Hypoxia and mitochondrial oxidative metabolism.
It is now clear that mitochondrial defects are associated with a large variety of clinical phenotypes. This is the result of the mitochondria's central role in energy production, reactive oxygen species homeostasis, and cell death. These processes are interdependent and may occur under various stressing conditions, among which low oxygen levels (hypoxia) are certainly prominent. Cells exposed to hypoxia respond acutely with endogenous metabolites and proteins promptly regulating metabolic pathways, but if low oxygen levels are prolonged, cells activate adapting mechanisms, the master switch being the hypoxia-inducible factor 1 (HIF-1). Activation of this factor is strictly bound to the mitochondrial function, which in turn is related with the oxygen level. Therefore in hypoxia, mitochondria act as [O2] sensors, convey signals to HIF-1 directly or indirectly, and contribute to the cell redox potential, ion homeostasis, and energy production. Although over the last two decades cellular responses to low oxygen tension have been studied extensively, mechanisms underlying these functions are still indefinite. Here we review current knowledge of the mitochondrial role in hypoxia, focusing mainly on their role in cellular energy and reactive oxygen species homeostasis in relation with HIF-1 stabilization. In addition, we address the involvement of HIF-1 and the inhibitor protein of F1F0 ATPase in the hypoxia-induced mitochondrial autophagy.
Solaini
Giancarlo
G
Department of Biochemistry G. Moruzzi, University of Bologna, Bologna, Italy. giancarlo.solaini@unibo.it
Baracca
Alessandra
A
Lenaz
Giorgio
G
Sgarbi
Gianluca
G
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D004579:Electron Transport; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000097795:ATPase Inhibitory Protein
D045222:Electron Transport Chain Complex Proteins; D051793:Hypoxia-Inducible Factor 1; D025261:Mitochondrial Proton-Translocating ATPases; D010100:Oxygen; D011506:Proteins; D017382:Reactive Oxygen Species; D000097795:ATPase Inhibitory Protein