Taurine rescues mitochondria-related metabolic impairments in the patient-derived induced pluripotent stem cells and epithelial-mesenchymal transition in the retinal pigment epithelium
Kohei Homma, Ph.D.,
Eriko Toda,
Hideto Osada,
Norihiro Nagai, M.D., Ph.D.,
Takumi Era, M.D., Ph.D.,
Kazuo Tsubota, M.D., Ph.D.,
Hideyuki Okano, M.D., Ph.D.,
Yoko Ozawa, M.D., Ph.D.
Affiliations
Kohei Homma, Ph.D.
Laboratory of Retinal Cell Biology, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan; Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan
Eriko Toda
Laboratory of Retinal Cell Biology, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan; Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan
Hideto Osada
Laboratory of Retinal Cell Biology, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan; Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan
Norihiro Nagai, M.D., Ph.D.
Laboratory of Retinal Cell Biology, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan; Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan
Takumi Era, M.D., Ph.D.
Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Chuo-ku, Kumamoto, 860-0811, Japan
Kazuo Tsubota, M.D., Ph.D.
Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan
Hideyuki Okano, M.D., Ph.D.
Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan
Yoko Ozawa, M.D., Ph.D.
Laboratory of Retinal Cell Biology, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan; Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan; Department of Ophthalmology, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan; St. Luke's International University, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan; Corresponding author. Laboratory Chief & Assistant Professor, Laboratory of Retinal Cell Biology Department of Ophthalmology, Keio University School of Medicine; 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Mitochondria participate in various metabolic pathways, and their dysregulation results in multiple disorders, including aging-related diseases. However, the metabolic changes and mechanisms of mitochondrial disorders are not fully understood. Here, we found that induced pluripotent stem cells (iPSCs) from a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) showed attenuated proliferation and survival when glycolysis was inhibited. These deficits were rescued by taurine administration. Metabolomic analyses showed that the ratio of the reduced (GSH) to oxidized glutathione (GSSG) was decreased; whereas the levels of cysteine, a substrate of GSH, and oxidative stress markers were upregulated in MELAS iPSCs. Taurine normalized these changes, suggesting that MELAS iPSCs were affected by the oxidative stress and taurine reduced its influence. We also analyzed the retinal pigment epithelium (RPE) differentiated from MELAS iPSCs by using a three-dimensional culture system and found that it showed epithelial mesenchymal transition (EMT), which was suppressed by taurine. Therefore, mitochondrial dysfunction caused metabolic changes, accumulation of oxidative stress that depleted GSH, and EMT in the RPE that could be involved in retinal pathogenesis. Because all these phenomena were sensitive to taurine treatment, we conclude that administration of taurine may be a potential new therapeutic approach for mitochondria-related retinal diseases.
