Vancouver, ISO, and other styles

10

Kojer, Kerstin, Valentina Peleh, Gaetano Calabrese, Johannes M. Herrmann, and Jan Riemer. "Kinetic control by limiting glutaredoxin amounts enables thiol oxidation in the reducing mitochondrial intermembrane space." Molecular Biology of the Cell 26, no. 2 (January 15, 2015): 195–204. http://dx.doi.org/10.1091/mbc.e14-10-1422.

Full text

Abstract:

The mitochondrial intermembrane space (IMS) harbors an oxidizing machinery that drives import and folding of small cysteine-containing proteins without targeting signals. The main component of this pathway is the oxidoreductase Mia40, which introduces disulfides into its substrates. We recently showed that the IMS glutathione pool is maintained as reducing as that of the cytosol. It thus remained unclear how equilibration of protein disulfides with the IMS glutathione pool is prevented in order to allow oxidation-driven protein import. Here we demonstrate the presence of glutaredoxins in the IMS and show that limiting amounts of these glutaredoxins provide a kinetic barrier to prevent the thermodynamically feasible reduction of Mia40 substrates by the IMS glutathione pool. Moreover, they allow Mia40 to exist in a predominantly oxidized state. Consequently, overexpression of glutaredoxin 2 in the IMS results in a more reduced Mia40 redox state and a delay in oxidative folding and mitochondrial import of different Mia40 substrates. Our findings thus indicate that carefully balanced glutaredoxin amounts in the IMS ensure efficient oxidative folding in the reducing environment of this compartment.

APA, Harvard, Vancouver, ISO, and other styles

11

Dickson-Murray, Eleanor, Kenza Nedara, Nazanine Modjtahedi, and Kostas Tokatlidis. "The Mia40/CHCHD4 Oxidative Folding System: Redox Regulation and Signaling in the Mitochondrial Intermembrane Space." Antioxidants 10, no. 4 (April 12, 2021): 592. http://dx.doi.org/10.3390/antiox10040592.

Full text

Abstract:

Mitochondria are critical for several cellular functions as they control metabolism, cell physiology, and cell death. The mitochondrial proteome consists of around 1500 proteins, the vast majority of which (about 99% of them) are encoded by nuclear genes, with only 13 polypeptides in human cells encoded by mitochondrial DNA. Therefore, it is critical for all the mitochondrial proteins that are nuclear-encoded to be targeted precisely and sorted specifically to their site of action inside mitochondria. These processes of targeting and sorting are catalysed by protein translocases that operate in each one of the mitochondrial sub-compartments. The main protein import pathway for the intermembrane space (IMS) recognises proteins that are cysteine-rich, and it is the only import pathway that chemically modifies the imported precursors by introducing disulphide bonds to them. In this manner, the precursors are trapped in the IMS in a folded state. The key component of this pathway is Mia40 (called CHCHD4 in human cells), which itself contains cysteine motifs and is subject to redox regulation. In this review, we detail the basic components of the MIA pathway and the disulphide relay mechanism that underpins the electron transfer reaction along the oxidative folding mechanism. Then, we discuss the key protein modulators of this pathway and how they are interlinked to the small redox-active molecules that critically affect the redox state in the IMS. We present also evidence that the mitochondrial redox processes that are linked to iron–sulfur clusters biogenesis and calcium homeostasis coalesce in the IMS at the MIA machinery. The fact that the MIA machinery and several of its interactors and substrates are linked to a variety of common human diseases connected to mitochondrial dysfunction highlight the potential of redox processes in the IMS as a promising new target for developing new treatments for some of the most complex and devastating human diseases.

APA, Harvard, Vancouver, ISO, and other styles

12

Ramos Rego, Inês, Beatriz Santos Cruz, António Francisco Ambrósio, and Celso Henrique Alves. "TRAP1 in Oxidative Stress and Neurodegeneration." Antioxidants 10, no. 11 (November 19, 2021): 1829. http://dx.doi.org/10.3390/antiox10111829.

Full text

Abstract:

Tumor necrosis factor receptor-associated protein 1 (TRAP1), also known as heat shock protein 75 (HSP75), is a member of the heat shock protein 90 (HSP90) chaperone family that resides mainly in the mitochondria. As a mitochondrial molecular chaperone, TRAP1 supports protein folding and contributes to the maintenance of mitochondrial integrity even under cellular stress. TRAP1 is a cellular regulator of mitochondrial bioenergetics, redox homeostasis, oxidative stress-induced cell death, apoptosis, and unfolded protein response (UPR) in the endoplasmic reticulum (ER). TRAP1 has attracted increasing interest as a therapeutical target, with a special focus on the design of TRAP1 specific inhibitors. Although TRAP1 was extensively studied in the oncology field, its role in central nervous system cells, under physiological and pathological conditions, remains largely unknown. In this review, we will start by summarizing the biology of TRAP1, including its structure and related pathways. Thereafter, we will continue by debating the role of TRAP1 in the maintenance of redox homeostasis and protection against oxidative stress and apoptosis. The role of TRAP1 in neurodegenerative disorders will also be discussed. Finally, we will review the potential of TRAP1 inhibitors as neuroprotective drugs.

APA, Harvard, Vancouver, ISO, and other styles

13

Ferreiro, E., I. Baldeiras, I. L. Ferreira, R. O. Costa, A. C. Rego, C. F. Pereira, and C. R. Oliveira. "Mitochondrial- and Endoplasmic Reticulum-Associated Oxidative Stress in Alzheimer's Disease: From Pathogenesis to Biomarkers." International Journal of Cell Biology 2012 (2012): 1–23. http://dx.doi.org/10.1155/2012/735206.

Full text

Abstract:

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, affecting several million of people worldwide. Pathological changes in the AD brain include the presence of amyloid plaques, neurofibrillary tangles, loss of neurons and synapses, and oxidative damage. These changes strongly associate with mitochondrial dysfunction and stress of the endoplasmic reticulum (ER). Mitochondrial dysfunction is intimately linked to the production of reactive oxygen species (ROS) and mitochondrial-driven apoptosis, which appear to be aggravated in the brain of AD patients. Concomitantly, mitochondria are closely associated with ER, and the deleterious crosstalk between both organelles has been shown to be involved in neuronal degeneration in AD. Stimuli that enhance expression of normal and/or folding-defective proteins activate an adaptive unfolded protein response (UPR) that, if unresolved, can cause apoptotic cell death. ER stress also induces the generation of ROS that, together with mitochondrial ROS and decreased activity of several antioxidant defenses, promotes chronic oxidative stress. In this paper we discuss the critical role of mitochondrial and ER dysfunction in oxidative injury in AD cellular and animal models, as well as in biological fluids from AD patients. Progress in developing peripheral and cerebrospinal fluid biomarkers related to oxidative stress will also be summarized.

APA, Harvard, Vancouver, ISO, and other styles

14

Klöppel, Christine, Yutaka Suzuki, Kerstin Kojer, Carmelina Petrungaro, Sebastian Longen, Sebastian Fiedler, Sandro Keller, and Jan Riemer. "Mia40-dependent oxidation of cysteines in domain I of Ccs1 controls its distribution between mitochondria and the cytosol." Molecular Biology of the Cell 22, no. 20 (October 15, 2011): 3749–57. http://dx.doi.org/10.1091/mbc.e11-04-0293.

