Prkdc participates in mitochondrial genome maintenance and prevents adriamycin-induced nephropathy in mice

Natalia Papeta, Zongyu Zheng, Eric A. Schon, Sonja Brosel, Mehmet M. Altintas, Samih H. Nasr, Jochen Reiser, Vivette D. D'Agati, Ali G. Gharavi

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

Adriamycin (ADR) is a commonly used chemotherapeutic agent that also produces significant tissue damage. Mutations to mitochondrial DNA (mtDNA) and reductions in mtDNA copy number have been identified as contributors to ADR-induced injury. ADR nephropathy only occurs among specific mouse inbred strains, and this selective susceptibility to kidney injury maps as a recessive trait to chromosome 16A1-B1. Here, we found that sensitivity to ADR nephropathy in mice was produced by a mutation in the Prkdc gene, which encodes a critical nuclear DNA double-stranded break repair protein. This finding was confirmed in mice with independent Prkdc mutations. Overexpression of Prkdc in cultured mouse podocytes significantly improved cell survival after ADR treatment. While Prkdc protein was not detected in mitochondria, mice with Prkdc mutations showed marked mtDNA depletion in renal tissue upon ADR treatment. To determine whether Prkdc participates in mtDNA regulation, we tested its genetic interaction with Mpv17, which encodes a mitochondrial protein mutated in human mtDNA depletion syndromes (MDDSs). While single mutant mice were asymptomatic, Prkdc/Mpv17 double-mutant mice developed mtDNA depletion and recapitulated many MDDS and ADR injury phenotypes. These findings implicate mtDNA damage in the development of ADR toxicity and identify Prkdc as a MDDS modifier gene and a component of the mitochondrial genome maintenance pathway.

Original languageEnglish (US)
Pages (from-to)4055-4064
Number of pages10
JournalJournal of Clinical Investigation
Volume120
Issue number11
DOIs
StatePublished - Nov 1 2010

ASJC Scopus subject areas

  • Medicine(all)

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    Papeta, N., Zheng, Z., Schon, E. A., Brosel, S., Altintas, M. M., Nasr, S. H., Reiser, J., D'Agati, V. D., & Gharavi, A. G. (2010). Prkdc participates in mitochondrial genome maintenance and prevents adriamycin-induced nephropathy in mice. Journal of Clinical Investigation, 120(11), 4055-4064. https://doi.org/10.1172/JCI43721