SENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40

Abstract SUMOylation, a reversible post‐translational modification, regulates various mitochondrial processes, including biogenesis, dynamics, mitophagy, and the mitochondrial unfolded protein response. Although SUMOylation is shown to be triggered by mitochondrial protein import failure in yeast, its impact on mammalian mitochondrial protein import remains unclear. Here, it is demonstrated that SENP6 knockdown‐induced SUMOylation causes loss of mitochondrial proteostasis, which impairs mitochondrial morphology and function. Mechanistically, SENP6 knockdown dampens TOM complex assembly by SUMOylating TOM40, thereby hindering the mitochondrial protein import process, including TOM40 precursor, and ultimately disrupts mitochondrial homeostasis. Additionally, it is observed that CCCP treatment resulted in a decrease of SENP6 within mitochondria fraction, accompanied by increased TOM40 SUMOylation in the brains of 3×Tg‐Alzheimer's disease (AD) mice or Aβ 1‐42 peptide‐stimulated cells. Collectively, the results suggest that Aβ 1‐42 accumulation may enhance TOM40 SUMOylation by suppressing SENP6, thereby impairing mitochondrial homeostasis through protein import failure and potentially contributing to the pathological process of AD. This study elucidates the role of TOM40 SUMOylation/deSUMOylation in regulating the mitochondrial import process during mitochondrial stress.