Noh Mi Ra, Kim Ki Young, Han Sang Jun, Kim Jee In, Kim Hwa-Young, Park Kwon Moo
1 Department of Anatomy and BK21 Plus, Kyungpook National University School of Medicine , Junggu, Daegu, Republic of Korea.
2 Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine , Namgu, Daegu, Republic of Korea.
Antioxid Redox Signal. 2017 Oct 10;27(11):727-741. doi: 10.1089/ars.2016.6874. Epub 2017 Mar 20.
Methionine sulfoxide reductase A (MsrA), which is abundantly localized in the mitochondria, reduces methionine-S-sulfoxide, scavenging reactive oxygen species (ROS). Cisplatin, an anticancer drug, accumulates at high levels in the mitochondria of renal cells, causing mitochondrial impairment that ultimately leads to nephrotoxicity. Here, we investigated the role of MsrA in cisplatin-induced mitochondrial damage and kidney cell death using MsrA gene-deleted (MsrA) mice.
Cisplatin injection resulted in increases of ROS production, methionine oxidation, and oxidative damage in the kidneys. This oxidative stress was greater in MsrA mouse kidneys than in wild-type (MsrA) mouse kidneys. MsrA gene deletion exacerbated cisplatin-induced reductions in the expression and activity of MsrA and MsrBs, and the expression of thioredoxin 1, glutathione peroxidase 1 and 4, mitochondrial superoxide dismutase, cystathionine-β-synthase, and cystathionine-γ-lyase. Cisplatin induced swelling, cristae loss, and fragmentation of mitochondria with increased lipid peroxidation, more so in MsrA than in MsrA kidneys. The ratio of mitochondrial fission regulator (Fis1) to fusion regulator (Opa1) was higher in MsrA than MsrA mice. MsrA deletion exacerbated cisplatin-induced increases in Bax to Bcl-2 ratio, cleaved caspase-3 level, and apoptosis, whereas MsrA overexpression attenuated cisplatin-induced oxidative stress and apoptosis.
MsrA gene deletion in mice exacerbates cisplatin-induced renal injury through increases of mitochondrial susceptibility, whereas MsrA overexpression protects cells against cisplatin.
This study demonstrates that MsrA protects kidney cells against cisplatin-induced methionine oxidation, oxidative stress, mitochondrial damage, and apoptosis, suggesting that MsrA could be a useful target protein for the treatment of cisplatin-induced nephrotoxicity. Antioxid. Redox Signal. 27, 727-741.
甲硫氨酸亚砜还原酶A（MsrA）大量定位于线粒体中，可还原甲硫氨酸-S-亚砜，清除活性氧（ROS）。顺铂作为一种抗癌药物，在肾细胞线粒体中大量蓄积，导致线粒体损伤，最终引起肾毒性。在此，我们使用MsrA基因敲除（MsrA-/-）小鼠研究了MsrA在顺铂诱导的线粒体损伤和肾细胞死亡中的作用。
注射顺铂导致肾脏中ROS生成增加、甲硫氨酸氧化和氧化损伤。这种氧化应激在MsrA-/-小鼠肾脏中比野生型（MsrA+/+）小鼠肾脏中更严重。MsrA基因敲除加剧了顺铂诱导的MsrA和MsrBs表达及活性降低，以及硫氧还蛋白1、谷胱甘肽过氧化物酶1和4、线粒体超氧化物歧化酶、胱硫醚-β-合酶和胱硫醚-γ-裂合酶的表达降低。顺铂诱导线粒体肿胀、嵴丢失和碎片化，并伴有脂质过氧化增加，MsrA-/-小鼠比MsrA+/+小鼠更明显。MsrA-/-小鼠中线粒体分裂调节因子（Fis1）与融合调节因子（Opa1）的比值高于MsrA+/+小鼠。MsrA基因敲除加剧了顺铂诱导的Bax与Bcl-2比值增加、裂解的半胱天冬酶-3水平升高和细胞凋亡，而MsrA过表达减轻了顺铂诱导的氧化应激和细胞凋亡。
小鼠中MsrA基因敲除通过增加线粒体易感性加剧顺铂诱导的肾损伤，而MsrA过表达可保护细胞免受顺铂损伤。
本研究表明，MsrA可保护肾细胞免受顺铂诱导的甲硫氨酸氧化、氧化应激、线粒体损伤和细胞凋亡，提示MsrA可能是治疗顺铂诱导的肾毒性的有用靶蛋白。《抗氧化与氧化还原信号》27, 727 - 741。
