REVIEW article
Front. Neurol.
Sec. Dementia and Neurodegenerative Diseases
The Metabolic-Epigenetic Interface: Lysine Succinylation Orchestrates Bidirectional Crosstalk in Neurodegenerative Disorders
Provisionally accepted
- 1First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, China
- 2Heilongjiang University of Chinese Medicine Affiliated Second Hospital, Harbin, China
- 3Heilongjiang Provincial Hospital, Harbin, China
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Succinylation, a nexus between metabolism and epigenetic regulation, is a central factor in the onset and progression of neurodegenerative diseases (NDDs). Research has demonstrated a close association between NDDs and neuronal metabolic disorders. Succinylation regulates the interaction between energy metabolism and epigenetic networks, establishing the pathological mechanism of "metabolic-epigenetic bidirectional regulation." In metabolic stress, such as mitochondrial dysfunction or enhanced glycolysis, succinyl-CoA increases, causing uncontrolled succinylation. These modifications impair the function of proteins associated with synaptic plasticity, leading to disorders in synaptic transmission and neuronal damage. Concurrently, succinylation regulates the activity of enzymes involved in DNA methylation and epigenetic reprogramming, impairing neuronal recovery and creating a vicious cycle. This regulatory network displays bidirectional self-reinforcing characteristics. Metabolic disorders influence epigenetic states through succinylation. Epigenetic abnormalities inhibit the transcription of genes associated with mitochondrial metabolism, exacerbating energy metabolism defects and oxidative stress. This leads to irreversible degenerative changes in neurons. At the therapeutic level, targeting succinylation can disrupt the metabolic-epigenetic pathological loop and restore synaptic function. In short, understanding how succinylation is regulated may lead to new treatment options for neurodegenerative diseases.
Keywords: Metabolic-Epigenetic Crosstalk, Mitochondria, NDD, Sirt5, succinylation
Received: 03 Aug 2025; Accepted: 30 Nov 2025.
Copyright: © 2025 Chai, Liu, Liu and Zou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Wei Zou
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