SIRT5 downregulation in Alzheimer's disease permits excessive succinylation of HNRNPC, which stabilizes and upregulates YME1L1, disrupting mitochondrial fission-fusion balance and triggering neuronal death. Restoring SIRT5 activity reverses this cascade in mouse models, suggesting a targetable pathway for AD intervention.
Key Points
- SIRT5 loss enables HNRNPC succinylation, amplifying YME1L1 expression in AD
- YME1L1 dysregulation impairs OPA1 proteolysis, causing mitochondrial fission-fusion imbalance
- SIRT5 overexpression restores cognitive function and reduces amyloid burden in mice
Longevity Analysis
This research maps a molecular cascade linking protein modification status to mitochondrial energy production failure—a cornerstone of neurodegeneration. The pathway reveals how a single enzyme's reduced activity (SIRT5) triggers a protective mechanism to deteriorate, ultimately compromising the cell's ability to manage oxidative stress and maintain structural integrity. Because this axis operates through reversible biochemical regulation rather than genetic mutation, it identifies a window for intervention before irreversible neuronal loss occurs. The finding validates targeting post-translational modifications as a strategy to restore cellular energy metabolism and defend neuronal populations against Alzheimer's pathology.
Original published by Wiley Aging Cell, by Xuewei Li, Fan Yang, Yuyan Jiang, Fei Zhao, Fan Liu .