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


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 2alpha 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.
Endo
Jin
J
Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
Sano
Motoaki
M
Katayama
Takaharu
T
Hishiki
Takako
T
Shinmura
Ken
K
Morizane
Shintaro
S
Matsuhashi
Tomohiro
T
Katsumata
Yoshinori
Y
Zhang
Yan
Y
Ito
Hideyuki
H
Nagahata
Yoshiko
Y
Marchitti
Satori
S
Nishimaki
Kiyomi
K
Wolf
Alexander Martin
AM
Nakanishi
Hiroki
H
Hattori
Fumiyuki
F
Vasiliou
Vasilis
V
Adachi
Takeshi
T
Ohsawa
Ikuroh
I
Taguchi
Ryo
R
Hirabayashi
Yoshio
Y
Ohta
Shigeo
S
Suematsu
Makoto
M
Ogawa
Satoshi
S
Fukuda
Keiichi
K
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000222:Adaptation, Physiological / Q000502:physiology; D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D004452:Echocardiography; D004789:Enzyme Activation / Q000502:physiology; D004790:Enzyme Induction / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D055442:Metabolome / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000502:physiology*; D010427:Pentose Phosphate Pathway / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology
D000447:Aldehydes; C081452:Atf4 protein, mouse; D051701:Activating Transcription Factor 4; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D005978:Glutathione; D005947:Glucose