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Hypoxia signaling pathways: modulators of oxygen-related organelles.

Schönenberger MJ, Kovacs WJ - Front Cell Dev Biol (2015)

Bottom Line: We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability.HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders.We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Institute of Molecular Health Sciences ETH Zurich, Zurich, Switzerland.

ABSTRACT
Oxygen (O2) is an essential substrate in cellular metabolism, bioenergetics, and signaling and as such linked to the survival and normal function of all metazoans. Low O2 tension (hypoxia) is a fundamental feature of physiological processes as well as pathophysiological conditions such as cancer and ischemic diseases. Central to the molecular mechanisms underlying O2 homeostasis are the hypoxia-inducible factors-1 and -2 alpha (HIF-1α and EPAS1/HIF-2α) that function as master regulators of the adaptive response to hypoxia. HIF-induced genes promote characteristic tumor behaviors, including angiogenesis and metabolic reprogramming. The aim of this review is to critically explore current knowledge of how HIF-α signaling regulates the abundance and function of major O2-consuming organelles. Abundant evidence suggests key roles for HIF-1α in the regulation of mitochondrial homeostasis. An essential adaptation to sustained hypoxia is repression of mitochondrial respiration and induction of glycolysis. HIF-1α activates several genes that trigger mitophagy and represses regulators of mitochondrial biogenesis. Several lines of evidence point to a strong relationship between hypoxia, the accumulation of misfolded proteins in the endoplasmic reticulum, and activation of the unfolded protein response. Surprisingly, although peroxisomes depend highly on molecular O2 for their function, there has been no evidence linking HIF signaling to peroxisomes. We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability. HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders. We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health.

No MeSH data available.


Related in: MedlinePlus

Receptor-mediated mitophagy. (A) Atg32-mediated mitophagy in S. cerevisiae. Atg32 is an outer mitochondrial membrane protein whose expression is induced upon mitophagy-inducing conditions. Atg32 interacts with Atg8 and Atg11 via distinct domains. Casein kinase 2 (CK2) phosphorylates Atg32 upon mitophagy-inducing conditions, which is essential for the Atg11 interaction without affecting Atg32-Atg8 binding. (B) NIX/BNIP3-mediated mitophagy in mammalian cells. NIX and BNIP3 are outer mitochondrial membrane proteins that interact with LC3 through LIR motifs in their N-terminal region. Upon hypoxia, NIX and BNIP3 are transcriptionally induced in a HIF-α-dependent manner. Phosphorylation of BNIP3 promotes its binding to LC3 and subsequent mitophagy. The kinase for BNIP3 phosphorylation is unknown. (C) FUNDC1-mediated mitophagy in mammalian cells. FUNDC1 is an outer mitochondrial membrane protein that interacts with LC3 through a LIR domain at its cytosol-exposed N-terminus. Under normal physiological conditions, FUNDC1 is phosphorylated by SRC and CK2, thereby preventing LC3 binding. Upon hypoxia or loss of mitochondrial membrane potential (Δψm), the expression of SRC is strongly suppressed and PGAM5 dephosphorylates FUNDC1. Dephosphorylation of FUNDC1 enhances the interaction between FUNDC1 and LC3 and promotes mitophagy. Phosphorylation of FUNDC1 by ULK1 enhances its binding to LC3.
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Figure 3: Receptor-mediated mitophagy. (A) Atg32-mediated mitophagy in S. cerevisiae. Atg32 is an outer mitochondrial membrane protein whose expression is induced upon mitophagy-inducing conditions. Atg32 interacts with Atg8 and Atg11 via distinct domains. Casein kinase 2 (CK2) phosphorylates Atg32 upon mitophagy-inducing conditions, which is essential for the Atg11 interaction without affecting Atg32-Atg8 binding. (B) NIX/BNIP3-mediated mitophagy in mammalian cells. NIX and BNIP3 are outer mitochondrial membrane proteins that interact with LC3 through LIR motifs in their N-terminal region. Upon hypoxia, NIX and BNIP3 are transcriptionally induced in a HIF-α-dependent manner. Phosphorylation of BNIP3 promotes its binding to LC3 and subsequent mitophagy. The kinase for BNIP3 phosphorylation is unknown. (C) FUNDC1-mediated mitophagy in mammalian cells. FUNDC1 is an outer mitochondrial membrane protein that interacts with LC3 through a LIR domain at its cytosol-exposed N-terminus. Under normal physiological conditions, FUNDC1 is phosphorylated by SRC and CK2, thereby preventing LC3 binding. Upon hypoxia or loss of mitochondrial membrane potential (Δψm), the expression of SRC is strongly suppressed and PGAM5 dephosphorylates FUNDC1. Dephosphorylation of FUNDC1 enhances the interaction between FUNDC1 and LC3 and promotes mitophagy. Phosphorylation of FUNDC1 by ULK1 enhances its binding to LC3.

