Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress

Yoshiyuki Ikeda, Akihiro Shirakabe, Yasuhiro Maejima, Peiyong Zhai, Sebastiano Sciarretta, Jessica Toli, Masatoshi Nomura, Katsuyoshi Mihara, Kensuke Egashira, Mitsuru Ohishi, Maha Abdellatif, Junichi Sadoshima

研究成果: ジャーナルへの寄稿記事

169 引用 (Scopus)

抄録

RATIONALE:: Both fusion and fission contribute to mitochondrial quality control. How unopposed fusion affects survival of cardiomyocytes and left ventricular function in the heart is poorly understood. OBJECTIVE:: We investigated the role of dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission, in mediating mitochondrial autophagy, ventricular function, and stress resistance in the heart. METHODS AND RESULTS:: Drp1 downregulation induced mitochondrial elongation, accumulation of damaged mitochondria, and increased apoptosis in cardiomyocytes at baseline. Drp1 downregulation also suppressed autophagosome formation and autophagic flux at baseline and in response to glucose deprivation in cardiomyocytes. The lack of lysosomal translocation of mitochondrially targeted Keima indicates that Drp1 downregulation suppressed mitochondrial autophagy. Mitochondrial elongation and accumulation of damaged mitochondria were also observed in tamoxifen-inducible cardiac-specific Drp1 knockout mice. After Drp1 downregulation, cardiac-specific Drp1 knockout mice developed left ventricular dysfunction, preceded by mitochondrial dysfunction, and died within 13 weeks. Autophagic flux is significantly suppressed in cardiac-specific Drp1 knockout mice. Although left ventricular function in cardiac-specific Drp1 heterozygous knockout mice was normal at 12 weeks of age, left ventricular function decreased more severely after 48 hours of fasting, and the infarct size/area at risk after ischemia/reperfusion was significantly greater in cardiac-specific Drp1 heterozygous knockout than in control mice. CONCLUSIONS:: Disruption of Drp1 induces mitochondrial elongation, inhibits mitochondrial autophagy, and causes mitochondrial dysfunction, thereby promoting cardiac dysfunction and increased susceptibility to ischemia/reperfusion.

元の言語英語
ページ(範囲)264-278
ページ数15
ジャーナルCirculation research
116
発行部数2
DOI
出版物ステータス出版済み - 1 16 2015

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Dynamins
Autophagy
Proteins
Knockout Mice
Down-Regulation
Left Ventricular Function
Cardiac Myocytes
Reperfusion
Mitochondria
Ischemia
Mitochondrial Dynamics
Ventricular Function
GTP Phosphohydrolases
Left Ventricular Dysfunction
Tamoxifen
Quality Control
Fasting

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

これを引用

Ikeda, Y., Shirakabe, A., Maejima, Y., Zhai, P., Sciarretta, S., Toli, J., ... Sadoshima, J. (2015). Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circulation research, 116(2), 264-278. https://doi.org/10.1161/CIRCRESAHA.116.303356

Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. / Ikeda, Yoshiyuki; Shirakabe, Akihiro; Maejima, Yasuhiro; Zhai, Peiyong; Sciarretta, Sebastiano; Toli, Jessica; Nomura, Masatoshi; Mihara, Katsuyoshi; Egashira, Kensuke; Ohishi, Mitsuru; Abdellatif, Maha; Sadoshima, Junichi.

:: Circulation research, 巻 116, 番号 2, 16.01.2015, p. 264-278.

研究成果: ジャーナルへの寄稿記事

Ikeda, Y, Shirakabe, A, Maejima, Y, Zhai, P, Sciarretta, S, Toli, J, Nomura, M, Mihara, K, Egashira, K, Ohishi, M, Abdellatif, M & Sadoshima, J 2015, 'Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress', Circulation research, 巻. 116, 番号 2, pp. 264-278. https://doi.org/10.1161/CIRCRESAHA.116.303356
Ikeda, Yoshiyuki ; Shirakabe, Akihiro ; Maejima, Yasuhiro ; Zhai, Peiyong ; Sciarretta, Sebastiano ; Toli, Jessica ; Nomura, Masatoshi ; Mihara, Katsuyoshi ; Egashira, Kensuke ; Ohishi, Mitsuru ; Abdellatif, Maha ; Sadoshima, Junichi. / Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. :: Circulation research. 2015 ; 巻 116, 番号 2. pp. 264-278.
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abstract = "RATIONALE:: Both fusion and fission contribute to mitochondrial quality control. How unopposed fusion affects survival of cardiomyocytes and left ventricular function in the heart is poorly understood. OBJECTIVE:: We investigated the role of dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission, in mediating mitochondrial autophagy, ventricular function, and stress resistance in the heart. METHODS AND RESULTS:: Drp1 downregulation induced mitochondrial elongation, accumulation of damaged mitochondria, and increased apoptosis in cardiomyocytes at baseline. Drp1 downregulation also suppressed autophagosome formation and autophagic flux at baseline and in response to glucose deprivation in cardiomyocytes. The lack of lysosomal translocation of mitochondrially targeted Keima indicates that Drp1 downregulation suppressed mitochondrial autophagy. Mitochondrial elongation and accumulation of damaged mitochondria were also observed in tamoxifen-inducible cardiac-specific Drp1 knockout mice. After Drp1 downregulation, cardiac-specific Drp1 knockout mice developed left ventricular dysfunction, preceded by mitochondrial dysfunction, and died within 13 weeks. Autophagic flux is significantly suppressed in cardiac-specific Drp1 knockout mice. Although left ventricular function in cardiac-specific Drp1 heterozygous knockout mice was normal at 12 weeks of age, left ventricular function decreased more severely after 48 hours of fasting, and the infarct size/area at risk after ischemia/reperfusion was significantly greater in cardiac-specific Drp1 heterozygous knockout than in control mice. CONCLUSIONS:: Disruption of Drp1 induces mitochondrial elongation, inhibits mitochondrial autophagy, and causes mitochondrial dysfunction, thereby promoting cardiac dysfunction and increased susceptibility to ischemia/reperfusion.",
author = "Yoshiyuki Ikeda and Akihiro Shirakabe and Yasuhiro Maejima and Peiyong Zhai and Sebastiano Sciarretta and Jessica Toli and Masatoshi Nomura and Katsuyoshi Mihara and Kensuke Egashira and Mitsuru Ohishi and Maha Abdellatif and Junichi Sadoshima",
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T1 - Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress

