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, i.e., bioenergetics, is the 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-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 driven by the loss of NDUFS4, a subunit of mitochondrial complex I. 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.

线粒体复合体 I 再生 NAD+ 和质子泵，分别用于 TCA 循环功能和 ATP 生产。线粒体复合体 I 功能障碍与许多脑病有关，包括 Leigh 综合征和帕金森病。我们试图确定 NAD+ 再生或质子泵送（即生物能量学）是否是线粒体复合物 I 在保护免受大脑病理学影响方面的主要功能。我们生成了一种有条件地表达酵母 NADH 脱氢酶 (NDI1) 的小鼠，这是一种可以在没有质子泵的情况下取代 45 亚基哺乳动物线粒体复合物 I 的 NAD+ 再生能力的单一酶。NDI1 表达足以显着延长寿命，而不会显着改善由 NDUFS4 缺失驱动的 Leigh 综合征小鼠模型的运动功能，