The AMPK-related kinase NUAK1 controls cortical axons branching though a local modulation of mitochondrial metabolic functions

Abstract

The precise regulation of the cellular mechanisms underlying axonal morphogenesis is essential to the formation of functional neuronal networks. We previously identified the autism-candidate kinase NUAK1 as a central regulator of axon branching in mouse cortical neurons through the control of mitochondria trafficking. How does local mitochondrial position or function regulate axon branching during development? Here, we characterized the metabolic regulation in the developing axon and report a marked metabolic decorrelation between axon elongation and collateral branching. We next solved the cascade of event leading to presynaptic clustering and mitochondria recruitment during spontaneous branch formation. Interestingly and contrary to peripheral neurons, mitochondria are recruited after but not prior to branch formation in cortical neurons. Using flux metabolomics and fluorescent biosensors, we observed that NUAK1 deficiency significantly impairs mitochondrial metabolism and axonal ATP concentration. Upregulation of mitochondrial function is sufficient to rescue axonal branching in NUAK1 null neurons in vitro and in vivo. Altogether, our results indicate that NUAK1 exerts a dual function during axon branching through its ability to control mitochondria distribution and activity, and suggest that a mitochondrial-dependent remodeling of local metabolic homeostasis plays a critical role during axon morphogenesis. RESULTS Cortical axon elongation and collateral branching rely on distinct metabolic pathways

Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

“…The MAF target gene ARK5 was implicated in maintaining mitochondrial function in neuronal cells and could therefore be involved in the regulation of OXPHOS. In agreement, deletion of ARK5 in neuronal cultures decreased both the basal and maximal respiratory rate but did not affect glycolysis, indicating a defect in OXPHOS [ 292 ]. Interestingly, ARK5 possesses distinct cytosolic and nuclear functions, and subcellular localization of the protein differs between cell lines and redox state, as oxidative stress can induce cytosolic accumulation of ARK5 [ 293 ].…”

Genetic architecture of the structural connectome

“…The fifth-most significant variant, rs12146713 (chr12:106,476,805), is an intronic variant in NUAK1. NUAK1 dose-dependently regulates axon elongation and branching via effects on mitochondrial metabolism and trafficking [91][92][93] . NUAK1 is a candidate gene for autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD) and intellectual disability.…”

Central Causation of Autism/ASDs via Excessive [Ca2+]i Impacting Six Mechanisms Controlling Synaptogenesis during the Perinatal Period: The Role of Electromagnetic Fields and Chemicals and the NO/ONOO(-) Cycle, as Well as Specific Mutations

“…However, it also has established roles in lowering NF-kappaB and lowering inflammation, and is reported to lower superoxide production and therefore, oxidative stress in mitochondria. There are several studies suggesting that agents raising AMPK may be useful in autism/ASD treatment (Bakoui [255]; Alsaqati et al [256]; Lanfranchi et al [257]; Diaz-Gerevini et al [258]; Gantois et al [259]).…”