Synaptic Function Section, The Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Room 2B-215, 35 Convent Drive, Bethesda, MD 20892-3706, USA.
Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of Medicine, 320 W. 15th Street, Indianapolis, IN 46202, USA.
Curr Biol. 2021 Jul 26;31(14):3098-3114.e7. doi: 10.1016/j.cub.2021.04.079. Epub 2021 Jun 3.
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.
线粒体提供三磷酸腺苷（ATP），这是神经元存活和再生所必需的。脑损伤和缺血会引发急性线粒体损伤和局部能量危机，导致神经变性。因此，在成年大脑中，增加损伤轴突中的局部 ATP 供应对于满足神经修复和再生期间增加的能量需求至关重要，在成年大脑中，线粒体基本上保持静止。在这里，我们阐明了一种内在的能量修复信号轴，该信号轴通过响应成熟神经元和成年大脑中的急性损伤-缺血应激，重新编程线粒体运输和锚定，从而增加轴突的能量供应。P21 激活激酶 5（PAK5）是一种脑线粒体激酶，在成熟神经元中的表达下降。PAK5 的合成和信号在对缺血应激和轴突损伤的反应中在轴突中被时空激活。PAK5 信号通过磷酸化开关重新动员和替换受损的线粒体，该磷酸化开关关闭了轴突线粒体锚定蛋白 syntaphilin。损伤-缺血损伤会触发 AKT 生长信号，从而激活 PAK5 并增加局部能量供应，从而保护轴突存活并促进体外和体内模型中的再生。我们的研究揭示了一种轴突线粒体信号轴，该信号轴通过重新动员受损的线粒体进行替换来响应损伤和缺血，从而维持局部能量供应，以支持中枢神经系统（CNS）的存活和再生。
