Department of Biomedical Sciences, University of Lausanne, CH-1005 Lausanne, Switzerland; Institute of Sport Sciences, University of Lausanne, CH-1015 Lausanne, Switzerland.
The Aging and Bone Metabolism Laboratory, Service of Geriatric Medicine and Geriatric Rehabilitation, University of Lausanne Hospital Centre, CH-1005 Lausanne, Switzerland.
Prog Neurobiol. 2022 Aug;215:102289. doi: 10.1016/j.pneurobio.2022.102289. Epub 2022 May 28.
Mitochondrial health is based on a delicate balance of specific mitochondrial functions (e.g. metabolism, signaling, dynamics) that are impaired in neurodegenerative diseases. Rescuing mitochondrial function by selectively targeting mitochondrial stressors, such as reactive oxygen species, inflammation or proteotoxic insults ("bottom-up" approaches) thus is a widely investigated therapeutic strategy. While successful in preclinical studies, these approaches have largely failed to show clear clinical benefits. Promoting the capacity of mitochondria - and other cellular components - to restore a healthy cellular environment is a promising complementary or alternative approach. Herein, we provide a non-technical overview for neurologists and scientists interested in brain metabolism on neuroprotective strategies targeting mitochondria and focus on top-down interventions such as metabolic modulators, exercise, dietary restriction, brain stimulation and conditioning. We highlight general conceptual differences to bottom-up approaches and provide hypotheses on how these mechanistically comparatively poorly characterized top-down therapies may work, discussing notably mitochondrial stress responses and mitohormesis.
线粒体健康基于特定线粒体功能（如代谢、信号转导、动态平衡）的微妙平衡，这些功能在神经退行性疾病中受到损害。通过有针对性地靶向线粒体应激源（如活性氧、炎症或蛋白毒性损伤）来恢复线粒体功能（“自下而上”的方法），因此是一种广泛研究的治疗策略。虽然在临床前研究中取得了成功，但这些方法在很大程度上未能显示出明显的临床益处。促进线粒体——以及其他细胞成分——恢复健康细胞环境的能力是一种有前途的互补或替代方法。本文为对大脑代谢感兴趣的神经科医生和科学家提供了一个非技术性的概述，介绍了针对线粒体的神经保护策略，重点介绍了代谢调节剂、运动、饮食限制、脑刺激和训练等自上而下的干预措施。我们强调了与自下而上方法的一般概念差异，并提供了关于这些机制上描述较差的自上而下治疗方法如何发挥作用的假设，特别是讨论了线粒体应激反应和线粒体激素作用。
