Mitochondrial Metabolism Power SIRT2-Dependent Deficient Traffic Causing Alzheimer's-Disease Related Pathology.
Multiple lines of evidence state a major role for mitochondrial dysfunction in sporadic Alzheimer's disease (AD) etiopathogenesis. However, the molecular mechanism(s) triggered by mitochondrial deficits that lead to neurodegeneration remain elusive. Herein, we propose a new mechanism by which mitochondrial loss of potential leads to a dysfunction in autophagy/mitophagy due to the overactivation of SIRT2, a tubulin deacetylase that regulates microtubule network acetylation, and provide insights into the association between metabolism, phosphorylation, and Aβ aggregation. We observed an increase in SIRT2 levels and a decrease in the acetylation of lys40 of tubulin in AD cells containing patient mtDNA as well as in AD brains. SIRT2 loss of function either with AK1 (a specific SIRT2 inhibitor) or by SIRT2 knockout recovers microtubule stabilization and improves autophagy, favoring cell survival through the elimination of toxic Aβ oligomers. Our data provide strong evidence for a functional role of tubulin acetylation on autophagic vesicle traffic and mitochondria degradation. We propose that SIRT2 inhibition may improve microtubule assembly thus representing a valid approach as disease-modifying therapy for AD.
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|CNC-IBILI, University of Coimbra, Coimbra, Portugal.
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Silva
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|CNC-IBILI, University of Coimbra, Coimbra, Portugal.
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Esteves
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|CNC-IBILI, University of Coimbra, Coimbra, Portugal.|Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
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Oliveira
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. cardoso.sandra.m@gmail.com.|CNC-IBILI, University of Coimbra, Coimbra, Portugal. cardoso.sandra.m@gmail.com.|Institute of Cellular and Molecular Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. cardoso.sandra.m@gmail.com.
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Cardoso
D000107:Acetylation; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001343:Autophagy; D001921:Brain / Q000473:pathology; D002454:Cell Differentiation; D060825:Cognitive Dysfunction / Q000150:complications / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D008954:Models, Biological; D015203:Reproducibility of Results; D056565:Sirtuin 2 / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
D014404:Tubulin; D056565:Sirtuin 2
Alzheimer’s disease (AD); Autophagic-lysosomal pathway (ALP); Microtubules; Mitochondrial dynamics; Sirtuin-2 (SIRT2)