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

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 sus-tain 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 res-piration with substrates of complex I, II, and IV and lowered thioredoxin-2/glutathione (GSH) pools as the main processes ac-counting for impaired state 4→3 energetic transition shown by mitochondria from hearts of type 2 diabetic db/db mice upon chal-lenge with high glucose (HG) and the b-agonist isoproterenol (ISO). By mimicking clinically relevant conditions in type 2 dia-betic patients, this regimen triggers a major overflow of reactive oxygen species (ROS) from mitochondria that directly perturbs cardiac electro-contraction coupling, ultimately leading to hear