HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells.

By R. Fukuda, Huafeng Zhang, Jung-whan Kim, L. Shimoda, C. V. Dang, G. Semenza. Cell, 2007

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O(2) is the ultimate electron acceptor for mitochondrial respiration, a process catalyzed by cytochrome c oxidase (COX). In yeast, COX subunit composition is regulated by COX5a and COX5b gene transcription in response to high and low O(2), respectively. Here we demonstrate that in mammalian cells, expression of the COX4-1 and COX4-2 isoforms is O(2) regulated. Under conditions of reduced O(2) availability, hypoxia-inducible factor 1 (HIF-1) reciprocally regulates COX4 subunit expression by activating transcription of the genes encoding COX4-2 and LON, a mitochondrial protease that is required for COX4-1 degradation. The effects of manipulating COX4 subunit expression on COX activity, ATP production, O(2) consumption, and reactive oxygen species generation indicate that the COX4 subunit switch is a homeostatic response that optimizes the efficiency of respiration at different O(2) concentrations. Thus, mammalian cells respond to hypoxia by altering COX subunit composition, as previously observed in yeast, but by a completely different molecular mechanism.

Subfields: Cancer Research, Cell Biology, Genetics

View Paper: https://www.semanticscholar.org/paper/d002df5e4abaab201593960a6d25e8cb2afe09f7

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Citations in the corpus

Hypoxia and cancer (2007, background): “Thereby, HIF not only channels glucose towards glycolysis by repressing mitochondrial respiration but it also optimizes low levels of respiration by regulating the ratio of isoforms of cytochrome c oxidase, components of the electron transport chain [29].”
Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. (2013, background): “In HIF-1a LT-HSCs, mitochondrial volume and expression of the mitochondrial respiratory component COX41 (Fukuda et al., 2007) were higher than that seen in wild-type LT-HSCs (Figures 3G and 3H).”
MicroRNA-210 Controls Mitochondrial Metabolism during Hypoxia by Repressing the Iron-Sulfur Cluster Assembly Proteins ISCU1/2 (2009, positive): “Second, HIF-1a induces a COX4-1 to COX4-2 subunit switch during hypoxia to improve the efficiency of electron transfer to oxygen at Complex IV (Fukuda et al., 2007).”
Mitochondrial Energetics and Therapeutics (2010, neutral): “As a result, the kinetics of complex IV is altered to sustain ATP production at low oxygen tension (200, 204).”
Regulation of glycolysis by the hypoxia‐inducible factor (HIF): implications for cellular physiology (2020, background): “Furthermore, hypoxia reduces respiratory capacity by regulating cytochrome oxidase subunit expression in a HIF-1-dependent manner to limit ROS generation under hypoxic conditions, thereby promoting the evasion of oxidative stress-induced cell death (Fukuda et al. 2007).”
Tumor cell metabolism: cancer's Achilles' heel. (2008, background): “In addition, HIF-1 facilitates the adaptation of mitochondria to hypoxia by transactivating the cytochrome c oxidase (COX) subunit COX4-2 and LON, a protease that degrades COX4-1 (Fukuda et al., 2007).”
Hypoxia-Inducible Factors in Physiology and Medicine (2012, background): “HIF-1 also mediates a subunit switch in cytochrome c oxidase that improves the efficiency of electron transfer under hypoxic conditions (Fukuda et al., 2007).”
The Histone Deacetylase SIRT6 Regulates Glucose Homeostasis via Hif1α (2010, neutral): “Recent studies indicate that Hif1a also diminishes mitochondrial activity through inhibition of the Cytochrome Oxidase Subunit Cox4-1 and the coactivator PGC-1b (Fukuda et al., 2007; Zhang et al., 2007).”
INHIBITION OF MITOCHONDRIAL TRANSLATION AS A THERAPEUTIC STRATEGY FOR HUMAN ACUTE MYELOID LEUKEMIA (2011, background): “Interestingly, the 13 mt-DNA-encoded subunits of the electron transport chain are important for functional regulation of oxidative phosphorylation (Fukuda et al., 2007).”