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 TaguchiYoshio Hirabayashi, Shigeo Ohta, Makoto Suematsu, Satoshi Ogawa, Keiichi Fukuda

Research output: Contribution to journalArticlepeer-review

125 Citations (Scopus)


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
Issue number11
Publication statusPublished - 2009 Nov


  • Aldehyde
  • Cardiac metabolism
  • Oxidative stress
  • Stress response

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


Dive into the research topics of 'Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart'. Together they form a unique fingerprint.

Cite this