Mitochondria in Parkinson disease: Genetic and epigenetic components
TL;DR
Advances in understanding mitochondrial biology have enabled the development of novel therapeutic approaches, including activators of the PINK1/Parkin pathway, inhibitors of LRRK2 and α-synuclein aggregation, and strategies promoting mitochondrial biogenesis and intercellular transfer, offering potential for disease modification.
Abstract
This review aims to elucidate the genetic and epigenetic mechanisms underlying mitochondrial dysfunction in Parkinson’s disease (PD) and to explore how these insights inform emerging therapeutic strategies. A comprehensive analysis of current literature was conducted to integrate evidence on mitochondrial homeostasis, mitophagy regulation, and genome stability, with a focus on mutations in SNCA, LRRK2, VPS35, PINK1, PARK2, DJ-1, and POLG, as well as epigenetic alterations affecting mitochondrial DNA. Genetic mutations disrupt mitochondrial dynamics, impair autophagy, and cause oxidative stress, leading to dopaminergic neuron degeneration. Epigenetic modifications—such as altered DNA methylation, histone acetylation, and non-coding RNA regulation—further exacerbate mitochondrial instability and neuronal apoptosis. Mitochondrial impairment represents a common denominator linking hereditary and sporadic forms of PD, providing a unifying model of disease pathogenesis. Advances in understanding mitochondrial biology have enabled the development of novel therapeutic approaches, including activators of the PINK1/Parkin pathway, inhibitors of LRRK2 and α-synuclein aggregation, and strategies promoting mitochondrial biogenesis and intercellular transfer, offering potential for disease modification.