Research Progress on Drp1 in the Pathological Mechanisms and Therapeutic Interventions of Stroke, Based on the Imbalance in the Dynamic Equilibrium of Mitochondrial Fission and Fusion.
TL;DR
This article provides a comprehensive review of the molecular regulatory networks and cell-type-specific effects of Drp1 in ischemic and haemorrhagic stroke, covering key processes such as neuronal apoptosis, inflammatory polarisation of glial cells, and disruption of the vascular endothelial barrier.
Abstract
Ischemic and haemorrhagic strokes together constitute the leading cause of death and disability worldwide, and their pathological mechanisms involve an imbalance in mitochondrial dynamics. Dynamin-related protein 1 (Drp1), a key GTPase driving mitochondrial fission, is overexpressed in response to post-stroke pathological signals (calcium overload, oxidative stress, and inflammatory factors), leading to fragmentation of the mitochondrial network and subsequently triggering energy depletion, reactive oxygen species (ROS) bursts, and various forms of programmed cell death. This article provides a comprehensive review of the molecular regulatory networks and cell-type-specific effects of Drp1 in ischemic and haemorrhagic stroke, covering key processes such as neuronal apoptosis, inflammatory polarisation of glial cells, and disruption of the vascular endothelial barrier. The literature was synthesized based on a thematic rather than a formal systematic approach, with emphasis on high-quality mechanistic studies and preclinical evidence published over the past decade. Building upon a summary of preclinical evidence for the protective effects of pharmacological inhibitors such as Mdivi-1, P110 and Drpitor1, the paper provides an in-depth analysis of the bottlenecks currently facing translation, including core challenges such as the narrow therapeutic time window, insufficient blood-brain barrier permeability, the need to strike a balance between physiological and pathological fission, and the lack of biomarkers. Finally, this paper outlines next-generation intervention strategies based on nanodelivery systems, precise temporal regulation and multi-omics integration, emphasising a paradigm shift from 'complete blockade' to 'fine-tuning', thereby providing a theoretical basis for the development of innovative Drp1-targeted therapies for stroke.