‡Oklahoma Medical Research Foundation, Free Radical Biology & Aging Research Program, 825NE 13th Street, Oklahoma City, OK 73104, U.S.A.
*Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78245, U.S.A.
Biochem J. 2014 Sep 1;462(2):359-71. doi: 10.1042/BJ20140291.
Mutations in SURF1 (surfeit locus protein 1) COX (cytochrome c oxidase) assembly protein are associated with Leigh's syndrome, a human mitochondrial disorder that manifests as severe mitochondrial phenotypes and early lethality. In contrast, mice lacking the SURF1 protein (Surf1-/-) are viable and were previously shown to have enhanced longevity and a greater than 50% reduction in COX activity. We measured mitochondrial function in heart and skeletal muscle, and despite the significant reduction in COX activity, we found little or no difference in ROS (reactive oxygen species) generation, membrane potential, ATP production or respiration in isolated mitochondria from Surf1-/- mice compared with wild-type. However, blood lactate levels were elevated and Surf1-/- mice had reduced running endurance, suggesting compromised mitochondrial energy metabolism in vivo. Decreased COX activity in Surf1-/- mice is associated with increased markers of mitochondrial biogenesis [PGC-1α (peroxisome-proliferator-activated receptor γ co-activator 1α) and VDAC (voltage-dependent anion channel)] in both heart and skeletal muscle. Although mitochondrial biogenesis is a common response in the two tissues, skeletal muscle has an up-regulation of the UPRMT (mitochondrial unfolded protein response) and heart exhibits induction of the Nrf2 (nuclear factor-erythroid 2-related factor 2) antioxidant response pathway. These data are the first to show induction of the UPRMT in a mammalian model of decreased COX activity. In addition, the results of the present study suggest that impaired mitochondrial function can lead to induction of mitochondrial stress pathways to confer protective effects on cellular homoeostasis.
SURF1（过剩基因座蛋白 1）COX（细胞色素 c 氧化酶）组装蛋白中的突变与 Leigh 综合征有关，Leigh 综合征是一种人类线粒体疾病，表现为严重的线粒体表型和早期致死性。相比之下，缺乏 SURF1 蛋白的小鼠（Surf1-/-）是有活力的，并且之前已显示出延长寿命和 COX 活性降低 50%以上。我们测量了心脏和骨骼肌中的线粒体功能，尽管 COX 活性显著降低，但我们发现从 Surf1-/- 小鼠分离的线粒体中活性氧（ROS）生成、膜电位、ATP 产生或呼吸几乎没有差异或差异较小。然而，血液中乳酸盐水平升高，Surf1-/- 小鼠的跑步耐力降低，这表明体内线粒体能量代谢受损。Surf1-/- 小鼠 COX 活性降低与心脏和骨骼肌中增加的线粒体生物发生标志物（PGC-1α（过氧化物酶体增殖物激活受体 γ 共激活物 1α）和 VDAC（电压依赖性阴离子通道））相关。虽然线粒体生物发生是两种组织中的共同反应，但骨骼肌中 UPFRMT（线粒体未折叠蛋白反应）上调，而心脏则表现出 Nrf2（核因子-红细胞 2 相关因子 2）抗氧化反应途径的诱导。这些数据首次表明，在 COX 活性降低的哺乳动物模型中诱导 UPFRMT。此外，本研究的结果表明，线粒体功能受损可导致诱导线粒体应激途径，从而对细胞内稳态产生保护作用。
