Dissertationen zum Thema „Mitochondria fusion“
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Heller, Anne Sabine [Verfasser], und Achim [Akademischer Betreuer] Göpferich. „Targeting mitochondria by mitochondrial fusion, mitochondria-specific peptides and nanotechnology / Anne Sabine Heller. Betreuer: Achim Göpferich“. Regensburg : Universitätsbibliothek Regensburg, 2013. http://d-nb.info/103321664X/34.
Der volle Inhalt der QuelleMacchi, Marc. „Contribution à l' étude de la morphogénèse des mitochondries chez la drosophile“. Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM4051/document.
Der volle Inhalt der QuelleMitochondria are organelles which are a few micrometers long and are originated from the incorporation of an alpha-proteobacteria in the cytoplasm of eukaryotic cells through endosymbiosis. In eukaryotic cells, mitochondria play a central role in ATP production as well as in programmed cell death and in the biosynthesis of many molecules. Mitochondria are highly polymorphic in size and form. Their organization also varies considerably according to the cell type or physiological or pathological state of the cell. In the last two decades, the study of the mechanisms controlling morphogenesis, dynamic of mitochondrial fission and fusion and their physiological roles has become a major research field of mitochondria. In addition, the progress in video-microscopy enable to record mitochondrial dynamics in the cytoplasm of living cells. I participated in the research on the characterization of gene function called Pantagruelian Mitochondria I (PMI), a novel determinant of the mitochondrial morphology that we discovered in Drosophila. PMI, a protein of the inner membrane, is involved in its membrane organization and essential to form tubular mitochondria. I also contributed to the development of experimental tools and protocols to visualize and study the mitochondrial dynamics in living Drosophila embryos. Interestingly, a stereotyped process of mitochondrial remodeling during Drosophila embryogenesis has been found and it raised a question about its role in developmental processes through my work
Sauvanet, Cécile. „Caractérisation des acteurs et des mécanismes de la fusion mitochondriale“. Thesis, Bordeaux 2, 2011. http://www.theses.fr/2011BOR21883/document.
Der volle Inhalt der QuelleMitochondria are dynamic organelles that continuously fuse and divide. This dynamic is required for mitochondrial biogenesis, function and degradation. The cross-talk between OXPHOS and dynamics and the mechanisms ensuring modulation of dynamics remain largely unraveled. We have investigated the relationship between fusion and OXPHOS in yeast cells carrying point mutations in the mitochondrial ATP6 gene that are associated to human diseases. We show that OXPHOS defects provoke severe defects of inner membrane, but not outer membrane fusion. Selective inhibition of inner membrane fusion can be recapitulated by ionophores that dissipate the inner membrane potential, but not by inhibitors of OXPHOS. We show a dominant inhibition of fusion that further provides a mechanism for the exclusion of defective mitochondria from the functional mitochondrial network, a pre-requisite for their selective targeting to mitophagy. These results suggest that defects of fusion could contribute to the pathology of diseases caused by mtDNA mutations. Moreover, these results imply that in cells, inhibition of dominant fusion could allow the exclusion of dysfunctional mitochondria mitochondrial network. Mitochondrial fusion involves many proteins of the superfamily of dynamin. If these proteins have been identified, the molecular mechanisms of fusion remain undetermined. In order to understand these mechanisms, we choose to characterize Mitofusin 1 and 2 proteins, essential for outer mitochondrial membrane fusion. These transmembrane proteins are consisting of two coiled-coil domains and one N-terminal GTPase domain. We have characterized GTPase activity of Mitofusin and reconstituted Mitofusins or fragments of Mitofusins into liposomes to study their capacity to fuse these liposomes. Full-length mitofusins can fuse liposomes containing cardiolipins. Surprisingly, these fusion events are independent of GTP but require Mg2+ in the buffer. Using electron microscopy, we show that mitofusin 1 and 2 induce local deformation of liposomes. This capacity of mitofusins to locally create highly curved (and thus fusogenic) membrane regions opens a new angle to understand the molecular mechanisms of mitochondrial fusion
Wang, Xinglong. „Impaired Balance of Mitochondria Fission and Fusion in Alzheimer Disease“. Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1228318762.
Der volle Inhalt der QuelleDe, Vecchis Dario. „Gaining insights into mitochondrial membrane fusion through a structural and dynamic atomistic model of the mitofusin Fzo1p“. Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC001.
Der volle Inhalt der QuelleMitochondria are dynamic organelles whose morphology is determined by fusion and fission of their membranes. This essential process is known as mitochondrial dynamics. Defects in mitochondrial dynamics are associated with neurological disorders making the investigation of physiological relevance. However, the precise sequence of events that lead mitochondrial dynamics are still not well characterised. Fzo1p, a large GTPase of the Dynamin-Related Proteins superfamily, is a key component in mitochondrial outer membrane fusion in yeast. During this PhD project I built a model of the protein Fzo1p. The structure and dynamics of the model was investigated through molecular modelling and all-atom molecular dynamics simulation in a fully hydrated lipid bilayer environment. The Fzo1p structural model integrates information from several template structures, experimental knowledge, as well as ab initio models of the transmembrane segments. The model is validated experimentally through directed mutagenesis, for instance charge-swap mutations confirm predicted long-distance salt bridges. A series of mutants indicate that coiled-coil domains are required for protein function at variance with its N-terminal region. Overall, the experimental and in silico approaches pinpoint the hinge domains involved in the putative conformational change and identifies critical residues affecting protein stability. Finally, key Fzo1p-GDP interactions provide insights about the molecular mechanism of membrane fusion catalysis. The model provides insight on atomic level and proposes a structure that will be instructional to understanding mitochondrial membrane fusion
Macchi, Marc. „Contribution à l' étude de la morphogénèse des mitochondries chez la drosophile“. Electronic Thesis or Diss., Aix-Marseille, 2012. http://www.theses.fr/2012AIXM4051.
Der volle Inhalt der QuelleMitochondria are organelles which are a few micrometers long and are originated from the incorporation of an alpha-proteobacteria in the cytoplasm of eukaryotic cells through endosymbiosis. In eukaryotic cells, mitochondria play a central role in ATP production as well as in programmed cell death and in the biosynthesis of many molecules. Mitochondria are highly polymorphic in size and form. Their organization also varies considerably according to the cell type or physiological or pathological state of the cell. In the last two decades, the study of the mechanisms controlling morphogenesis, dynamic of mitochondrial fission and fusion and their physiological roles has become a major research field of mitochondria. In addition, the progress in video-microscopy enable to record mitochondrial dynamics in the cytoplasm of living cells. I participated in the research on the characterization of gene function called Pantagruelian Mitochondria I (PMI), a novel determinant of the mitochondrial morphology that we discovered in Drosophila. PMI, a protein of the inner membrane, is involved in its membrane organization and essential to form tubular mitochondria. I also contributed to the development of experimental tools and protocols to visualize and study the mitochondrial dynamics in living Drosophila embryos. Interestingly, a stereotyped process of mitochondrial remodeling during Drosophila embryogenesis has been found and it raised a question about its role in developmental processes through my work
Norton, Matthew. „Genome-wide RNAi Screen Identifies Romo1 as a Novel Regulator of Mitochondrial Fusion and Cristae Integrity“. Thesis, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/23701.
