Depolysulfidation of Drp1 induced by low-dose methylmercury exposure increases cardiac vulnerability to hemodynamic overload

Akiyuki Nishimura, Kakeru Shimoda, Tomohiro Tanaka, Takashi Toyama, Kazuhiro Nishiyama, Yasuhiro Shinkai, Takuro Numaga-Tomita, Daiju Yamazaki, Yasunari Kanda, Takaaki Akaike, Yoshito Kumagai, Motohiro Nishida

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Chronic exposure to methylmercury (MeHg), an environmental electrophilic pollutant, reportedly increases the risk of human cardiac events. We report that exposure to a low, non-neurotoxic dose of MeHg precipitated heart failure induced by pressure overload in mice. Exposure to MeHg at 10 ppm did not induce weight loss typical of higher doses but caused mitochondrial hyperfission in myocardium through the activation of Drp1 by its guanine nucleotide exchange factor filamin-A. Treatment of neonatal rat cardiomyocytes with cilnidipine, an inhibitor of the interaction between Drp1 and filamin-A, suppressed mitochondrial hyperfission caused by low-dose MeHg exposure. Modification of cysteine residues in proteins with polysulfides is important for redox signaling and mitochondrial homeostasis in mammalian cells. We found that MeHg targeted rat Drp1 at Cys624, a redox-sensitive residue whose SH side chain forms a bulky and nucleophilic polysulfide (Cys624-S(n)H). MeHg exposure induced the depolysulfidation of Cys624-S(n)H in Drp1, which led to filamin-dependent activation of Drp1 and mitochondrial hyperfission. Treatment with NaHS, which acts as a donor for reactive polysulfides, reversed MeHg-evoked Drp1 depolysulfidation and vulnerability to mechanical load in rodent and human cardiomyocytes and mouse hearts. These results suggest that depolysulfidation of Drp1 at Cys624-S(n)H by low-dose MeHg increases cardiac fragility to mechanical load through filamin-dependent mitochondrial hyperfission.

元の言語英語
記事番号eaaw1920
ジャーナルScience Signaling
12
発行部数587
DOI
出版物ステータス出版済み - 2019

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Nishimura, A., Shimoda, K., Tanaka, T., Toyama, T., Nishiyama, K., Shinkai, Y., Numaga-Tomita, T., Yamazaki, D., Kanda, Y., Akaike, T., Kumagai, Y., & Nishida, M. (2019). Depolysulfidation of Drp1 induced by low-dose methylmercury exposure increases cardiac vulnerability to hemodynamic overload. Science Signaling, 12(587), [eaaw1920]. https://doi.org/10.1126/scisignal.aaw1920