MTFR1L is a cardiac antiaging factor for maintenance of mitochondrial homeostasis.

MTFR1L binds phospho-S65-ubiquitin (p-S65-Ub), a key signal amplifying the PINK1/Parkin mitophagy axis.

• MTFR1L was identified as a regulator of mitophagy through its interaction with p-S65-Ub.
• This interaction positions MTFR1L as a component of the PINK1/Parkin signaling pathway.
• The binding to p-S65-Ub suggests MTFR1L acts as a reader or effector of this ubiquitin phosphorylation mark.

MTFR1L is enriched in metabolically active tissues, particularly in the heart, where it regulates Parkin signaling.

• Expression analysis revealed preferential enrichment of MTFR1L in metabolically active tissues.
• The heart showed particularly high MTFR1L expression compared to other tissues.
• MTFR1L's role in regulating Parkin signaling was demonstrated specifically in cardiac tissue.

Genetic deletion of Mtfr1l in mice impairs stress-induced mitophagy and Parkin activation.

• Mtfr1l knockout mice showed defective mitophagy under stress conditions.
• Parkin activation was impaired in the absence of MTFR1L.
• These defects resulted in accumulation of damaged mitochondria in cardiac tissue.
• The impaired mitophagy was demonstrated in a stress-induced context, indicating MTFR1L is required for the mitophagic response to damage.

Loss of Mtfr1l in mice leads to increased inflammation, senescence, and accelerated age-related cardiac dysfunction.

• Mtfr1l knockout mice exhibited increased inflammatory markers in the heart.
• Cellular senescence was elevated in the hearts of Mtfr1l-deficient mice.
• Age-related cardiac dysfunction was accelerated in mice lacking Mtfr1l.
• These phenotypes collectively indicate that MTFR1L is required for maintaining cardiac homeostasis during aging.

Cardiac expression of MTFR1L progressively decreases with aging in mice, primates, and humans.

• Age-dependent decline in MTFR1L expression was observed across three species: mice, non-human primates, and humans.
• The decline in MTFR1L expression coincided with cardiomyocyte senescence.
• Lipofuscin accumulation, a marker of cellular aging, also coincided with the loss of MTFR1L expression.
• The conservation of this age-related decline across species suggests an evolutionarily relevant mechanism.

Age-associated loss of MTFR1L may contribute to age-related cardiac dysfunction through impaired mitochondrial homeostasis.

• The progressive decline of MTFR1L with aging parallels the accumulation of mitochondrial damage seen in aging hearts.
• The authors propose that loss of MTFR1L disrupts the p-S65-Ub/Parkin mitophagy axis during cardiac aging.
• This mechanism connects the well-established hallmark of mitochondrial dysfunction in aging to a specific molecular regulator.
• The authors propose a therapeutic paradigm for prevention of heart aging by restoring MTFR1L function.

Mitochondrial dysfunction and impaired mitophagy are established hallmarks of aging and contributors to cardiovascular disease.

• The PINK1/Parkin pathway is a key axis for mitophagy, the selective autophagic removal of damaged mitochondria.
• p-S65-Ub is described as 'a key signal amplifying the PINK1/Parkin axis.'
• Molecular pathways safeguarding mitochondrial homeostasis in the aging heart were described as 'poorly understood' prior to this study.