Post-Translational Modifications of DRP1 in Alzheimer's Disease

Abstract

Mitochondrial dysfunction is increasingly recognized as a central feature in the pathophysiology of Alzheimer’s disease (AD). Among the mitochondrial alterations implicated in AD, aberrant mitochondrial fission, principally mediated by dynamin-related protein 1 (DRP1), has emerged as a critical pathological mechanism. This review delineates the role of post-translational modifications (PTMs) in regulating DRP1 function and highlights emerging evidence on its pathological interactions and therapeutic targeting in AD. PTMs dynamically modulate DRP1 activity, stability, and subcellular localization in response to AD-related cellular stressors, including amyloid-b (Ab) accumulation, oxidative stress, and calcium dysregulation. Hyperphosphorylation of DRP1 has been shown to enhance its translocation to mitochondria, promoting excessive fragmentation. In addition, alternative PTMs, including O-GlcNAcylation, S-nitrosylation, and ISGylation, influence DRP1 function, either enhancing or suppressing its pathological activity. Proteolytic cleavage of DRP1 by calpain further disrupts its integrity, contributing to mitochondrial dysfunction and synaptic degeneration. In addition to being regulated by PTMs, DRP1 is abnormally activated through direct interactions with Ab and phosphorylated tau (pTau), contributing to excessive fission and impaired mitophagy. Together, these findings underscore DRP1 as a pivotal regulatory node whose modulation, through both PTMs and pathological interactions with Ab and pTau, disrupts mitochondrial dynamics in AD. Therapeutic strategies aimed at targeting DRP1 activity offer promising avenues to restore mitochondrial homeostasis and mitigate neurodegeneration.