Abstract Tu translation elongation factor, mitochondrial (TUFM) is a highly conserved, nuclear-encoded GTPase that is indispensable for mitochondrial protein synthesis. Beyond this canonical function, TUFM has emerged as a central regulator of mitochondrial quality control (MQC), orchestrating mitochondrial biogenesis, dynamics, and mitophagy through a location-dictates-function paradigm. Its subcellular localization and activity are precisely regulated by post-translational modifications, including phosphorylation, lactylation, ubiquitination, and acetylation, which collectively dictate its functional outputs in cellular homeostasis and stress responses. TUFM also serves as a critical interface in host-pathogen interactions, where viruses often hijack its pro-mitophagic function to evade mitochondrial antiviral signaling. Functioning as a cellular fate switch, the TUFM-MQC axis determines context-dependent pathological outcomes: its hyperactivation promotes cell growth and fuels oncogenesis, whereas its deficiency exacerbates cell death and contributes to neurodegeneration, inflammatory damage, and metabolic dysfunction. This review synthesizes current mechanistic insights into TUFM as a central MQC coordinator and delineates how its functional imbalance redirects cellular trajectories toward survival or death. Deciphering the regulatory logic and spatiotemporal dynamics of this pivotal hub offers promising avenues for developing targeted strategies to restore cellular homeostasis across a spectrum of diseases.
Li et al. (Sat,) studied this question.