NAD+ regeneration rescues lifespan but not ataxia in a mouse model of brain mitochondrial complex I dysfunction

Mitochondrial complex I regenerates NAD+ and proton pumps for TCA cycle function and ATP production, respectively. Mitochondrial complex I dysfunction has been implicated in many brain pathologies including Leigh Syndrome and Parkinson’s disease. We sought to determine whether NAD+ regeneration or proton pumping is the dominant function of mitochondrial complex I in protection from brain pathology. We generated a mouse that conditionally expresses the yeast NDI1 protein, a single enzyme that can replace the NAD+ regeneration capability of the 45-subunit mammalian mitochondrial complex I without proton pumping. NDI1 expression was sufficient to dramatically prolong lifespan without significantly improving motor function in a mouse model of Leigh Syndrome. Therefore, mitochondrial complex I activity in the brain supports organismal survival through its NAD+ regeneration capacity, while optimal motor control requires the bioenergetic function of mitochondrial complex I.

线粒体复合物I（Mitochondrial complex I）可分别再生烟酰胺腺嘌呤二核苷酸（NAD+）与介导质子泵转运，以支撑三羧酸循环（TCA cycle）功能及三磷酸腺苷（ATP）生成。线粒体复合物I功能异常已被证实与多种脑部病理过程相关，包括利氏综合征（Leigh Syndrome）与帕金森病（Parkinson’s disease）。本研究旨在明确：在抵御脑部病理的过程中，线粒体复合物I的核心功能为NAD+再生还是质子泵转运。我们构建了可条件性表达酵母NDI1蛋白（yeast NDI1 protein）的小鼠模型——该单酶可替代拥有45个亚基的哺乳动物线粒体复合物I的NAD+再生功能，但不具备质子泵转运活性。在利氏综合征小鼠模型中，酵母NDI1蛋白的表达足以显著延长小鼠生存期，但未对其运动功能产生明显改善作用。因此，脑部线粒体复合物I可通过其NAD+再生能力维持机体存活，而实现最优运动控制则依赖于线粒体复合物I的生物能功能。