PERM1 Gene Therapy Prevents Pressure Overload-induced Heart Failure Through a Sarcomere-Mitochondria Energetic Microdomain

ABSTRACT: Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired contractile function and mitochondrial dysfunction, yet therapies that simultaneously restore cardiac energetics and mechanical performance remain limited. Here, we demonstrate that adeno-associated virus (AAV)-mediated PERM1 gene delivery prevents pressure overload-induced HFrEF in mice. AAV-PERM1 preserved mitochondrial respiration, maintained compact mitochondrial morphology and mitochondrial DNA content, and attenuated pathological hypertrophy and fibrosis. Unexpectedly, these effects occurred despite persistent suppression of oxidative phosphorylation and fatty acid oxidation transcripts, revealing a mechanism independent of transcriptional metabolic reprogramming. Instead, PERM1 localized to a mitochondria-sarcomere microdomain, whereas it associates 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 PERM1 as a previously unrecognized organizer of a sarcomere-mitochondria energetic microdomain that preserves mitochondrial protein homeostasis and couples energy production to force generation, thereby conferring resilience against heart failure.

ORGANISM(S): Mus musculus

PROVIDER: GSE338319 | GEO | 2026/09/30

REPOSITORIES: GEO