Mitochondrial genome (mitochondrial DNA, mtDNA) lesions that unbalance bioenergetic and oxidative outputs are an important cause of human disease. A major impediment in our understanding of the pathophysiology of mitochondrial disorders is the complexity with which mtDNA mutations are spatiotemporally distributed and managed within individual cells, tissues, and organs. Unlike the comparatively static nuclear genome, accumulating evidence highlights the variability, dynamism, and modifiability of the mtDNA nucleotide sequence between individual cells over time. In this review, we summarize and discuss the impact of mtDNA defects on disease within the context of a mosaic and shifting mutational landscape.
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