AU - Ikeda, Yoshiyuki

AU - Shirakabe, Akihiro

AU - Maejima, Yasuhiro

AU - Zhai, Peiyong

AU - Sciarretta, Sebastiano

AU - Toli, Jessica

AU - Nomura, Masatoshi

AU - Mihara, Katsuyoshi

AU - Egashira, Kensuke

AU - Ohishi, Mitsuru

AU - Abdellatif, Maha

AU - Sadoshima, Junichi

PY - 2015/1/16

Y1 - 2015/1/16

N2 - RATIONALE:: Both fusion and fission contribute to mitochondrial quality control. How unopposed fusion affects survival of cardiomyocytes and left ventricular function in the heart is poorly understood. OBJECTIVE:: We investigated the role of dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission, in mediating mitochondrial autophagy, ventricular function, and stress resistance in the heart. METHODS AND RESULTS:: Drp1 downregulation induced mitochondrial elongation, accumulation of damaged mitochondria, and increased apoptosis in cardiomyocytes at baseline. Drp1 downregulation also suppressed autophagosome formation and autophagic flux at baseline and in response to glucose deprivation in cardiomyocytes. The lack of lysosomal translocation of mitochondrially targeted Keima indicates that Drp1 downregulation suppressed mitochondrial autophagy. Mitochondrial elongation and accumulation of damaged mitochondria were also observed in tamoxifen-inducible cardiac-specific Drp1 knockout mice. After Drp1 downregulation, cardiac-specific Drp1 knockout mice developed left ventricular dysfunction, preceded by mitochondrial dysfunction, and died within 13 weeks. Autophagic flux is significantly suppressed in cardiac-specific Drp1 knockout mice. Although left ventricular function in cardiac-specific Drp1 heterozygous knockout mice was normal at 12 weeks of age, left ventricular function decreased more severely after 48 hours of fasting, and the infarct size/area at risk after ischemia/reperfusion was significantly greater in cardiac-specific Drp1 heterozygous knockout than in control mice. CONCLUSIONS:: Disruption of Drp1 induces mitochondrial elongation, inhibits mitochondrial autophagy, and causes mitochondrial dysfunction, thereby promoting cardiac dysfunction and increased susceptibility to ischemia/reperfusion.

AB - RATIONALE:: Both fusion and fission contribute to mitochondrial quality control. How unopposed fusion affects survival of cardiomyocytes and left ventricular function in the heart is poorly understood. OBJECTIVE:: We investigated the role of dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission, in mediating mitochondrial autophagy, ventricular function, and stress resistance in the heart. METHODS AND RESULTS:: Drp1 downregulation induced mitochondrial elongation, accumulation of damaged mitochondria, and increased apoptosis in cardiomyocytes at baseline. Drp1 downregulation also suppressed autophagosome formation and autophagic flux at baseline and in response to glucose deprivation in cardiomyocytes. The lack of lysosomal translocation of mitochondrially targeted Keima indicates that Drp1 downregulation suppressed mitochondrial autophagy. Mitochondrial elongation and accumulation of damaged mitochondria were also observed in tamoxifen-inducible cardiac-specific Drp1 knockout mice. After Drp1 downregulation, cardiac-specific Drp1 knockout mice developed left ventricular dysfunction, preceded by mitochondrial dysfunction, and died within 13 weeks. Autophagic flux is significantly suppressed in cardiac-specific Drp1 knockout mice. Although left ventricular function in cardiac-specific Drp1 heterozygous knockout mice was normal at 12 weeks of age, left ventricular function decreased more severely after 48 hours of fasting, and the infarct size/area at risk after ischemia/reperfusion was significantly greater in cardiac-specific Drp1 heterozygous knockout than in control mice. CONCLUSIONS:: Disruption of Drp1 induces mitochondrial elongation, inhibits mitochondrial autophagy, and causes mitochondrial dysfunction, thereby promoting cardiac dysfunction and increased susceptibility to ischemia/reperfusion.

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JF - Circulation Research

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