Der volle Inhalt der QuelleNguyen, Phuc Minh Chau. „Fusion Mitochondriale et Effets Vasculaires : rôle de OPA 1 dans l'hypertension artérielle et le vieillissement“. Thesis, Angers, 2015. http://www.theses.fr/2015ANGE0073.
Der volle Inhalt der QuelleDefects in mitochondrial dynamics have been associated with various disorders, including cardiovascular diseases. OPA1 is essential for mitochondrial inner membrane fusion. Mutation in Opa1 is associated with the autosomal dominant optic atrophy (ADOA). Since then, OPA1 has been reported to be associated with cell apoptosis, cell proliferation, mitochondrial ATP synthesis, calcium homeostasis and ROS production. These data suggest that OPA1 has a potential role in vascular cells and subsequently affects vascular function. On the other hand,OPA1 is also associated with age-related changes of mitochondria and simultaneously contribute to the development of many dysfunctions in different organs. In this study, we investigated impacts of OPA1 mutation on vascular function in physiological and pathological condition like hypertension and vascular aging. By using an Opa1+/- heterozygote mouse model, we show that the OPA1 protein plays a protective role in the vascular system. Indeed, Opa1+/- mice developed a hypertension more severe than WT mice which was associated with more important endothelial dysfunction and altered vascular remodeling. In addition, although initial vascular function was normal, at 12 months, Opa1+/- mice displayed vascular dysfunction which might predict onset of vascular diseases at a later time. These results suggest for the first time that mitochondrial dynamics might play an important role in vascular function and adaptation in pathological conditions and in vascular aging. More studies are needed to clarify the role of the protein OPA1 in hypertension. These data may help to identify novel therapeutic targets to prevent complications of hypertension and vascular age-related diseases
Frezza, Christian. „OPA1, a mitochondrial pro-fusion protein, regulates the cristae remodelling pathway during apoptosis“. Doctoral thesis, Università degli studi di Padova, 2007. http://hdl.handle.net/11577/3426739.
Der volle Inhalt der QuelleAlsayyah, Cynthia. „Régulation de la fusion mitochondriale par le Système Ubiquitine Protéasome et les contacts physiques mitochondrie - peroxysomes chez la levure Saccharomyces cerevisiae“. Electronic Thesis or Diss., Université Paris sciences et lettres, 2021. https://theses.hal.science/tel-03810525.
Der volle Inhalt der QuelleMitochondria are highly dynamic organelles that undergo constant fission and fusion of their outer and inner membranes. These processes are critical to maintain essential mitochondrial functions such as oxidative phosphorylation or calcium signaling. On a molecular basis, mitochondrial fusion and fission both depend on large GTPases of the Dynamin-Related Protein (DRP) family. The DRPs that mediate attachment and fusion of mitochondrial outer membranes are called the Mitofusins. The yeast mitofusin Fzo1 is located in the mitochondrial outer membrane. Its oligomerization promotes mitochondrial tethering followed by mitochondrial outer membrane fusion. Fzo1 has recently been proposed as a potential tether between peroxisomes and mitochondria when overexpressed. However, whether Fzo1 is present on peroxisomal membranes in WT cells or whether this extra-mitochondrial localization is a consequence of overexpression is unknown. In addition, we still don’t know how peroxisomal and mitochondrial Fzo1 mediate these contacts and their purpose in the cell. In my thesis, we were able to prove that Fzo1 naturally localizes to peroxisomes and oligomerizes with the mitochondrial Fzo1 thus creating Fzo1-Fzo1 contacts between peroxisomes and mitochondria which we will now call “Fzo1-mediated permit” contacts. We found that these contacts are modulated by Fzo1 levels which are tightly regulated by an SCF ubiquitin ligase called Mdm30 but also depending on fatty acid desaturation levels in the cell. From a functional standpoint, we found that the role of Fzo1-mediated permit contacts is to regulate mitochondrial fusion through the glyoxylate cycle, a process which allows cells to convert C2 unit compounds to C4 precursors for amino acid and carbohydrate biosynthesis. We discovered that Fzo1-mediated permit contacts allow the mitochondrial transfer of early byproducts of the glyoxylate cycle to stimulate mitochondrial fusion. In fine, the results obtained during my thesis enriched our knowledge on organelle contacts and allowed us to prove that Fzo1 is localized on both mitochondrial and peroxisomal membranes in wild type cells. Our studies also show that Fzo1-mediated permit contacts are modulated according to the cell’s needs as they play a crucial role in upkeeping mitochondrial fusion by providing a possible shortcut for byproducts of the glyoxylate cycle to reach mitochondria when direly needed
Zhou, Ying [Verfasser], und Regine [Akademischer Betreuer] Süss. „Mito-liposomes: a potential delivery strategy for mitochondrial targeting via membrane fusion activity : : investigations on isolated mitochondria = Mito-Liposomen: eine potentielle Targetingstrategie für Mitochondrien mittels Membranfusion : Untersuchungen an isolierten Mitochondrien“. Freiburg : Universität, 2012. http://d-nb.info/1123471282/34.
Der volle Inhalt der QuelleHoulihan, Patrick Ryan. „The role of mitochondrial restructuring in neuronal calcium homeostasis and excitotoxicity“. Diss., University of Iowa, 2013. https://ir.uiowa.edu/etd/2522.
Der volle Inhalt der QuelleAcquistapace, Adrien. „Reprogrammation nucléaire de cardiomyocytes vers un stade progéniteur par fusion partielle avec des cellules souches adultes“. Thesis, Paris Est, 2011. http://www.theses.fr/2011PEST0078/document.
Der volle Inhalt der QuelleRegenerative cell therapy offers potential applications in many diseases involving cell loss. However, following myocardial infarction and the dramatic decrease in the number of cardiomyocytes, the injection of stem cells led to a poor and transient improvement of cardiac function. Therefore stem cell-based therapy to treat myocardial infarction requires a better understanding of the mechanisms brought into play by stem cells in heart regeneration. Among the different hypothesis raised, cell fusion between stem cells and cardiomyocytes has been described in several studies. However, the respective physiological impact of cell fusion remains unknown. During my thesis, I investigated this cell fusion mechanism in vitro in a coculture model between human multipotent adipose-derived stem cells (hMADS) and murine fully differentiated cardiomyocytes. We showed intercellular exchanges of cytoplasmic and nuclear material between both cell types, followed by a heterologous cell fusion process promoting cardiomyocyte reprogramming back to a progenitor-like state. The resulting hybrid cells expressed early cardiac commitment and proliferation markers and exhibited a mouse genotype. We provided evidence that cardiac hybrid cells were preferentially generated through partial cell fusion mediated by intercellular structures composed of f-actin and microtubule filaments. Furthermore, we showed that stem cell mitochondria were transferred into cardiomyocytes and were required for somatic cell reprogramming. In conclusion, by providing new insights into previously reported cell fusion processes, our results might contribute to a better understanding of stem cell-mediated regenerative mechanisms and thus, the development of more efficient stem cell-based heart therapies
Magosi, Lerato E. „Role of Snx9 in the Regulation of Mitochondrial Morphology“. Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/22924.
Der volle Inhalt der QuellePrecht, Thomas A. „Regulation of neuronal apoptosis by the mitochondria /“. Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2008.
Den vollen Inhalt der Quelle findenTypescript. Includes bibliographical references (leaves 112-125). Free to UCD Anschutz Medical Campus. Online version available via ProQuest Digital Dissertations;
Almazan, Annabel Vivian P. „Overexpression of the human optic atrophy-associated OPA1 gene induces mitochondrial and cellular fitness defects in yeast“. Wright State University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=wright1590861295140841.
Der volle Inhalt der QuelleTrevisan, Tatiana. „Ruolo della morfologia e della funzionalità mitocondriale sulla distribuzione intracellulare dei mitocondri in neuroni di Drosophila“. Doctoral thesis, Università degli studi di Padova, 2016. http://hdl.handle.net/11577/3424418.
Der volle Inhalt der QuelleRIASSUNTO I mitocondri sono organelli essenziali per la cellula e la loro funzione primaria è di produrre energia sottoforma di ATP. I mitocondri sono organelli altamente dinamici:processi di fusione e fissione delle membrane mitocondriali ne controllano la forma, la lunghezza e il numero e un equilibrio tra i due meccanismi è fondamentale per una corretta morfologia mitocondriale. Numerose proteine sono coinvolte nei processi di fusione e fissione mitocondriale: Mitofusina 1 e Mitofusina 2 (Mfn1 e Mfn2) e Optic atrophy 1 (Opa1) regolano i processi di fusione mitocondriale, mentre Dynamin-related protein 1 (Drp1)mediala fissione. Drosophila possiede il gene mitochondrial assembly regulatory factor (MARF), espresso in modo ubiquitario ed omologo al gene MFN2. Nel tessuto muscolare la riduzione di espressione di Marf induce frammentazione e alterazione della morfologia del mitocondrio. Inoltre, mutanti di Marf mostrano una severa deplezione dei mitocondri nelle giunzioni neuromuscolari (NMJs) ed un’alterazione della morfologia della giunzione caratterizzata dall’aumento nel numero e da una riduzione nella dimensione dei bottoni sinaptici. Un altro aspetto della dinamica mitocondriale, oltre ai processi di fusione e fissione, è la motilità dei mitocondri, che deve essere altamente regolata soprattutto in cellule come i neuroni. Il trasporto mitocondriale e la continua ridistribuzione dei mitocondri lungo l’assone è essenziale per il mantenimento dell’integrità assonale e delle normali funzioni della cellula. Studi hanno messo in evidenza come la mancanza di mitocondri a livello delle giunzioni neuromuscolari in Drosophila comprometta la trasmissione sinaptica e come difetti nel trasporto mitocondriale assonale siano implicati nello sviluppo di disordini neurologici e malattie neurodegenerative (Chan, 2006). Lo scopo di questo lavoro è quello di capire il ruolo della morfologia e della funzione mitocondriale nella distribuzione intracellulare dei mitocondri nei neuroni. Per fare questo abbiamo utilizzato Drosophila melanogaster, organismo modello efficace per l’analisi della funzione genica, inclusa quella di geni responsabili di patologie umane. L’analisi della morfologia mitocondriale è stata effettuata utilizzando linee di Drosophilache esprimono in vivo un transgene per RNA interference e che permette di ridurre l’espressione di geni endogeni coinvolti nei processi di fusione e fissione mitocondriale, quali Marf, Opa1 e Drp1. Abbiamo inoltre creato linee che esprimono contemporaneamente i trangeni per RNAi di Marf e Drp1 o Opa1 e Drp1, con lo scopo di bilanciare i meccanismi di fusione e/o fissione. Ci siamo soffermati in particolare sullo studio di due aspetti principali, la morfologia e la funzionalità mitocondriale, per capire se difetti nella morfologia e nella funzionalità mitocondriale siano collegate e concorrano insieme allo sviluppo di patologie.Numerose patologie neurodegenerative sono infatti caratterizzate da alterazioni del trasporto mitocondriale e spesso questo è associato a difetti nella morfologia e nella funzionalità mitocondriale. Per studiare la morfologia mitocondriale, le linee UAS-RNAi sono state incrociate con una linea che contiene il promotore ELAV per l’espressione tessuto-specifica nei neuroni ed esprime una GFP mitocondriale. Abbiamo analizzato la morfologia dei mitocondri, sia nel corpo cellulare sia negli assoni e la distribuzione mitocondriale in assoni lunghi come i motoneuroni e assoni corti come quelli del nervo ottico e la distribuzione mitocondriale nella giunzione neuromuscolare.I risultati ottenuti mostrano che frammentazione dei mitocondri e alterazione della distribuzione mitocondriale assonale in individui in cui sia ridotta l’espressione di proteine di fusione. Inoltre si osserva una diminuzione della percentuale dei mitocondri mobili e del numero assoluto dei mitocondri anterogradi e retrogradi. Questi dati dimostrano che vi è una stretta correlazione tra morfologia mitocondriale e distribuzione dei mitocondri, in particolare in assoni lunghi. Inoltre analizzando le linee Marf RNAi Drp1 RNAi e Opa1 RNAi Drp1 RNAi, nelle quali gli eventi di fusione e fissione ridotti ma sono in equilibrio tra loro, si osserva un miglioramento la morfologia, la distribuzione e il trasporto mitocondriale assonale in modo particolare nel caso di Opa1 e non nel caso di Marf. Abbiamo cercato di capire quindi se in questi individui vi fossero alterazioni delle funzionalità mitocondriali attraverso l’analisi della capacità respiratoria mitocondriale, dell’attività dei complessi della catena respiratoria e della capacità di produzione di ATP. I risultati ottenuti dimostrano che morfologia e funzionalità mitocondriale non sempre sono collegate tra loro hanno effetti diversi nella modulazione della distribuzione mitocondriale assonale. In conclusione possiamo affermare che solamente la morfologia e la dimensione del mitocondrio sembrano essere essenziali per la corretta distribuzione mitocondriale assonale.
