Renal Section, Boston Medical Center, Boston, Massachusetts, United States of America.
PLoS One. 2012;7(1):e31074. doi: 10.1371/journal.pone.0031074. Epub 2012 Jan 26.
The role of mitofusin 2 (MFN2), a key regulator of mitochondrial morphology and function in the renal stress response is unknown. To assess its role, the MFN2 floxed gene was conditionally deleted in the kidney of mice (MFN2 cKO) by Pax2 promoter driven Cre expression (Pax2Cre). MFN2 cKO caused severe mitochondrial fragmentation in renal epithelial cells that are critical for normal kidney tubular function. However, despite a small (20%) decrease in nephron number, newborn cKO pups had organ or tubular function that did not differ from littermate Cre-negative pups. MFN2 deficiency in proximal tubule epithelial cells in primary culture induced mitochondrial fragmentation but did not significantly alter ATP turnover, maximal mitochondrial oxidative reserve capacity, or the low level of oxygen consumption during cyanide exposure. MFN2 deficiency also did not increase apoptosis of tubule epithelial cells under non-stress conditions. In contrast, metabolic stress caused by ATP depletion exacerbated mitochondrial outer membrane injury and increased apoptosis by 80% in MFN2 deficient vs. control cells. Despite similar stress-induced Bax 6A7 epitope exposure in MFN2 deficient and control cells, MFN2 deficiency significantly increased mitochondrial Bax accumulation and was associated with greater release of both apoptosis inducing factor and cytochrome c. In conclusion, MFN2 deficiency in the kidney causes mitochondrial fragmentation but does not affect kidney or tubular function during development or under non-stress conditions. However, MFN2 deficiency exacerbates renal epithelial cell injury by promoting Bax-mediated mitochondrial outer membrane injury and apoptosis.
线粒体融合蛋白 2（MFN2）是调节线粒体形态和功能的关键调节因子，其在肾脏应激反应中的作用尚不清楚。为了评估其作用，通过 Pax2 启动子驱动的 Cre 表达（Pax2Cre）在肾脏中将 MFN2 基因条件性敲除（MFN2 cKO）。MFN2 cKO 导致肾脏上皮细胞中线粒体严重碎片化，这对正常肾小管功能至关重要。然而，尽管肾单位数量减少了 20%，新生的 cKO 幼鼠的器官或肾小管功能与 Cre 阴性同窝幼鼠没有差异。原代培养的近端肾小管上皮细胞中 MFN2 的缺失诱导了线粒体碎片化，但并没有显著改变 ATP 周转率、最大线粒体氧化储备能力或氰化物暴露时的低水平耗氧量。MFN2 缺失也不会在非应激条件下增加肾小管上皮细胞的凋亡。相比之下，由 ATP 耗竭引起的代谢应激加剧了线粒体外膜损伤，并使 MFN2 缺失的细胞比对照细胞的凋亡增加了 80%。尽管 MFN2 缺失和对照细胞中应激诱导的 Bax 6A7 表位暴露相似，但 MFN2 缺失显著增加了线粒体 Bax 的积累，并与凋亡诱导因子和细胞色素 c 的更大释放相关。总之，肾脏中 MFN2 的缺失导致线粒体碎片化，但在发育过程中或在非应激条件下不会影响肾脏或肾小管功能。然而，MFN2 缺失通过促进 Bax 介导的线粒体外膜损伤和凋亡加剧了肾上皮细胞损伤。
