Mitochondria and Oxidative Stress in the Cardiorenal Metabolic Syndrome

Abstract

Mitochondria play a fundamental role in the maintenance of normal structure, function, and survival of tissues. There is considerable evidence for mitochondrial dysfunction in association with metabolic diseases including insulin resistance, obesity, diabetes, and the cardiorenal metabolic syndrome. The phenomenon of reactive oxygen species (ROS)-induced ROS release through interactions between cytosolic and mitochondrial oxidative stress contributes to a vicious cycle of enhanced oxidative stress and mitochondrial dysfunction. Activation of the cytosolic and mitochondrial NADPH oxidase system, impairment of the mitochondrial electron transport, activation of p66shc pathway-targeting mitochondria, endoplasmic reticular stress, and activation of the mammalian target of the rapamycin-S6 kinase pathway underlie dysregulation of mitochondrial dynamics and promote mitochondrial oxidative stress. These processes are further modulated by acetyltransferases including sirtuin 1 and sirtuin 3, the former regulating nuclear acetylation and the latter regulating mitochondrial acetylation. The regulation of mitochondrial functions by microRNAs forms an additional layer of molecular control of mitochondrial oxidative stress. Alcohol further exacerbates mitochondrial oxidative stress induced by overnutrition and promotes the development of metabolic diseases.

Sensory Nerve Terminal Mitochondrial Dysfunction Activates Airway Sensory Nerves via Transient Receptor Potential (TRP) Channels

“…As such, we predict that mitochondrial-TRPA1 interactions may contribute to nociceptor activation in these pathologies. In the airways, mitochondrial dysfunction and oxidative stress has been demonstrated for an array of cell types both in asthma and chronic obstructive bronchitis (Rabinovich et al, 2007;Reddy, 2011) and can be initiated by a wide variety of inflammatory signaling pathways common in respiratory diseases: e.g., tumor necrosis factor a (Corda et al, 2001), neurotrophins via p75NTR (Pehar et al, 2007), microRNAs (Aroor et al, 2012), transforming growth factor b (Michaeloudes et al, 2011), and Toll-like receptors (West et al, 2011). Airway vagal nociceptor activation and hyperexcitability contribute to cough, dyspnea, bronchospasm, and hypersecretion (Carr and Undem, 2003).…”

“…Although the mechanism of mitochondrial dysfunction in chronic inflammatory diseases is not well understood, numerous inflammatory signaling pathways increase mitochondrial ROS production either: 1) through the inhibition of complexes I or III [e.g., tumor necrosis factor a (Corda et al, 2001), neurotrophins via p75NTR (Pehar et al, 2007), and Toll-like receptors (West et al, 2011)]; or 2) through downregulation of mitochondrial antioxidant enzymes by microRNAs (Aroor et al, 2012) and transforming growth factor b (Michaeloudes et al, 2011).…”

DPP-4 Inhibitors as Therapeutic Modulators of Immune Cell Function and Associated Cardiovascular and Renal Insulin Resistance in Obesity and Diabetes

“…Insulin signaling occurs through two different pathways: the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB) (Akt) signaling pathway eliciting mainly metabolic responses and the mitogen-activated protein kinase (MAPK) signaling pathway eliciting growth responses [24,25,26,27,28,29,30,31,32,33]. The major converging point contributing to insulin resistance is the docking protein insulin receptor substrate (IRS).…”

“…The major converging point contributing to insulin resistance is the docking protein insulin receptor substrate (IRS). The phosphorylation of serine residues of IRS by protein kinase C (PKC), c-Jun kinase (JNK), and ribosomal p70 S6 kinase promotes phosphorylation of serine residues on IRS-1, which triggers proteasome-de-pendent degradation and attenuates IRS-1 tyrosine phosphorylation, association with p85 subunit of PI3-K, and downstream metabolic signaling [26,27,28,29,30,31,32,33]. Phosphorylation of tyrosine residues in the IRS results in the engagement of Src homology 2 (SH2) domain-binding motifs for SH2 domain signaling molecules, including PI3-K and Grb-2.…”

“…This molecule then binds to the pleckstrin homology domain in 3-phosphoinositide-dependent protein kinase-1 (PDK-1), resulting in its phosphorylation and the activation of other downstream kinases, including PKB (Akt) and atypical PKC isoforms, which mediate a number of metabolic actions including glucose transporter-4 (GLUT-4) translocation to the membrane, leading to glucose uptake in myocardial tissue and skeletal muscle as well as nitric oxide (NO) production in blood vessels. Binding of tyrosine-phosphorylated IRS-1 or Shc to the SH2 domain of Grb-2 activates MAPK to augment insulin growth effects and associated myocardial remodeling, hypertrophy, and cardiac fibrosis [26,33]. …”