TY - JOUR
T1 - Apomorphine rescues reactive oxygen species-induced apoptosis of fibroblasts with mitochondrial disease
AU - Miyauchi, Akihiko
AU - Kouga, Takeshi
AU - Jimbo, Eriko F.
AU - Matsuhashi, Tetsuro
AU - Abe, Takaaki
AU - Yamagata, Takanori
AU - Osaka, Hitoshi
N1 - Funding Information:
This research was supported by a grant for the Project for Health Research on Infants, Children, Adolescents, and Young Adults from the Agency of Medical Research and Development, a grant from the Japan Agency for Medical Research and Development Grant Number 17ek0109270s0301 (H.O.), and a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science, and in part by The Japan Society for the Promotion of Science KAKENHI Grant Number 18H0822 (T.A.), 18K15659 (T.M.). We thank the patients and their families as well as all of the staff working, especially Shiho Aoki, Tomomi Oyama and Narumi Omika in Jichi Children Medical Center Tochigi and Jichi Medical University Hospital.
Funding Information:
This research was supported by a grant for the Project for Health Research on Infants, Children, Adolescents, and Young Adults from the Agency of Medical Research and Development, a grant from the Japan Agency for Medical Research and Development Grant Number 17ek0109270s0301 (H.O.), and a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science , and in part by The Japan Society for the Promotion of Science KAKENHI Grant Number 18H0822 (T.A.), 18K15659 (T.M.).
Publisher Copyright:
© 2019 Elsevier B.V. and Mitochondria Research Society
PY - 2019/11
Y1 - 2019/11
N2 - Mitochondrial disease is a genetic disorder in which individuals suffer from energy insufficiency. The various clinical phenotypes of mitochondrial disease include Leigh syndrome (LS), myopathy encephalopathy lactic acidosis and stroke-like episodes (MELAS). Thus far, no curative treatment is available, and effective treatment options are eagerly awaited. We examined the cell protective effect of an existing commercially available chemical library on fibroblasts from four patients with LS and MELAS and identified apomorphine as a potential therapeutic drug for mitochondrial disease. We conducted a cell viability assay under oxidative stress induced by L-butionine (S, R)-sulfoximine (BSO), a glutathione synthesis inhibitor. Among the chemicals of library, 4 compounds (apomorphine, olanzapine, phenothiazine and ethopropazine) rescued cells from death induced by oxidative stress much more effectively than idebenone, which was used as a positive control. The EC50 value showed that apomorphine was the most effective compound. Apomorphine also significantly improved all of the assessed oxygen consumption rate values by the extracellular flux analyzer for fibroblasts from LS patients with complex I deficiency. In addition, the elevation of the Growth Differentiation Factor-15 (GDF-15), a biomarker of mitochondrial disease, was significantly reduced by apomorphine. Among 441 apomorphine-responsive genes identified by the microarray, apomorphine induced the expression of genes that inhibit the mammalian target of rapamycin (mTOR) activity and inflammatory responses, suggesting that apomorphine induced cell survival via a new potential pathway. In conclusion, apomorphine rescued fibroblasts from cell death under oxidative stress and improved the mitochondrial respiratory activity and appears to be potentially useful for treating mitochondrial disease.
AB - Mitochondrial disease is a genetic disorder in which individuals suffer from energy insufficiency. The various clinical phenotypes of mitochondrial disease include Leigh syndrome (LS), myopathy encephalopathy lactic acidosis and stroke-like episodes (MELAS). Thus far, no curative treatment is available, and effective treatment options are eagerly awaited. We examined the cell protective effect of an existing commercially available chemical library on fibroblasts from four patients with LS and MELAS and identified apomorphine as a potential therapeutic drug for mitochondrial disease. We conducted a cell viability assay under oxidative stress induced by L-butionine (S, R)-sulfoximine (BSO), a glutathione synthesis inhibitor. Among the chemicals of library, 4 compounds (apomorphine, olanzapine, phenothiazine and ethopropazine) rescued cells from death induced by oxidative stress much more effectively than idebenone, which was used as a positive control. The EC50 value showed that apomorphine was the most effective compound. Apomorphine also significantly improved all of the assessed oxygen consumption rate values by the extracellular flux analyzer for fibroblasts from LS patients with complex I deficiency. In addition, the elevation of the Growth Differentiation Factor-15 (GDF-15), a biomarker of mitochondrial disease, was significantly reduced by apomorphine. Among 441 apomorphine-responsive genes identified by the microarray, apomorphine induced the expression of genes that inhibit the mammalian target of rapamycin (mTOR) activity and inflammatory responses, suggesting that apomorphine induced cell survival via a new potential pathway. In conclusion, apomorphine rescued fibroblasts from cell death under oxidative stress and improved the mitochondrial respiratory activity and appears to be potentially useful for treating mitochondrial disease.
KW - Apomorphine
KW - Inflammation
KW - Mammalian target of rapamycin (mTOR)
KW - Mitochondrial disease
KW - Mitochondrial respiratory activity
KW - Oxidative stress
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U2 - 10.1016/j.mito.2019.07.006
DO - 10.1016/j.mito.2019.07.006
M3 - Article
C2 - 31356884
AN - SCOPUS:85073705791
VL - 49
SP - 111
EP - 120
JO - Mitochondrion
JF - Mitochondrion
SN - 1567-7249
ER -