Abstract
Mitochondria, the centers of energy metabolism, have been shown to participate in epigenetic regulation of neurodegenerative diseases. Epigenetic modification of nuclear genes encoding mitochondrial proteins has an impact on mitochondria homeostasis, including mitochondrial biogenesis, and quality, which plays role in the pathogenesis of neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. On the other hand, intermediate metabolites regulated by mitochondria such as acetyl-CoA and NAD+, in turn, may regulate nuclear epigenome as the substrate for acetylation and a cofactor of deacetylation, respectively. Thus, mitochondria are involved in epigenetic regulation through bidirectional communication between mitochondria and nuclear, which may provide a new strategy for neurodegenerative diseases treatment. In addition, emerging evidence has suggested that the abnormal modification of mitochondria DNA contributes to disease development through mitochondria dysfunction. In this review, we provide an overview of how mitochondria are involved in epigenetic regulation and discuss the mechanisms of mitochondria in regulation of neurodegenerative diseases from epigenetic perspective.
Highlights
Mitochondria originated from Alphaproteobacteria with a circular genome packaged into DNA– protein assemblies
The extent of mitochondria DNA (mtDNA) methylation varies among neurodegenerative diseases (Blanch et al, 2016; Stoccoro et al, 2020)
Available literatures indicate acetyl-CoA and NAD+ provided by mitochondria may indirectly affect the histone acetylation and deacetylation, respectively, in the research of neurodegenerative diseases
Summary
Mitochondria originated from Alphaproteobacteria with a circular genome packaged into DNA– protein assemblies. Α-Ketoglutarate, a key intermediate in the tricarboxylic acid (TCA) cycle of oxidative phosphorylation (OXPHOS), is required for Jumonji C domain demethylases and DNA demethylase translocation (TET) as cofactors (Xu et al, 2011; Figure 1) These intermediates may directly or indirectly provide by mitochondria and affect the epigenetic regulation of the nuclear genome. A number of studies have shown the importance of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD; Lin and Beal, 2006; Yao et al, 2009; Chaturvedi and Flint Beal, 2013) In these diseases, mitochondria are characterized by decreased activity of respiratory chain enzyme, abnormal morphology, and more mutations in mtDNA (Chaturvedi and Flint Beal, 2013). APP and PS1 promoter methylation rates increased and APP, PS1, and Aβ protein levels decreased (Li et al, 2015)
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