Li Tao, Zhang Zhen, Kolwicz Stephen C, Abell Lauren, Roe Nathan D, Kim Maengjo, Zhou Bo, Cao Yang, Ritterhoff Julia, Gu Haiwei, Raftery Daniel, Sun Haipeng, Tian Rong
West China-Washington Mitochondria and Metabolism Center and Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, PRC; Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
Cell Metab. 2017 Feb 7;25(2):374-385. doi: 10.1016/j.cmet.2016.11.005.
Elevated levels of branched-chain amino acids (BCAAs) have recently been implicated in the development of cardiovascular and metabolic diseases, but the molecular mechanisms are unknown. In a mouse model of impaired BCAA catabolism (knockout [KO]), we found that chronic accumulation of BCAAs suppressed glucose metabolism and sensitized the heart to ischemic injury. High levels of BCAAs selectively disrupted mitochondrial pyruvate utilization through inhibition of pyruvate dehydrogenase complex (PDH) activity. Furthermore, downregulation of the hexosamine biosynthetic pathway in KO hearts decreased protein O-linked N-acetylglucosamine (O-GlcNAc) modification and inactivated PDH, resulting in significant decreases in glucose oxidation. Although the metabolic remodeling in KO did not affect baseline cardiac energetics or function, it rendered the heart vulnerable to ischemia-reperfusion injury. Promoting BCAA catabolism or normalizing glucose utilization by overexpressing GLUT1 in the KO heart rescued the metabolic and functional outcome. These observations revealed a novel role of BCAA catabolism in regulating cardiac metabolism and stress response.
近期研究表明，支链氨基酸（BCAAs）水平升高与心血管疾病和代谢性疾病的发生发展有关，但其分子机制尚不清楚。在BCAA分解代谢受损的小鼠模型（基因敲除[KO]）中，我们发现BCAAs的长期积累会抑制葡萄糖代谢，并使心脏对缺血性损伤更加敏感。高水平的BCAAs通过抑制丙酮酸脱氢酶复合体（PDH）的活性，选择性地破坏线粒体丙酮酸的利用。此外，KO心脏中己糖胺生物合成途径的下调会降低蛋白质O-连接的N-乙酰葡糖胺（O-GlcNAc）修饰，并使PDH失活，导致葡萄糖氧化显著减少。尽管KO中的代谢重塑并未影响基线心脏能量代谢或功能，但它使心脏易受缺血-再灌注损伤。通过在KO心脏中过表达GLUT1来促进BCAA分解代谢或使葡萄糖利用正常化，可挽救代谢和功能结局。这些观察结果揭示了BCAA分解代谢在调节心脏代谢和应激反应中的新作用。
