Targeting mitochondria as therapeutic strategy for metabolic disorders

Abstract

Mitochondria are critical regulator of cell metabolism; thus, mitochondrial dysfunction is associated with many metabolic disorders. Defects in oxidative phosphorylation, ROS production, or mtDNA mutations are the main causes of mitochondrial dysfunction in many pathological conditions such as IR/diabetes, metabolic syndrome, cardiovascular diseases, and cancer. Thus, targeting mitochondria has been proposed as therapeutic approach for these conditions, leading to the development of small molecules to be tested in the clinical scenario. Here we discuss therapeutic interventions to treat mitochondrial dysfunction associated with two major metabolic disorders, metabolic syndrome, and cancer. Finally, novel mechanisms of regulation of mitochondrial function are discussed, which open new scenarios for mitochondria targeting.

Figure 1

Mitochondrial dysfunction regulates insulin signaling. Insulin interacts with α-subunits of its receptor (IR) on cell membrane. In response to stimuli, tyrosine residues undergo autophosphorylation, and the IR phosphorylates the insulin-receptor substrate-1 (IRS-1) in serine residues, activating Akt, with phosphorylation of the type 4 glucose transporter (GLUT4) to the cell membrane and facilitation of glucose uptake. Mitochondrial dysfunction inhibits insulin signaling, leading to insulin resistance, by (1) interfering with oxidation of fatty acyl-CoA and consequent accumulation of diacylglycerol, with consequent activation of protein kinase C and phosphorylation of IRS-1 in tyrosine residues preventing its activation, and (2) through the generation of ROS, which inhibits IRS phosphorylation in serine residues.

Figure 2

Mitochondrial dysfunction and hypoxia in cancer. Schematic representation of the role of mitochondrial dysfunction in tumorigenesis. Damaged mitochondria release ROS which on turn activates HIF1α. Finally, HIF1α activates the tumorigenic hypoxia pathway by initiating transcription of genes involved in glucose metabolism, angiogenesis, and survival.