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
Volume16
Issue6
Pagination1352-1378
Date Published2024 Jun
ISSN1757-4684
KeywordsAnimals, Cardiomyopathies, Diet, High-Fat, Disease Models, Animal, Fatty Acids, Female, Gene Expression Profiling, Gene Knock-In Techniques, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Heart, Mitochondrial Proteins, Mutation, Peripartum Cardiomyopathy, Pregnancy, Proteotoxic Stress
Abstract

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.

DOI10.1038/s44321-024-00067-5
Alternate JournalEMBO Mol Med
PubMed ID38724625
PubMed Central IDPMC11178915
Grant List2021-01 / / NextGenALS/Project ALS /
MDA602894 / / Muscular Dystrophy Association (MDA) /
961871-01 / / Muscular Dystrophy Association (MDA) /
NS122209-02S1 / / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) /
R35 NS122209 / NS / NINDS NIH HHS / United States
Related Faculty: 
Annarita Di Lorenzo, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700