Full text

Abstract:

Superoxide dismutase 1 (Sod1) is an important antioxidative enzyme that converts superoxide anions to hydrogen peroxide and water. Active Sod1 is a homodimer containing one zinc ion, one copper ion, and one disulfide bond per subunit. Maturation of Sod1 depends on its copper chaperone (Ccs1). Sod1 and Ccs1 are dually localized proteins that reside in the cytosol and in the intermembrane space of mitochondria. The import of Ccs1 into mitochondria depends on the mitochondrial disulfide relay system. However, the exact mechanism of this import process has been unclear. In this study we detail the import and folding pathway of Ccs1 and characterize its interaction with the oxidoreductase of the mitochondrial disulfide relay Mia40. We identify cysteines at positions 27 and 64 in domain I of Ccs1 as critical for mitochondrial import and interaction with Mia40. On interaction with Mia40, these cysteines form a structural disulfide bond that stabilizes the overall fold of domain I. Although the cysteines are essential for the accumulation of functional Ccs1 in mitochondria, they are dispensable for the enzymatic activity of cytosolic Ccs1. We propose a model in which the Mia40-mediated oxidative folding of domain I controls the cellular distribution of Ccs1 and, consequently, active Sod1.

APA, Harvard, Vancouver, ISO, and other styles

15

Kunová, Nina, Henrieta Havalová, Gabriela Ondrovičová, Barbora Stojkovičová, Jacob A. Bauer, Vladena Bauerová-Hlinková, Vladimir Pevala, and Eva Kutejová. "Mitochondrial Processing Peptidases—Structure, Function and the Role in Human Diseases." International Journal of Molecular Sciences 23, no. 3 (January 24, 2022): 1297. http://dx.doi.org/10.3390/ijms23031297.

Full text

Abstract:

Mitochondrial proteins are encoded by both nuclear and mitochondrial DNA. While some of the essential subunits of the oxidative phosphorylation (OXPHOS) complexes responsible for cellular ATP production are synthesized directly in the mitochondria, most mitochondrial proteins are first translated in the cytosol and then imported into the organelle using a sophisticated transport system. These proteins are directed mainly by targeting presequences at their N-termini. These presequences need to be cleaved to allow the proper folding and assembly of the pre-proteins into functional protein complexes. In the mitochondria, the presequences are removed by several processing peptidases, including the mitochondrial processing peptidase (MPP), the inner membrane processing peptidase (IMP), the inter-membrane processing peptidase (MIP), and the mitochondrial rhomboid protease (Pcp1/PARL). Their proper functioning is essential for mitochondrial homeostasis as the disruption of any of them is lethal in yeast and severely impacts the lifespan and survival in humans. In this review, we focus on characterizing the structure, function, and substrate specificities of mitochondrial processing peptidases, as well as the connection of their malfunctions to severe human diseases.

APA, Harvard, Vancouver, ISO, and other styles

16

Backes, Sandra, Sriram G. Garg, Laura Becker, Valentina Peleh, Rudi Glockshuber, Sven B. Gould, and Johannes M. Herrmann. "Development of the Mitochondrial Intermembrane Space Disulfide Relay Represents a Critical Step in Eukaryotic Evolution." Molecular Biology and Evolution 36, no. 4 (January 22, 2019): 742–56. http://dx.doi.org/10.1093/molbev/msz011.

Full text

Abstract:

Abstract The mitochondrial intermembrane space evolved from the bacterial periplasm. Presumably as a consequence of their common origin, most proteins of these compartments are stabilized by structural disulfide bonds. The molecular machineries that mediate oxidative protein folding in bacteria and mitochondria, however, appear to share no common ancestry. Here we tested whether the enzymes Erv1 and Mia40 of the yeast mitochondrial disulfide relay could be functionally replaced by corresponding components of other compartments. We found that the sulfhydryl oxidase Erv1 could be replaced by the Ero1 oxidase or the protein disulfide isomerase from the endoplasmic reticulum, however at the cost of respiration deficiency. In contrast to Erv1, the mitochondrial oxidoreductase Mia40 proved to be indispensable and could not be replaced by thioredoxin-like enzymes, including the cytoplasmic reductase thioredoxin, the periplasmic dithiol oxidase DsbA, and Pdi1. From our studies we conclude that the profound inertness against glutathione, its slow oxidation kinetics and its high affinity to substrates renders Mia40 a unique and essential component of mitochondrial biogenesis. Evidently, the development of a specific mitochondrial disulfide relay system represented a crucial step in the evolution of the eukaryotic cell.

APA, Harvard, Vancouver, ISO, and other styles

17

Chen, Danica. "The Mitochondrial Metabolic Checkpoint and Reversing Stem Cell Aging." Blood 128, no. 22 (December 2, 2016): SCI—34—SCI—34. http://dx.doi.org/10.1182/blood.v128.22.sci-34.sci-34.

Full text

Abstract:

Abstract Cell cycle checkpoints are surveillance mechanisms in eukaryotic cells that monitor the condition of the cell, repair cellular damages, and allow the cell to progress through the various phases of the cell cycle when conditions become favorable. Recent advances in hematopoietic stem cell (HSC) biology highlight a mitochondrial metabolic checkpoint that is essential for HSCs to return to the quiescent state. As quiescent HSCs enter the cell cycle, mitochondrial biogenesis is induced, which is associated with increased mitochondrial protein folding stress and mitochondrial oxidative stress. Mitochondrial unfolded protein response and mitochondrial oxidative stress response are activated to alleviate stresses and allow HSCs to exit the cell cycle and return to quiescence. Other mitochondrial maintenance mechanisms include mitophagy and asymmetric segregation of aged mitochondria. Because loss of HSC quiescence results in the depletion of the HSC pool and compromised tissue regeneration, deciphering the molecular mechanisms that regulate the mitochondrial metabolic checkpoint in HSCs will increase our understanding of hematopoiesis and how it becomes dysregulated under pathological conditions and during aging. More broadly, this knowledge is instrumental for understanding the maintenance of cells that convert between quiescence and proliferation to support their physiological functions. Disclosures No relevant conflicts of interest to declare.

APA, Harvard, Vancouver, ISO, and other styles

18

Pająk, Beata, Elżbieta Kania, and Arkadiusz Orzechowski. "Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer’s Disease." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–17. http://dx.doi.org/10.1155/2016/1805304.

Full text

Abstract:

This review is focused on the possible causes of mitochondrial dysfunction in AD, underlying molecular mechanisms of this malfunction, possible causes and known consequences of APP, Aβ, and hyperphosphorylated tau presence in mitochondria, and the contribution of altered lipid metabolism (nonsterol isoprenoids) to pathological processes leading to increased formation and accumulation of the aforementioned hallmarks of AD. Abnormal protein folding and unfolded protein response seem to be the outcomes of impaired glycosylation due to metabolic disturbances in geranylgeraniol intermediary metabolism. The origin and consecutive fate of APP, Aβ, and tau are emphasized on intracellular trafficking apparently influenced by inaccurate posttranslational modifications. We hypothesize that incorrect intracellular processing of APP determines protein translocation to mitochondria in AD. Similarly, without obvious reasons, the passage of Aβand tau to mitochondria is observed. APP targeted to mitochondria blocks the activity of protein translocase complex resulting in poor import of proteins central to oxidative phosphorylation. Besides, APP, Aβ, and neurofibrillary tangles of tau directly or indirectly impair mitochondrial biochemistry and bioenergetics, with concomitant generation of oxidative/nitrosative stress. Limited protective mechanisms are inadequate to prevent the free radical-mediated lesions. Finally, neuronal loss is observed in AD-affected brains typically by pathologic apoptosis.

