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Updated: May 9, 2026
Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
Published on: January 7, 2013
Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice
Natalia Papeta1, Zongyu Zheng, Eric A Schon
1Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
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.
Insights
Adriamycin (ADR) causes kidney damage partly due to mitochondrial DNA (mtDNA) issues. A mutation in the Prkdc gene increases ADR sensitivity, highlighting its role in DNA repair and mtDNA maintenance.
Area of Science:
- Cellular and Molecular Biology
- Genetics
- Toxicology
Background:
- Adriamycin (ADR) is a chemotherapy drug causing significant tissue damage, particularly nephropathy in susceptible mouse strains.
- Mutations in mitochondrial DNA (mtDNA) and reduced mtDNA copy number are linked to ADR-induced kidney injury.
- Susceptibility to ADR nephropathy in mice is a recessive trait linked to chromosome 16A1-B1.
Purpose of the Study:
- To identify the genetic basis for ADR-induced nephropathy in mice.
- To investigate the role of the Prkdc gene in ADR toxicity and mitochondrial genome maintenance.
- To explore the interaction between Prkdc and Mpv17 in the context of mtDNA depletion syndromes (MDDS).
Main Methods:
- Genetic mapping to identify the causative gene for ADR nephropathy.
- Confirmation of Prkdc mutation effects using independent mutant mouse lines.
- In vitro studies using cultured mouse podocytes to assess Prkdc function.
- Generation and analysis of Prkdc/Mpv17 double-mutant mice.
Main Results:
- A mutation in the Prkdc gene, encoding a DNA repair protein, was identified as the cause of ADR nephropathy sensitivity.
- Overexpression of Prkdc enhanced podocyte survival after ADR treatment.
- Prkdc-mutant mice exhibited mtDNA depletion in renal tissue upon ADR exposure.
- Prkdc/Mpv17 double mutants displayed mtDNA depletion and phenotypes resembling MDDS and ADR injury.
Conclusions:
- Prkdc plays a crucial role in protecting against ADR-induced kidney damage, potentially through its involvement in mtDNA maintenance.
- Prkdc acts as a modifier gene in mitochondrial DNA depletion syndromes.
- These findings link nuclear DNA repair pathways to mitochondrial genome stability and drug toxicity.
