Wuest 2018 MiPschool Tromso D3
Wuest RC (2018)
Event: MiPschool Tromso-Bergen 2018
Optimal mitochondrial function is crucial for cardiac function, and mitochondrial ATP production is linked to contractile activity (‘energetic-contraction coupling’), as well as the excitation by calcium (‘excitation-energetic coupling’). Maintaining cardiac energy homeostasis requires optimal substrate sensing, transport, storage, and utilization; the interplay between these factors is coined ‘metabolic flexibility’. Cardiac metabolic flexibility is required to optimally integrate energy production and demand in order to maintain energy homeostasis and cardiac contractility. The major energy-providing substrates of the heart include triglycerides, long-chain fatty acids, glucose and glycogen, while lactate, ketone bodies and a variety of branched-chain amino acids are contributing substrates.
Patients with Type 2 Diabetes Mellitus (T2DM) and insulin resistance often suffer from circulating hypertriglyceridemia and hyperglycemia. This increased free fatty acid availability leads to increased FA uptake and reduced insulin-mediated myocardial glucose uptake in the heart in patients with uncomplicated T2DM without overt cardiomyopathy. This preferential supply of FFAs to the myocardium in early and late diabetes shifts myocardial substrate metabolism towards almost exclusively FA oxidation for cardiac ATP production, causing metabolic inflexibility. Cellular FFA accumulation can result in cellular oxidative stress, and we showed that cytosolic and mitochondrial calcium homeostasis is impaired in the diabetic heart. We also observed in various animal models of diabetes (pigs, rats, mice) that particularly NADH-coupled mitochondrial OXPHOS was more vulnerable to be affected in the diabetic heart, whereas succinate/rotenone-coupled respiration was less affected. During my talk, I will also highlight some recent work on compounds that worsen mitochondrial dysfunction and cause further cardiac contractile dysfunction in mice with T2DM.
- Amsterdam UMC, Univ Amsterdam, Biomedical Engineering Physics, Amsterdam Cardiovascular Sciences, The Netherlands
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Diabetes
Organism: Pig, Mouse, Rat Tissue;cell: Heart
Regulation: Fatty acid Coupling state: OXPHOS Pathway: N, S HRR: Oxygraph-2k Event: D3, Oral