Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy
Nicole M. Sayles,
Nneka Southwell,
Kevin McAvoy,
Kihwan Kim,
Alba Pesini,
Corey J. Anderson,
Catarina Quinzii,
Suzanne Cloonan,
Hibiki Kawamata,
Giovanni Manfredi
Affiliations
Nicole M. Sayles
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY 10065, USA; Neuroscience Graduate Program, Weill Cornell Graduate School of Medical Sciences, 1300 York Avenue, New York, NY 10065, USA
Nneka Southwell
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY 10065, USA; Neuroscience Graduate Program, Weill Cornell Graduate School of Medical Sciences, 1300 York Avenue, New York, NY 10065, USA
Kevin McAvoy
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY 10065, USA
Kihwan Kim
Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
Alba Pesini
Department of Neurology, Columbia University, 710 West 168th Street, New York, NY 10032, USA
Corey J. Anderson
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY 10065, USA
Catarina Quinzii
Department of Neurology, Columbia University, 710 West 168th Street, New York, NY 10032, USA
Suzanne Cloonan
Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; The School of Medicine, Trinity Biomedical Science Institute, Trinity College Dublin, Pearse St, Dublin 2 52-160, Ireland; Tallaght University Hospital, Tallaght, Dublin 24 D24 NR0A, Ireland
Hibiki Kawamata
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY 10065, USA
Giovanni Manfredi
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY 10065, USA; Corresponding author
Summary: Mitochondrial cardiomyopathies are fatal diseases, with no effective treatment. Alterations of heart mitochondrial function activate the mitochondrial integrated stress response (ISRmt), a transcriptional program affecting cell metabolism, mitochondrial biogenesis, and proteostasis. In humans, mutations in CHCHD10, a mitochondrial protein with unknown function, were recently associated with dominant multi-system mitochondrial diseases, whose pathogenic mechanisms remain to be elucidated. Here, in CHCHD10 knockin mutant mice, we identify an extensive cardiac metabolic rewiring triggered by proteotoxic ISRmt. The stress response arises early on, before the onset of bioenergetic impairments, triggering a switch from oxidative to glycolytic metabolism, enhancement of transsulfuration and one carbon (1C) metabolism, and widespread metabolic imbalance. In parallel, increased NADPH oxidases elicit antioxidant responses, leading to heme depletion. As the disease progresses, the adaptive metabolic stress response fails, resulting in fatal cardiomyopathy. Our findings suggest that early interventions to counteract metabolic imbalance could ameliorate mitochondrial cardiomyopathy associated with proteotoxic ISRmt.
