@article{oai:repo.qst.go.jp:00046258,
 author = {Yoshii, Yukie and Yoneda, Makoto and Ikawa, Masamichi and Furukawa, Takako and Kiyono, Yasushi and Mori, Tetsuya and Yoshii, Hiroshi and Oyama, Nobuyuki and Okazawa, Hidehiko and Saga, Tsuneo and Fujibayashi, Yasuhisa and 吉井 幸恵 and 古川 高子 and 清野 泰 and 吉井 裕 and 佐賀 恒夫 and 藤林 康久},
 issue = {12},
 journal = {Nuclear Medicine and Biology},
 month = {Oct},
 note = {Objectives
Radiolabeled Cu-diacetyl-bis (N4-methylthiosemicarbazone) ('Cu-ATSM), including 60/62/64Cu-ATSM, is a potential imaging agent of hypoxic tumors for positron emission tomography (PET). We have reported that 'Cu-ATSM is trapped in tumor cells under intracellular overreduced states, e.g., hypoxia. Here we evaluated 'Cu-ATSM as an indicator of intracellular overreduced states in mitochondrial disorders using cell lines with mitochondrial dysfunction.
\nMethods
Mitochondrial DNA-less p0206 cells; the parental 143B human osteosarcoma cells; the cybrids carrying mutated mitochondria from a patient of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) (2SD); and that carrying wild-type one (2SA) were used. Cells were treated under normoxia or hypoxia, and 64Cu-ATSM uptake was examined to compare it with levels of biological reductant NADH and NADPH.
\nResults
p0206 cells showed higher 64Cu-ATSM uptake than control 143B cells under normoxia, whereas 64Cu-ATSM uptake was not significantly increased under hypoxia in p0206 cells. Additionally, 64Cu-ATSM uptake showed correlate change to the NADH and NADPH levels, but not oxygenic conditions. 2SD cells showed increased 64Cu-ATSM uptake under normoxia as compared with the control 2SA, and 64Cu-ATSM uptake followed NADH and NADPH levels, but not oxygenic conditions.
\nConclusions
64Cu-ATSM accumulated in cells with overreduced states due to mitochondrial dysfunction, even under normoxia. We recently reported that 62Cu-ATSM-PET can visualize stroke-like episodes maintaining oxygen supply in MELAS patients. Taken together, our data indicate that 'Cu-ATSM uptake reflects overreduced intracellular states, despite oxygenic conditions; thus, 'Cu-ATSM would be a promising marker of intracellular overreduced states for disorders with mitochondrial dysfunction, such as MELAS, Parkinson's disease and Alzheimer's disease.
\nAbbreviations: Cu-ATSM, Cu-diacetyl-bis (N4-methylthiosemicarbazone); MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; mtDNA, mitochondrial DNA; PET, positron emission tomography},
 pages = {177--185},
 title = {Radiolabeled Cu-ATSM as a novel indicator of overreduced intracellular state due to mitochondrial dysfunction: studies with mitochondrial DNA-less p0  cells and cybrids carrying MELAS mitochondrial DNA mutation},
 volume = {39},
 year = {2011}
}