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Updated: Mar 19, 2026
Author Spotlight: Decoding Mitochondrial Aging
Published on: June 30, 2023
Mitochondrial Metabolism Power SIRT2-Dependent Deficient Traffic Causing Alzheimer's-Disease Related Pathology
D F Silva1,2, A R Esteves1,2, C R Oliveira1,2,3
1CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Abstract:
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.
Insights
Mitochondrial dysfunction in Alzheimer's disease (AD) is linked to impaired autophagy via overactive SIRT2. Inhibiting SIRT2 restores microtubule function and autophagy, clearing toxic Aβ and promoting cell survival.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Mitochondrial dysfunction is implicated in Alzheimer's disease (AD) pathogenesis.
- The precise molecular mechanisms linking mitochondrial deficits to neurodegeneration are not fully understood.
Purpose of the Study:
- To elucidate a novel mechanism involving mitochondrial dysfunction, SIRT2, and autophagy in AD.
- To investigate the role of tubulin acetylation in regulating autophagy and mitophagy.
- To explore the therapeutic potential of SIRT2 inhibition in AD.
Main Methods:
- Analysis of SIRT2 levels and tubulin acetylation in AD cells and brains.
- Utilizing a SIRT2 inhibitor (AK1) and SIRT2 knockout models.
- Assessing autophagy, mitophagy, microtubule stability, and Aβ aggregation.
Main Results:
- Increased SIRT2 levels and decreased tubulin acetylation observed in AD models.
- SIRT2 inhibition or knockout normalized microtubule acetylation and stabilized microtubules.
- Restored microtubule function improved autophagy and mitophagy, leading to clearance of toxic Aβ oligomers and enhanced cell survival.
Conclusions:
- SIRT2 overactivation contributes to impaired autophagy/mitophagy in AD through altered tubulin acetylation.
- Tubulin acetylation is crucial for autophagic vesicle transport and mitochondria degradation.
- Targeting SIRT2 represents a promising disease-modifying therapeutic strategy for Alzheimer's disease.
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