Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice.
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.
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Natalia
N
Papeta
Zongyu
Z
Zheng
Eric A
EA
Schon
Sonja
S
Brosel
Mehmet M
MM
Altintas
Samih H
SH
Nasr
Jochen
J
Reiser
Vivette D
VD
D'Agati
Ali G
AG
Gharavi
D000595:Amino Acid Sequence; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D020022:Genetic Predisposition to Disease; D054629:Genome, Mitochondrial; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment
D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C065292:Mpv17 protein, mouse; D009687:Nuclear Proteins; D004317:Doxorubicin; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse