Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart

Jin Endo, Motoaki Sano, Takaharu Katayama, Takako Hishiki, Ken Shinmura, Shintaro Morizane, Tomohiro Matsuhashi, Yoshinori Katsumata, Yan Zhang, Hideyuki Ito, Yoshiko Nagahata, Satori Marchitti, Kiyomi Nishimaki, Alexander Martin Wolf, Hiroki Nakanishi, Fumiyuki Hattori, Vasilis Vasiliou, Takeshi Adachi, Ikuroh Ohsawa, Ryo Taguchi & 5 others Yoshio Hirabayashi, Shigeo Ohta, Makoto Suematsu, Satoshi Ogawa, Keiichi Fukuda

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

RATIONALE:: Aldehyde accumulation is regarded as a pathognomonic feature of oxidative stress-associated cardiovascular disease. OBJECTIVE:: We investigated how the heart compensates for the accelerated accumulation of aldehydes. METHODS AND RESULTS:: Aldehyde dehydrogenase 2 (ALDH2) has a major role in aldehyde detoxification in the mitochondria, a major source of aldehydes. Transgenic (Tg) mice carrying an Aldh2 gene with a single nucleotide polymorphism (Aldh2*2) were developed. This polymorphism has a dominant-negative effect and the Tg mice exhibited impaired ALDH activity against a broad range of aldehydes. Despite a shift toward the oxidative state in mitochondrial matrices, Aldh2*2 Tg hearts displayed normal left ventricular function by echocardiography and, because of metabolic remodeling, an unexpected tolerance to oxidative stress induced by ischemia/reperfusion injury. Mitochondrial aldehyde stress stimulated eukaryotic translation initiation factor 2α phosphorylation. Subsequent translational and transcriptional activation of activating transcription factor-4 promoted the expression of enzymes involved in amino acid biosynthesis and transport, ultimately providing precursor amino acids for glutathione biosynthesis. Intracellular glutathione levels were increased 1.37-fold in Aldh2*2 Tg hearts compared with wild-type controls. Heterozygous knockout of Atf4 blunted the increase in intracellular glutathione levels in Aldh2*2 Tg hearts, thereby attenuating the oxidative stress-resistant phenotype. Furthermore, glycolysis and NADPH generation via the pentose phosphate pathway were activated in Aldh2*2 Tg hearts. (NADPH is required for the recycling of oxidized glutathione.) CONCLUSIONS:: The findings of the present study indicate that mitochondrial aldehyde stress in the heart induces metabolic remodeling, leading to activation of the glutathione-redox cycle, which confers resistance against acute oxidative stress induced by ischemia/reperfusion.

Original languageEnglish
Pages (from-to)1118-1127
Number of pages10
JournalCirculation Research
Volume105
Issue number11
DOIs
Publication statusPublished - 2009 Nov

Fingerprint

Aldehydes
Oxidative Stress
Glutathione
NADP
Transgenic Mice
Activating Transcription Factor 4
Eukaryotic Initiation Factor-2
Eukaryotic Initiation Factors
Amino Acids
Pentose Phosphate Pathway
Aldehyde Dehydrogenase
Glutathione Disulfide
Recycling
Glycolysis
Reperfusion Injury
Left Ventricular Function
Transcriptional Activation
Reperfusion
Oxidation-Reduction
Single Nucleotide Polymorphism

Keywords

  • Aldehyde
  • Cardiac metabolism
  • Oxidative stress
  • Stress response

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart. / Endo, Jin; Sano, Motoaki; Katayama, Takaharu; Hishiki, Takako; Shinmura, Ken; Morizane, Shintaro; Matsuhashi, Tomohiro; Katsumata, Yoshinori; Zhang, Yan; Ito, Hideyuki; Nagahata, Yoshiko; Marchitti, Satori; Nishimaki, Kiyomi; Wolf, Alexander Martin; Nakanishi, Hiroki; Hattori, Fumiyuki; Vasiliou, Vasilis; Adachi, Takeshi; Ohsawa, Ikuroh; Taguchi, Ryo; Hirabayashi, Yoshio; Ohta, Shigeo; Suematsu, Makoto; Ogawa, Satoshi; Fukuda, Keiichi.

In: Circulation Research, Vol. 105, No. 11, 11.2009, p. 1118-1127.

