Perspectives on Oxygen Sensing

Abstract

Institute of Genetic Medicine utilized when one compares acute and chronic responses or responses in depolarizable and nondepolar-The Johns Hopkins University School of Medicine izable cells. Progress in this field has been slow because of the limitations inherent to the use of pharmacologic Baltimore, Maryland 21287 tools to dissect complex pathways of fundamental physiologic importance, and genetic approaches to the problem have been lacking. Physiological Perspective A priori, one could postulate a variety of mechanisms Regardless of whether bacteria, yeast, invertebrates, or by which cells might measure O 2 concentration. In the

Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals

“…At nanomolar concentrations, NO binds to cytochrome c (Cyt c) oxidase (complex IV, COX-IV), the terminal enzyme in the mitochondrial electron-transport chain, inhibiting its activity reversibly and in competition with O 2 (3)(4)(5). NO-dependent regulation of mitochondrial respiration and membrane potential contributes to acute O 2 sensing by the cells (6)(7)(8)(9). Furthermore, binding of NO to COX-IV leads to a switch to glycolysis in competent cells, redistribution of O 2 , and regulation of the levels of the hypoxia-inducible factor 1 ␣, thus contributing to long-term adaptation to hypoxic conditions (10,11).…”

Novel murine clonal cell lines either express slow or mixed (fast and slow) muscle markers following differentiation in vitro

“…A small number of transcription factors have been recently identified that could be implicated in directing the phenotype of striated muscle fibers. They are as diverse as SIX1, for the specification of fast-glycolytic myofibers (Grifone et al, 2004), BERF1 that inhibits ␤-enolase expression in slow-oxidative myofibers (Passantino et al, 1998), PPAR␦ implicated in mitochondrial oxidative metabolism (Feige et al, 2006) and HIF-1␣ involved in the response to hypoxia and controlling glycolytic metabolism (Semenza, 1999). Work is in progress in our laboratory designed to manipulate the expression of such factors in the 9.…”

Mitochondrial complex III regulates hypoxic activation of HIF

“…[10][11][12][13] HIFs bind to hypoxia-responsive elements, consensus sequences in the promoter region of more than one hundred genes, activating the transcription of genes that allow the cell to adapt to and survive in the hypoxic environment. 14,15 Genes regulated by HIFs include glucose transporter that allow the cells to efficiently import glucose to continue generating ATP despite reduced nutrient availability; and genes that reorganize the microenvironment to bring in oxygen, such as vascular endothelial growth factor, which stimulates formation of new blood vessels. [16][17][18] Importantly for tumorigenesis, HIF also turns on genes such as insulin-like growth factor 2,19 which induces cellular survival and proliferation, as well as those that promote tumor invasion and migration, such as matrix metalloproteinase-2.…”