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 2␣ 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.

Aldehyde Dehydrogenase 1B1: Molecular Cloning and Characterization of a Novel Mitochondrial Acetaldehyde-Metabolizing Enzyme

“…Another study reported that the dynamic expression of ALDH1B1 correlated with granulocytic development of hematopoietic stem cells; in this report, the author proposed a possible role of ALDH1B1 in retinoic acid metabolism mediating the effect (Luo et al, 2007). A transgenic mouse line having forced expression of the human ALDH2*2 variant exhibited distinct phenotypes, including small body size, reduced muscle mass, diminished fat content, and osteopenia (Endo et al, 2009), all of which are absent from ALDH2-null mice (Yu et al, 2009). One hypothesis to explain such a discrepancy is that the ALDH2*2 mutant subunit not only inactivates the ALDH2 wild-type subunit but also inactivates other ALDHs by forming heterotetramers, thereby blocking their functions.…”

Hydrogen Inhalation During Normoxic Resuscitation Improves Neurological Outcome in a Rat Model of Cardiac Arrest Independently of Targeted Temperature Management

“…Cellular redox homeostasis is maintained by a delicate balance between ROS production and antioxidant defences. 35 When ROS are produced excessively or endogenous antioxidant capacity is diminished, indiscriminate oxidation leads to potentially damaging oxidative stress. The hydroxyl radical (•OH) is a major trigger of the chain reaction forming free radicals, 36 and once occurring on biomembranes, it continues and expands, causing serious cellular damage.…”

Cardioprotection by Hormetic Responses to Aldehyde

“…28 Consistent with the mitochondrial localization of the Aldh2*2 protein, levels of 4-HNE adduct proteins were increased in the mitochondrial, but not cytosolic, fraction of Aldh2*2 transgenic (Tg) hearts. Interestingly, despite significant accumulation of 4-HNE adduct proteins in the mitochondrial matrices, left ventricular function in the Aldh2*2 Tg mice was equivalent to that in their wild-type littermates until at least 2 years of age.…”