Research output: Contribution to journalArticle

Endo, J, Sano, M, Katayama, T, Hishiki, T, Shinmura, K, Morizane, S, Matsuhashi, T, Katsumata, Y, Zhang, Y, Ito, H, Nagahata, Y, Marchitti, S, Nishimaki, K, Wolf, AM, Nakanishi, H, Hattori, F, Vasiliou, V, Adachi, T, Ohsawa, I, Taguchi, R, Hirabayashi, Y, Ohta, S, Suematsu, M, Ogawa, S & Fukuda, K 2009, 'Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart', Circulation Research, vol. 105, no. 11, pp. 1118-1127. https://doi.org/10.1161/CIRCRESAHA.109.206607
Endo, Jin ; Sano, Motoaki ; Katayama, Takaharu ; Hishiki, Takako ; Shinmura, Ken ; Morizane, Shintaro ; Matsuhashi, Tomohiro ; Katsumata, Yoshinori ; Zhang, Yan ; Ito, Hideyuki ; Nagahata, Yoshiko ; Marchitti, Satori ; Nishimaki, Kiyomi ; Wolf, Alexander Martin ; Nakanishi, Hiroki ; Hattori, Fumiyuki ; Vasiliou, Vasilis ; Adachi, Takeshi ; Ohsawa, Ikuroh ; Taguchi, Ryo ; Hirabayashi, Yoshio ; Ohta, Shigeo ; Suematsu, Makoto ; Ogawa, Satoshi ; Fukuda, Keiichi. / Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart. In: Circulation Research. 2009 ; Vol. 105, No. 11. pp. 1118-1127.
@article{eb689295b306433c831adcb8378abd60,
title = "Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart",
abstract = "RATIONALE:: Aldehyde accumulation is regarded as a pathognomonic feature of oxidative stress-associated cardiovascular disease. OBJECTIVE:: We investigated how the heart compensates for the accelerated accumulation of aldehydes. METHODS AND RESULTS:: Aldehyde dehydrogenase 2 (ALDH2) has a major role in aldehyde detoxification in the mitochondria, a major source of aldehydes. Transgenic (Tg) mice carrying an Aldh2 gene with a single nucleotide polymorphism (Aldh2*2) were developed. This polymorphism has a dominant-negative effect and the Tg mice exhibited impaired ALDH activity against a broad range of aldehydes. Despite a shift toward the oxidative state in mitochondrial matrices, Aldh2*2 Tg hearts displayed normal left ventricular function by echocardiography and, because of metabolic remodeling, an unexpected tolerance to oxidative stress induced by ischemia/reperfusion injury. Mitochondrial aldehyde stress stimulated eukaryotic translation initiation factor 2α phosphorylation. Subsequent translational and transcriptional activation of activating transcription factor-4 promoted the expression of enzymes involved in amino acid biosynthesis and transport, ultimately providing precursor amino acids for glutathione biosynthesis. Intracellular glutathione levels were increased 1.37-fold in Aldh2*2 Tg hearts compared with wild-type controls. Heterozygous knockout of Atf4 blunted the increase in intracellular glutathione levels in Aldh2*2 Tg hearts, thereby attenuating the oxidative stress-resistant phenotype. Furthermore, glycolysis and NADPH generation via the pentose phosphate pathway were activated in Aldh2*2 Tg hearts. (NADPH is required for the recycling of oxidized glutathione.) CONCLUSIONS:: The findings of the present study indicate that mitochondrial aldehyde stress in the heart induces metabolic remodeling, leading to activation of the glutathione-redox cycle, which confers resistance against acute oxidative stress induced by ischemia/reperfusion.",
keywords = "Aldehyde, Cardiac metabolism, Oxidative stress, Stress response",
author = "Jin Endo and Motoaki Sano and Takaharu Katayama and Takako Hishiki and Ken Shinmura and Shintaro Morizane and Tomohiro Matsuhashi and Yoshinori Katsumata and Yan Zhang and Hideyuki Ito and Yoshiko Nagahata and Satori Marchitti and Kiyomi Nishimaki and Wolf, {Alexander Martin} and Hiroki Nakanishi and Fumiyuki Hattori and Vasilis Vasiliou and Takeshi Adachi and Ikuroh Ohsawa and Ryo Taguchi and Yoshio Hirabayashi and Shigeo Ohta and Makoto Suematsu and Satoshi Ogawa and Keiichi Fukuda",
year = "2009",
month = "11",
doi = "10.1161/CIRCRESAHA.109.206607",
language = "English",
volume = "105",
pages = "1118--1127",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "11",

