The Genetic and Epigenetic Mechanisms of mtDNA in Regulation of Inflammation and Metabolism

ABSTRACT Mitochondria serve as the primary cellular powerhouses, generating ATP through oxidative phosphorylation (OXPHOS) to sustain essential cellular processes. Beyond energy production, mitochondria function as critical regulators of metabolic homeostasis, intracellular signaling networks, and programmed cell death pathways. The mitochondrial genome comprises 37 genes encoding 13 OXPHOS subunits, 22 transfer RNAs, and 2 ribosomal RNAs, all transcribed and translated within the organelle. Mitochondrial DNA integrity becomes compromised through diverse pathological stimuli, including metabolic dysregulation, oxidative stress, and inflammatory cascades, contributing to disease pathogenesis across multiple organ systems. This review synthesizes current knowledge on the multifaceted roles of mtDNA in health and disease. We propose a framework of three interconnected mechanisms through which mtDNA exerts its effects: (1) retrograde signaling to the nucleus, reprogramming nuclear gene expression; (2) cytosolic and extracellular release of mtDNA as a damage‐associated molecular pattern (DAMP), activating innate immune pathways like cGAS‐STING and NLRP3; and (3) intrinsic epigenetic modifications that directly modulate mitochondrial gene expression. We critically evaluate the evidence linking mtDNA alterations to a spectrum of diseases, including cancer, cardiovascular and metabolic disorders, neurodegeneration, and psychiatric conditions. We conclude that a comprehensive understanding of mtDNA's multifaceted nature, moving beyond its perception as a mere DAMP, is essential for translating mitochondrial biology into effective clinical interventions.