Modulation of mitochondrial membrane permeability in pathogenesis, autophagy and control of metabolism.
The mitochondrial inner and outer membranes have contrasting permeability characteristics. The outer membrane is non-specifically permeable to all low-molecular-weight solutes, whereas the inner membrane is impermeable except through specific transporters. After stresses and sometimes in normal physiology, the permeability of the two membranes can reverse. In the inner membrane, permeability transition pores open to cause the mitochondrial permeability transition (MPT). As the MPT involves more and more mitochondria, autophagy, apoptosis and necrosis progressively develop linked to the proportion of mitochondria injured and the extent of adenosine triphosphate (ATP) depletion, a phenomenon of necrapoptosis. By contrast, the outer membrane may decrease its permeability after certain stresses via closure of voltage-dependent anion channels (VDAC). The VDAC closure globally suppresses mitochondrial function to prevent futile ATP hydrolysis in hypoxia-ischemia and possibly the release of toxic superoxide under conditions of oxidative stress. The VDAC closure may also facilitate selective oxidation of acetaldehyde after ethanol exposure and promote aerobic glycolysis in cancer cells. By contrast, VDAC opening is proposed to stimulate oxidative phosphorylation and promote insulin release by glucose-stimulated pancreatic beta cells. Thus, VDAC serves as a global regulator, or governator, of mitochondrial function. Understanding of how these mitochondrial membrane permeability changes are themselves regulated remains incomplete and requires future study.
Lemasters
John J
JJ
Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA. jjlemasters@musc.edu
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002463:Cell Membrane Permeability / Q000502:physiology; D006801:Humans; D008930:Mitochondria, Liver / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000502:physiology*; D018384:Oxidative Stress; D050994:Voltage-Dependent Anion Channels / Q000502:physiology*
D050994:Voltage-Dependent Anion Channels; D000255:Adenosine Triphosphate