biostudies-literatureHu LGuangdong Basic and Applied Basic Research FoundationBasic and Applied Basic Research Foundation of Guangdong ProvinceNational Natural Science Foundation of ChinaNational Key Research and Development Program of Chinae03408https://www.ebi.ac.uk/biostudies/studies/S-EPMC12561365biostudies-literatureUnknown12(40)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 resulteAdvanced science (Weinheim, Baden-Wurttemberg, Germany)SENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40.PMC1256136592049304820300392022A05050500413227081032170772824015262021YFA080490002022A1515140040324300492021A151501122782370576823705962023B151512008982071340Li JZhou QHuang JLuo ZJu ZSu LWang HDong PXiong WLiu XLiu YGuo HWang WHu LfalseSENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40.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 resulte2025-01-01T00:00:00Z2025 Oct2026-06-05T07:26:10.336Z2026-05-14T03:13:01.128ZS-EPMC125613654072974010.1002/advs.202503408