Overexpression of TFAM or twinkle increases mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress

Masataka Ikeda, Tomomi Ide, Takeo Fujino, Shinobu Arai, Keita Saku, Takamori Kakino, Henna Tyynismaa, Toshihide Yamasaki, Ken Ichi Yamada, Dongchon Kang, Anu Suomalainen, Kenji Sunagawa

研究成果: ジャーナルへの寄稿記事

49 引用 (Scopus)

抄録

Background: Mitochondrial DNA (mtDNA) copy number decreases in animal and human heart failure (HF), yet its role in cardiomyocytes remains to be elucidated. Thus, we investigated the cardioprotective function of increased mtDNA copy number resulting from the overexpression of human transcription factor A of mitochondria (TFAM) or Twinkle helicase in volume overload (VO)-induced HF. Methods and Results: Two strains of transgenic (TG) mice, one overexpressing TFAM and the other overexpressing Twinkle helicase, exhibit an approximately 2-fold equivalent increase in mtDNA copy number in heart. These TG mice display similar attenuations in eccentric hypertrophy and improved cardiac function compared to wild-type (WT) mice without any deterioration of mitochondrial enzymatic activities in response to VO, which was accompanied by a reduction in matrix-metalloproteinase (MMP) activity and reactive oxygen species after 8 weeks of VO. Moreover, acute VO-induced MMP-2 and MMP-9 upregulation was also suppressed at 24 h in both TG mice. In isolated rat cardiomyocytes, mitochondrial reactive oxygen species (mitoROS) upregulated MMP-2 and MMP-9 expression, and human TFAM (hTFAM) overexpression suppressed mitoROS and their upregulation. Additionally, mitoROS were equally suppressed in H9c2 rat cardiomyoblasts that overexpress hTFAM or rat Twinkle, both of which exhibit increased mtDNA copy number. Furthermore, mitoROS and mitochondrial protein oxidation from both TG mice were suppressed compared toWT mice. Conclusions: The overexpression of TFAM or Twinkle results in increased mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress. Our findings suggest that increasing mtDNA copy number could be a useful therapeutic strategy to target mitoROS in HF.

元の言語英語
記事番号e0119687
ジャーナルPloS one
10
発行部数3
DOI
出版物ステータス出版済み - 3 30 2015

Fingerprint

Mitochondria
Oxidative stress
Mitochondrial DNA
reactive oxygen species
Reactive Oxygen Species
Oxidative Stress
mitochondria
mitochondrial DNA
Transcription Factors
oxidative stress
transcription factors
Transgenic Mice
mice
heart failure
genetically modified organisms
Rats
gelatinase A
gelatinase B
Heart Failure
Matrix Metalloproteinase 2

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

これを引用

Overexpression of TFAM or twinkle increases mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress. / Ikeda, Masataka; Ide, Tomomi; Fujino, Takeo; Arai, Shinobu; Saku, Keita; Kakino, Takamori; Tyynismaa, Henna; Yamasaki, Toshihide; Yamada, Ken Ichi; Kang, Dongchon; Suomalainen, Anu; Sunagawa, Kenji.

:: PloS one, 巻 10, 番号 3, e0119687, 30.03.2015.

研究成果: ジャーナルへの寄稿記事

Ikeda, Masataka ; Ide, Tomomi ; Fujino, Takeo ; Arai, Shinobu ; Saku, Keita ; Kakino, Takamori ; Tyynismaa, Henna ; Yamasaki, Toshihide ; Yamada, Ken Ichi ; Kang, Dongchon ; Suomalainen, Anu ; Sunagawa, Kenji. / Overexpression of TFAM or twinkle increases mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress. :: PloS one. 2015 ; 巻 10, 番号 3.
@article{906e059ed11048818a7c215c0260cff1,
title = "Overexpression of TFAM or twinkle increases mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress",
abstract = "Background: Mitochondrial DNA (mtDNA) copy number decreases in animal and human heart failure (HF), yet its role in cardiomyocytes remains to be elucidated. Thus, we investigated the cardioprotective function of increased mtDNA copy number resulting from the overexpression of human transcription factor A of mitochondria (TFAM) or Twinkle helicase in volume overload (VO)-induced HF. Methods and Results: Two strains of transgenic (TG) mice, one overexpressing TFAM and the other overexpressing Twinkle helicase, exhibit an approximately 2-fold equivalent increase in mtDNA copy number in heart. These TG mice display similar attenuations in eccentric hypertrophy and improved cardiac function compared to wild-type (WT) mice without any deterioration of mitochondrial enzymatic activities in response to VO, which was accompanied by a reduction in matrix-metalloproteinase (MMP) activity and reactive oxygen species after 8 weeks of VO. Moreover, acute VO-induced MMP-2 and MMP-9 upregulation was also suppressed at 24 h in both TG mice. In isolated rat cardiomyocytes, mitochondrial reactive oxygen species (mitoROS) upregulated MMP-2 and MMP-9 expression, and human TFAM (hTFAM) overexpression suppressed mitoROS and their upregulation. Additionally, mitoROS were equally suppressed in H9c2 rat cardiomyoblasts that overexpress hTFAM or rat Twinkle, both of which exhibit increased mtDNA copy number. Furthermore, mitoROS and mitochondrial protein oxidation from both TG mice were suppressed compared toWT mice. Conclusions: The overexpression of TFAM or Twinkle results in increased mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress. Our findings suggest that increasing mtDNA copy number could be a useful therapeutic strategy to target mitoROS in HF.",
author = "Masataka Ikeda and Tomomi Ide and Takeo Fujino and Shinobu Arai and Keita Saku and Takamori Kakino and Henna Tyynismaa and Toshihide Yamasaki and Yamada, {Ken Ichi} and Dongchon Kang and Anu Suomalainen and Kenji Sunagawa",
year = "2015",
month = "3",
day = "30",
doi = "10.1371/journal.pone.0119687",
language = "English",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "3",

