MTFR1L is a cardiac antiaging factor for maintenance of mitochondrial homeostasis
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (21)
Le Shi
Zehui Sun
Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry
Yingxue Cao
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-Sen University
Yuying Li
Wenjie Qing
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-Sen University
Lingli Zhou
Department of Ophthalmology, Johns Hopkins School of Medicine
Mingming Xu
Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy
Xiaomei Mai
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-Sen University
Lechun Ou
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-Sen University
Xiaoping Yang
Anhui Province Key Laboratory of Low-Energy Quantum Materials and Devices, High Magnetic Field Laboratory, HFIPS
Delaram Shakiba
NSF Science and Technology Center for Engineering Mechanobiology, Washington University in St. Louis
Kaoru Ri
Department of Ophthalmology, Johns Hopkins School of Medicine
Wangsheng Ou
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-Sen University
Jun Chen
Avi Rosenberg
Department of Pathology, Johns Hopkins Medical Institutions
Jean-François Trempe
Edward A. Fon
Xialin Liu
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-Sen University
Yihai Cao
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet
Elia J. Duh
Department of Ophthalmology, Johns Hopkins School of Medicine
Wei Yi
Obesity and Metabolism Medicine-Engineering Integration Laboratory, Department of General Surgery, The Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu