Cardiac Mitochondrial Respiratory Dysfunction and Tissue Damage in Chronic Hyperglycemia Correlate with Reduced Aldehyde Dehydrogenase-2 Activity

Abstract

Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial isozyme of the heart involved in the metabolism of toxic aldehydes produced from oxidative stress. We hypothesized that hyperglycemia-mediated decrease in ALDH2 activity may impair mitochondrial respiration and ultimately result in cardiac damage. A single dose (65 mg/kg; i.p.) streptozotocin injection to rats resulted in hyperglycemia with blood glucose levels of 443 ± 9 mg/dl versus 121 ± 7 mg/dl in control animals, p<0.0001, N = 7–11. After 6 months of diabetes mellitus (DM) induction, the rats were sacrificed after recording the functionality of their hearts. Increase in the cardiomyocyte cross sectional area (446 ± 32 μm2 Vs 221 ± 10 μm2; p<0.0001) indicated cardiac hypertrophy in DM rats. Both diastolic and systolic dysfunctions were observed with DM rats compared to controls. Most importantly, myocardial ALDH2 activity and levels were reduced, and immunostaining for 4HNE protein adducts was increased in DM hearts compared to controls. The mitochondrial oxygen consumption rate (OCR), an index of mitochondrial respiration, was decreased in mitochondria isolated from DM hearts compared to controls (p<0.0001). Furthermore, the rate of mitochondrial respiration and the increase in carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP)-induced maximal respiration were also decreased with chronic hyperglycemia. Chronic hyperglycemia reduced mitochondrial OXPHOS proteins. Reduced ALDH2 activity was correlated with mitochondrial dysfunction, pathological remodeling and cardiac dysfunction, respectively. Our results suggest that chronic hyperglycemia reduces ALDH2 activity, leading to mitochondrial respiratory dysfunction and consequently cardiac damage and dysfunction.

A selenoprotein T‐derived peptide protects the heart against ischaemia/reperfusion injury through inhibition of apoptosis and oxidative stress

“…To compare the Cyt c content in mitochondrial and cytosolic fractions, mitochondria were isolated from the ventricles as previously described. 65 At the end of perfusion, ventricle samples of Sham, I/R and PSELT 5 nmol/L groups were harvested and homogenized in mitochondrial isolation buffer ([IBc]: 0.1 mol/L Tris-MOPS, 0.1 mol/L EGTA-Tris and 1 mol/L sucrose, pH 7.4). Homogenates were centrifuged at 2000 9 g for 10 minutes at 4°C, and the supernatants were collected and centrifuged again at 5000 9 g for 10 minutes at 4°C.…”

Cardiac Function is not Susceptible to Moderate Disassembly of Mitochondrial Respiratory Supercomplexes

“…In the cytoplasm, alcohol dehydrogenase converts ethanol into acetaldehyde which is metabolized in the mitochondria by aldehyde dehydrogenase [37]. Acetaldehyde accumulation and activation of aldehyde dehydrogenase 2, a mitochondrial isozyme of aldehyde dehydrogenase, have been shown to diminish mitochondrial respiration [38]. Our data demonstrated that acetaldehyde reduces respirasome levels in mitochondria incubated in respiration buffer ( Figure 5D,E), suggesting that active ETC is necessary for acetaldehyde to disrupt the respirasome.…”

4‐Hydroxy‐2‐nonenal attenuates 8‐oxoguanine DNA glycosylase 1 activity

“…20 In type-1 and type-2 diabetic models, we found increased 4-hydroxy-2-nonenal (4HNE) protein adducts in diabetic tissue. 21,22 Previous studies support aberrant posttranslational modification of OGG-1 contributes to decreased OGG-1 activity: in type 1 diabetic mice, O-GlcNAcylation of OGG-1 was increased corresponding to decreased OGG-1 activity. 23 Therefore, taken altogether, we hypothesize that 4HNE decreases OGG-1 activity by forming adducts with OGG-1 on critical sites in diabetic tissue.…”

“…The Western blot analysis was performed as described earlier. 22,25 In brief, protein samples from heart tissue PAN ET AL.…”