VDAC1 regulates stress-associated matrix localization of DJ-1 to support mitochondrial homeostasis and neuronal survival

Authors

Taday, J., Im, D. S., Hewitt, S. J., Kaushik, G., Callaghan, S. M., Anilkumar, U., Brini, M., Figeys, D., Khan, Z., Khan, N., Slack, R. S., Park, D. S., Joselin, A.

Abstract

DJ-1 is a redox-sensitive protein implicated in early-onset Parkinson's disease, and its mitochondrial localization protects against oxidative stress, but the mechanisms regulating its submitochondrial targeting and functional impact on mitochondrial integrity remain poorly understood. We identify voltage-dependent anion channel 1 (VDAC1) as a regulator of the submitochondrial distribution of DJ-1 during stress. Endogenous DJ-1 interacted with VDAC1, and loss of VDAC1 reduced stress-induced DJ-1 accumulation within the mitochondrial matrix. VDAC1-deficient neurons exhibited mitochondrial fragmentation, impaired oxidative phosphorylation, reduced ATP levels, altered reactive oxygen species (ROS) responses, and increased sensitivity to MPP+;. Matrix-targeted, but not outer-membrane-targeted, DJ-1 rescued basal, ATP-linked, and maximal respiration, improved mitochondrial morphology, and enhanced neuronal survival. ATP synthase inhibition also rapidly increased mitochondrial DJ-1, suggesting bioenergetic stress promotes its mitochondrial accumulation. Our findings identify compartment-specific localization as a key determinant of DJ-1 function and establish VDAC1-dependent matrix targeting as a critical mechanism supporting mitochondrial integrity during stress.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 03 Sep 2026.

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