Proceedings of the National Academy of Sciences of the United States of AmericaJan 23, 2026

MTFR1L helps protect the heart from aging by keeping mitochondria healthy

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 24, 2026

Abstract

MTFR1L levels decrease with aging in mice, primates, and humans, which may contribute to age-related cardiac dysfunction.

Mitochondrial dysfunction is linked to aging and age-related diseases, particularly cardiovascular disease.
MTFR1L regulates the process of mitophagy by interacting with a signal that enhances the PINK1/Parkin pathway.
Genetic deletion of MTFR1L in mice disrupts stress-induced mitophagy and Parkin activation, resulting in damaged mitochondria.
This impairment leads to increased inflammation, cellular aging, and accelerated cardiac dysfunction.
The decline of MTFR1L expression correlates with signs of cellular aging in heart tissue.

Simplified

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 ofin 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. Mtfr1l

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Competing interests

Competing interests statement:The authors declare no competing interest.

PubMed

MTFR1L helps protect the heart from aging by keeping mitochondria healthy

Abstract

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Funding

Competing interests

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