Dagda, Ruben Karim. „Structure and function of a mitochondrial PP2A holoenzyme that regulates neuronal survival“. Diss., University of Iowa, 2006. http://ir.uiowa.edu/etd/84.
Der volle Inhalt der QuelleLegros, Frédéric. „Étude de la dynamique du compartiment mitochondrial et des mutations hétéroplasmiques de l'ADN mitochondrial“. Paris 7, 2002. http://www.theses.fr/2002PA077109.
Der volle Inhalt der QuelleCICERI, DALILA. „Cell-based analysis of dynamic aspects of molecular mechanism involved in the pathogenesis of Parkinson's disease“. Doctoral thesis, Università degli Studi di Milano-Bicocca, 2010. http://hdl.handle.net/10281/10302.
Der volle Inhalt der QuelleSubra, Mélody. „VAP-A, un gymnaste moléculaire engagé dans les sites de contact membranaire“. Electronic Thesis or Diss., Université Côte d'Azur, 2023. http://www.theses.fr/2023COAZ6013.
Der volle Inhalt der QuelleVAP-A is a receptor at the surface of the endoplasmic reticulum (ER) for hundreds of proteins containing a FFAT motif and having a wide range of structures and functions. VAP-A is also required for creating multiple membrane contact sites (MCSs) between the ER and other compartments, which notably enable non-vesicular lipid exchanges between membranes. For example, the lipid-transfer protein (LTP) OSBP interacts with VAP at ER/Golgi MCS to transport cholesterol through coupled counter-exchange and hydrolysis of PI4P. It is well known that VAP-A partners contain a FFAT motif specifically recognized by the Major-Sperm-Protein (MSP) domain of VAP, however, how this receptor adapts to its different targets in MCSs that are so different in geometry and lifetime is not understood.In this study, we used a multidisciplinary approach to demonstrate that VAP-A contains two intrinsically disordered linkers that provide it with a high degree of flexibility to enable functional organization of different MCSs. A VAP-A mutant without flexible linkers is restricted in its subcellular localization, and does not support lipid transport by OSBP and CERT at ER/Golgi MCS. However, this mutant is present at ER/mitochondria MCS by interacting with VPS13A and PTPIP51, and thus facilitates lipid transport contributing to cardiolipin metabolism and mitochondrial fusion.In conclusion, this work indicates that VAP-A conformational flexibility mediated by its intrinsically disordered regions is key to ensure membrane tethering especially at short-lived MCSs; it also demonstrates the implication of VAP-A in mitochondrial fusion
Sacks, Jessica Erin. „Targeting Mitochondrial Pathways in Obesity and Type 2 Diabetes“. Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1522935947635474.
Der volle Inhalt der QuelleSava, Radović. „Uloga insulinskih i IGF1 receptora u regulaciji steroidogeneze i mitohondrijallne biogenze u Leydigovim ćelijama“. Phd thesis, Univerzitet u Novom Sadu, Prirodno-matematički fakultet u Novom Sadu, 2019. https://www.cris.uns.ac.rs/record.jsf?recordId=110282&source=NDLTD&language=en.
Der volle Inhalt der QuelleLeydig cells of testes are the primary site of the male sex hormones synthesis. These hormones are indispensable for both reproductive and general health since serious health problems are often associated with their reduced production. Insulin and insulin-like growth factor 1, IGF1 (insulin like growth factor 1), and signaling triggered through their receptors (INSR and IGF1R), are one of the key factors that regulate specific development of tissue including gonads. However, the role and mechanisms of these receptors action in steroidogenic tissues are not known enough. This study was designed to observe the role of INSR and IGF1R in regulating the differentiation and steroidogenic function of Leydig cells by using the model of prepubertal (P21) and adult (P80) male mice with the conditional deletion of the Insr and Igf1r genes in steroidogenic cells (Insr/Igf1r-DKO). In addition, male and female P21 mice with the samedeletion were used to monitor the expression of the main markers of mitochondrial biogenesis and fusion/architecture in Leydig cells, ovaries and adrenal glands. The results confirmed that deletion of Insr and Igf1r in steroidogenic tissues influences differentiation and functional characteristics of Leydig cells isolated from P21 and P80 mice, suggesting an appearance of "feminization". The number of Leydig cells isolated from both P21 and P80 Insr/Igf1r-DKO mice was reduced. Morphology and ultrastructure of Leydig cells were disturbed in P21 Insr/Igf1r-DKO mice. Steroidogenic capacity and activity, as well as expression of the main elements of steroidogenic machinery (Lhcgr, Star, Cyp11a1, Cyp17a1, Hsd3b1 and 6, Hsd17b3, Sf1) were decreased in Leydig cells from P21 and P80 Insr/Igf1r-DKO mice, while the expression of transcriptional repressors of steroidogenesis (Arr19 and Dax1) was increased in the same cells, but not in the rest of the testes. Transcription profile of the male sex markers (Sry, Sox9, Amh) was altered in Leydig cells from P21 and P80 Insr/Igf1r-DKO mice. Transcription of the female sex markers (Rspo1, Wnt4) in the testes, as well as Cyp19a1 expression and estradiol (E2) production in Leydig cells, from P21 and P80 Insr/Igf1rDKO mice were increased. Transcription of mitochondrial biogenesis markers (Ppargc1a, Tfam, Mtnd1) was declined in Leydig cells from P21 Insr/Igf1r-DKO mice, while changes were absent in the ovaries of the same genotype. Transcription of the same markers was increased in the adrenal glands of both sexes. The mitochondrial fusion/architecture markers (Mfn1 and Mfn2) were increased in Leydig cells from Insr/Igf1r-DKO mice and followed by disturbedmitochondrial phase of steroidogenesis (progesterone production), as well as decreased number and disturbed morphology of mitochondria. Expression of the same markers in the ovaries was unchanged. In summary, results of this study showed that INSR and IGF1R are important in differentiation and steroidogenic function of Leydig cells from P21 and P80 mice. Also, these receptors are important regulators of mitochondrial biogenesis and fusion/architecture markers in steroidogenic cells of P21 male mice, but not in steroidogenic cells of ovaries.
Giedt, Randy James. „Mitochondrial Network Dynamics in Vascular Endothelial Cells Exposed to Mechanochemical Stimuli: Experimental and Mathematical Analysis“. The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1333985787.
Der volle Inhalt der QuelleGuillou, Emmanuelle. „Msp1, un régulateur de la dynamique mitochondriale chez schizosaccharomyces pombe“. Toulouse 3, 2005. http://www.theses.fr/2005TOU30179.
