Fig. 1: Enhanced mtDNA replication in Mutators causes neonatal heart failure, multi-organ damage, and early death.

a Summary of genetic manipulations of mice and their effects on mtDNA. b Mouse genotype array and naming. c Representative WT and Polg^MutTwOE mouse phenotypes, postnatal (P) days P1 and P7. d Weight of the P7 transgenic mice. e Relative Twnk mRNA expression, P1 heart. f Relative mtDNA amount to nuclear Rbm15; mtDNA probes: mt-Rnr2, mt-Co1, and mt-Nd4 genes, P7 heart. g Heart-to-body weight ratio, P7. h Representative P7 hearts; hematoxylin/eosin and Masson’s trichrome staining. Hemorrhagic, fibrotic lesions (black arrowhead), vacuolation (white arrowhead), and interstitial fibrosis (black arrowhead) (n = 3 WT, 2 Polg^Het, 7 Polg^Mut, 7 TwOE, 7 Polg^HetTwOE, 3 Polg^MutTwOE). i Myofibrillar structure (black arrowhead), and mitochondrial ultrastructure (white arrowhead) in transmission electron-micrograph (n = 3 WT, 3 Polg^Mut, 3 TwOE, 1 Polg^HetTwOE, 5 Polg^MutTwOE). j, k Representative heart cardiomyocyte immunostaining; P7; laminin (j) and DAPI (k) (n = 3 WT, 1 Polg^Het, 3 Polg^Mut, 5 TwOE, 2 Polg^HetTwOE, 4 Polg^MutTwOE). l, m Polg^MutTwOE dilated cardiomyopathy and heart failure; echocardiography, quantified indicators: Ejection fraction (%), left-ventricular volume (µL), left-ventricular wall thickness (mm). mtDNA = mitochondrial DNA; POLG = DNA Polymerase Gamma; H&E = hematoxylin and eosin staining; Masson’s = Masson’s trichrome stain; EF = ejection fraction; LV = left ventricle. Bar plots represent mean ± SEM, boxplot representing median, Q1-Q3 as box bounds and minima-maxima as whiskers, p values from Kruskal-Wallis/Dunn’s test with Bonferroni correction, compared to WT (p < 0.05*, 0.01**, 0.001***).