Source: europepmc · Origin: CN · Yuan H, Hu W, Lv X, Cao Y, Hu K, Li Y, Chen Z, Yang J, Wang Y, Zhao J, Xu C. · Biology direct · 2026-05-25
URL: https://pubmed.ncbi.nlm.nih.gov/42186063/
AI rationale (4/5, tier: preliminary): Core cardiolipin biology mechanism (TAMM41) in human cancer cells; lacks clinical translation or aging/neurodegeneration context.
Mitochondrial metabolic reprogramming is essential for lung adenocarcinoma (LUAD) progression, yet the regulatory mechanisms governing mitochondrial phospholipid synthesis remain poorly understood. TAMM41 is a mitochondrial inner-membrane enzyme required for cardiolipin biosynthesis, but its role in LUAD has not been defined. Here, we show that TAMM41 is significantly upregulated in LUAD tissues and cell lines, and its high expression correlates with poor patient prognosis. Functional studies demonstrate that TAMM41 promotes LUAD cell proliferation, migration, and invasion, whereas genetic ablation of TAMM41 suppresses malignant phenotypes. Mechanistically, TAMM41 maintains mitochondrial complex I activity, ATP production, and redox homeostasis, thereby limiting oxidative stress and apoptosis. We identify the E3 ubiquitin ligase UBR5 as a specific regulator of TAMM41 stability through ubiquitination at lysine 206. Moreover, the mitochondrial desuccinylase SIRT5 directly interacts with TAMM41 and removes succinylation at lysine 45, enhancing UBR5 binding and promoting TAMM41 degradation. In vivo, TAMM41 knockout markedly inhibits LUAD xenograft growth, accompanied by impaired mitochondrial respiration and increased apoptosis. Collectively, these findings identify TAMM41 as a mitochondrial oncogenic driver in LUAD and reveal a SIRT5-TAMM41-UBR5 axis that links lysine succinylation to mitochondrial metabolic control, highlighting TAMM41 as a potential therapeutic target.