Der volle Inhalt der QuelleKukat, Christian. „Fusion, Fission und Nucleoids in Megamitochondrien“. kostenfrei, 2008. http://www.opus-bayern.de/uni-wuerzburg/volltexte/2009/3046/.
Der volle Inhalt der QuelleBertholet, Ambre. „Influence de la protéine de fusion mitochondriale OPA1 sur le métabolisme oxydatif neuronal et la transmission synaptique“. Toulouse 3, 2011. http://thesesups.ups-tlse.fr/2180/.
Der volle Inhalt der QuelleIn the past few years, multiple findings have suggested that disruptions of mitochondrial functions and dynamics contribute to neurodegenerative diseases. Mitochondrial functions in neurons include regulation of calcium and redox signaling, developmental and synaptic plasticity as well as the arbitration of cell survival and death. Mitochondrial dynamics controls the organelle's morphology via a delicate balance of two opposing forces: mitochondrial fusion and fission that are regulated by large dynamin-related GTPases evolutionary conserved from yeast to human. We have previously demonstrated that the fusion protein OPA1 loss or mutations led to mitochondrial inner membrane dysfunctions and apoptosis of particular importance in optic nerve pathologies like ADOA1 (autosomal dominant optic atrophy). While links emerge between defects in mitochondrial fusion and neurodegeneration, the processes involved are still largely unknown. To understand the mechanisms by which alterations of mitochondrial dynamics could contribute to mitochondria dysfunction, eventually leading to neurodegeneration, we studied the effects of OPA1 loss of function in neurons ex vivo. In cortical neurons, RNA interference of the fusion protein OPA1 led to mitochondrial fragmentation without altering neither mitochondrial distribution nor neuronal death rate. While there was no incidence on dendrites and axon size and numbers, the quantity of several synaptic proteins was reduced, suggesting synaptic impairment. In these conditions, the redox state of OPA1 depleted-neurons was impaired and specific respiratory complex proteins quantities were decreased. Finally, electrophysiological recordings showed that OPA1 depletion induced changes in synaptic transmission, particularly in decreasing of EPSC frequency and by increasing IPSC frequency. Interestingly, forskolin treatment rescue these electrophysiological defaults. In conclusion, our data may offer new insights not only into mitochondrial dynamics-linked neurodegenerative diseases like ADOA1 but to other neurodegenerative pathologies correlated with oxidative metabolism such as Huntington's, Parkinson's and Alzheimer's diseases
Versini, Raphaëlle. „Structural basis of outer-mitochondrial membrane mitofusin-guided fusion“. Electronic Thesis or Diss., Sorbonne université, 2023. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2023SORUS653.pdf.
Der volle Inhalt der QuelleThe Phd project is the structural study of mitofusins (Mfn1/2 in humans and Fzo1 in yeasts) using mainly modeling-based methods such as molecular dynamics or structure prediction methods based on artificial intelligence (mainly AlphaFold). This project is a part of an ANR (MITOFUSION) shared between different partners (Laboratoire de Biochimie Théorique: Antoine Taly, Marc Baaden, Laboratoire des Biomolécules: Patrick Fuchs, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes: Mickaël Cohen, Institut de Psychiatrie et Neurosciences de Paris: David Tareste) whose goal is to understand the structure-function relationships of the mitofusin. Mitochondria form a complex network inside the cells, undergoing continuous fusion and fission events. These processes shape mitochondrial dynamics and are essential for the maintenance, function, distribution and inheritance of mitochondria. The morphology of the latter therefore respond to the ever-changing physiological changes of the cell. The large GTPase involved in the tethering and fusion of the mitochondrial outer membranes (OM) are transmembrane proteins called mitofusins. The mitofusins Mfn1 and Mfn2 can be found in mammals. Fzo1 (Fuzzy Onion 1) is the unique mitofusin homologue in Saccharomyces cerevisiae. The mitochondrial inner membrane fusion and cristea organisation is mediated by human OPA1 (Optic Atrophy 1) and yeast Mgm1 (Mitochondrial Genome Maintenance 1). Mitochondrial fusion dysfonction is related to several neurodegenerative disorders, such as Parkinson, Alzheimer and Huntingtion diseases. As a matter of fact, research has shown that mutations in Mfn2 induce the development and progression of muscular dystrophies, such as Charcot-Marie-Tooth Type 2A, the most common form of axonal CMT disease. The exact mechanism by which the mitofusins contributes to mitochondria dysfunction as well as the exact molecular fusion mechanism is not fully understood yet. Overall, mitochondrial fusion plays an important role in CMT2A, it is thus of paramount importance to get a full understanding of the process at the molecular level. The structure of both Mfn1 and Mfn2 was partially solved, the transmembrane domain being excluded, and no solved structure are available for Fzo1. With our ANR partners, we decided to work on the yeast version of Mitofusin (named Fzo1) as it is a good model (of homology with human Mfn1 and Mfn2) as yeast are convenient hosts for testing how other protein partners are involved in the process (e.g. Ugo1). Fzo1 is embedded in the mitochondrial OM as it possesses two transmembrane domains, exposing N- and C- terminal portions towards the cytosol and a loop towards the intermembrane space. On the N-terminal side can be found two coiled-coil heptad repeats (HRs) domains, HRN (in yeast only) and HR1, flanking a GTPase domain. A third coiled-coil heptad repeats domain HR2 is on the C-terminal portion. Some models of Fzo1 were built based on the mitofusin related bacterial dynamin-like protein (BDLP). BDLP is involved in membrane remodelling and exists in two conformational states, a closed compact version which changes to an opened extended structure, upon GTP-binding, on which the built models were based. The goal of the PhD is to update the model of Fzo1 built in 2017, by working on the transmembrane domains using multiscale molecular dynamics, and then update the overall structure using artificial intelligence methods. An other project consisted in studying the amphipathic helix of HR1 domain of Mfn1 (MfnA-AH), test its membrane binding capabilities. Initially, we employed coarse-grained simulations, establishing a robust foundation for evaluating the predictive capacity of the MARTINI family of force fields. Using other simulations ran with the penetratin, we were able to provide a comparative analysis for the AH-membranes interactions in the MARTINI force-fields. The Mfn1-AH was then further characterized using all-atom simulations
Fongy, Anais. „Implication potentielle des protéines de fusion mitochondriale dans l'ontogenèse des processus bioénergétiques musculaires chez l'oiseau“. Thesis, Lyon 1, 2013. http://www.theses.fr/2013LYO10276/document.