}

TY - JOUR

T1 - Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart

AU - Endo, Jin

AU - Sano, Motoaki

AU - Katayama, Takaharu

AU - Hishiki, Takako

AU - Shinmura, Ken

AU - Morizane, Shintaro

AU - Matsuhashi, Tomohiro

AU - Katsumata, Yoshinori

AU - Zhang, Yan

AU - Ito, Hideyuki

AU - Nagahata, Yoshiko

AU - Marchitti, Satori

AU - Nishimaki, Kiyomi

AU - Wolf, Alexander Martin

AU - Nakanishi, Hiroki

AU - Hattori, Fumiyuki

AU - Vasiliou, Vasilis

AU - Adachi, Takeshi

AU - Ohsawa, Ikuroh

AU - Taguchi, Ryo

AU - Hirabayashi, Yoshio

AU - Ohta, Shigeo

AU - Suematsu, Makoto

AU - Ogawa, Satoshi

AU - Fukuda, Keiichi

PY - 2009/11

Y1 - 2009/11

N2 - RATIONALE:: Aldehyde accumulation is regarded as a pathognomonic feature of oxidative stress-associated cardiovascular disease. OBJECTIVE:: We investigated how the heart compensates for the accelerated accumulation of aldehydes. METHODS AND RESULTS:: Aldehyde dehydrogenase 2 (ALDH2) has a major role in aldehyde detoxification in the mitochondria, a major source of aldehydes. Transgenic (Tg) mice carrying an Aldh2 gene with a single nucleotide polymorphism (Aldh2*2) were developed. This polymorphism has a dominant-negative effect and the Tg mice exhibited impaired ALDH activity against a broad range of aldehydes. Despite a shift toward the oxidative state in mitochondrial matrices, Aldh2*2 Tg hearts displayed normal left ventricular function by echocardiography and, because of metabolic remodeling, an unexpected tolerance to oxidative stress induced by ischemia/reperfusion injury. Mitochondrial aldehyde stress stimulated eukaryotic translation initiation factor 2α phosphorylation. Subsequent translational and transcriptional activation of activating transcription factor-4 promoted the expression of enzymes involved in amino acid biosynthesis and transport, ultimately providing precursor amino acids for glutathione biosynthesis. Intracellular glutathione levels were increased 1.37-fold in Aldh2*2 Tg hearts compared with wild-type controls. Heterozygous knockout of Atf4 blunted the increase in intracellular glutathione levels in Aldh2*2 Tg hearts, thereby attenuating the oxidative stress-resistant phenotype. Furthermore, glycolysis and NADPH generation via the pentose phosphate pathway were activated in Aldh2*2 Tg hearts. (NADPH is required for the recycling of oxidized glutathione.) CONCLUSIONS:: The findings of the present study indicate that mitochondrial aldehyde stress in the heart induces metabolic remodeling, leading to activation of the glutathione-redox cycle, which confers resistance against acute oxidative stress induced by ischemia/reperfusion.

AB - RATIONALE:: Aldehyde accumulation is regarded as a pathognomonic feature of oxidative stress-associated cardiovascular disease. OBJECTIVE:: We investigated how the heart compensates for the accelerated accumulation of aldehydes. METHODS AND RESULTS:: Aldehyde dehydrogenase 2 (ALDH2) has a major role in aldehyde detoxification in the mitochondria, a major source of aldehydes. Transgenic (Tg) mice carrying an Aldh2 gene with a single nucleotide polymorphism (Aldh2*2) were developed. This polymorphism has a dominant-negative effect and the Tg mice exhibited impaired ALDH activity against a broad range of aldehydes. Despite a shift toward the oxidative state in mitochondrial matrices, Aldh2*2 Tg hearts displayed normal left ventricular function by echocardiography and, because of metabolic remodeling, an unexpected tolerance to oxidative stress induced by ischemia/reperfusion injury. Mitochondrial aldehyde stress stimulated eukaryotic translation initiation factor 2α phosphorylation. Subsequent translational and transcriptional activation of activating transcription factor-4 promoted the expression of enzymes involved in amino acid biosynthesis and transport, ultimately providing precursor amino acids for glutathione biosynthesis. Intracellular glutathione levels were increased 1.37-fold in Aldh2*2 Tg hearts compared with wild-type controls. Heterozygous knockout of Atf4 blunted the increase in intracellular glutathione levels in Aldh2*2 Tg hearts, thereby attenuating the oxidative stress-resistant phenotype. Furthermore, glycolysis and NADPH generation via the pentose phosphate pathway were activated in Aldh2*2 Tg hearts. (NADPH is required for the recycling of oxidized glutathione.) CONCLUSIONS:: The findings of the present study indicate that mitochondrial aldehyde stress in the heart induces metabolic remodeling, leading to activation of the glutathione-redox cycle, which confers resistance against acute oxidative stress induced by ischemia/reperfusion.

KW - Aldehyde

KW - Cardiac metabolism

KW - Oxidative stress

KW - Stress response

UR - http://www.scopus.com/inward/record.url?scp=73349110116&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73349110116&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.109.206607

DO - 10.1161/CIRCRESAHA.109.206607

M3 - Article

VL - 105

SP - 1118

EP - 1127

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 11

ER -