Overactive mitochondrial DNA replisome causes neonatal heart failure via ferroptosis

Abstract

Increasing mitochondrial DNA (mtDNA) replication and amount have been proposed as therapeutic approaches for mitochondrial dysfunction, but also as a mechanism of premature aging. We addressed this fascinating paradox by enhancing mtDNA replication via two mechanisms: increasing both mtDNA replication licensing and processivity. We crossed mice overexpressing Twinkle helicase (boosting mtDNA replication initiation) with mtDNA mutator mice (exonuclease-deficient mtDNA replicase, increasing mtDNA mutagenesis and replication processivity). The former model is asymptomatic by two years of age, whereas the latter manifests with progeroid symptoms at six months. Surprisingly, the double transgenics demonstrate postnatally halted growth and devastating cardiomyopathy, fatal within weeks. The mice show high mtDNA replication preventing cardiac maturation and the postnatal shift to oxidative metabolism, causing ferroptotic cardiomyocyte death. Our findings emphasize the critical importance of mtDNA replisome regulation for perinatal cardiac maturation. Furthermore, the data implicate ferroptosis as a cell death mechanism for neonatal mitochondrial cardiomyopathies.