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Significance Failure to maintain mtDNA integrity can lead to a wide variety of neuromuscular disorders. Despite its central role in the development of these disorders, many mechanistic details of mtDNA maintenance are still unclear. In the present work, we have studied the role of PrimPol, an unusual primase-polymerase, in mammalian mtDNA maintenance. We report here that PrimPol is specifically required for replication reinitiation after DNA damage. PrimPol synthesizes DNA primers on an ssDNA template, which can be elongated by the mitochondrial replicative polymerase γ, a solution to reprime replication beyond DNA lesions and to facilitate lagging-strand replication. Our findings show that PrimPol has biological relevance for mtDNA maintenance.

Defects of mitochondrial DNA (mtDNA) maintenance have recently been associated with inherited neurodegenerative and muscle diseases and the aging process. Twinkle is a nuclear-encoded mtDNA helicase, dominant mutations of which cause adult-onset progressive external ophthalmoplegia (PEO) with multiple mtDNA deletions. We have generated transgenic mice expressing mouse Twinkle with PEO patient mutations. Multiple mtDNA deletions accumulate in the tissues of these mice, resulting in progressive respiratory dysfunction and chronic late-onset mitochondrial disease starting at 1 year of age. The muscles of the mice faithfully replicate all of the key histological, genetic, and biochemical features of PEO patients. Furthermore, the mice have progressive deficiency of cytochrome c oxidase in distinct neuronal populations. These “deletor” mice do not, however, show premature aging, indicating that subtle accumulation of mtDNA deletions and progressive respiratory chain dysfunction are not sufficient to accelerate aging. This model is a valuable tool for therapy development and testing for adult-onset mitochondrial disorders.