Department of Nephrology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medcine, University of Science and Technology of China, Hefei, China.
National Clinical Research Center for Kidney Diseases, Nanjing University School of Medicine, Nanjing, China.
Clin Sci (Lond). 2023 Aug 14;137(15):1195-1208. doi: 10.1042/CS20230164.
MPV17 is a mitochondrial inner membrane protein, and its deficiency can cause mitochondrial DNA (mtDNA) depletion, increase reactive oxygen species (ROS), and promote apoptosis in several cell types, suggesting that MPV17 plays a protective role in cells although the underlying mechanism remains unknown. To test whether MPV17 is also protective in diabetic kidney disease, we treated Mpv17-deficient mice with streptozotocin (STZ) and surprisingly found that they were resistant to diabetes. Mpv17 deficiency was also found to confer resistance to the diabetes induced by an insulin mutation (Ins2Akita), which represents a mouse model of monogenic diabetes characterized by proinsulin misfolding and β-cell failure. In both STZ and Ins2Akita models, Mpv17 mutants had significantly less severe β-cell loss and apoptosis compared with the wild-type mice. We next showed that MPV17 is expressed in β-cells of mice normally, suggesting that MPV17 acts β-cells autonomously to facilitate apoptosis. Consistently, Mpv17 knockdown improved the viability and ameliorated the apoptosis of cultured MIN6 cells treated with STZ and palmitic acid (PA), respectively, accompanied by prevention of caspase 3 activation. The proapoptotic effect of MPV17 in β-cells is in contrast with its known anti-apoptotic effect in other cell types. Thus, we have identified a novel regulator of β-cell death in diabetes development.
MPV17 是一种线粒体内膜蛋白，其缺失可导致线粒体 DNA（mtDNA）耗竭，增加活性氧（ROS），并促进几种细胞类型的凋亡，这表明 MPV17 在细胞中发挥保护作用，尽管其潜在机制尚不清楚。为了测试 MPV17 在糖尿病肾病中是否也具有保护作用，我们用链脲佐菌素（STZ）处理 Mpv17 缺陷型小鼠，令人惊讶的是，我们发现它们对糖尿病具有抗性。还发现 Mpv17 缺失赋予了对胰岛素突变（Ins2Akita）诱导的糖尿病的抗性，Ins2Akita 代表一种单基因糖尿病的小鼠模型，其特征是胰岛素前体错误折叠和β细胞衰竭。在 STZ 和 Ins2Akita 模型中，与野生型小鼠相比，MPV17 突变体的β细胞丢失和凋亡明显减轻。我们接下来表明，MPV17 在正常小鼠的β细胞中表达，这表明 MPV17 自主作用于β细胞以促进凋亡。一致地，MPV17 的敲低提高了用 STZ 和棕榈酸（PA）处理的培养的 MIN6 细胞的活力，并改善了细胞凋亡，同时伴随着 caspase 3 激活的预防。MPV17 在β细胞中的促凋亡作用与它在其他细胞类型中已知的抗凋亡作用相反。因此，我们已经确定了糖尿病发展中β细胞死亡的一种新的调节剂。
