Single-nucleoid imaging in whole cells defines the dynamics of the mtDNA life cycle
Wolf, D. M.; Mjeku, E.; Segawa, M.; Casey, A. M.; Belaadi, N.; Franklin, R.; Murphy, M. P.; Prudent, J.; Jones, N. S.; Chinnery, P. F.
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The mitochondrial genome (mtDNA) is essential for oxidative phosphorylation, and mammalian cells typically contain hundreds or thousands of copies. Although specific aspects of mtDNA replication and degradation have been explored, a complete account of the mtDNA life cycle has remained elusive, particularly for nondividing cells. Using super-resolution and 4D lattice light-sheet imaging, we quantified the full mtDNA life cycle in quiescent primary human cells. We show that cells maintain steady state by replicating and degrading 1.5 {+/-} 0.2% of total mtDNA content each hour, a remarkably rapid flux. Younger mtDNA molecules are closer to the nucleus, spared from degradation, and serve as foci for further replication events. Non-proliferative cells regulate nucleoid density within the mitochondrial network, and the mitochondrial membrane potential sustains mtDNA copy number. These findings provide a foundational understanding of the dynamics underlying mtDNA homeostasis and a mechanism explaining how mutations accumulate in aging and disease.
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