Der volle Inhalt der QuelleCold-exposed young birds maintain their homeothermy by stimulating mitochondrial oxidations in skeletal muscle. Prolonged cold exposure enhances muscle thermogenic capacities through mitochondrial bioenergetics plasticity which control still remains hypothetical. In mammals, fusion proteins (mitofusins (Mfns) and OPA1 (Optic Atrophy 1)) contribute to the permanent and dynamic changes in mitochondrial networks in multiple cell types. The aim of our work was to characterize the expression of avian homologues of mammalian fusion proteins and to study the variations of their expression during the establishment of bioenergetics processes in growing birds, during an acute or a prolonged cold exposure and finally during nutritional or endocrine challenges. Methodologically, an integrative approach has been used from whole animal (indirect calorimetry) to protein (western-blot) or gene (RT-PCR) expression through measurements of the bioenergetics functionality of permeabilized muscle fibers and isolated mitochondria. Two animal models were used, a species naturally adapted to Antarctica harsh conditions, the Adélie penguin (Pygoscelis adeliae), and a laboratory model, the Muscovy duck (Cairina moschata).Our results allowed us to characterize, in birds, the expression of immunoreactive fusion proteins (Mfn2, OPA1) which were homologous to those of mammals. The sequencing of a part of the coding sequence of Mfns genes showed a great similitude between avian and mammalian species. In penguins, the relative abundance of these proteins in muscle mitochondria was modified by growth in the cold and was positively correlated with muscle bioenergetics capacities. In ducks, the respiratory activity and the relative abundance of these proteins were also correlated after a 60h fasting period or,though a lesser extent, after a pharmacological alteration of thyroid status. Our results show, for the first time in birds, the expression of proteins homologous to mammalian fusion proteins. The association between the changes in expression of these proteins and the bioenergetics modifications in skeletal muscle indicates that these proteins could contribute to thebioenergetics plasticity observed in growing chicks. These results suggest that potential modifications of the muscle mitochondrial network organization could play a role in the adaptive responses of organisms to the environmental constraints
Detmer, Scott A. Bjorkman Pamela Jane. „The role of the mitofusin proteins in mitochondrial fusion and disease /“. Diss., Pasadena, Calif. : Caltech, 2007. http://resolver.caltech.edu/CaltechETD:etd-04132007-181115.
Der volle Inhalt der QuelleMalka, Florence. „La fusion mitochondriale : échanges moléculaires, mécanismes cellulaires et implications fonctionnelles“. Paris 6, 2006. http://www.theses.fr/2006PA066201.
Der volle Inhalt der QuelleMesserschmitt, Marlies. „Identifizierung und Charakterisierung von Proteinen, die Fusion und Teilung von Mitochondrien vermitteln“. Diss., [S.l.] : [s.n.], 2004. http://edoc.ub.uni-muenchen.de/archive/00002298.
Der volle Inhalt der QuelleBaker, Nicole. „Muscle Stem Cell Fate is Directed by the Mitochondrial Fusion Protein OPA1“. Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/41974.
Der volle Inhalt der QuelleYu, Yiyi. „Functions and Kinetics of Mitochondrial Fusion and Fission in the Axon: a Quantitative Study“. Research Showcase @ CMU, 2015. http://repository.cmu.edu/dissertations/648.
Der volle Inhalt der QuelleD'HONT, ANGELIQUE. „Analyse des genomes nucleaire, chloroplastique et mitochondrial de plantes issues de fusion de protoplastes de medicago; etude de la recombinaison de l'adn mitochondrial“. Paris 11, 1990. http://www.theses.fr/1990PA112001.
Der volle Inhalt der QuelleBaker, Bianca Nicole. „Molecular and Cellular Mechanisms Responsible for Low-grade Stress and Inflammation Triggered By Super-low Dose Endotoxin“. Diss., Virginia Tech, 2014. http://hdl.handle.net/10919/56732.
Der volle Inhalt der QuellePh. D.
Rajasimha, Harsha Karur. „Insights Into Mitochondrial Genetic and Morphologic Dynamics Gained by Stochastic Simulation“. Diss., Virginia Tech, 2007. http://hdl.handle.net/10919/29961.
Der volle Inhalt der QuellePh. D.
Langston, Rachel Elizabeth. „Specific Protein Isoforms of Miro and Milton Have Divergent Roles Controlling Mitochondrial Transport, Fusion & Fission, and Health“. Thesis, The University of Arizona, 2012. http://hdl.handle.net/10150/244404.
Der volle Inhalt der QuelleRaković, Aleksandar [Verfasser]. „Impact of Parkinson disease-related mutations in PINK1 on Parkin and mitochondrial fusion/fission factors in human-derived cells / Aleksandar Raković“. Lübeck : Zentrale Hochschulbibliothek Lübeck, 2014. http://d-nb.info/1046713515/34.
Der volle Inhalt der QuelleAcquistapace, Adrien, und Adrien Acquistapace. „Reprogrammation nucléaire de cardiomyocytes vers un stade progéniteur par fusion partielle avec des cellules souches adultes“. Phd thesis, Université Paris-Est, 2011. http://tel.archives-ouvertes.fr/tel-00733068.
Der volle Inhalt der QuelleDassa, Emmanuel. „Le transporteur mitochondrial d'ADP/ATP (ANC2) de saccharomyces cerevisiae. Elaboration et caractérisation de formes colorées par voie chimique ou par fusion génique, en vue d'approches cristallographiques“. Université Joseph Fourier (Grenoble), 2004. http://www.theses.fr/2004GRE10051.
Der volle Inhalt der QuelleThe mitochondrial adenine nucleotide carrier is a membrane protein which catalyses the exchange of cytoplasmic ADP against ATP synthésized in the matrix. The present work concerns the coloration of the Anc2p carrier from Saccharomyces cerevisiae with the aim at facilitating its crystallization in lipidic cubic phase. The first part presents results from a chemical coloration approach based on the use of thiol reactive compounds. The second part reports on coloration of carrier following a gene fusion strategy. We elaborated two chimera proteins, namely Anc2-Cycl (His6)p and Cycl-Anc2 (His6)p, in which the S. Cerevisiae cytochrome c was fused to the carrier. Both fusion proteins are functional and have been characterized in detail. Anc2-Cycl (His6)p has been purified to homogeneity to undertake cristallization trials
El, Fissi Najla. „Caractérisation d'allèles de mitofusine associés à la maladie de Charcot-Marie-Tooth : mise en évidence de l'implication d'un déséquilibre entre fusion et fission mitochondriale dans le dysfonctionnement des neurones“. Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0250/document.
