MA-5 attenuates disease-associated transcriptomic aging and pathological microglial states in Gaucher disease
TL;DR
Overall, MA-5 suppresses neuroinflammation and reverses accelerated transcriptomic aging, supporting its potential as a therapeutic strategy for GD and other lysosomal storage disorders, as well as for diseases characterized by mitochondrial dysfunction, chronic inflammation, and pathological accumulation.
Abstract
Chronic inflammation and mitochondrial dysfunction are hallmarks of neurodegeneration and aging, yet how mitochondrial damage contributes to inflammatory and aging-like cellular programs remains poorly understood. Gaucher disease (GD) is a lysosomal storage disorder caused by GBA1 mutations, which also represent a major genetic risk factor for Parkinson’s disease. In a GD mouse model, we identified marked mitochondrial cristae disorganization accompanied by mitochondrial DNA release, activation of the cGAS–STING and NLRP3 inflammasome pathways, and subsequent inflammatory microglial activation. Circulating galectin-3 was also elevated in both model mice and patients with GD, supporting its potential relevance as a systemic marker of disease-associated inflammation. Mitochonic acid-5 (MA-5) is a mitochondria-targeting compound that interacts with mitofilin/MIC60 in the mitochondrial inner membrane and enhances ATP production. In a GD mouse model and patient-derived iPSC microglia, MA-5 increased ATP levels, preserved mitochondrial cristae integrity, limited mtDNA release, and suppressed cGAS–STING and NLRP3 inflammasome signaling, thereby attenuating microglial innate immune activation and galectin-3 expression. MA-5 also prolonged survival and reversed accelerated transcriptomic aging across multiple brain cell types, with particularly prominent effects in microglia. In the liver, GD was similarly associated with inflammatory, stress-related, and aging-associated transcriptional changes, whereas MA-5 improved liver function, restored mitochondrial morphology, suppressed inflammatory and stress responses, restored metabolic programs, and reduced transcriptomic age. Overall, MA-5 suppresses neuroinflammation and reverses accelerated transcriptomic aging, supporting its potential as a therapeutic strategy for GD and other lysosomal storage disorders, as well as for diseases characterized by mitochondrial dysfunction, chronic inflammation, and pathological accumulation.