Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease in which motor neurons are gradually lost, leading to muscle weakness and, as the disease advances, difficulties with breathing and swallowing. Existing medicines can slow disease progression to some extent, but no treatment has been established that fundamentally reverses the disease process. Mitochondrial dysfunction is considered a potential therapeutic target because mitochondria play a central role in cellular energy production and are frequently impaired in ALS.
A collaborative research team led by Tohoku University, together with Kyoto University, the National Center of Neurology and Psychiatry, and Keio University, investigated Mitochonic acid 5 (MA-5), a small molecule developed by the Tohoku University group to enhance mitochondrial function. The team evaluated MA-5 in a fruit fly model of ALS, skin fibroblasts obtained from people with ALS, and motor neurons generated from patient-derived induced pluripotent stem cells (iPS cells). This three-pronged approach enabled a comprehensive preclinical evaluation of MA-5 across multiple ALS models.
"ALS has diverse genetic and biological causes, so what works for one patient may not work for another," explains Takafumi Toyohara (Tohoku University). "However, mitochondrial dysfunction is a potential therapeutic target that may be shared across a broad range of patients."
In the fruit fly model, MA-5 improved impaired locomotor function. It also restored cellular ATP levels, increased mitochondrial membrane potential, and improved abnormal mitochondrial morphology in muscle.
In patient-derived fibroblasts and iPS cell-derived motor neurons, MA-5 increased ATP production and enhanced mitochondrial movement within nerve cells. Similar positive effects were observed in models derived from patients with SOD1 mutations, FUS mutations, and sporadic ALS, suggesting that MA-5 may exert similar cellular effects across multiple ALS backgrounds.
"When mitochondrial function is impaired, cells may struggle to produce sufficient ATP to maintain normal cellular function," says Toyohara. "MA-5 helps maintain mitochondrial structure and supports cellular energy production."
In addition, gene expression and metabolomic analyses suggested that MA-5 alters the expression of genes related to the mitochondrial respiratory chain and suppresses the glycerol phosphate shuttle, a metabolic pathway associated with oxidative stress. These findings may provide additional clues to the mechanisms through which MA-5 affects ALS-related cellular abnormalities.
The researchers further identified C7orf31 and C3orf62 as candidate biomarkers for predicting or monitoring responses to MA-5. Blood C7orf31 concentrations tended to be higher in patients with SOD1-mutant ALS than in patients with sporadic ALS or other neurological diseases, suggesting its potential as a candidate diagnostic biomarker for this ALS subtype.
Across the three experimental systems, MA-5 improved several ALS-associated phenotypes, particularly those related to mitochondrial function and cellular energy metabolism. These findings support further investigation of mitochondrial dysfunction as a potential therapeutic target in ALS. MA-5 has undergone a Phase I clinical trial for mitochondrial disease, providing preliminary information on its safety in humans, but it has not yet been tested in people with ALS. The present study was conducted primarily in fruit flies and cultured cells, and it remains unknown whether MA-5 can improve motor function or slow disease progression in mammalian ALS models or in people with ALS. Further preclinical studies and clinical trials in people with ALS will therefore be needed.
The findings will be published in JCI Insight on September 23, 2026.
<Publication Details>
Title: Mitochonic acid-5 alleviates amyotrophic lateral sclerosis phenotypes via mitochondrial augmentation
Authors: Yoshitsugu Oikawa*, Yuhan Luo*, Naoki Suzuki, Tomoko Kasahara, Yoshiyasu Tongu, Yuki Yoshida, Tsukasa Tominari, Shogo Tanabe, Yoshiko Suto, Hitomi Kashiwagi, Saki Saito, Kensuke Ikeda, Chitose Suzuki, Arata Kuranaga, Tetsuya Akiyama, Satoru Morimoto, Yoshitsugu Aoki, Rieko Muramatsu, Tomoyoshi Soga, Masashi Aoki, Hideyuki Okano, Tetsuhiro Tanaka, Takaaki Abe, Erina Kuranaga**, and Takafumi Toyohara**. *These authors contributed equally to this work. **Corresponding authors: Erina Kuranaga and Takafumi Toyohara.
Journal: JCI Insight
DOI: 10.1172/jci.insight.200761.
<Contact>
Takafumi Toyohara
Regenerative and Biomedical Engineering,
Graduate School of Medicine
Email: takafumi.toyohara.e6@tohoku.ac.jp