Der volle Inhalt der QuelleMitochondria form a dynamic network remodeled by two antagonistic processes called mitochondrial fusion and fission. While mitochondrial fusion creates interconnections between mitochondria, mitochondrial fission result in fragmentation. These processes are mediated by Dynamin-related GTPases, the outer-membrane fusion protein mitofusin, and the fission factor DPR1.The main aim of my resaearch was to characterize the impact of an imbalance between mitochondrial fusion and fission in neurons in the context of a severe hereditary neuropathy called Charcot-Marie-Tooth type 2A (CMT2A). Indeed, this disease is caused by dominant mutations in the mitofusinMFN2.In order to dissect the mechanisms by which these mutations alter mitofusin properties and neuronal function, we developed four drosophila models of CMT2A expressing the two most frequent substitutions (R94Q, R364W) and two others localizing to similar domains (T105M, L76P). The four alleles resulted in mitochondrial depletion at neuromuscular junctions, decreased oxidative metabolism, increased mtDNA mutations, and impaired locomotion that were associated with aberrant mitochondrial morphology. Interestingly, while GTPase domain-associated mutations (R94Q, T105M) aggregate unfused mitochondria, mutations within helix bundle 1 (R364W, L76P) unexpectedly enhance mitochondrial fusion, as demonstrated by rescue of mitochondrial morphology and locomotion provided by the DRP1 fission factor. In conclusion, we show that both dominant negative and dominant active forms of mitofusin can cause CMT2A, and propose for the first time that excessive mitochondrial fusion drives CMT2A pathogenesis in a large number of patients
Tavares, Sara B. „Social associations, relatedness and population genetic structure of killer whales (Orcinus orca) in Iceland“. Thesis, University of St Andrews, 2017. http://hdl.handle.net/10023/12061.
Der volle Inhalt der QuelleRujiviphat, Jarungjit. „Understanding the Molecular Mechanism of Mgm1 Function in Mitochondrial Dynamics“. Thesis, 2014. http://hdl.handle.net/1807/65737.
Der volle Inhalt der QuelleLin, Szu-Ting, und 林思廷. „Study of the role of CAP2 and Polymethoxylated flavones on mitochondria fusion and fission in mammalian cells“. Thesis, 2011. http://ndltd.ncl.edu.tw/handle/96313516130367271451.
Der volle Inhalt der Quelle國立清華大學
生物科技研究所
99
Mitochondria are dynamic organelles that involved in ATP synthesis, calcium concentration regulations and apoptosis. Aberrant mitochondrial morphology caused by abnormal equivalence of fusion and fission in were found in neurodegenerative patients. The aim of my thesis is to study the regulation of mitochondria dynamics. In the first part, I focused on the protein that interacts with mitochondria fission Drp1 called CAP2 (cyclase associated protein 2). CAP2 is a highly conserved protein that plays critical roles in regulating acting dynamics and Ras/cAMP signaling pathway. I manipulated CAP2 expression levels by transfecting either overexpression vectors or RNAi and applied confocal microscope to monitor mitochondrial morphology. My experiments found that overexpression of CAP2 caused mitochondria fragmentation and inhibition of CAP2 lead to elongation. These results indicated that CAP2 does involved in regulating mitochondria dynamics. The second part of my thesis is focus on the effects of nature products on mitochondria dynamics. The dehydrated citrus peels used in traditional Chinese medicine contain the most common flavones: polymethoxylated flavones (PMFs). Both nobiletin and tangeretin are abundant PMFs in citrus peels. Many researches had demonstrated that PMF and 5-OH PMFs involved in anti-inflammatory, antioxidants, antithrombotic and anticarcinogenic processes and affected apoptosis. In my experiments, the survival rates of Hela cells treated with different concentrations of nobiletin, tangeretin, 5-OH nobiletin and 5-OH tangeretin were dosage dependent. In addition, 10 μM PMFs treatments altered mitochondrial dynsmics in HeLa cells. Our results of PMFs suggested these molecules may be therapeutically useful in treating the neurodegenerative disorders caused by mitochondrial fusion and fission regulation defects.
Hsiung, Kuei Ching, und 熊桂慶. „C. elegans W02B12.15, a homologous gene of human cisd1, is involved in oxygen consumption and mitochondria fusion“. Thesis, 2014. http://ndltd.ncl.edu.tw/handle/46872418014998999853.
Der volle Inhalt der QuelleVoleman, Luboš. „Úloha SNARE proteinu v biogenezi mitosomů Giardia intestinalis“. Master's thesis, 2011. http://www.nusl.cz/ntk/nusl-312461.
Der volle Inhalt der QuelleKukat, Alexandra. „Mitochondriale Fusions- und Fissionsvorgänge am Modellsystem von Mega-Mitochondrien einer rho0-Zelllinie“. Doctoral thesis, 2007. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-26484.
Der volle Inhalt der QuelleA variety of mitochondrial features are based on processes involving mitochondrially encoded as well as nuclear encoded gene products. By means of these manifold interactions it is difficult to discern the influences of the single components. One effort to overcome these difficulties was the development of cells devoid of endogenous mtDNA (so called rho0 cells) and therefore to exclude the mitochondrial genetic component. The aim of this thesis was the investigation of the metabolic, proliferative and morphologic characteristics of a rho0 cell line (143B.TK-K7) based on a 143B.TK- background. This cell line was developed by the expression of a mitochondrially targeted restriction endonuclease. During the cultivation and proceeding acidification of the culture medium by lactic acid megamitochondria developed in the cytoplasm of the 143B.TK-K7 cells. These megamitochondria form both by multiple fusion events and an additional increase in water influx into the matrix. All mitochondria then exist as large spherical structures with diameters of up to 7 µm and therefore receive the smallest surface area to a given volume. The formation of megamitochondria is dependent on a high proton production level additional to a sufficient amount of lactate (lactic acid) in the medium. Furthermore it is possibly to induce megamitochondria in cells still possessing a mitochondrial genome by these conditions. The formation of megamitochondria is not a sign of apoptotic processes per se, because the back-formation of the megamitochondria into a rho0-like network can be induced very fast by the exchange of the acidulated medium. Initial deformations of the megamitochondria are followed by tubulation in progressive mitochondria tubules and numerous fission events. Metabolic analyses show that this backformation only depends on a sufficient low concentration of protons in the medium. When the given threshold is not being traversed the megamitochondria persist. Immunocytological investigations both of the fusion protein MFN2 and the protein of the fission machinery DNM1L demonstrate a constant mitochondrial distribution in focal regions of the outer mitochondrial membrane during formation as well as back-formation of megamitochondria. By overexpressing the fission proteins hFis1 and DNM1L respectively in 143B.TK-K7 cells, it should be tested whether or not megamitochondria develop. The enhanced expression of hFis1 led to the formation of aggregated mitochondria that indeed swell but persist after changing the medium. The overexpression of DNM1L has no influence on the formation as well as the back-formation of the megamitochondria. Incubation of the cells with inhibitors for the tubulin respectively actin cytoskeleton evidenced that the destruction of the tubulin cytoskeleton has no consequence for the formation and back-formation of megamitochondria. Unclear results were obtained with inhibitors of the actin cytoskeleton probably due to secondary effects of the inhibitors to the cells. However the findings showed that the megamitochondria are embedded into the actin cytoskeleton. Additionally the megamitochondria were used as a model system for mitochondrial fusion and fission events. For this purpose fluorescent protein markers for the inner and outer mitochondrial membrane were created. With these tools it was possible to observe directly mitochondrial fusion and fission in living cells by confocal microscopy. Furthermore this led to the classification of fusion processes of the mitochondria in a mode 1 with temporally coupled fusion of outer and inner membrane and a mode 2 where the fusion of outer membrane occurs independent of the inner membrane fusion. In a similar way the fission of mitochondria can be sub-classified: mode 1 is featured during the back-formation of megamitochondria by increasing tubulation events in long mitochondrial tubules with thin diameters. Only at this point very fast fission events could be observed. Furthermore in a fission mode 2 that results from an incomplete fusion of inner mitochondrial membranes, the outer membrane invaginates from one side along the unfused inner membranes until two separate mitochondrial units exist. During the megamitochondria formation on electron microscopic level drastic changes occur from fuzzy onion like structures to a decrease of inner membranes and electron density in the matrix. Additionally inversions and inclusions consisting of one membrane and also double membranes are evident. Comparisons with confocal microscopy images show that these inclusions apparently accomplish undirected movements with high velocity. In the present thesis it was possible to observe for the first time these movements as well as mitochondrial fusion and fission in living cells with an outstanding optical and temporal resolution
Santos, Daniel Ferreira dos. „Mitochondrial fusion and fission regulation in Parkinson’s Disease“. Master's thesis, 2011. http://hdl.handle.net/10316/25876.
