In vivo real‐time ATP imaging in zebrafish hearts reveals G0s2 induces ischemic tolerance

Most eukaryotic cells generate adenosine triphosphate (ATP) through the oxidative phosphorylation system (OXPHOS) to support cellular activities. In cultured cell‐based experiments, we recently identified the hypoxia‐inducible protein G0/G1 switch gene 2 (G0s2) as a positive regulator of OXPHOS, and...

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Bibliographic Details
Published in:The FASEB journal 2020-02, Vol.34 (2), p.2041-2054
Main Authors: Kioka, Hidetaka, Kato, Hisakazu, Fujita, Takeshi, Asano, Yoshihiro, Shintani, Yasunori, Yamazaki, Satoru, Tsukamoto, Osamu, Imamura, Hiromi, Kogo, Mikihiko, Kitakaze, Masafumi, Sakata, Yasushi, Takashima, Seiji
Format: Article
Language:English
Subjects:
ATP
energy metabolism
FRET
in vivo imaging
ischemic tolerance
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Summary:Most eukaryotic cells generate adenosine triphosphate (ATP) through the oxidative phosphorylation system (OXPHOS) to support cellular activities. In cultured cell‐based experiments, we recently identified the hypoxia‐inducible protein G0/G1 switch gene 2 (G0s2) as a positive regulator of OXPHOS, and showed that G0s2 protects cultured cardiomyocytes from hypoxia. In this study, we examined the in vivo protective role of G0s2 against hypoxia by generating both loss‐of‐function and gain‐of‐function models of g0s2 in zebrafish. Zebrafish harboring transcription activator‐like effector nuclease (TALEN)‐mediated knockout of g0s2 lost hypoxic tolerance. Conversely, cardiomyocyte‐specific transgenic zebrafish hearts exhibited strong tolerance against hypoxia. To clarify the mechanism by which G0s2 protects cardiac function under hypoxia, we introduced a mitochondrially targeted FRET‐based ATP biosensor into zebrafish heart to visualize ATP dynamics in in vivo beating hearts. In addition, we employed a mosaic overexpression model of g0s2 to compare the contraction and ATP dynamics between g0s2‐expressing and non‐expressing cardiomyocytes, side‐by‐side within the same heart. These techniques revealed that g0s2‐expressing cardiomyocyte populations exhibited preserved contractility coupled with maintained intra‐mitochondrial ATP concentrations even under hypoxic condition. Collectively, these results demonstrate that G0s2 provides ischemic tolerance in vivo by maintaining ATP production, and therefore represents a promising therapeutic target for hypoxia‐related diseases.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.201901686R