Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration

Mitochondria generate ATP essential for neuronal growth, function, and regeneration. Due to their polarized structures, neurons face exceptional challenges to deliver mitochondria to and maintain energy homeostasis throughout long axons and terminal branches where energy is in high demand. Chronic mitochondrial dysfunction accompanied by bioenergetic failure is a pathological hallmark of major neurodegenerative diseases. Brain injury triggers acute mitochondrial damage and a local energy crisis that accelerates neuron death. Thus, mitochondrial maintenance defects and axonal energy deficits emerge as central problems in neurodegenerative disorders and brain injury. Recent studies have started to uncover the intrinsic mechanisms that neurons adopt to maintain (or reprogram) axonal mitochondrial density and integrity, and their bioenergetic capacity, upon sensing energy stress. In this review, we discuss recent advances in how neurons maintain a healthy pool of axonal mitochondria, as well as potential therapeutic strategies that target bioenergetic restoration to power neuronal survival, function, and regeneration.