MTFR1L is a mitochondrial protein that serves as a critical regulator of mitochondrial dynamics and homeostasis, with emerging roles in aging and disease. Functionally, MTFR1L mediates mitochondrial morphology control and coordinates AMPK-dependent stress-induced mitochondrial fragmentation through OPA1 regulation 1. Beyond fission regulation, MTFR1L functions as a regulator of mitophagy by binding phosphorylated ubiquitin (p-S65-Ub), amplifying the PINK1/Parkin axis to facilitate clearance of damaged mitochondria 2. The protein undergoes post-translational modification via persulfidation at cysteine residues 222 and 230, which modulates its activity in maintaining mitochondrial integrity and ATP production 3. Clinically, MTFR1L shows significant relevance to aging and age-related diseases. Cardiac MTFR1L expression progressively declines with aging in mice, primates, and humans, correlating with cardiomyocyte senescence and accelerated cardiac dysfunction 2. Loss of MTFR1L impairs stress-induced mitophagy and increases damaged mitochondria accumulation, inflammation, and senescence 2. In pregnancy, reduced MTFR1L expression in pre-eclamptic placentas correlates with impaired cytotrophoblast invasion and migration 3. Additionally, MTFR1L exhibits sex-specific associations with cognitive trajectories in Alzheimer's disease, suggesting potential as a sex-specific biomarker 4.