Mitochondrial Quality Control Imbalance in the Heterogeneity of Parkinson’s Disease: From Selective Vulnerability to Stratified Transformation

Abstract

Parkinson’s disease (PD) is a clinically and biologically heterogeneous neurodegenerative disorder in which variable symptom profiles, progression rates, and treatment responses likely reflect distinct but partially convergent pathogenic mechanisms. Among these, mitochondrial dysfunction recurs across both familial and sporadic PD; however, this broad concept alone cannot explain disease heterogeneity. To preserve mitochondrial homeostasis, cells rely on a complex mitochondrial quality control (MQC) system that encompasses protein import and proteostasis, redox surveillance, organellar dynamics and positioning, biogenesis, and selective elimination of damaged mitochondria. MQC also depends on coordination with other organelles, particularly the endoplasmic reticulum and lysosomes. In this review, we discuss how different layers of MQC maintain mitochondrial integrity and how these pathways are functionally coupled. We further consider how an MQC-based framework may help explain the clinical heterogeneity of PD, including selective neuronal vulnerability, subtype formation, and divergent disease progression, and how it can frame recent therapeutic advances aimed at biologically stratified intervention.