Molecular mechanisms by which mitochondrial dysfunction drives neuromuscular junction degeneration in amyotrophic lateral sclerosis

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive degeneration of motor neurons and early deterioration of neuromuscular junctions (NMJs). Increasing evidence indicates that mitochondrial dysfunction plays a pivotal role in driving NMJ degeneration in ALS.

Objective: This review aims to comprehensively summarize the molecular mechanisms by which mitochondrial defects contribute to NMJ instability, with a particular focus on bioenergetics, calcium homeostasis, oxidative stress, and impaired mitochondrial biogenesis.

Conclusion: Mitochondrial dysfunction is a core driver of NMJ degeneration in ALS. Targeting mitochondrial biogenesis and metabolism-particularly through the PGC-1α pathway-represents a promising strategy to preserve NMJ integrity and slow disease progression.

Keywords: Amyotrophic lateral sclerosis; Calcium homeostasis; Mitochondria; Mitochondrial biogenesis; Neuromuscular junction; PGC-1α; ROS.