Academic literature on the topic 'Mitoepigenetics'

Mitochondria are organelles responsible for several functions involved in cellular balance, including energy generation and apoptosis. For decades now, it has been well-known that mitochondria have their own genetic material (mitochondrial DNA), which is different from nuclear DNA in many ways. More recently, studies indicated that, much like nuclear DNA, mitochondrial DNA is regulated by epigenetic factors, particularly DNA methylation and non-coding RNAs (ncRNAs). This field is now called mitoepigenetics. Additionally, it has also been established that nucleus and mitochondria are constantly communicating to each other to regulate different cellular pathways. However, little is known about the mechanisms underlying mitoepigenetics and nuclei–mitochondria communication, and also about the involvement of the ncRNAs in mitochondrial functions and related diseases. In this context, this review presents the state-of-the-art knowledge, focusing on ncRNAs as new players in mitoepigenetic regulation and discussing future perspectives of these fields.

AbstractMitochondria, intracellular organelles with their own genome, have been shown capable of interacting with epigenetic mechanisms in at least four different ways. First, epigenetic mechanisms that regulate the expression of nuclear genome influence mitochondria by modulating the expression of nuclear-encoded mitochondrial genes. Second, a cell-specific mitochondrial DNA content (copy number) and mitochondrial activity determine the methylation pattern of nuclear genes. Third, mitochondrial DNA variants influence the nuclear gene expression patterns and the nuclear DNA (ncDNA) methylation levels. Fourth and most recent line of evidence indicates that mitochondrial DNA similar to ncDNA also is subject to epigenetic modifications, particularly by the 5-methylcytosine and 5-hydroxymethylcytosine marks. The latter interaction of mitochondria with epigenetics has been termed ‘mitochondrial epigenetics’. Here we summarize recent developments in this particular area of epigenetic research. Furthermore, we propose the term ‘mitoepigenetics’ to include all four above-noted types of interactions between mitochondria and epigenetics, and we suggest a more restricted usage of the term ‘mitochondrial epigenetics’ for molecular events dealing solely with the intra-mitochondrial epigenetics and the modifications of mitochondrial genome.

There are currently no validated biomarkers which can be used to accurately diagnose Alzheimer’s disease (AD) or to distinguish it from other dementia-causing neuropathologies. Moreover, to date, only symptomatic treatments exist for this progressive neurodegenerative disorder. In the search for new, more reliable biomarkers and potential therapeutic options, epigenetic modifications have emerged as important players in the pathogenesis of AD. The aim of the article was to provide a brief overview of the current knowledge regarding the role of epigenetics (including mitoepigenetics) in AD, and the possibility of applying these advances for future AD therapy. Extensive research has suggested an important role of DNA methylation and hydroxymethylation, histone posttranslational modifications, and non-coding RNA regulation (with the emphasis on microRNAs) in the course and development of AD. Recent studies also indicated mitochondrial DNA (mtDNA) as an interesting biomarker of AD, since dysfunctions in the mitochondria and lower mtDNA copy number have been associated with AD pathophysiology. The current evidence suggests that epigenetic changes can be successfully detected, not only in the central nervous system, but also in the cerebrospinal fluid and on the periphery, contributing further to their potential as both biomarkers and therapeutic targets in AD.

