Mitochondrial Dysfunction and Targeted Drugs: A Focus on Diabetes

Abstract

Diabetes is a severe, heterogeneous, multifactorial, chronic disease. Diabetes and oxidative stress are related to continuous and acute overproduction of reactive oxygen species (ROS). These ROS are released principally from mitochondria, but also have other sources. Oxidative stress seems to play an important role in mitochondria-mediated disease processes, though the exact molecular mechanisms responsible remain elusive. ROS are necessary for the proper functioning of the cell, but their excessive production can be harmful, making antioxidant defenses essential. Some substances with antioxidant properties, such as vitamins C and E, have been used to eradicate the oxidative stress associated with diabetes. The results of clinical trials employing anti-oxidative stress reagents in patients with diabetes are contradictory, perhaps due to inadequate study design or the specific targets selected. This review considers the process of diabetes from a mitochondrial perspective and evaluates strategies currently under development for the targeted delivery of antioxidants or other molecules to mitochondria. The evidence compiled herein endorses the selective targeting of specific molecules to mitochondria as an effective strategy for modulating mitochondrial respiration and ROS production and protecting mitochondria against oxidative stress.

Oncostatin M (OSM) protects against cardiac ischaemia/reperfusion injury in diabetic mice by regulating apoptosis, mitochondrial biogenesis and insulin sensitivity

“…Mitochondria are the main source of ROS, which are fundamental factors in the development of diabetic complications [9,26,27]. Therefore, eradicating mitochondrial ROS has become important to ameliorate complications related with diabetes [25].…”

Hyperglycemia, Hypoglycemia and Dementia: Role of Mitochondria and Uncoupling Proteins

“…H 2 O 2 can be scavenged by either the enzyme glutathione peroxidase (GPx) in the mitochondrial matrix that uses glutathione (GSH) as a reducing equivalent to reduce H 2 O 2 to form glutathione disulfide (GSSG) and water; or by the enzyme catalase in the cytosol, which converts H 2 O 2 to water and oxygen. GSH can remove selected oxygen radicals directly and assist in the recycling of the vitamins C and E [91]. Oxidative stress occurs when the antioxidant defenses are overwhelmed by the excessive production of ROS culminating in the oxidation of several biomolecules.…”

Screen for Small Molecules Increasing the Mitochondrial Membrane Potential

“…Compounds were added (5 µL) and incubated with cells for 24 h at 30 °C. Mitochondrial staining for membrane potential was completed with 10 µL DiOC 6 (3) (Molecular Probes, Sunnyvale, CA), 175 nM final, for 15 min. Medium and excess dye were removed by centrifugation (2 min 800 g) of the filter plates, and cells were washed twice with phosphate-buffered saline (PBS).…”

“…Fluorescence was measured after a 1-min centrifugation to pellet cells and reduce horizontal drifts within plates. Assay variability ranging from 15% to 20% when measuring DiOC 6 (3) fluorescence (485/535 nm) was attributed to the transfer step of high-density cell suspensions from filter plates to black plates. Standardization of DiOC 6 (3) fluorescence against cellular auto-fluorescence (360/465 nm) reduced within-plate variability to 9% to 11%.…”