APA, Harvard, Vancouver, ISO, and other styles

19

Phuong, Huong Thi, Yuki Ishiwata-Kimata, Yuki Nishi, Norie Oguchi, Hiroshi Takagi, and Yukio Kimata. "Aeration mitigates endoplasmic reticulum stress in Saccharomyces cerevisiae even without mitochondrial respiration." Microbial Cell 8, no. 4 (April 5, 2021): 77–86. http://dx.doi.org/10.15698/mic2021.04.746.

Full text

Abstract:

Saccharomyces cerevisiae is a facultative anaerobic organism that grows well under both aerobic and hypoxic conditions in media containing abundant fermentable nutrients such as glucose. In order to deeply understand the physiological dependence of S. cerevisiae on aeration, we checked endoplasmic reticulum (ER)-stress status by monitoring the splicing of HAC1 mRNA, which is promoted by the ER stress-sensor protein, Ire1. HAC1-mRNA splicing that was caused by conventional ER-stressing agents, including low concentrations of dithiothreitol (DTT), was more potent in hypoxic cultures than in aerated cultures. Moreover, growth retardation was observed by adding low-dose DTT into hypoxic cultures of ire1∆ cells. Unexpectedly, aeration mitigated ER stress and DTT-induced impairment of ER oxidative protein folding even when mitochondrial respiration was halted by the ro mutation. An ER-located protein Ero1 is known to directly consume molecular oxygen to initiate the ER protein oxidation cascade, which promotes oxidative protein folding of ER client proteins. Our further study using ero1-mutant strains suggested that, in addition to mitochondrial respiration, this Ero1-medaited reaction contributes to mitigation of ER stress by molecular oxygen. Taken together, here we demonstrate a scenario in which aeration acts beneficially on S. cerevisiae cells even under fermentative conditions.

APA, Harvard, Vancouver, ISO, and other styles

20

Neal, Sonya E., Deepa V. Dabir, Juwina Wijaya, Cennyana Boon, and Carla M. Koehler. "Osm1 facilitates the transfer of electrons from Erv1 to fumarate in the redox-regulated import pathway in the mitochondrial intermembrane space." Molecular Biology of the Cell 28, no. 21 (October 15, 2017): 2773–85. http://dx.doi.org/10.1091/mbc.e16-10-0712.

Full text

Abstract:

Prokaryotes have aerobic and anaerobic electron acceptors for oxidative folding of periplasmic proteins. The mitochondrial intermembrane space has an analogous pathway with the oxidoreductase Mia40 and sulfhydryl oxidase Erv1, termed the mitochondrial intermembrane space assembly (MIA) pathway. The aerobic electron acceptors include oxygen and cytochrome c, but an acceptor that can function under anaerobic conditions has not been identified. Here we show that the fumarate reductase Osm1, which facilitates electron transfer from fumarate to succinate, fills this gap as a new electron acceptor. In addition to microsomes, Osm1 localizes to the mitochondrial intermembrane space and assembles with Erv1 in a complex. In reconstitution studies with reduced Tim13, Mia40, and Erv1, the addition of Osm1 and fumarate completes the disulfide exchange pathway that results in Tim13 oxidation. From in vitro import assays, mitochondria lacking Osm1 display decreased import of MIA substrates, Cmc1 and Tim10. Comparative reconstitution assays support that the Osm1/fumarate couple accepts electrons with similar efficiency to cytochrome c and that the cell has strategies to coordinate expression of the terminal electron acceptors. Thus Osm1/fumarate is a new electron acceptor couple in the mitochondrial intermembrane space that seems to function in both aerobic and anaerobic conditions.

APA, Harvard, Vancouver, ISO, and other styles

21

Fischer, Manuel, and Jan Riemer. "The Mitochondrial Disulfide Relay System: Roles in Oxidative Protein Folding and Beyond." International Journal of Cell Biology 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/742923.

Full text

Abstract:

Disulfide bond formation drives protein import of most proteins of the mitochondrial intermembrane space (IMS). The main components of this disulfide relay machinery are the oxidoreductase Mia40 and the sulfhydryl oxidase Erv1/ALR. Their precise functions have been elucidated in molecular detail for the yeast and human enzymesin vitroand in intact cells. However, we still lack knowledge on how Mia40 and Erv1/ALR impact cellular and organism physiology and whether they have functions beyond their role in disulfide bond formation. Here we summarize the principles of oxidation-dependent protein import mediated by the mitochondrial disulfide relay. We proceed by discussing recently described functions of Mia40 in the hypoxia response and of ALR in influencing mitochondrial morphology and its importance for tissue development and embryogenesis. We also include a discussion of the still mysterious function of Erv1/ALR in liver regeneration.

APA, Harvard, Vancouver, ISO, and other styles

22

Marada, Adinarayana, Praveen Kumar Allu, Anjaneyulu Murari, BhoomiReddy PullaReddy, Prasad Tammineni, Venkata Ramana Thiriveedi, Jayasree Danduprolu, and Naresh Babu V. Sepuri. "Mge1, a nucleotide exchange factor of Hsp70, acts as an oxidative sensor to regulate mitochondrial Hsp70 function." Molecular Biology of the Cell 24, no. 6 (March 15, 2013): 692–703. http://dx.doi.org/10.1091/mbc.e12-10-0719.

Full text

Abstract:

Despite the growing evidence of the role of oxidative stress in disease, its molecular mechanism of action remains poorly understood. The yeast Saccharomyces cerevisiae provides a valuable model system in which to elucidate the effects of oxidative stress on mitochondria in higher eukaryotes. Dimeric yeast Mge1, the cochaperone of heat shock protein 70 (Hsp70), is essential for exchanging ATP for ADP on Hsp70 and thus for recycling of Hsp70 for mitochondrial protein import and folding. Here we show an oxidative stress–dependent decrease in Mge1 dimer formation accompanied by a concomitant decrease in Mge1–Hsp70 complex formation in vitro. The Mge1-M155L substitution mutant stabilizes both Mge1 dimer and Mge1–Hsp70 complex formation. Most important, the Mge1-M155L mutant rescues the slow-growth phenomenon associated with the wild-type Mge1 strain in the presence of H2O2 in vivo, stimulation of the ATPase activity of Hsp70, and the protein import defect during oxidative stress in vitro. Furthermore, cross-linking studies reveal that Mge1–Hsp70 complex formation in mitochondria isolated from wild-type Mge1 cells is more susceptible to reactive oxygen species compared with mitochondria from Mge1-M155L cells. This novel oxidative sensor capability of yeast Mge1 might represent an evolutionarily conserved function, given that human recombinant dimeric Mge1 is also sensitive to H2O2.

APA, Harvard, Vancouver, ISO, and other styles

23

Choubey, Vinay, Akbar Zeb, and Allen Kaasik. "Molecular Mechanisms and Regulation of Mammalian Mitophagy." Cells 11, no. 1 (December 23, 2021): 38. http://dx.doi.org/10.3390/cells11010038.

