PERM1 Gene Therapy Prevents Pressure Overload-induced Heart Failure Through a Sarcomere-Mitochondria Energetic Microdomain
Abstract
Abstract Heart failure with reduced ejection fraction (HFrEF) remains a major cause of morbidity and mortality worldwide, characterized by impaired contractile function and mitochondrial dysfunction, yet therapies that simultaneously restore cardiac energetics and mechanical performance remain limited. Here, we show that adeno-associated virus-mediated overexpression of PERM1 (AAV-PERM1), a striated muscle-specific mitochondrial regulator, prevents pressure overload-induced HFrEF through a non-transcriptional mechanism that preserves both mitochondrial function and contractility. AAV-PERM1 mitigated declines in mitochondrial respiration and mitochondrial DNA content, maintained mitochondrial morphology under pressure overload, and attenuated pathological hypertrophy and fibrosis. Unexpectedly, these cardioprotective effects occurred despite persistent suppression of oxidative phosphorylation and fatty acid oxidation transcripts. Instead, PERM1 localized to a mitochondria-sarcomere microdomain, where it associated with ribosomal proteins and a creatine kinase-troponin C complex, suppressed pathological O-GlcNAcylation, and post-transcriptionally preserved electron transport chain protein abundance. Functionally, PERM1 enhanced myofibrillar force generation. These findings identify a previously unrecognized mechanism by which PERM1 preserves mitochondrial protein homeostasis and couples energy production to force generation, establishing a new paradigm for post-transcriptional…
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