Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure

The classical mtDNA mutator mouse expresses a proofreading-deficient mtDNA polymerase (POLGD257A) and accumulates mtDNA mutations across all tissues leading to premature ageing. However, this model cannot resolve whether the ageing phenotype results from systemic dysfunction or cell-intrinsic effects of somatic mtDNA mutations.

To overcome this limitation, we generated PolgiMut mice allowing spatial and temporal control of POLGD257A expression. We demonstrate here that mtDNA mutations induced in cardiomyocytes cause progressive contractile dysfunction and respiratory chain deficiency in the heart without accompanying systemic pathology. Proteomic analyses link cardiac mosaic OXPHOS dysfunction to a progressive immune response, characterized by upregulation of antigen-processing proteins and immune cell infiltration.