Der volle Inhalt der QuelleA doença de Parkinson é a segunda doença neurodegenerativa mais comum e a doença neurodegenerativa associada ao movimento mais comum. É causada pela perda dos neurónios dopaminérgicos na substantia nigra pars compacta levando a um défice de dopamina no estriado. Perceber a base molecular da doença de Parkinson tem se revelado um grande desafio no campo das doenças neurodegenerativas. Apesar de terem sido propostas várias hipóteses para explicar os mecanismos subjacentes a patogenia da doença de Parkinson, um crescente corpo de evidencias tem enfatizado o papel da disrupção da dinâmica mitocôndrial como um grande contribuidor para a etiopatogenia da doença de Parkinson. Tem se vindo a acumular dados que sugerem que uma dinâmica mitocondrial anormal se encontra envolvida na disfunção mitocôndrial ou medeia a morte neuronal em diferentes modelos da doença de Parkinson. Aliás, a integração da fissão, fusão e autofagia mitocondrial forma um mecanismo de manutenção de qualidade mitocôndrial da homeostase mitocôndrial na qual defeitos na função mitocôndrial têm sido associados à doença de Parkinson. A maioria dos casos surge como condição esporádica e os restantes são herdados com mutações em vários genes que tem sido ligados a essas formas genéticas da doença. Os estudos de duas das proteínas ligadas as formas familiares da doença, nomeadamente a PINK1 e a Parkin, forneceram evidências que estas duas proteínas actuam na mesma via regulando a fissão e fusão mitocôndria e a mitofagia. Uma vez que uma dinâmica mitocôndrial anormal tem sido cada vez mais implicada na patogenia da doença de Parkinson, nesta tese, investigámos a regulação da dinâmica mitocôndrial em diferentes modelos celulares da doença de Parkinson. Nos observamos que uma diminuta localização mitocôndrial da OPA1 leva a um dano da dinâmica mitocôndrial na maioria dos modelos celulares de 13 Parkinson. Para além do mais, a clivagem das isoformas longas da Opa1 parecem ser responsáveis pelo padrão de fragmentação observado nos modelos celulares de PD esporádicos derivados da mitocôndria. A sobrexpressão da alpha-synucleina induz a tubulação da rede mitocondrial com estruturas elongadas que são o oposto do observado em modelos celulares de PD. Inesperadamente, a sobrexpressao da Opa1 não resgatou o aumento de produção de espécies reactivas de oxigénio induzida pelo MPP+. Globalmente, as nossas observações sugerem que uma fusão mitocondrial dependente da Opa1 desempenha um papel crucial na mediação nas anormalidades mitocôndriais e disfunção celular induzida MPP+/mtDNA. Estes estudos sugerem que a dinâmica mitocôndrial desempenha um papel importante na patogenia da doença de Parkinson, e um melhor entendimento destes mecanismos podem levar à descoberta de novos alvos terapêuticos para esta doença.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the most common neurodegenerative movement disorder. It is caused by the loss of dopaminergic neurons in the substantia nigra pars compacta leading to a dopamine deficit in the striatum. Understanding the molecular basis of PD has proven to be a major challenge in the field of neurodegenerative diseases. Although several hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of PD, a growing body of evidence has highlighted the role of mitochondrial dynamics disruption as a major contributor to PD etiopathogenesis. Accumulating data suggests that abnormal mitochondrial dynamics is involved in mitochondrial dysfunction or mediates neuronal death in different PD models. Moreover, integration of mitochondrial fusion, fission and mitochondrial autophagy forms a quality maintenance mechanism of mitochondrial homeostasis that defects in mitochondrial function have been associated with PD. Most of the cases arise as sporadic conditions and the others are inherited with mutations in several genes being linked to these genetic forms of PD. Studies of two of the proteins linked to the familial forms of the disease, namely PINK1 and Parkin, provided evidence that these two proteins act in the same pathway regulating mitochondrial fusion, fission and mitophagy. Because abnormal mitochondrial dynamics are increasingly implicated in the pathogenesis of PD, in this thesis, we investigated the regulation mitochondrial dynamics in different PD cellular models. We observed that a decreased OPA1 mitochondrial localization-drive mitochondrial dynamics impairment in most cellular PD models. Moreover, OPA1 long isoforms cleavage seems to be responsible for mitochondrial fragmented pattern observed in sporadic mitochondrial-driven cellular PD models. Alpha-synuclein overexpression induces a tubular mitochondrial network 15 with elongated structures that is the opposite of what was observed in mitochondrial PD cellular models. Unexpectedly, OPA1 overexpression did not rescued MPP+-induced increase in reactive oxygen species (ROS). Overall, our findings suggest that OPA1-dependent mitochondrial fusion plays a crucial role in mediating MPP+/mtDNA induced mitochondria abnormalities and cellular dysfunction. These studies suggest that mitochondrial dynamics can play an important role in PD pathogenesis, and a better understanding of these mechanisms can lead to the discover of new therapeutical targets for this disease.
Griffin, Erik Edmund. „Mechanisms of mitochondrial fusion and fission“. Thesis, 2006. https://thesis.library.caltech.edu/2010/1/Thesis.pdf.
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