Work

LRRK2 controls COX assembly through regulation of redox status of mitochondrial copper chaperones

Year: 2026

Type: article

Abstract: Mitochondrial dysfunction is a common pathological hallmark of neurodegenerative diseases. In Parkinson's disease (PD), the most popular age-related movement disorder, the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is closely associated with mitochondrial energetic deficits, reflecting their exceptionally high metabolic demand. The electron transport chain (ETC), essential for ATP production, comprises multiple protein complexes that require coordinated assembly and redox-sensitive regulation. In this study, we identified LRRK2-the most common genetic contributor to both familial and sporadic PD-as a regulator of cytochrome c oxidase (COX), the terminal enzyme of the ETC, through its control of the redox status of mitochondrial copper chaperones. Expression of pathogenic LRRK2 G2019S mutant increased the proportion of reduced (Cu-deficient) forms of COX11 and SCO1, two chaperones essential for COX metalation, thereby impairing COX assembly and promoting ETC dysfunction. Within this regulatory hierarchy, COX19 functions as a downstream effector of LRRK2 and an upstream modulator of COX11 and SCO1 redox status. Moreover, LRRK2 and COX19 reciprocally regulate each other's expression and cooperatively disrupted COX biogenesis. In vivo, exogenous expression of COX19 via AAV gene delivery induced dopaminergic neurodegeneration and motor deficits, which were effectively rescued by pharmacological inhibition of LRRK2 kinase activity. Together, these findings define a positive feedback LRRK2-COX19 signaling axis that governs mitochondrial redox homeostasis and COX assembly, highlighting a promising therapeutic target for PD and related mitochondrial disorders.

Source: Redox Biology

DOI: 10.1016/j.redox.2026.104061

Authors: Tae Young Kim, Eun-Hae Jang, Yun-Hee Bae, Eun-Mi Hur, Byoung Dae Lee

Institutions: Kyung Hee University, Seoul National University, Research Institute for Veterinary Science

Language: English

Topic: Parkinson's Disease Mechanisms and Treatments

Subfield: Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,310