Full text

Abstract:

Mitochondria in the cell are the center for energy production, essential biomolecule synthesis, and cell fate determination. Moreover, the mitochondrial functional versatility enables cells to adapt to the changes in cellular environment and various stresses. In the process of discharging its cellular duties, mitochondria face multiple types of challenges, such as oxidative stress, protein-related challenges (import, folding, and degradation) and mitochondrial DNA damage. They mitigate all these challenges with robust quality control mechanisms which include antioxidant defenses, proteostasis systems (chaperones and proteases) and mitochondrial biogenesis. Failure of these quality control mechanisms leaves mitochondria as terminally damaged, which then have to be promptly cleared from the cells before they become a threat to cell survival. Such damaged mitochondria are degraded by a selective form of autophagy called mitophagy. Rigorous research in the field has identified multiple types of mitophagy processes based on targeting signals on damaged or superfluous mitochondria. In this review, we provide an in-depth overview of mammalian mitophagy and its importance in human health and diseases. We also attempted to highlight the future area of investigation in the field of mitophagy.

APA, Harvard, Vancouver, ISO, and other styles

24

Schapira, Anthony H. V., and Matthew Gegg. "Mitochondrial Contribution to Parkinson's Disease Pathogenesis." Parkinson's Disease 2011 (2011): 1–7. http://dx.doi.org/10.4061/2011/159160.

Full text

Abstract:

The identification of the etiologies and pathogenesis of Parkinson's disease (PD) should play an important role in enabling the development of novel treatment strategies to prevent or slow the progression of the disease. The last few years have seen enormous progress in this respect. Abnormalities of mitochondrial function and increased free radical mediated damage were described in post mortem PD brain before the first gene mutations causing familial PD were published. Several genetic causes are now known to induce loss of dopaminergic cells and parkinsonism, and study of the mechanisms by which these mutations produce this effect has provided important insights into the pathogenesis of PD and confirmed mitochondrial dysfunction and oxidative stress pathways as central to PD pathogenesis. Abnormalities of protein metabolism including protein mis-folding and aggregation are also crucial to the pathology of PD. Genetic causes of PD have specifically highlighted the importance of mitochondrial dysfunction to PD: PINK1, parkin, DJ-1 and most recently alpha-synuclein proteins have been shown to localise to mitochondria and influence function. The turnover of mitochondria by autophagy (mitophagy) has also become a focus of attention. This review summarises recent discoveries in the contribution of mitochondrial abnormalities to PD etiology and pathogenesis.

APA, Harvard, Vancouver, ISO, and other styles

25

Friedman, Jeffrey S., Mary F. Lopez, Mark D. Fleming, Alicia Rivera, Florent M. Martin, Megan L. Welsh, Ashleigh Boyd, Susan R. Doctrow, and Steven J. Burakoff. "SOD2-deficiency anemia: protein oxidation and altered protein expression reveal targets of damage, stress response, and antioxidant responsiveness." Blood 104, no. 8 (October 15, 2004): 2565–73. http://dx.doi.org/10.1182/blood-2003-11-3858.

Full text

Abstract:

Abstract SOD2 is an antioxidant protein that protects cells against mitochondrial superoxide. Hematopoietic stem cells (HSCs) lacking SOD2 are capable of rescuing lethally irradiated hosts, but reconstituted animals display a persistent hemolytic anemia characterized by increased oxidative damage to red cells, with morphologic similarity to human “sideroblastic” anemia. We report further characterization of this novel SOD2-deficiency anemia. Electron micrographs of SOD2-deficient reticulocytes reveal striking mitochondrial proliferation and mitochondrial membrane thickening. Peripheral blood smears show abundant iron-stainable granules in mature red cells (siderocytes). Fluorescence-activated cell sorting (FACS) analysis of cells labeled with oxidation-sensitive dyes demonstrates enhanced production of superoxide and hydrogen peroxide by SOD2-deficient cells. Oxidative damage to proteins is increased in SOD2-deficient cells, with much of the damage affecting membrane/insoluble proteins. Red cell proteome analysis demonstrates that several proteins involved in folding/chaperone function, redox regulation, adenosine triphosphate (ATP) synthesis, and red cell metabolism show altered expression in SOD2-deficient cells. This data, combined with information on how protein expression levels change upon antioxidant therapy, will aid in identification of proteins that are sensitive to oxidative damage in this model, and by extension, may have a role in the regulation of red cell lifespan in other hemolytic disorders.

APA, Harvard, Vancouver, ISO, and other styles

26

Jankovic, Milena, Ivana Novakovic, Phepy Gamil Anwar Dawod, Ayman Gamil Anwar Dawod, Aleksandra Drinic, Fayda I. Abdel Motaleb, Sinisa Ducic, and Dejan Nikolic. "Current Concepts on Genetic Aspects of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis." International Journal of Molecular Sciences 22, no. 18 (September 11, 2021): 9832. http://dx.doi.org/10.3390/ijms22189832.

Full text

Abstract:

Amyotrophic Lateral Sclerosis (ALS), neurodegenerative motor neuron disorder is characterized as multisystem disease with important contribution of genetic factors. The etiopahogenesis of ALS is not fully elucidate, but the dominant theory at present relates to RNA processing, as well as protein aggregation and miss-folding, oxidative stress, glutamate excitotoxicity, inflammation and epigenetic dysregulation. Additionally, as mitochondria plays a leading role in cellular homeostasis maintenance, a rising amount of evidence indicates mitochondrial dysfunction as a substantial contributor to disease onset and progression. The aim of this review is to summarize most relevant findings that link genetic factors in ALS pathogenesis with different mechanisms with mitochondrial involvement (respiratory chain, OXPHOS control, calcium buffering, axonal transport, inflammation, mitophagy, etc.). We highlight the importance of a widening perspective for better understanding overlapping pathophysiological pathways in ALS and neurodegeneration in general. Finally, current and potentially novel therapies, especially gene specific therapies, targeting mitochondrial dysfunction are discussed briefly.

APA, Harvard, Vancouver, ISO, and other styles

27

Fraga, Hugo, and Salvador Ventura. "Oxidative Folding in the Mitochondrial Intermembrane Space in Human Health and Disease." International Journal of Molecular Sciences 14, no. 2 (January 30, 2013): 2916–27. http://dx.doi.org/10.3390/ijms14022916.

Full text

APA, Harvard, Vancouver, ISO, and other styles

28

Fraga, Hugo, and Salvador Ventura. "Protein Oxidative Folding in the Intermembrane Mitochondrial Space: More than Protein Trafficking." Current Protein & Peptide Science 13, no. 3 (May 1, 2012): 224–31. http://dx.doi.org/10.2174/138920312800785012.

Full text

APA, Harvard, Vancouver, ISO, and other styles

29

Koch, Johanna R., and Franz X. Schmid. "Mia40 Is Optimized for Function in Mitochondrial Oxidative Protein Folding and Import." ACS Chemical Biology 9, no. 9 (July 10, 2014): 2049–57. http://dx.doi.org/10.1021/cb500408n.

Full text

APA, Harvard, Vancouver, ISO, and other styles

30

Eun, Su Yong, and Sung-Cherl Jung. "Pathophysiological roles and the molecular mechanism of mitochondria in neuronal calcium regulation." Journal of Medicine and Life Science 6, no. 4 (September 1, 2009): 200–205. http://dx.doi.org/10.22730/jmls.2009.6.4.200.

