Synthetic molecule improves mitochondrial function in ALS models and patient-derived stem cells

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease resulting from the loss of motor neurons, causing muscle weakness and difficulties in breathing and swallowing. Existing medications can slow disease progression, but reversing the disease process remains unattainable. Mitochondrial dysfunction is considered a promising therapeutic target due to mitochondria's crucial role in cellular energy production and frequent impairment in ALS.

Tohoku University, in collaboration with Kyoto University, the National Center of Neurology and Psychiatry, and Keio University, explored a small molecule called Mitochonic acid 5 (MA-5) to enhance mitochondrial function. The team assessed MA-5 in various ALS models, such as a fruit fly model, skin fibroblasts from ALS patients, and motor neurons derived from patient-derived induced pluripotent stem cells.

MA-5 has shown promise in improving impaired locomotor function in fruit flies and increasing ATP production, enhancing mitochondrial movement, and maintaining mitochondrial structure in patient-derived cells. These results suggest that MA-5 may help maintain cellular energy production and structure across various ALS backgrounds.

Furthermore, gene expression and metabolomic analyses indicate that MA-5 alters mitochondrial respiratory chain gene expression and suppresses the glycerol phosphate shuttle. Candidates for biomarkers predicting or monitoring responses to MA-5, namely C7orf31 and C3orf62, were identified. Higher C7orf31 blood concentrations were associated with patients having SOD1-mutant ALS.

While MA-5 showed positive effects in several ALS-associated phenotypes, it remains uncertain whether MA-5 can improve motor function or slow disease progression in mammalian ALS models or humans. Further preclinical studies and clinical trials are required to determine whether MA-5 can effectively alleviate ALS progression in humans.