Boosting mitochondrial health to counteract neurodegeneration

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.