Advances around technologies investigating mitochondrial function and insights gained by their applications

Diabetes mellitus is defined as a state of persistently high levels of blood glucose and insulin deficiency, and resistance to it is considered as the cause(s). However, the metabolic abnormalities of diabetes are not limited to glucose, but encompass the entire metabolism. Insulin controls not only glucose, but fat and protein metabolism as well. Furthermore, body structures of patients with this disease become abnormal, termed complications, which eventually lead to the death of patients. The mitochondrion is an intracellular organelle that plays a central role in the metabolism. Here are the Krebs cycle enzymes and the electron transfer chain (ETC) enzymes, which transduce energy substrates into a usable form of energy, adenosine triphosphate (ATP) and heat. Mitochondrion literally burns glucose, fatty acids and amino acids into CO2 and water, consuming oxygen. Free energy in those molecules is released in the form of hydrogen, and transferred to the ETC through hydrogenated nicotine amide dinucleotide and flavin adenine dinucleotide, which are then pumped into the intermembranous space by ETC complexes 1, 3 and 4. The huge electrochemical gradient (reaching approximately -170 mV; proton motive force [DΨ]) thus generated is used for ATP synthesis (ATP synthase or complex 5), which compresses inorganic phosphate (Pi) into adenosine diphosphate (ADP) in making ATP. Excessive build-up of DΨ is prevented by the action of uncoupling proteins (UCP), which dissipates DΨ (Figure 1). One might imagine this energy transforming system as being made of four modules: a turbine engine (tri-acetic acid (TCA) cycle or hydrogen generator); an electricity grid connecting the engine to the plant (ETC complexes 1, 2 and 3, all feeding into complex 4); a plant, making energy currency (complex 5); and controllers. It is now appreciated that these five complexes form one supercomplex, which exists in a dynamic state; its function of this supercomplex change according to the need of extracting energy depending on the relative abundance of the nutrients to burn, which in turn reflects the composition of foods consumed. The mitochondrion is a highly sophisticated machine, but rather fragile, as it has to handle electrons. Electrons are transferred easily to reactive molecules. As electron leak is inevitable, it forms superoxide (a reactive oxygen species [ROS]) by reacting with oxygen, which could damage the mitochondrial genome, the mitochondrial membrane (its proteins and fats). Hydrogen peroxide (H2O2) is another potential toxic product, which is monitored by the nucleus. Animals have evolved delicate protective and repair systems for this reason, and it is under very delicate control. If the mitochondrion is damaged, however, it is either entirely removed or the cell carrying the damaged mitochondrion dies and is removed (termed mitophagy and apoptosis, respectively). The mitochondrion is under delicate control, and easily changes its morphology