MTFR1L is a cardiac antiaging factor for maintenance of mitochondrial homeostasis
- Le Shi
- Zehui Sun
- Yingxue Cao
- Yuying Li
- Wenjie Qing
- Lingli Zhou
- Mingming Xu
- Xiaomei Mai
- Lechun Ou
- Xiaoping Yang
- Delaram Shakiba
- Kaoru Ri
- Wangsheng Ou
- Jun Chen
- Avi Rosenberg
- Jean-François Trempe
- Edward A. Fon
- Xialin Liu
- Yihai Cao
- Elia J. Duh
- Wei Yi
2026-01-23
Mitochondrial dysfunction is a hallmark of aging and a key contributor to age-related diseases including cardiovascular disease. However, molecular pathways that safeguard mitochondrial homeostasis in the aging heart remain poorly understood. Here, we identify MTFR1L as a regulator of mitophagy that binds p-S65-Ub, a key signal amplifying the PINK1/Parkin axis. We find that MTFR1L is enriched in metabolically active tissues, particularly in the heart, where it regulates Parkin signaling. Genetic deletion of Mtfr1l in mice impairs stress-induced mitophagy and Parkin activation, leading to accumulation of damaged mitochondria, increased inflammation and senescence, and accelerated age-related cardiac dysfunction. Strikingly, cardiac expression of MTFR1L progressively decreases along with aging in mice, primates, and humans, coinciding with cardiomyocyte senescence and lipofuscin accumulation. Together, these findings uncover a role for MTFR1L in regulation of the p-S65-Ub/Parkin mitophagy axis and maintenance of mitochondrial homeostasis during cardiac aging and suggest that age-associated loss of MTFR1L may contribute to age-related cardiac dysfunction. Based on these findings, we propose a therapeutic paradigm for the prevention of heart aging by restoring MTFR1L function.