Department of Anesthesiology, University of California-San Diego, La Jolla, California 92161, USA.
FASEB J. 2012 Nov;26(11):4637-49. doi: 10.1096/fj.12-215798. Epub 2012 Aug 2.
We show here that the apposition of plasma membrane caveolae and mitochondria (first noted in electron micrographs >50 yr ago) and caveolae-mitochondria interaction regulates adaptation to cellular stress by modulating the structure and function of mitochondria. In C57Bl/6 mice engineered to overexpress caveolin specifically in cardiac myocytes (Cav-3 OE), localization of caveolin to mitochondria increases membrane rigidity (4.2%; P<0.05), tolerance to calcium, and respiratory function (72% increase in state 3 and 23% increase in complex IV activity; P<0.05), while reducing stress-induced generation of reactive oxygen species (by 20% in cellular superoxide and 41 and 28% in mitochondrial superoxide under states 4 and 3, respectively; P<0.05) in Cav-3 OE vs. TGneg. By contrast, mitochondrial function is abnormal in caveolin-knockout mice and Caenorhabditis elegans with null mutations in caveolin (60% increase free radical in Cav-2 C. elegans mutants; P<0.05). In human colon cancer cells, mitochondria with increased caveolin have a 30% decrease in apoptotic stress (P<0.05), but cells with disrupted mitochondria-caveolin interaction have a 30% increase in stress response (P<0.05). Targeted gene transfer of caveolin to mitochondria in C57Bl/6 mice increases cardiac mitochondria tolerance to calcium, enhances respiratory function (increases of 90% state 4, 220% state 3, 88% complex IV activity; P<0.05), and decreases (by 33%) cardiac damage (P<0.05). Physical association and apparently the transfer of caveolin between caveolae and mitochondria is thus a conserved cellular response that confers protection from cellular damage in a variety of tissues and settings.
我们在这里表明，质膜小窝和线粒体的并列（早在 50 多年前的电子显微镜照片中就已首次注意到）以及小窝-线粒体相互作用通过调节线粒体的结构和功能来调节细胞应激的适应。在专门在心肌细胞中过表达小窝蛋白的 C57Bl/6 小鼠（Cav-3 OE）中，小窝蛋白定位于线粒体增加了膜刚性（4.2%；P<0.05），提高了钙耐受性和呼吸功能（状态 3 增加 72%，复合物 IV 活性增加 23%；P<0.05），同时减少应激诱导的活性氧生成（细胞超氧化物中的生成减少 20%，在状态 4 和 3 下线粒体超氧化物分别减少 41%和 28%；P<0.05）在 Cav-3 OE 与 TGneg 之间。相比之下，小窝蛋白敲除小鼠和小窝蛋白缺失突变的秀丽隐杆线虫的线粒体功能异常（Cav-2 秀丽隐杆线虫突变体中的自由基增加 60%；P<0.05）。在人结肠癌细胞中，具有增加的小窝蛋白的线粒体凋亡应激减少 30%（P<0.05），但线粒体-小窝蛋白相互作用中断的细胞应激反应增加 30%（P<0.05）。C57Bl/6 小鼠中 Cav-3 的靶向基因转移到线粒体可增加心肌线粒体对钙的耐受性，增强呼吸功能（状态 4 增加 90%，状态 3 增加 220%，复合物 IV 活性增加 88%；P<0.05），并减少（33%）心脏损伤（P<0.05）。因此，质膜小窝和线粒体之间的小窝蛋白的物理关联和显然转移是一种保守的细胞反应，可在多种组织和环境中提供免受细胞损伤的保护。
