The role of TOMM20 in Mediating TERT translocation to mitochondria and its impact on mitophagy in membranous nephropathy

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BACKGROUND: In idiopathic membranous nephropathy (MN)—now a leading glomerular cause of end-stage kidney disease—mitochondrial quality control via mitophagy is increasingly recognized as a determinant of podocyte fate, yet the molecular switches governing this process remain undefined. We postulated that translocase of the outer mitochondrial membrane 20 (TOMM20), a gatekeeper of mitochondrial import, transcriptionally regulates telomerase reverse transcriptase (TERT) and thereby modulates podocyte mitophagy and disease progression. METHODS: Bioinformatics analysis was performed to identify common targets between mitophagy-related genes and differentially expressed genes in membranous nephropathy. An in vitro model of membranous nephropathy was established by treating human podocytes with Zymosan-Activated Serum (ZAS). Subsequently, cells were transfected to overexpress TOMM20 or knock down TERT. Cellular viability, apoptosis, and levels of inflammatory cytokines (IL-6, IL-1β) were assessed. Additionally, indicators related to mitophagy, including reactive oxygen species (ROS), mitochondrial membrane potential (MMP), LC3-II/I ratio, PTEN-induced putative kinase 1 (PINK1), Mitochondrial-associated Parkin protein (mito-Parkin), and p62 levels, were measured in each group. An in vivo model of membranous nephropathy was established by intravenously injecting rats with sheep anti-rat FX1A serum. The expression of TOMM20 was inhibited to investigate its effects on mitophagy and TERT mitochondrial translocation in membranous nephropathy. RESULT: Bioinformatics analysis identified TOMM20 as a key target for intervening in the progression of membranous nephropathy via the mitochondrial pathway. In vitro, compared with human podocytes treated with heat-inactivated serum (HIS), ZAS intervention resulted in decreased cell viability, increased apoptosis, elevated levels of IL-6, IL-1β, and ROS, reduced MMP, decreased LC3-II/I ratio, PINK1, and mito-Parkin, and enhanced p62 expression. Overexpression of TOMM20 ameliorated ZAS-induced cell injury and enhanced mitophagy. Additionally, compared with the ZAS + Ctrl-siRNA group, knockdown of TERT exacerbated ZAS-induced cell injury and inhibited mitophagy. However, co-overexpression of TOMM20 promoted TERT mitochondrial translocation and mitigated the adverse effects of TERT-siRNA transfection in human podocytes. In vivo, upregulation of TOMM20 improved renal function in rats, promoted TERT mitochondrial translocation, and activated mitophagy. CONCLUSION: TOMM20 activates mitophagy in membranous nephropathy by promoting the mitochondrial translocation and expression of TERT (The graphical abstract was shown in Fig. 1).

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