Metabolic dysfunction occurs in many age-related neurodegenerative diseases, yet its role in disease etiology remains poorly understood. We recently discovered a potential causal link between the branched-chain amino acid transferase BCAT-1 and the neurodegenerative movement disorder Parkinson’s disease (PD). RNAi-mediated knockdown of Caenorhabditis elegans bcat-1 is known to recapitulate PD-like features, including progressive motor deficits and neurodegeneration with age, yet the underlying mechanisms have remained unknown. Using transcriptomic, metabolomic, and imaging approaches, we show here that bcat-1 knockdown increases mitochondrial respiration and induces oxidative damage in neurons through mammalian target of rapamycin-independent mechanisms. Increased mitochondrial respiration, or “mitochondrial hyperactivity,” is required for bcat-1(RNAi) neurotoxicity. Moreover, we show that post–disease-onset administration of the type 2 diabetes medication metformin reduces mitochondrial respiration to control levels and significantly improves both motor function and neuronal viability. Taken together, our findings suggest that mitochondrial hyperactivity may be an early event in the pathogenesis of PD, and that strategies aimed at reducing mitochondrial respiration may constitute a surprising new avenue for PD treatment.

代谢功能障碍发生在许多与年龄相关的神经退行性疾病中，但其在疾病病因学中的作用仍知之甚少。我们最近发现支链氨基酸转移酶BCAT-1与神经退行性运动障碍帕金森病 (PD) 之间存在潜在因果关系。 RNAi 介导的秀丽隐杆线虫 bcat-1敲低已知可重现 PD 样特征，包括随着年龄的增长而出现进行性运动缺陷和神经退行性变，但其潜在机制仍不清楚。使用转录组学、代谢组学和成像方法，我们在此表明​​ bcat-1敲低会增加线粒体呼吸，并通过哺乳动物靶标的雷帕霉素独立机制诱导神经元氧化损伤。 bcat-1(RNAi)神经毒性需要增加线粒体呼吸或“线粒体过度活跃”。此外，我们发现，发病后服用 2 型糖尿病药物二甲双胍可将线粒体呼吸降低至控制水平，并显着改善运动功能和神经元活力。综上所述，我们的研究结果表明线粒体过度活跃可能是帕金森病发病机制的早期事件，而旨在减少线粒体呼吸的策略可能构成帕金森病治疗的令人惊讶的新途径。