Mitochondrial Dysfunction in Metabolic Syndrome and Asthma

Figure 1

Mitochondrial dysfunction and defective mitochondrial biogenesis lead to insulin resistance and other risk factors of metabolic syndrome. Various etiological factors lead to impair cell metabolism to nutrient overload which increases 12/15-LOX expression in the adipocytes. ER stress and unfolded protein response (UPR) induced by 12/15-LOX increase the adipocyte inflammation and recruits macrophages into the adipocytes. Resultant increase of proinflammatory mediators and imbalance in adipokines reduced eNOS expression. The reduction in eNOS reduces the formation of nitric oxide which impairs mitochondrial biogenesis via cGMP/PGC-1α pathway. This decreases beta oxidation of fatty acids and lipid accumulation in adipocytes. The resultant adiposity and release of free fatty acids caused mitochondrial dysfunction and paradoxical reduction in oxidative phosphorylation and increase in the formation of oxidative free radicals. They further activate JNK and PKCs which cause serine phosphorylation of IRS-1/2 leading to insulin resistance by decreasing PI3-K/PDK-1/Akt signaling. This causes the development of type 2 diabetes which along with central adiposity amplifies the risk of cardiovascular diseases in metabolic syndrome. 12/15-LOX: 12/15-lipoxygenase; UPRer: unfolded protein response in endoplasmic reticulum (ER); UPRmt: unfolded protein response in mitochondria; eNOS: endothelial nitric oxide synthase; cGMP: cyclic guanosine monophosphate; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1 alpha; NRF-1: nuclear respiratory factor-1; Tfam: mitochondrial transcription factor; DG: diacylglycerols; ROS: reactive oxygen species; PKC: protein kinase C; JNK: c-Jun NH(2)-terminal kinase; IRS, insulin receptor substrates; PI3 kinase: phosphoinositide 3-kinase; PDK-1: phosphoinositide-dependent kinase-1.