| First Author | Shi L | Year | 2026 |
| Journal | Proc Natl Acad Sci U S A | Volume | 123 |
| Issue | 4 | Pages | e2527247123 |
| PubMed ID | 41576098 | Mgi Jnum | J:390197 |
| Mgi Id | MGI:8395100 | Doi | 10.1073/pnas.2527247123 |
| Citation | Shi L, et al. (2026) MTFR1L is a cardiac antiaging factor for maintenance of mitochondrial homeostasis. Proc Natl Acad Sci U S A 123(4):e2527247123 |
| abstractText | 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. |