Full text

Abstract:

Calcium is an important signaling molecule involved in the regulation of many physiological as well as pathological cellular responses. Especially, the spatiotemporal pattern of local calcium signaling is critical for the specificity of cellular responses. We reviewed here pathophysiol0gical roles and the molecular mechanism of mitochondria as well as endoplasmic reticulum (ER) in neuronal calcium regulation. The Iiving cells evoke calcium influx outside the cells and also induce calcium release from ER in response to many stimuli. However, severe and sustained calcium release from ER induces calcium uptake into mitochondria. Pathologically elevated mitochondrial calcium responses are accompanied by mitochondria depolarization. mitochondria permeability transition pore (mtPTP) opining and subsequent mitochondria-dependent apoptosis. Ratiometric realtime measurements of intramitochondrial local Ca suggest that high mitochondrial Ca2+ is the crucial factor determinating whether cells : undergo apoptosis. On the other hand, calcium depletion in ER also induces ER stress which evokes protein folding defects and ER stress-dependent apoptosis. The recent growing body of evidence on pathophysiological roles and the molecular mechanism of mitochondria as well as ER could provide an insight for the development of new drug to treat neurodegenerative diseases in which pathogenesis either calcium overload or oxidative dative stress is involved.

APA, Harvard, Vancouver, ISO, and other styles

31

Tienson, Heather L., Deepa V. Dabir, Sonya E. Neal, Rachel Loo, Samuel A. Hasson, Pinmanee Boontheung, Sung-Kun Kim, Joseph A. Loo, and Carla M. Koehler. "Reconstitution of the Mia40-Erv1 Oxidative Folding Pathway for the Small Tim Proteins." Molecular Biology of the Cell 20, no. 15 (August 2009): 3481–90. http://dx.doi.org/10.1091/mbc.e08-10-1062.

Full text

Abstract:

Mia40 and Erv1 execute a disulfide relay to import the small Tim proteins into the mitochondrial intermembrane space. Here, we have reconstituted the oxidative folding pathway in vitro with Tim13 as a substrate and determined the midpoint potentials of Mia40 and Tim13. Specifically, Mia40 served as a direct oxidant of Tim13, and Erv1 was required to reoxidize Mia40. During oxidation, four electrons were transferred from Tim13 with the insertion of two disulfide bonds in succession. The extent of Tim13 oxidation was directly dependent on Mia40 concentration and independent of Erv1 concentration. Characterization of the midpoint potentials showed that electrons flowed from Tim13 with a more negative midpoint potential of −310 mV via Mia40 with an intermediate midpoint potential of −290 mV to the C130-C133 pair of Erv1 with a positive midpoint potential of −150 mV. Intermediary complexes between Tim13-Mia40 and Mia40-Erv1 were trapped. Last, mutating C133 of the catalytic C130-C133 pair or C30 of the shuttle C30-C33 pair in Erv1 abolished oxidation of Tim13, whereas mutating the cysteines in the redox-active CPC motif, but not the structural disulfide linkages of the CX9C motif of Mia40, prevented Tim13 oxidation. Thus, we demonstrate that Mia40, Erv1, and oxygen are the minimal machinery for Tim13 oxidation.

APA, Harvard, Vancouver, ISO, and other styles

32

Gomes, Cláudio M., and Renata Santos. "Neurodegeneration in Friedreich’s Ataxia: From Defective Frataxin to Oxidative Stress." Oxidative Medicine and Cellular Longevity 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/487534.

Full text

Abstract:

Friedreich’s ataxia is the most common inherited autosomal recessive ataxia and is characterized by progressive degeneration of the peripheral and central nervous systems and cardiomyopathy. This disease is caused by the silencing of theFXNgene and reduced levels of the encoded protein, frataxin. Frataxin is a mitochondrial protein that functions primarily in iron-sulfur cluster synthesis. This small protein with anα/βsandwich fold undergoes complex processing and imports into the mitochondria, generating isoforms with distinct N-terminal lengths which may underlie different functionalities, also in respect to oligomerization. Missense mutations in theFXNcoding region, which compromise protein folding, stability, and function, are found in 4% of FRDA heterozygous patients and are useful to understand how loss of functional frataxin impacts on FRDA physiopathology. In cells, frataxin deficiency leads to pleiotropic phenotypes, including deregulation of iron homeostasis and increased oxidative stress. Increasing amount of data suggest that oxidative stress contributes to neurodegeneration in Friedreich’s ataxia.

APA, Harvard, Vancouver, ISO, and other styles

33

Fan, Yuxiang, and Thomas Simmen. "Mechanistic Connections between Endoplasmic Reticulum (ER) Redox Control and Mitochondrial Metabolism." Cells 8, no. 9 (September 12, 2019): 1071. http://dx.doi.org/10.3390/cells8091071.

Full text

Abstract:

The past decade has seen the emergence of endoplasmic reticulum (ER) chaperones as key determinants of contact formation between mitochondria and the ER on the mitochondria-associated membrane (MAM). Despite the known roles of ER–mitochondria tethering factors like PACS-2 and mitofusin-2, it is not yet entirely clear how they mechanistically interact with the ER environment to determine mitochondrial metabolism. In this article, we review the mechanisms used to communicate ER redox and folding conditions to the mitochondria, presumably with the goal of controlling mitochondrial metabolism at the Krebs cycle and at the electron transport chain, leading to oxidative phosphorylation (OXPHOS). To achieve this goal, redox nanodomains in the ER and the interorganellar cleft influence the activities of ER chaperones and Ca2+-handling proteins to signal to mitochondria. This mechanism, based on ER chaperones like calnexin and ER oxidoreductases like Ero1α, controls reactive oxygen production within the ER, which can chemically modify the proteins controlling ER–mitochondria tethering, or mitochondrial membrane dynamics. It can also lead to the expression of apoptotic or metabolic transcription factors. The link between mitochondrial metabolism and ER homeostasis is evident from the specific functions of mitochondria–ER contact site (MERC)-localized Ire1 and PERK. These functions allow these two transmembrane proteins to act as mitochondria-preserving guardians, a function that is apparently unrelated to their functions in the unfolded protein response (UPR). In scenarios where ER stress cannot be resolved via the activation of mitochondrial OXPHOS, MAM-localized autophagosome formation acts to remove defective portions of the ER. ER chaperones such as calnexin are again critical regulators of this MERC readout.

APA, Harvard, Vancouver, ISO, and other styles

34

Fu, Yu-Hsuan, Chi-Yang Tseng, Jeng-Wei Lu, Wen-Hui Lu, Pei-Qi Lan, Chien-Yuan Chen, Da-Liang Ou, and Liang-In Lin. "Deciphering the Role of Pyrvinium Pamoate in the Generation of Integrated Stress Response and Modulation of Mitochondrial Function in Myeloid Leukemia Cells through Transcriptome Analysis." Biomedicines 9, no. 12 (December 9, 2021): 1869. http://dx.doi.org/10.3390/biomedicines9121869.

