研究揭示NAD+在壽命和共濟失調中的作用
作者：
小柯機器人發布時間：2020/6/23 15:43:33
美國西北大學Navdeep S. Chandel研究組利用腦線粒體複合體I功能障礙的小鼠模型發現，NAD+再生可挽救壽命，但不能挽救共濟失調。2020年6月22日，《細胞—代謝》在線發表了這一成果。
研究人員測試了NAD+再生或質子泵，即生物能學，是否是線粒體複合體I在預防腦部病理學方面的主要功能。研究人員構建了一種小鼠，其能夠條件性表達酵母NADH脫氫酶（NDI1），這是一種無需質子泵就能代替含有45個亞基的哺乳動物線粒體複合體I的NAD+產生酶。在由NDUFS4（線粒體複合體I的亞基）缺失驅動的Leigh症候群小鼠模型中，NDI1表達足以顯著延長壽命，而不會顯著改善運動功能。
因此，大腦中的線粒體複合物I活性通過其NAD+再生能力來支持機體存活，而最佳的運動控制則需要其生物能功能。
據了解，線粒體複合體I分別再生NAD+和質子泵用於TCA循環和ATP產生。線粒體複合物I功能障礙與許多腦部疾病有關，包括Leigh氏症候群和帕金森氏病。
附：英文原文
Title: NAD+ Regeneration Rescues Lifespan, but Not Ataxia, in a Mouse Model of Brain Mitochondrial Complex I Dysfunction
Author: Gregory S. McElroy, Colleen R. Reczek, Paul A. Reyfman, Divakar S. Mithal, Craig M. Horbinski, Navdeep S. Chandel
Issue&Volume: 2020-06-22
Abstract: Mitochondrial complex I regenerates NAD+ and proton pumps for TCA cycle function andATP production, respectively. Mitochondrial complex I dysfunction has been implicatedin many brain pathologies including Leigh syndrome and Parkinson’s disease. We soughtto determine whether NAD+ regeneration or proton pumping, i.e., bioenergetics, isthe dominant function of mitochondrial complex I in protection from brain pathology.We generated a mouse that conditionally expresses the yeast NADH dehydrogenase (NDI1),a single enzyme that can replace the NAD+ regeneration capability of the 45-subunitmammalian mitochondrial complex I without proton pumping. NDI1 expression was sufficientto dramatically prolong lifespan without significantly improving motor function ina mouse model of Leigh syndrome driven by the loss of NDUFS4, a subunit of mitochondrialcomplex I. Therefore, mitochondrial complex I activity in the brain supports organismalsurvival through its NAD+ regeneration capacity, while optimal motor control requiresthe bioenergetic function of mitochondrial complex I.
DOI: 10.1016/j.cmet.2020.06.003
Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30304-1