The Mitochondria in Diabetic Heart Failure: From Pathogenesis to Therapeutic Promise

Abstract

Significance: Diabetes is an important risk factor for the development of heart failure (HF). Given the increasing prevalence of diabetes in the population, strategies are needed to reduce the burden of HF in these patients. Recent Advances: Diabetes is associated with several pathologic findings in the heart including dysregulated metabolism, lipid accumulation, oxidative stress, and inflammation. Emerging evidence suggests that mitochondrial dysfunction may be a central mediator of these pathologic responses. The development of therapeutic approaches targeting mitochondrial biology holds promise for the management of HF in diabetic patients. Critical Issues: Despite significant data implicating mitochondrial pathology in diabetic cardiomyopathy, the optimal pharmacologic approach to improve mitochondrial function remains undefined. Future Directions: Detailed mechanistic studies coupled with more robust clinical phenotyping will be necessary to develop novel approaches to improve cardiac function in diabetes. Moreover, understanding the interplay between diabetes and other cardiac stressors (hypertension, ischemia, and valvular disease) will be of the utmost importance for clinical translation of scientific discoveries made in this field. Antioxid. Redox Signal. 22, 1515Signal. 22, -1526

Reactive oxygen species signalling in the diabetic heart: emerging prospect for therapeutic targeting

“…Elevated intracellular FFAs also drive accumulation of cardiotoxic lipid intermediates (eg, ceramide), reduced mitochondrial calcium uptake and mitochondrial permeability transition pore (MPTP) opening 14. Together, such changes decrease enzymatic activity (eg, pyruvate dehydrogenase), causing impaired ATP production and caspase-mediated cell death, while aberrant myocardial insulin signalling drives further mitochondrial dysfunction 15. In addition to metabolic abnormalities, the diabetic heart displays major CHF-independent microvascular changes (eg, perivascular/subendothelial fibrosis, endothelial dysfunction, abnormal capillary permeability/density, microaneurysms, aberrant angiogenesis),2 highlighting likely contribution to associated remodelling.…”

“…Mitochondria represent the main cardiomyocyte energy source due to highly efficient metabolism of glucose/FFA to acetyl-CoA, providing high-energy electrons to the mitochondrial ETC, thereby generating abundant ATP 15. Normally 1%–2% of electrons leak from the mitochondria which are scavenged or donated to molecular oxygen to form superoxide, although ROS increase significantly with mitochondrial dysfunction in diabetes 23.…”

“…Indeed, excess ROS may themselves drive mitochondrial uncoupling by directly impairing the ETC while also promoting electron leak, causing reduced myocardial energy generation, increased superoxide, contractile dysfunction and CHF 24. With insulin resistance, mitochondria are progressively unable to use glucose, resulting in switching to FFA oxidation and further ROS generation 15. One suggested mechanism involves upregulation of proton leak channels, UCP2/UCP3, causing reduced mitochondrial membrane potential, mitochondrial uncoupling/dysfunction and impaired myocardial efficiency 15.…”

“…With insulin resistance, mitochondria are progressively unable to use glucose, resulting in switching to FFA oxidation and further ROS generation 15. One suggested mechanism involves upregulation of proton leak channels, UCP2/UCP3, causing reduced mitochondrial membrane potential, mitochondrial uncoupling/dysfunction and impaired myocardial efficiency 15. Elevated mitochondrial ROS in diabetes may also drive adverse remodelling, particularly cardiomyocyte apoptosis, secondary to MPTP opening and mitochondrial swelling, which is exacerbated by PKC-dependent activation of redox-sensitive KATP channels 21.…”

“…Indeed, characteristic switching from glucose to FFA metabolism in T2D causes impaired mitochondrial respiration, increased ROS generation, ETC uncoupling, reduced ATP synthesis and cardiac dysfunction. Conversely, when energy demand is low, excess FFAs are preferentially oxidised to superoxide by the mitochondrial ETC 15. Notably, increased FFA uptake/metabolism is regulated by PPARα, which controls oxidative phosphorylation and mitochondrial biogenesis, so activation in diabetes could represent an adaptive response to prevent cardiomyocyte FFA accumulation,15 although persistent upregulation, for example, PPARα-overexpressing mice fed high-fat diet, causes cardiac dysfunction 14.…”