Full text

Abstract:

Pyrvinium pamoate, a widely-used anthelmintic agent, reportedly exhibits significant anti-tumor effects in several cancers. However, the efficacy and mechanisms of pyrvinium against myeloid leukemia remain unclear. The growth inhibitory effects of pyrvinium were tested in human AML cell lines. Transcriptome analysis of Molm13 myeloid leukemia cells suggested that pyrvinium pamoate could trigger an unfolded protein response (UPR)-like pathway, including responses to extracellular stimulus [p-value = 2.78 × 10−6] and to endoplasmic reticulum stress [p-value = 8.67 × 10−7], as well as elicit metabolic reprogramming, including sulfur compound catabolic processes [p-value = 2.58 × 10−8], and responses to a redox state [p-value = 5.80 × 10−5]; on the other hand, it could elicit a pyrvinium blunted protein folding function, including protein folding [p-value = 2.10 × 10−8] and an ATP metabolic process [p-value = 3.95 × 10−4]. Subsequently, pyrvinium was verified to induce an integrated stress response (ISR), demonstrated by activation of the eIF2α-ATF4 pathway and inhibition of mTORC1 signaling, in a dose- and time-dependent manner. Additionally, pyrvinium could co-localize with mitochondria and then decrease the mitochondrial basal oxidative consumption rate, ultimately dysregulating the mitochondrial function. Similar effects were observed in cabozantinib-resistant Molm13-XR cell lines. Furthermore, pyrvinium treatment retarded Molm13 and Molm13-XR xenograft tumor growth. Thus, we concluded that pyrvinium exerts anti-tumor activity, at least, via the modulation of the mitochondrial function and by triggering ISR.

APA, Harvard, Vancouver, ISO, and other styles

35

Semenovich, Dmitry S., Egor Yu Plotnikov, Oksana V. Titko, Elena P. Lukiyenko, and Nina P. Kanunnikova. "Effects of Panthenol and N-Acetylcysteine on Changes in the Redox State of Brain Mitochondria under Oxidative Stress In Vitro." Antioxidants 10, no. 11 (October 27, 2021): 1699. http://dx.doi.org/10.3390/antiox10111699.

Full text

Abstract:

The glutathione system in the mitochondria of the brain plays an important role in maintaining the redox balance and thiol–disulfide homeostasis, whose violations are the important component of the biochemical shifts in neurodegenerative diseases. Mitochondrial dysfunction is known to be accompanied by the activation of free radical processes, changes in energy metabolism, and is involved in the induction of apoptotic signals. The formation of disulfide bonds is a leading factor in the folding and maintenance of the three-dimensional conformation of many specific proteins that selectively accumulate in brain structures during neurodegenerative pathology. In this study, we estimated brain mitochondria redox status and functioning during induction of oxidative damage in vitro. We have shown that the development of oxidative stress in vitro is accompanied by inhibition of energy metabolism in the brain mitochondria, a shift in the redox potential of the glutathione system to the oxidized side, and activation of S-glutathionylation of proteins. Moreover, we studied the effects of pantothenic acid derivatives—precursors of coenzyme A (CoA), primarily D-panthenol, that exhibit high neuroprotective activity in experimental models of neurodegeneration. Panthenol contributes to the significant restoration of the activity of enzymes of mitochondrial energy metabolism, normalization of the redox potential of the glutathione system, and a decrease in the level of S-glutathionylated proteins in brain mitochondria. The addition of succinate and glutathione precursor N-acetylcysteine enhances the protective effects of the drug.

APA, Harvard, Vancouver, ISO, and other styles

36

Konno, Tasuku, Eduardo Pinho Melo, Carlos Lopes, Ilir Mehmeti, Sigurd Lenzen, David Ron, and Edward Avezov. "ERO1-independent production of H2O2 within the endoplasmic reticulum fuels Prdx4-mediated oxidative protein folding." Journal of Cell Biology 211, no. 2 (October 26, 2015): 253–59. http://dx.doi.org/10.1083/jcb.201506123.

Full text

Abstract:

The endoplasmic reticulum (ER)–localized peroxiredoxin 4 (PRDX4) supports disulfide bond formation in eukaryotic cells lacking endoplasmic reticulum oxidase 1 (ERO1). The source of peroxide that fuels PRDX4-mediated disulfide bond formation has remained a mystery, because ERO1 is believed to be a major producer of hydrogen peroxide (H2O2) in the ER lumen. We report on a simple kinetic technique to track H2O2 equilibration between cellular compartments, suggesting that the ER is relatively isolated from cytosolic or mitochondrial H2O2 pools. Furthermore, expression of an ER-adapted catalase to degrade lumenal H2O2 attenuated PRDX4-mediated disulfide bond formation in cells lacking ERO1, whereas depletion of H2O2 in the cytosol or mitochondria had no similar effect. ER catalase did not effect the slow residual disulfide bond formation in cells lacking both ERO1 and PRDX4. These observations point to exploitation of a hitherto unrecognized lumenal source of H2O2 by PRDX4 and a parallel slow H2O2-independent pathway for disulfide formation.

APA, Harvard, Vancouver, ISO, and other styles

37

Chen, Qun, Jeremy Thompson, Ying Hu, and Edward J. Lesnefsky. "Tunicamycin-Induced Endoplasmic Reticulum Stress Damages Complex I in Cardiac Mitochondria." Life 12, no. 8 (August 9, 2022): 1209. http://dx.doi.org/10.3390/life12081209.

Full text

Abstract:

Background: Induction of acute ER (endoplasmic reticulum) stress using thapsigargin contributes to complex I damage in mouse hearts. Thapsigargin impairs complex I by increasing mitochondrial calcium through inhibition of Ca2+-ATPase in the ER. Tunicamycin (TUNI) is used to induce ER stress by inhibiting protein folding. We asked if TUNI-induced ER stress led to complex I damage. Methods: TUNI (0.4 mg/kg) was used to induce ER stress in C57BL/6 mice. Cardiac mitochondria were isolated after 24 or 72 h following TUNI treatment for mitochondrial functional analysis. Results: ER stress was only increased in mice following 72 h of TUNI treatment. TUNI treatment decreased oxidative phosphorylation with complex I substrates compared to vehicle with a decrease in complex I activity. The contents of complex I subunits including NBUPL and NDUFS7 were decreased in TUNI-treated mice. TUNI treatment activated both cytosolic and mitochondrial calpain 1. Our results indicate that TUNI-induced ER stress damages complex I through degradation of its subunits including NDUFS7. Conclusion: Induction of the ER stress using TUNI contributes to complex I damage by activating calpain 1.

APA, Harvard, Vancouver, ISO, and other styles

38

Chatzi, Afroditi, and Kostas Tokatlidis. "The Mitochondrial Intermembrane Space: A Hub for Oxidative Folding Linked to Protein Biogenesis." Antioxidants & Redox Signaling 19, no. 1 (July 2013): 54–62. http://dx.doi.org/10.1089/ars.2012.4855.

Full text

APA, Harvard, Vancouver, ISO, and other styles

39

Mordas, Amelia, and Kostas Tokatlidis. "The MIA Pathway: A Key Regulator of Mitochondrial Oxidative Protein Folding and Biogenesis." Accounts of Chemical Research 48, no. 8 (July 27, 2015): 2191–99. http://dx.doi.org/10.1021/acs.accounts.5b00150.

Full text

APA, Harvard, Vancouver, ISO, and other styles

40

Haute, Lindsey Van, Alan G. Hendrick, Aaron R. D’Souza, Christopher A. Powell, Pedro Rebelo-Guiomar, Michael E. Harbour, Shujing Ding, Ian M. Fearnley, Byron Andrews, and Michal Minczuk. "METTL15 introduces N4-methylcytidine into human mitochondrial 12S rRNA and is required for mitoribosome biogenesis." Nucleic Acids Research 47, no. 19 (September 6, 2019): 10267–81. http://dx.doi.org/10.1093/nar/gkz735.

