Mitochondria‐Homing Drug Mitochonic Acid 5 Improves Barth Syndrome Myopathy in a Human‐Induced Pluripotent Stem Cell Model and Barth Syndrome <i>Drosophila</i> Model

Barth syndrome (BTHS) is a rare disease caused by mutations in the tafazzin gene that affects the heart and muscles; however, to date, no clinically effective drugs are available. In BTHS, mitochondrial function is reduced owing to changes in cardiolipin metabolism. We developed mitochonic acid 5 (MA-5), a small-molecule compound that increases ATP levels, improves mitochondrial dynamics, and is effective in treating mitochondrial and muscle diseases. Therefore, this study examined the effectiveness of MA-5 in treating BTHS. The mitochondrial functions of four isolated BTHS skin fibroblasts were examined. Human BTHS induced pluripotent stem cell (iPSC) were differentiated into myoblasts and cardiolipin metabolism and mitochondrial functions were analyzed. RNA-seq was performed to clarify the metabolic changes. Using a Drosophila melanogaster model of BTHS, the effects of MA-5 on motor performance and cardiac phenotype were examined. MA-5 improved mitochondrial function and reduced cell death due to oxidative stress in skin fibroblasts of patients with BTHS. MA-5 promoted ATP production and reduced oxidative stress in human BTHS iPS cell-derived myoblasts. RNA-seq analysis revealed that MA-5 alleviated endoplasmic reticulum stress in BTHS cells. Administration of MA-5 to BTHS Drosophila improved locomotor ability and tachycardia observed in patients with BTHS. Protein interaction analyses suggested colocalization of ATPase and the MA-5-binding protein mitofilin. These data suggested that MA-5 improves BTHS dysfunction and may serve as a novel therapeutic agent for BTHS.

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Journal
The FASEB Journal
Published
2025-06-21
DOI
https://doi.org/10.1096/fj.202401856rrr
Primary Topic
Mitochondrial Function and Pathology
Type
article
Field-Weighted Citation Impact
0.00

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article

Mitochondria‐Homing Drug Mitochonic Acid 5 Improves Barth Syndrome Myopathy in a Human‐Induced Pluripotent Stem Cell Model and Barth Syndrome Drosophila Model

Takamasa Ishikawa, Ryota Akimoto, Yoshitsugu Oikawa, Takafumi Toyohara et al.
The FASEB Journal
Mitochondrial Function and Pathology
article

Mitochondria‐Homing Drug Mitochonic Acid 5 Improves Barth Syndrome Myopathy in a Human‐Induced Pluripotent Stem Cell Model and Barth Syndrome Drosophila Model

Takamasa Ishikawa, Ryota Akimoto, Yoshitsugu Oikawa, Takafumi Toyohara, Akihiko Muto, Shin-ichiro Kanno, Sayaka Sekine, Tomoyoshi Soga, Shinji Fukuda, Yuhan Luo, Shun Watanabe, Erina Kuranaga, Chitose Suzuki, Hirofumi Kashiwagi, Shun Itai, Takaaki Abe, Takeya Sato, Tomoko Kasahara, Takehiro Suzuki, Yusuke Okubo, Yoshikazu Tanaka, M. Suzuki, Kei Murayama, Hidetaka Tokuno, Yoshiyasu Tongu, Chiharu Kawabe, Tetsuro Matsuhashi, Kyohei Sato, Kôichi Kikuchi, Kazuhiko Igarashi
article en

Abstract

Barth syndrome (BTHS) is a rare disease caused by mutations in the tafazzin gene that affects the heart and muscles; however, to date, no clinically effective drugs are available. In BTHS, mitochondrial function is reduced owing to changes in cardiolipin metabolism. We developed mitochonic acid 5 (MA-5), a small-molecule compound that increases ATP levels, improves mitochondrial dynamics, and is effective in treating mitochondrial and muscle diseases. Therefore, this study examined the effectiveness of MA-5 in treating BTHS. The mitochondrial functions of four isolated BTHS skin fibroblasts were examined. Human BTHS induced pluripotent stem cell (iPSC) were differentiated into myoblasts and cardiolipin metabolism and mitochondrial functions were analyzed. RNA-seq was performed to clarify the metabolic changes. Using a Drosophila melanogaster model of BTHS, the effects of MA-5 on motor performance and cardiac phenotype were examined. MA-5 improved mitochondrial function and reduced cell death due to oxidative stress in skin fibroblasts of patients with BTHS. MA-5 promoted ATP production and reduced oxidative stress in human BTHS iPS cell-derived myoblasts. RNA-seq analysis revealed that MA-5 alleviated endoplasmic reticulum stress in BTHS cells. Administration of MA-5 to BTHS Drosophila improved locomotor ability and tachycardia observed in patients with BTHS. Protein interaction analyses suggested colocalization of ATPase and the MA-5-binding protein mitofilin. These data suggested that MA-5 improves BTHS dysfunction and may serve as a novel therapeutic agent for BTHS.

The FASEB JournalVol. 39(12)
University of Tsukuba (JP), Kanagawa Institute of Technology (JP), Tohoku University (JP), Keio University (JP), Juntendo University (JP), Chiba Hospital (JP)
Japan Agency for Medical Research and Development, Okinaka Memorial Institute for Medical Research, Japan Society for the Promotion of Science
Good health and well-being
Openalex Percentile: Top 87%
Mitochondrial Function and Pathology
DOIOpen Access PDFOpenAlex
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