Mitochondria maintain continuous, dynamic communication with the nucleus and other organelles through a diverse array of signaling molecules, including tricarboxylic acid cycle intermediates, energy metabolites (ATP, ADP, AMP), reactive oxygen species, and other metabolic messengers. This process, termed mitocellular communication, orchestrates cellular adaptation to fluctuating energy demands and metabolic stress, serving as a central mechanism to preserve cellular function and survival.

We have shown that mild, targeted inhibition of mitochondrial complex I using small molecules activates this signaling axis, engaging multiple beneficial mechanisms. Treatment with these compounds promoted both healthspan and lifespan in wild-type mice. Benefits were observed in natural aging and in a high-fat diet model of accelerated aging. Treatment enhanced systemic energy homeostasis, reduced oxidative stress, and improved performance across multiple behavioral and cognitive assays. Integrated biochemical and systems biology approaches identified key regulatory pathways underpinning these outcomes, highlighting mechanisms essential to the therapeutic response.

Crucially, this strategy demonstrated strong efficacy in preclinical models of neurodegeneration. In multiple Alzheimer’s disease mouse models, treatment arrested neurodegeneration and preserved cognitive function. Similarly, in Huntington’s disease models, these compounds protected against neuronal loss and maintained motor performance. These results underscore the potential of mitocellular communication as a therapeutic axis, enabling simultaneous activation of multiple neuroprotective pathways, an approach that mimics polypharmacy and is well-suited to address the multifactorial nature of neurodegenerative diseases.

We have developed novel mitochondria-targeted molecules with excellent drug-like properties and demonstrated safety profiles, making them promising candidates for human clinical translation. Ongoing efforts are focused on advancing this strategy into clinical development, with broad potential applications beyond neurodegeneration, including mitochondrial and age-related metabolic and inflammatory diseases