Pregnancy precipitates metabolic imbalance and accelerates death in an animal model of mitochondrial cardiomyopathy.

During pregnancy, the heart undergoes major physiological and metabolic changes to increase cardiac workload, and the demand for energy production is especially elevated during the trial of labor. Normally, cardiac structure and metabolism revert to the pre-pregnancy state shortly after delivery. However, in some cases, peripartum/postpartum cardiomyopathy (PPCM) occurs, which increases a person's risk of major cardiac events following pregnancy. The molecular mechanisms underlying PPCM remain poorly understood. In this study, we investigate the transcriptional, metabolic, and bioenergetic profiles of postpartum (PP) hearts in a mouse model of cardiomyopathy caused by the pathogenic p.S55L mutation in the mitochondrial protein coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10). Heterozygote p.S55L mutant CHCHD10 mice develop acute heart failure during the immediate PP period. We observe cardiac remodeling, mitochondrial stress, and profound metabolic rewiring in PP mutant CHCHD10 hearts. Metabolic rewiring results in decreased levels of heme and the depletion of key cofactors of energy metabolism, including NAD(H) and ADP. These findings suggest that mutant CHCHD10 hearts fail to meet the increased energy demands associated with the trial of labor due to the insufficient turnover rate of NAD+/NADH and ADP/ATP. We propose that this metabolic insufficiency drives PP mortality in mutant CHCHD10 mice. In support of this hypothesis, dietary supplementation with nicotinamide riboside and pterostilbene, a naturally derived polyphenol, increased PP survival and cardiac energy metabolites in mutant CHCHD10 mice. Our work provides novel insights into the molecular mechanisms of PP cardiomyopathy associated with mitochondrial stress and suggests potential benefits of dietary NAD(H) supplementation.