Full text

Abstract:

Abstract Post-transcriptional RNA modifications, the epitranscriptome, play important roles in modulating the functions of RNA species. Modifications of rRNA are key for ribosome production and function. Identification and characterization of enzymes involved in epitranscriptome shaping is instrumental for the elucidation of the functional roles of specific RNA modifications. Ten modified sites have been thus far identified in the mammalian mitochondrial rRNA. Enzymes responsible for two of these modifications have not been characterized. Here, we identify METTL15, show that it is the main N4-methylcytidine (m4C) methyltransferase in human cells and demonstrate that it is responsible for the methylation of position C839 in mitochondrial 12S rRNA. We show that the lack of METTL15 results in a reduction of the mitochondrial de novo protein synthesis and decreased steady-state levels of protein components of the oxidative phosphorylation system. Without functional METTL15, the assembly of the mitochondrial ribosome is decreased, with the late assembly components being unable to be incorporated efficiently into the small subunit. We speculate that m4C839 is involved in the stabilization of 12S rRNA folding, therefore facilitating the assembly of the mitochondrial small ribosomal subunits. Taken together our data show that METTL15 is a novel protein necessary for efficient translation in human mitochondria.

APA, Harvard, Vancouver, ISO, and other styles

41

Dabir⁎, Deepa, Samuel A. Hasson, Robert Damoiseaux, Johannes Zimmerman, Meghan E. Johnson, and Carla M. Koehler. "Chemical inhibition of the Erv1 mitochondrial oxidative folding pathway by a small molecule inhibitor." Mitochondrion 11, no. 4 (July 2011): 638. http://dx.doi.org/10.1016/j.mito.2011.03.015.

Full text

APA, Harvard, Vancouver, ISO, and other styles

42

Sideris, Dionisia P., Nikos Petrakis, Nitsa Katrakili, Despina Mikropoulou, Angelo Gallo, Simone Ciofi-Baffoni, Lucia Banci, Ivano Bertini, and Kostas Tokatlidis. "A novel intermembrane space–targeting signal docks cysteines onto Mia40 during mitochondrial oxidative folding." Journal of Cell Biology 187, no. 7 (December 21, 2009): 1007–22. http://dx.doi.org/10.1083/jcb.200905134.

Full text

Abstract:

Mia40 imports Cys-containing proteins into the mitochondrial intermembrane space (IMS) by ensuring their Cys-dependent oxidative folding. In this study, we show that the specific Cys of the substrate involved in docking with Mia40 is substrate dependent, the process being guided by an IMS-targeting signal (ITS) present in Mia40 substrates. The ITS is a 9-aa internal peptide that (a) is upstream or downstream of the docking Cys, (b) is sufficient for crossing the outer membrane and for targeting nonmitochondrial proteins, (c) forms an amphipathic helix with crucial hydrophobic residues on the side of the docking Cys and dispensable charged residues on the other side, and (d) fits complementary to the substrate cleft of Mia40 via hydrophobic interactions of micromolar affinity. We rationalize the dual function of Mia40 as a receptor and an oxidase in a two step–specific mechanism: an ITS-guided sliding step orients the substrate noncovalently, followed by docking of the substrate Cys now juxtaposed to pair with the Mia40 active Cys.

APA, Harvard, Vancouver, ISO, and other styles

43

MacPherson, Lisa, and Kostas Tokatlidis. "Protein trafficking in the mitochondrial intermembrane space: mechanisms and links to human disease." Biochemical Journal 474, no. 15 (July 12, 2017): 2533–45. http://dx.doi.org/10.1042/bcj20160627.

Full text

Abstract:

Mitochondria fulfill a diverse range of functions in cells including oxygen metabolism, homeostasis of inorganic ions and execution of apoptosis. Biogenesis of mitochondria relies on protein import pathways that are ensured by dedicated multiprotein translocase complexes localized in all sub-compartments of these organelles. The key components and pathways involved in protein targeting and assembly have been characterized in great detail over the last three decades. This includes the oxidative folding machinery in the intermembrane space, which contributes to the redox-dependent control of proteostasis. Here, we focus on several components of this system and discuss recent evidence suggesting links to human proteopathy.

APA, Harvard, Vancouver, ISO, and other styles

44

Li, Na, Nannan Li, Siqi Wen, Biao Li, Yaying Zhang, Qing Liu, Shu Zheng, et al. "HSP60 Regulates Lipid Metabolism in Human Ovarian Cancer." Oxidative Medicine and Cellular Longevity 2021 (September 12, 2021): 1–21. http://dx.doi.org/10.1155/2021/6610529.

Full text

Abstract:

Accumulating evidence demonstrates that cancer is an oxidative stress-related disease, and oxidative stress is closely linked with heat shock proteins (HSPs). Lipid oxidative stress is derived from lipid metabolism dysregulation that is closely associated with the development and progression of malignancies. This study sought to investigate regulatory roles of HSPs in fatty acid metabolism abnormality in ovarian cancer. Pathway network analysis of 5115 mitochondrial expressed proteins in ovarian cancer revealed various lipid metabolism pathway alterations, including fatty acid degradation, fatty acid metabolism, butanoate metabolism, and propanoate metabolism. HSP60 regulated the expressions of lipid metabolism proteins in these lipid metabolism pathways, including ADH5, ECHS1, EHHADH, HIBCH, SREBP1, ACC1, and ALDH2. Further, interfering HSP60 expression inhibited migration, proliferation, and cell cycle and induced apoptosis of ovarian cancer cells in vitro. In addition, mitochondrial phosphoproteomics and immunoprecipitation-western blot experiments identified and confirmed that phosphorylation occurred at residue Ser70 in protein HSP60, which might regulate protein folding of ALDH2 and ACADS in ovarian cancers. These findings clearly demonstrated that lipid metabolism abnormality occurred in oxidative stress-related ovarian cancer and that HSP60 and its phosphorylation might regulate this lipid metabolism abnormality in ovarian cancer. It opens a novel vision in the lipid metabolism reprogramming in human ovarian cancer.

APA, Harvard, Vancouver, ISO, and other styles

45

Kritsiligkou, Paraskevi, Afroditi Chatzi, Georgia Charalampous, Aleksandr Mironov, Chris M. Grant, and Kostas Tokatlidis. "Unconventional Targeting of a Thiol Peroxidase to the Mitochondrial Intermembrane Space Facilitates Oxidative Protein Folding." Cell Reports 18, no. 11 (March 2017): 2729–41. http://dx.doi.org/10.1016/j.celrep.2017.02.053.

Full text

APA, Harvard, Vancouver, ISO, and other styles

46

Zanini, Giada, Valentina Selleri, Mara Malerba, Kateryna Solodka, Giorgia Sinigaglia, Milena Nasi, Anna Vittoria Mattioli, and Marcello Pinti. "The Role of Lonp1 on Mitochondrial Functions during Cardiovascular and Muscular Diseases." Antioxidants 12, no. 3 (February 28, 2023): 598. http://dx.doi.org/10.3390/antiox12030598.

