Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice
Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice
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DOI：
10.1172/jci43721
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发表时间：
2010-11-01
影响因子：
15.9
通讯作者：
Gharavi, Ali G.
中科院分区：
文献类型：
--
作者：
Papeta, Natalia;Zheng, Zongyu;Gharavi, Ali G.
阿霉素（ADR）是一种常用的化疗药物，也产生显着的组织损伤。线粒体DNA（mtDNA）的突变和mtDNA拷贝数的减少已被确定为ADR诱导的损伤的贡献者。ADR肾病仅发生在特定的小鼠近交系中，这种对肾损伤的选择性易感性作为隐性性状映射到染色体16 A1-B1。在这里，我们发现小鼠对ADR肾病的敏感性是由Prkdc基因突变产生的，该基因编码一种关键的核DNA双链断裂修复蛋白。这一发现在具有独立Prkdc突变的小鼠中得到证实。在培养的小鼠足细胞中过表达Prkdc显著提高ADR处理后的细胞存活率。虽然在线粒体中未检测到Prkdc蛋白，但具有Prkdc突变的小鼠在ADR治疗后在肾组织中显示出显著的mtDNA消耗。为了确定Prkdc是否参与mtDNA调控，我们测试了其与Mpv 17的遗传相互作用，Mpv 17编码在人类mtDNA耗竭综合征（MDDS）中突变的线粒体蛋白。虽然单突变小鼠无症状，Prkdc/Mpv 17双突变小鼠发生mtDNA耗竭，并重现了许多MDDS和ADR损伤表型。这些发现暗示了mtDNA损伤在ADR毒性的发展中，并将Prkdc鉴定为MDDS修饰基因和线粒体基因组维持途径的组分。
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.