Abstract Fetal exposure to an unfavorable intrauterine environment programs an individual to have a greater susceptibility later in life to non-communicable diseases, such as coronary heart disease, but the molecular processes are poorly understood. An article in Clinical Science recently reported novel details on the effects of maternal nutrient reduction (MNR) on fetal heart development using a primate model that is about 94% genetically similar to humans and is also mostly monotocous. MNR adversely impacted fetal left ventricular (LV) mitochondria in a sex-dependent fashion with a greater effect on male fetuses, although mitochondrial transcripts increased more so in females. Increased expression for several respiratory chain and adenosine triphosphate (ATP) synthase proteins were observed. However, fetal LV mitochondrial complex I and complex II/III activities were significantly decreased, likely contributing to a 73% decreased LV ATP content and increased LV lipid peroxidation. Moreover, MNR fetal LV mitochondria showed sparse and disarranged cristae. This study indicates that mitochondria are targets of the remodeling and imprinting processes in a sex-dependent manner. Mitochondrial ROS production and inadequate energy production add another layer of complexity. Altogether these observations raise the possibility that dysfunctional mitochondria in the fetus may contribute in turn to epigenetic memory of in utero stress in the adult. The role of mitoepigenetics and involvement of mitochondrial and genomic non-coding RNAs in mitochondrial functions and nuclei–mitochondria crosstalk with in utero stress awaits further investigation.

Neurodegenerative diseases (NDs) represent a group of disorders characterized by the progressive neuronal loss in specific areas of the central nervous system. NDs are incurable and often fatal shortly after diagnosis. The global prevalence of these disorders is dramatically increasing worldwide as populations age and life expectancies increase. The identification of valuable biomarkers for an early diagnosis is of outmost importance as it would promote early interventions able to prevent or delay as much as possible the onset of the disease. Despite their high heterogeneity and the differences in their primary etiologies, NDs share many common aspects in relation to their clinical, biochemical, and pathological features and multiple lines of evidence suggest that mitochondrial dysfunction is involved in the pathogenesis of many NDs, especially Alzheimer´s disease (AD), Parkinson´s disease (PD) and amyotrophic lateral sclerosis (ALS). To date, several papers showed that aberrant epigenetic mechanisms in the nuclear DNA may be involved in the onset and development of NDs, and several studies have found altered gene methylation levels in both post-mortem brain specimens and peripheral tissues from patients with these diseases. In recent years growing evidence for a potential role of altered mitochondrial DNA (mtDNA) methylation and hydroxymethylation in several diseases has emerged. Although mitochondrial impairment is a classical feature of neurodegeneration, little attention has been given until now to the role of the mitochondrial epigenome itself in NDs. Particularly, studies performed so far have investigated mtDNA methylation in animal models of ALS, and in brain tissue of patients with AD, PD and ALS. However, potential mtDNA methylation alterations in peripheral tissues of NDs patients have not been investigated in those studies. The main aim of the work presented in the current thesis was to investigate the presence of mitoepigenetic signatures in peripheral blood of patients with AD (Study 1), ALS (Study 2) and PD (Study 3). DNA methylation analysis of the mitochondrial D-loop region, which regulates mitochondrial transcription and replication, was performed by means of Methylation Sensitive-High Resolution Melting and Pyrosequencing techniques. In study 1 D-loop methylation levels were analyzed in people affected by AD with different clinical dementia impairment degrees and results suggest that mtDNA methylation could vary with the stage of the disease. In study 2 D-loop methylation levels were analyzed in ALS patients with mutations in SOD1, TARDBP, FUS or C9ORF72 genes, and in their relatives, and results showed that mtDNA methylation levels were decreased in ALS tissues, partcularly in carriers of SOD1 mutations. In study 3 higher Dloop methylation levels, although not statistically significant, were detected in peripheral blood from PD patients. Results presented in the current thesis indicate a potential involvement for impaired mtDNA methylation in NDs, which is detectable in peripheral blood suggesting that this field of research deserves to be further studied. Moreover, current results suggest that mtDNA methylation could be sensitive to different disease stages and dementia levels, thus adding a new layer of interest in the search for peripheral mitoepigenetic biomarkers for neurodegeneration. Given the pivotal role of mitochondrial dysfunction and of epigenetic mechanisms in neurodegeneration, the field of mitoepigenetics in neurodegenerative diseases is a timely and attractive recent area of investigation, where preliminary results really seem encouraging, but more research is warranted to clarify the connections between epigenetic changes occurring in the mitochondrial genome, mitochondrial DNA dynamics, and the neurodegenerative process.