High fat diet ameliorates mitochondrial cardiomyopathy in CHCHD10 mutant mice.

TitleHigh fat diet ameliorates mitochondrial cardiomyopathy in CHCHD10 mutant mice.
Publication TypeJournal Article
Year of Publication2024
AuthorsSouthwell N, Manzo O, Bacman S, Zhao D, Sayles NM, Dash J, Fujita K, D'Aurelio M, Di Lorenzo A, Manfredi G, Kawamata H
JournalEMBO Mol Med
Date Published2024 May 09

Mutations in CHCHD10, a mitochondrial protein with undefined functions, are associated with autosomal dominant mitochondrial diseases. Chchd10 knock-in mice harboring a heterozygous S55L mutation (equivalent to human pathogenic S59L) develop a fatal mitochondrial cardiomyopathy caused by CHCHD10 aggregation and proteotoxic mitochondrial integrated stress response (mtISR). In mutant hearts, mtISR is accompanied by a metabolic rewiring characterized by increased reliance on glycolysis rather than fatty acid oxidation. To counteract this metabolic rewiring, heterozygous S55L mice were subjected to chronic high-fat diet (HFD) to decrease insulin sensitivity and glucose uptake and enhance fatty acid utilization in the heart. HFD ameliorated the ventricular dysfunction of mutant hearts and significantly extended the survival of mutant female mice affected by severe pregnancy-induced cardiomyopathy. Gene expression profiles confirmed that HFD increased fatty acid utilization and ameliorated cardiomyopathy markers. Importantly, HFD also decreased accumulation of aggregated CHCHD10 in the S55L heart, suggesting activation of quality control mechanisms. Overall, our findings indicate that metabolic therapy can be effective in mitochondrial cardiomyopathies associated with proteotoxic stress.

Alternate JournalEMBO Mol Med
PubMed ID38724625
PubMed Central ID6571048
Grant ListR35 NS122209 / NS / NINDS NIH HHS / United States