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

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.

doi:10.64898/2026.08.27.747597

bioRxiv · 10.64898/2026.08.27.747597

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

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.

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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.

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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.. 2026-09-01. VDAC1 regulates stress-associated matrix localization of DJ-1 to support mitochondrial homeostasis and neuronal survival. https://doi.org/10.64898/2026.08.27.747597

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