Despite recent FDA approval of anti-amyloid antibodies for Alzheimer’s Disease, strategies that target early molecular mechanisms and could delay or change the disease trajectory are still needed. Mitochondria emerge as a signaling organelle that could modulate multiple molecular mechanisms to enhance cellular bioenergetics and promote neuronal survival. Approaches to enhance mitochondrial function could promote healthy aging delaying the onset of age-related diseases such as Alzheimer’s Disease. Some of these strategies have been recently tested in clinical trials. Emerging evidence demonstrates that in response to mild energetic stress, mitochondria could orchestrate a robust adaptive stress response activating multiple neuroprotective mechanism. The objective of this review is to highlight recent development of mitochondria-targeting therapeutics for neurodegenerative diseases, mitochondria complex I inhibitors in particular.