GSH or Palmitate Preserves Mitochondrial Energetic/Redox Balance, Preventing Mechanical Dysfunction in Metabolically Challenged Myocytes/Hearts From Type 2 Diabetic Mice

Abstract

In type 2 diabetes, hyperglycemia and increased sympathetic drive may alter mitochondria energetic/redox properties, decreasing the organelle’s functionality. These perturbations may prompt or sustain basal low-cardiac performance and limited exercise capacity. Yet the precise steps involved in this mitochondrial failure remain elusive. Here, we have identified dysfunctional mitochondrial respiration with substrates of complex I, II, and IV and lowered thioredoxin-2/glutathione (GSH) pools as the main processes accounting for impaired state 4→3 energetic transition shown by mitochondria from hearts of type 2 diabetic db/db mice upon challenge with high glucose (HG) and the β-agonist isoproterenol (ISO). By mimicking clinically relevant conditions in type 2 diabetic patients, this regimen triggers a major overflow of reactive oxygen species (ROS) from mitochondria that directly perturbs cardiac electro-contraction coupling, ultimately leading to heart dysfunction. Exogenous GSH or, even more so, the fatty acid palmitate rescues basal and β-stimulated function in db/db myocyte/heart preparations exposed to HG/ISO. This occurs because both interventions provide the reducing equivalents necessary to counter mitochondrial ROS outburst and energetic failure. Thus, in the presence of poor glycemic control, the diabetic patient’s inability to cope with increased cardiac work demand largely stems from mitochondrial redox/energetic disarrangements that mutually influence each other, leading to myocyte or whole-heart mechanical dysfunction.

Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose

“…4, A and B), and restoration of cellular/ mitochondrial cardiac redox balance in HG may play a causal rather than correlative role for preserving contractility (Fig. 5) (51). Together, these data suggest that GSH regeneration and ROS scavenging underlie enhanced contractility in T2DM.…”

“…Under loaded conditions the muscle is stretched to reach the optimal sarcomere length, thus different from unloaded Langendorff-perfused hearts (54). Also the detrimental effects of hyperglycemia were evident only in the presence of the higher energetic demand imposed by ␤-adrenergic stimulation in diabetic mice (51).…”

“…For Palm addition, FA plasma levels determined in 12-14 wk of age ZDF rats from published sources were taken as reference (Table 1). In all experiments, we used Palm bound to fatty acid-free albumin (4:1), prepared as described (51).…”

“…To avoid misinterpretation, herein the term "redox" refers to the four main redox couples: NADH/NAD ϩ , NADPH/NADP ϩ , GSH/GSSG, and TrxSH 2 /TrxSS (21,36). Little information is available on the mechanistic interactions between hyperglycemia and FAs on redox status in T2DM myocardium, although compelling evidence about the critical role played by perturbed cellular/mitochondrial redox, compromised mitochondrial energetics and elevated ROS at the origin of contractile impairment in diabetes, has been reported (1,51).…”

Differential sensing for the regio- and stereoselective identification and quantitation of glycerides

“…Studying the selectivity of these lipases has applications in understanding diseases, including fat malabsorption disorders, hypercholesterolemia, atherosclerosis, and diabetes (9,10). Research on metabolic disorders has shown that fatty acid accumulation can exert a toxic or a protective effect on a tissue, depending on the specific tissue type (e.g., liver, cardiac, or skeletal muscle) (11,12) and health state (e.g., diabetic) (13,14) as well as on the fatty acids (e.g., saturated or unsaturated) (15). Sequestration of fatty acids by esterification to glycerides is one pathway by which these effects are regulated (16).…”