Mitochondrial complex III regulates hypoxic activation of HIF

Abstract

Decreases in oxygen levels are observed in physiological processes, such as development, and pathological situations, such as tumorigenesis and ischemia. In the complete absence of oxygen (anoxia), mammalian cells are unable to generate sufficient energy for survival, so a mechanism for sensing a decrease in the oxygen level (hypoxia) before it reaches a critical point is crucial for the survival of the organism. In response to decreased oxygen levels, cells activate the transcription factors hypoxiainducible factors (HIFs), which lead to metabolic adaptation to hypoxia, as well as to generate new vasculature to increase oxygen supply. How cells sense decreases in oxygen levels to regulate HIF activation has been hotly debated. Emerging evidence indicates that reactive oxygen species (ROS) generated by mitochondrial complex III are required for hypoxic activation of HIF. This review examines the current knowledge about the role of mitochondrial ROS in HIF activation, as well as implications of ROS-level regulation in pathological processes such as cancer. Oxygen Homeostasis and HIF Maintaining oxygen homeostasis is critical for survival and proper function of cells and organisms. 1 Reduced oxygen levels (hypoxia) initiates proper placental and vascular development. Hypoxia also has a causal role in pathological conditions such as ischemia-related diseases and cancer. A complete absence of oxygen (anoxia) results in cell death. 2 ATP synthesis is ablated, and most cells undergo apoptosis soon after anoxia exposure. 3-5 Cells exposed to hypoxia, or reduced oxygen levels, on the other hand, are able to maintain normal ATP synthesis and survive. 5,6 However, as cells replicate in a hypoxic environment, they reduce the oxygen supply even further and generate levels of local anoxia. Therefore, cells must respond quickly to decreasing oxygen levels before reaching an anoxic state (Figure 1).Mammalian cells respond to hypoxia by activating broadaction transcription factors named hypoxia-inducible factors, or HIFs, which are expressed by virtually all cells of the body. 7-9 Three members of the HIF family exist, named HIF1, HIF2 and HIF-3. 10-13 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. 20 These factors contribute to tumor growth and invasion and metastasis, im...

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“…7 It has been suggested that the electron transport chain functions as an O 2 sensor by releasing reactive oxygen species (ROS) from complex III in response to hypoxia. 8,9 Oxidative stress increases with aging, and the accumulation of oxidative damage to mitochondrial DNA appears to be involved in the aging phenotype. Thus, impairment of mitochondria in response to oxidative stress accumulation may decrease mitochondrial oxygen sensing.…”

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“…Indeed, mutations in FH (Isaacs et al 2005) and SDH (Pollard et al 2005;Frezza et al 2011) are observed in renal cancers, paragangliomas, and pheochromocytomas. Additionally, mitochondrial reactive oxygen species (ROS) generated from complex III of the electron transport chain (ETC) also regulate hypoxic activation of Hif-1a (Klimova and Chandel 2008) and hypoxia-responsive gene expression. Thus, the metabolic state of a cell can also control its regulatory state, indicating a dynamic and reciprocal relationship between the two.…”