Redox signaling by hydrogen peroxide modulates axonal microtubule organization and induces a specific phosphorylation signature of microtubule proteins distinct from distress

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ABSTRACT Many life processes are regulated by physiological redox signals, referred to as oxidative eustress. However, excessive oxidative stress can damage biomolecules and contribute to disease. The neuronal microtubule system is critically involved in axon homeostasis, regulation of axonal transport, and neurodegenerative processes. However, whether and how physiological redox signals affect axonal microtubules is largely unknown. Using live cell imaging and super- resolution microscopy, we show that subtoxic concentrations of the central redox metabolite hydrogen peroxide increase axonal microtubule dynamics, alter the structure of the axonal microtubule array, and affect the efficiency of axonal transport. We report that the mitochondria-targeting antioxidant SkQ1 and the microtubule stabilizer EpoD abolish the increase in microtubule dynamics. We found that oxidative eustress and distress specifically modulate the phosphorylation state of the microtubule system and induce a largely non- overlapping phosphorylation pattern of MAP1B as the main target. Cell-wide phosphoproteome analysis revealed that different signaling pathways are inversely activated by oxidative eustress and distress. Signaling via casein kinase (CK2) and pyruvate dehydrogenase kinases (PDK) is activated during eustress and signaling via mammalian target of rapamycin (mTOR) and serum/glucocorticoid-regulated protein kinase (SGK) is activated during distress. The results suggest that the redox metabolite and second messenger hydrogen peroxide induces rapid and local reorganization of the microtubule array in response to mitochondrial activity or as a messenger from neighboring cells by activating specific signaling cascades.

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