Full text

Abstract:

The mitochondrial protease Lonp1 is a multifunctional enzyme that regulates crucial mitochondrial functions, including the degradation of oxidized proteins, folding of imported proteins and maintenance the correct number of copies of mitochondrial DNA. A series of recent studies has put Lonp1 at the center of the stage in the homeostasis of cardiomyocytes and muscle skeletal cells. During heart development, Lonp1 allows the metabolic shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation. Knock out of Lonp1 arrests heart development and determines cardiomyocyte apoptosis. In adults, Lonp1 acts as a cardioprotective protein, as its upregulation mitigates cardiac injury by preventing the oxidative damage of proteins and lipids, and by preserving mitochondrial redox balance. In skeletal muscle, Lonp1 is crucial for cell development, as it mediates the activation of PINK1/Parkin pathway needed for proper myoblast differentiation. Skeletal muscle-specific ablation of Lonp1 in mice causes reduced muscle fiber size and strength due to the accumulation of mitochondrial-retained protein in muscle. Lonp1 expression and activity decline with age in different tissues, including skeletal muscle, and are associated with a functional decline and structural impairment of muscle fibers. Aerobic exercise increases unfolded protein response markers including Lonp1 in the skeletal muscle of aged animals and is associated with muscle functional recovery. Finally, mutations of Lonp1 cause a syndrome named CODAS (Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies) characterized by the impaired development of multiple organs and tissues, including myocytes. CODAS patients show hypotonia and ptosis, indicative of skeletal muscle reduced performance. Overall, this body of observations points Lonp1 as a crucial regulator of mitochondrial functions in the heart and in skeletal muscle.

APA, Harvard, Vancouver, ISO, and other styles

47

Vascotto, Carlo, Elena Bisetto, Mengxia Li, Leo A. H. Zeef, Chiara D'Ambrosio, Rossana Domenis, Marina Comelli, et al. "Knock-in reconstitution studies reveal an unexpected role of Cys-65 in regulating APE1/Ref-1 subcellular trafficking and function." Molecular Biology of the Cell 22, no. 20 (October 15, 2011): 3887–901. http://dx.doi.org/10.1091/mbc.e11-05-0391.

Full text

Abstract:

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1) protects cells from oxidative stress via the base excision repair pathway and as a redox transcriptional coactivator. It is required for tumor progression/metastasis, and its up-regulation is associated with cancer resistance. Loss of APE1 expression causes cell growth arrest, mitochondrial impairment, apoptosis, and alterations of the intracellular redox state and cytoskeletal structure. A detailed knowledge of the molecular mechanisms regulating its different activities is required to understand the APE1 function associated with cancer development and for targeting this protein in cancer therapy. To dissect these activities, we performed reconstitution experiments by using wild-type and various APE1 mutants. Our results suggest that the redox function is responsible for cell proliferation through the involvement of Cys-65 in mediating APE1 localization within mitochondria. C65S behaves as a loss-of-function mutation by affecting the in vivo folding of the protein and by causing a reduced accumulation in the intermembrane space of mitochondria, where the import protein Mia40 specifically interacts with APE1. Treatment of cells with (E)-3-(2-[5,6-dimethoxy-3-methyl-1,4-benzoquinonyl])-2-nonyl propenoic acid, a specific inhibitor of APE1 redox function through increased Cys-65 oxidation, confirm that Cys-65 controls APE1 subcellular trafficking and provides the basis for a new role for this residue.

APA, Harvard, Vancouver, ISO, and other styles

48

Chortis, Vasileios, Angela E. Taylor, Craig L. Doig, Mark D. Walsh, Eirini Meimaridou, Carl Jenkinson, Giovanny Rodriguez-Blanco, et al. "Nicotinamide Nucleotide Transhydrogenase as a Novel Treatment Target in Adrenocortical Carcinoma." Endocrinology 159, no. 8 (April 20, 2018): 2836–49. http://dx.doi.org/10.1210/en.2018-00014.

Full text

Abstract:

Abstract Adrenocortical carcinoma (ACC) is an aggressive malignancy with poor response to chemotherapy. In this study, we evaluated a potential new treatment target for ACC, focusing on the mitochondrial reduced form of NAD phosphate (NADPH) generator nicotinamide nucleotide transhydrogenase (NNT). NNT has a central role within mitochondrial antioxidant pathways, protecting cells from oxidative stress. Inactivating human NNT mutations result in congenital adrenal insufficiency. We hypothesized that NNT silencing in ACC cells will induce toxic levels of oxidative stress. To explore this, we transiently knocked down NNT in NCI-H295R ACC cells. As predicted, this manipulation increased intracellular levels of oxidative stress; this resulted in a pronounced suppression of cell proliferation and higher apoptotic rates, as well as sensitization of cells to chemically induced oxidative stress. Steroidogenesis was paradoxically stimulated by NNT loss, as demonstrated by mass spectrometry–based steroid profiling. Next, we generated a stable NNT knockdown model in the same cell line to investigate the longer lasting effects of NNT silencing. After long-term culture, cells adapted metabolically to chronic NNT knockdown, restoring their redox balance and resilience to oxidative stress, although their proliferation remained suppressed. This was associated with higher rates of oxygen consumption. The molecular pathways underpinning these responses were explored in detail by RNA sequencing and nontargeted metabolome analysis, revealing major alterations in nucleotide synthesis, protein folding, and polyamine metabolism. This study provides preclinical evidence of the therapeutic merit of antioxidant targeting in ACC as well as illuminating the long-term adaptive response of cells to oxidative stress.

APA, Harvard, Vancouver, ISO, and other styles

49

Basu, Somsuvro, Joanne C. Leonard, Nishal Desai, Despoina A. I. Mavridou, Kong Ho Tang, Alan D. Goddard, Michael L. Ginger, Julius Lukeš, and James W. A. Allen. "Divergence of Erv1-Associated Mitochondrial Import and Export Pathways in Trypanosomes and Anaerobic Protists." Eukaryotic Cell 12, no. 2 (December 21, 2012): 343–55. http://dx.doi.org/10.1128/ec.00304-12.

Full text

Abstract:

ABSTRACT In yeast ( Saccharomyces cerevisiae ) and animals, the sulfhydryl oxidase Erv1 functions with Mia40 in the import and oxidative folding of numerous cysteine-rich proteins in the mitochondrial intermembrane space (IMS). Erv1 is also required for Fe-S cluster assembly in the cytosol, which uses at least one mitochondrially derived precursor. Here, we characterize an essential Erv1 orthologue from the protist Trypanosoma brucei (TbERV1), which naturally lacks a Mia40 homolog. We report kinetic parameters for physiologically relevant oxidants cytochrome c and O 2 , unexpectedly find O 2 and cytochrome c are reduced simultaneously, and demonstrate that efficient reduction of O 2 by TbERV1 is not dependent upon a simple O 2 channel defined by conserved histidine and tyrosine residues. Massive mitochondrial swelling following Tb ERV1 RNA interference (RNAi) provides evidence that trypanosome Erv1 functions in IMS protein import despite the natural absence of the key player in the yeast and animal import pathways, Mia40. This suggests significant evolutionary divergence from a recently established paradigm in mitochondrial cell biology. Phylogenomic profiling of genes also points to a conserved role for TbERV1 in cytosolic Fe-S cluster assembly. Conversely, loss of genes implicated in precursor delivery for cytosolic Fe-S assembly in Entamoeba , Trichomonas , and Giardia suggests fundamental differences in intracellular trafficking pathways for activated iron or sulfur species in anaerobic versus aerobic eukaryotes.

APA, Harvard, Vancouver, ISO, and other styles

50

Chatzi, Afroditi, Phanee Manganas, and Kostas Tokatlidis. "Oxidative folding in the mitochondrial intermembrane space: A regulated process important for cell physiology and disease." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1863, no. 6 (June 2016): 1298–306. http://dx.doi.org/10.1016/j.bbamcr.2016.03.023.

Full text

APA, Harvard, Vancouver, ISO, and other styles

Journal articles on the topic 'Mitochondrial oxidative folding'

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles