Mitochondria and its epigenetic dynamics: Insight into synaptic regulation and synaptopathies

Abstract

Mitochondria, the cellular powerhouses, are pivotal to neuronal function and health, particularly through their role in regulating synaptic structure and function. Spine reprogramming, which underlies synapse development, depends heavily on mitochondrial dynamics-such as biogenesis, fission, fusion, and mitophagy as well as functions including ATP production, calcium (Ca²⁺) regulation, and retrograde signaling. Mitochondria supply the energy necessary for assisting synapse development and plasticity, while also regulating intracellular Ca²⁺ homeostasis to prevent excitotoxicity and support synaptic neurotransmission. Additionally, the dynamic processes of mitochondria ensure mitochondrial quality and adaptability, which are essential for maintaining effective synaptic activity. Emerging evidence highlights the significant role of epigenetic modifications in regulating mitochondrial dynamics and function. Epigenetic changes influence gene expression, which in turn affects mitochondrial activity, ensuring coordinated responses necessary for synapse development. Furthermore, metabolic changes within mitochondria can impact the epigenetic machinery, thereby modulating gene expression patterns that support synaptic integrity. Altered epigenetic regulation affecting mitochondrial dynamics and functions is linked to several neurological disorders, including Amyotrophic Lateral Sclerosis, Huntington’s, Alzheimer’s, and Parkinson’s diseases, emphasizing its crucial function. The review delves into the molecular machinery involved in mitochondrial dynamics, ATP and Ca²⁺ regulation, highlighting the role of key proteins that facilitate the processes. Additionally, it also shed light on the emerging epigenetic factors influencing these regulations. It provides a thorough summary on the current understanding of the role of mitochondria in synapse development and emphasizes the importance of both molecular and epigenetic mechanisms in maintaining synaptic integrity.

Graphical abstract 

Effect of epigenetic regulation on mitochondrial processes that assist synapse development: This figure illustrates the intricate interplay between mitochondrial dynamics, bioenergetics, and epigenetic regulation, all of which are essential for synaptic function. A) Mitochondrial fission, driven by dynamin-related protein 1 (Drp1) and K-Ras, and C) Fusion, mediated by mitochondrial fusion protein 1 and 2 (Mfn1, Mfn2) and optic nerve atrophy 1 (Opa1), work together to maintain mitochondrial integrity and function. B) Biogenesis, regulated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mechanistic target of rapamycin (mTOR), and transcription factors, alongside mitophagy involving PARKIN, PTEN-induced kinase 1 (PINK1), and BCL2-interacting protein 3 (BNIP3), ensures mitochondrial quality control and adaptation. D) The tricarboxylic acid (TCA) cycle drives the production of electron donors for oxidative phosphorylation and is tightly regulated by calcium dynamics. E) ATP synthesis through oxidative phosphorylation by electron transport chain complexes (I–V) is also modulated by calcium signalling. (A-E) Epigenetic modifiers, including histone acetylation (←), DNA methylation (←), and miRNA regulation (←), control these mitochondrial functions. (D, F) The mitochondrial metabolites (denoted by ←) like acetyl-CoA links mitochondrial activity to nuclear transcription. Retrograde signaling by TCA cycle intermediates, such as citrate and α-ketoglutarate, further influences nuclear gene expression. Additionally, mitochondrial metabolism modulates epigenetic mechanisms, including histone acetylation, DNA methylation, and miRNA-mediated regulation, impacting chromatin remodeling and transcriptional control. Together, these processes highlight the integration of mitochondrial function and epigenetic regulation in maintaining cellular metabolic balance.