Integrating mitoepigenetics into research in mood disorders: a state-of-the-art review

Abstract

Mood disorders, including major depressive disorder and bipolar disorder, are highly prevalent and stand among the leading causes of disability. Despite the largely elusive nature of the molecular mechanisms underpinning these disorders, two pivotal contributors-mitochondrial dysfunctions and epigenetic alterations-have emerged as significant players in their pathogenesis. This state-of-the-art review aims to present existing data on epigenetic alterations in the mitochondrial genome in mood disorders, laying the groundwork for future research into their pathogenesis. Associations between abnormalities in mitochondrial function and mood disorders have been observed, with evidence pointing to notable changes in mitochondrial DNA (mtDNA). These changes encompass variations in copy number and oxidative damage. However, information on additional epigenetic alterations in the mitochondrial genome remains limited. Recent studies have delved into alterations in mtDNA and regulations in the mitochondrial genome, giving rise to the burgeoning field of mitochondrial epigenetics. Mitochondrial epigenetics encompasses three main categories of modifications: mtDNA methylation/hydroxymethylation, modifications of mitochondrial nucleoids, and mitochondrial RNA alterations. The epigenetic modulation of mitochondrial nucleoids, lacking histones, may impact mtDNA function. Additionally, mitochondrial RNAs, including non-coding RNAs, present a complex landscape influencing interactions between the mitochondria and the nucleus. The exploration of mitochondrial epigenetics offers valuable perspectives on how these alterations impact neurodegenerative diseases, presenting an intriguing avenue for research on mood disorders. Investigations into post-translational modifications and the role of mitochondrial non-coding RNAs hold promise to unravel the dynamics of mitoepigenetics in mood disorders, providing crucial insights for future therapeutic interventions.

Keywords: bipolar disorder; epigenetics; major depression; mitochondrial dysfunction; mitoepigenetics; mood disorders.

FIGURE 1

The research about mtDNA modifications focuses on changes in mtDNA copy numbers and oxidation levels, in addition to mitoepigenetic changes in mood disorders. Different types of modifications have been identified for mitoepigenetics. (1) mtDNA methylation/hydroxymethylation; (2) modifications of mitochondrial nucleoids; (3) mitochondrial RNA modifications and modulation of non-coding RNAs (ncRNA) originating from nuclear DNA or mtDNA. (Created with BioRender.com).