Safeguarding mitochondrial genomes in higher eukaryotes

Sfeir and colleagues consider recent insights into the pathways that process and repair damaged mitochondrial genomes, nuclear-mitochondrial cross-talk during mtDNA stress, and links between mtDNA dysfunction and innate immunity. Mitochondria respond to DNA damage and preserve their own genetic material in a manner distinct from that of the nucleus but that requires organized mito-nuclear communication. Failure to resolve mtDNA breaks leads to mitochondrial dysfunction and affects host cells and tissues. Here, we review the pathways that safeguard mitochondrial genomes and examine the insights gained from studies of cellular and tissue-wide responses to mtDNA damage and mito-nuclear genome incompatibility.