Succinate-driven PKM2 succinylation and dimerization accelerates age-associated cardiac fibrosis

Area of Science:

• Metabolic pathways in aging
• Cardiac fibrosis mechanisms
• Molecular basis of diastolic dysfunction

Background:

• Cardiac fibrosis is a hallmark of aging and a major cause of heart failure.
• The precise molecular mechanisms driving age-related cardiac fibrosis are not fully understood.
• Metabolic dysregulation is increasingly implicated in the aging process.

Purpose of the Study:

• To investigate the role of succinate in age-related cardiac fibrosis.
• To elucidate the molecular signaling pathways involved in succinate-mediated cardiac aging.
• To explore the therapeutic potential of targeting succinate accumulation.

Main Methods:

• Analysis of succinate levels in aged mice and human cardiac tissues.
• Biochemical assays to assess PKM2 succinylation and dimerization.
• Studies using SUCNR1 knockout mice to investigate succinate signaling.
• Investigation of the nuclear translocation of PKM2 and its interaction with HIF-1α.
• Assessment of metformin's effect on fibroblast activation and cardiac function.

Main Results:

• Elevated succinate levels were observed in aged mice and humans, correlating with cardiac fibrosis.
• Succinate promotes fibroblast activation and collagen production through succinylation of PKM2 at lysine 125, favoring its dimeric state.
• Succinate signaling via SUCNR1/GPR91 mediates PKM2 succinylation and dimerization, contributing to profibrotic networks and diastolic dysfunction.
• Dimeric PKM2 translocates to the nucleus, enhancing HIF-1α binding and upregulating fibrogenic genes.
• Metformin treatment reduced succinate accumulation and suppressed fibroblast activation.

Conclusions:

• Succinate accumulation is a key driver of age-related cardiac fibrosis and diastolic dysfunction.
• A novel succinate-PKM2 signaling axis, involving PKM2 succinylation and dimerization, mediates cardiac aging.
• Targeting metabolic dysregulation, specifically succinate accumulation, presents a potential therapeutic strategy for mitigating cardiac aging and heart failure.