Journal
CURRENT BIOLOGY
Volume 31, Issue 14, Pages 3098-+Publisher
CELL PRESS
DOI: 10.1016/j.cub.2021.04.079
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Funding
- NINDS, NIH [ZIA NS003029, ZIA NS002946]
- NIH [1R01NS100531, 1R01NS103481, 1R01NS111776]
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In mature neurons and adult brains, an intrinsic energetic repair signaling axis boosts axonal energy supply by reprogramming mitochondrial trafficking and anchoring in response to acute injury-ischemic stress. The brain mitochondrial kinase P21-activated kinase 5 (PAK5) is activated in axons in response to ischemic stress and axonal injury, leading to the remobilization and replacement of damaged mitochondria. This mechanism protects axon survival and facilitates regeneration in both in vitro and in vivo models, supporting central nervous system (CNS) survival and regeneration.
Mitochondria supply adenosine triphosphate (ATP) essential for neuronal survival and regeneration. Brain injury and ischemia trigger acute mitochondrial damage and a local energy crisis, leading to degeneration. Boosting local ATP supply in injured axons is thus critical to meet increased energy demand during nerve repair and regeneration in adult brains, where mitochondria remain largely stationary. Here, we elucidate an intrinsic energetic repair signaling axis that boosts axonal energy supply by reprogramming mitochondrial trafficking and anchoring in response to acute injury-ischemic stress in mature neurons and adult brains. P21-activated kinase 5 (PAK5) is a brain mitochondrial kinase with declined expression in mature neurons. PAK5 synthesis and signaling is spatiotemporally activated within axons in response to ischemic stress and axonal injury. PAK5 signaling remobilizes and replaces damaged mitochondria via the phosphorylation switch that turns off the axonal mitochondrial anchor syntaphilin. Injury-ischemic insults trigger AKT growth signaling that activates PAK5 and boosts local energy supply, thus protecting axon survival and facilitating regeneration in in vitro and in vivo models. Our study reveals an axonal mitochondrial signaling axis that responds to injury and ischemia by remobilizing damaged mitochondria for replacement, thereby maintaining local energy supply to support central nervous system (CNS) survival and regeneration.
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