}

TY - JOUR

T1 - Overexpression of TFAM or twinkle increases mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress

AU - Ikeda, Masataka

AU - Ide, Tomomi

AU - Fujino, Takeo

AU - Arai, Shinobu

AU - Saku, Keita

AU - Kakino, Takamori

AU - Tyynismaa, Henna

AU - Yamasaki, Toshihide

AU - Yamada, Ken Ichi

AU - Kang, Dongchon

AU - Suomalainen, Anu

AU - Sunagawa, Kenji

PY - 2015/3/30

Y1 - 2015/3/30

N2 - Background: Mitochondrial DNA (mtDNA) copy number decreases in animal and human heart failure (HF), yet its role in cardiomyocytes remains to be elucidated. Thus, we investigated the cardioprotective function of increased mtDNA copy number resulting from the overexpression of human transcription factor A of mitochondria (TFAM) or Twinkle helicase in volume overload (VO)-induced HF. Methods and Results: Two strains of transgenic (TG) mice, one overexpressing TFAM and the other overexpressing Twinkle helicase, exhibit an approximately 2-fold equivalent increase in mtDNA copy number in heart. These TG mice display similar attenuations in eccentric hypertrophy and improved cardiac function compared to wild-type (WT) mice without any deterioration of mitochondrial enzymatic activities in response to VO, which was accompanied by a reduction in matrix-metalloproteinase (MMP) activity and reactive oxygen species after 8 weeks of VO. Moreover, acute VO-induced MMP-2 and MMP-9 upregulation was also suppressed at 24 h in both TG mice. In isolated rat cardiomyocytes, mitochondrial reactive oxygen species (mitoROS) upregulated MMP-2 and MMP-9 expression, and human TFAM (hTFAM) overexpression suppressed mitoROS and their upregulation. Additionally, mitoROS were equally suppressed in H9c2 rat cardiomyoblasts that overexpress hTFAM or rat Twinkle, both of which exhibit increased mtDNA copy number. Furthermore, mitoROS and mitochondrial protein oxidation from both TG mice were suppressed compared toWT mice. Conclusions: The overexpression of TFAM or Twinkle results in increased mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress. Our findings suggest that increasing mtDNA copy number could be a useful therapeutic strategy to target mitoROS in HF.

AB - Background: Mitochondrial DNA (mtDNA) copy number decreases in animal and human heart failure (HF), yet its role in cardiomyocytes remains to be elucidated. Thus, we investigated the cardioprotective function of increased mtDNA copy number resulting from the overexpression of human transcription factor A of mitochondria (TFAM) or Twinkle helicase in volume overload (VO)-induced HF. Methods and Results: Two strains of transgenic (TG) mice, one overexpressing TFAM and the other overexpressing Twinkle helicase, exhibit an approximately 2-fold equivalent increase in mtDNA copy number in heart. These TG mice display similar attenuations in eccentric hypertrophy and improved cardiac function compared to wild-type (WT) mice without any deterioration of mitochondrial enzymatic activities in response to VO, which was accompanied by a reduction in matrix-metalloproteinase (MMP) activity and reactive oxygen species after 8 weeks of VO. Moreover, acute VO-induced MMP-2 and MMP-9 upregulation was also suppressed at 24 h in both TG mice. In isolated rat cardiomyocytes, mitochondrial reactive oxygen species (mitoROS) upregulated MMP-2 and MMP-9 expression, and human TFAM (hTFAM) overexpression suppressed mitoROS and their upregulation. Additionally, mitoROS were equally suppressed in H9c2 rat cardiomyoblasts that overexpress hTFAM or rat Twinkle, both of which exhibit increased mtDNA copy number. Furthermore, mitoROS and mitochondrial protein oxidation from both TG mice were suppressed compared toWT mice. Conclusions: The overexpression of TFAM or Twinkle results in increased mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress. Our findings suggest that increasing mtDNA copy number could be a useful therapeutic strategy to target mitoROS in HF.

UR - http://www.scopus.com/inward/record.url?scp=84926382602&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84926382602&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0119687

DO - 10.1371/journal.pone.0119687

M3 - Article

C2 - 25822152

AN - SCOPUS:84926382602

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 3

M1 - e0119687

ER -