Rab12 is a regulator of mitophagy and mitochondrial homeostasis.

Apr 10, 2026bioRxiv : the preprint server for biology

Rab12 controls the removal of damaged mitochondria and maintains mitochondrial health

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Knockdown or knockout of Rab12 increases clearance of damaged mitochondria.

Rab12 is identified as a negative regulator of mitophagy.
Depletion of Rab12 leads to increased mitochondrial content and lower mitochondrial membrane potential.
Cells lacking Rab12 show reduced mitochondrial DNA damage without changes in overall cellular energy capacity.
Loss of Rab12 allows accumulation of lower-functioning mitochondria that are more sensitive to stress that induces mitophagy.
Rab12 may link vesicular trafficking and mitochondrial quality control, potentially affecting neurodegenerative disorders and other related diseases.

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Rab GTPases orchestrate vesicular trafficking, but their contributions to mitochondrial quality control are not fully defined, despite links to multiple mitochondria-related human diseases. We conducted a family-wide siRNA-based screen using mt-mKeima/YFP-Parkin HeLa cells to identify regulators of depolarization-induced mitophagy. The screen identified several candidate Rabs, and follow-up studies validated Rab12 as a negative regulator of mitophagy. Rab12 knockdown or knockout augments clearance of damaged mitochondria basally and/or after FCCP-induced depolarization, with findings reproduced across distinct cell types. Rab12 depletion increased mitochondrial content, lowered mitochondrial membrane potential, and reduced mitochondrial DNA damage, without detectable changes in overall cellular bioenergetic capacity. Together, these results indicate that Rab12 restrains mitophagic engagement and its loss permits accumulation of lower-functioning mitochondria that are hypersensitive to mitophagy-inducing stress. Rab12 thus emerges as a novel effector linking vesicular trafficking machinery and mitochondrial homeostasis, with potential implications for neurodegenerative disorders and other Rab-associated diseases.

Rab12 is a regulator of mitophagy and mitochondrial homeostasis.

Abstract

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