Interaction between Microglia and Mitochondrial Metabolism in the Development of Amyotrophic Lateral Sclerosis (ALS)

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons, leading to muscle weakness and eventual paralysis. Although the precise mechanisms driving ALS are not yet fully elucidated, emerging evidence suggests a crucial role of neuroinflammation and mitochondrial dysfunction in disease progression. Microglia, the brain’s resident immune cells, play a central role in the neuroinflammatory response and undergo metabolic reprogramming during ALS, shifting from a homeostatic state to an inflammatory one. This reactivity is linked to mitochondrial dysfunction, which impairs energy production but allows microglia to maintain a pro-inflammatory phenotype through alternative pathways, such as glycolysis. This interaction between mitochondrial metabolism and microglial function exacerbates neuroinflammation, contributing to neuronal damage and accelerating ALS pathology. Mutations in genes like C9ORF72, SOD1, and TARDBP, commonly associated with ALS, also affect cellular processes such as RNA metabolism and mitochondrial function, further worsening the effects of the disease. This review explores the role of microglial mitochondrial metabolism in ALS, highlighting its importance in disease progression and identifying potential therapeutic targets to modulate neuroinflammation and metabolic dysfunction to slow ALS progression.