Mentions: Although mitophagy has been extensively studied in mammals, mitophagy-specific factors still remain controversial. In yeast Atg32 has been identified as receptor protein for mitophagy (Kanki et al., 2009, 2015; Okamoto et al., 2009). Atg32 localizes to the OMM, harbors a classical LIR consensus sequence and interacts with Atg8 and the scaffold protein Atg11 to enable the assembly of the core autophagy machinery around the cargo (Figure 3A). Casein kinase 2 (CK2) regulates mitophagy by phosphorylating Atg32, which stabilizes the Atg32-Atg11 interaction and promotes mitophagy. So far no mammalian homolog has been identified for Atg32.


Hypoxia signaling pathways: modulators of oxygen-related organelles.

Schönenberger MJ, Kovacs WJ - Front Cell Dev Biol (2015)

Receptor-mediated mitophagy. (A) Atg32-mediated mitophagy in S. cerevisiae. Atg32 is an outer mitochondrial membrane protein whose expression is induced upon mitophagy-inducing conditions. Atg32 interacts with Atg8 and Atg11 via distinct domains. Casein kinase 2 (CK2) phosphorylates Atg32 upon mitophagy-inducing conditions, which is essential for the Atg11 interaction without affecting Atg32-Atg8 binding. (B) NIX/BNIP3-mediated mitophagy in mammalian cells. NIX and BNIP3 are outer mitochondrial membrane proteins that interact with LC3 through LIR motifs in their N-terminal region. Upon hypoxia, NIX and BNIP3 are transcriptionally induced in a HIF-α-dependent manner. Phosphorylation of BNIP3 promotes its binding to LC3 and subsequent mitophagy. The kinase for BNIP3 phosphorylation is unknown. (C) FUNDC1-mediated mitophagy in mammalian cells. FUNDC1 is an outer mitochondrial membrane protein that interacts with LC3 through a LIR domain at its cytosol-exposed N-terminus. Under normal physiological conditions, FUNDC1 is phosphorylated by SRC and CK2, thereby preventing LC3 binding. Upon hypoxia or loss of mitochondrial membrane potential (Δψm), the expression of SRC is strongly suppressed and PGAM5 dephosphorylates FUNDC1. Dephosphorylation of FUNDC1 enhances the interaction between FUNDC1 and LC3 and promotes mitophagy. Phosphorylation of FUNDC1 by ULK1 enhances its binding to LC3.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
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Figure 3: Receptor-mediated mitophagy. (A) Atg32-mediated mitophagy in S. cerevisiae. Atg32 is an outer mitochondrial membrane protein whose expression is induced upon mitophagy-inducing conditions. Atg32 interacts with Atg8 and Atg11 via distinct domains. Casein kinase 2 (CK2) phosphorylates Atg32 upon mitophagy-inducing conditions, which is essential for the Atg11 interaction without affecting Atg32-Atg8 binding. (B) NIX/BNIP3-mediated mitophagy in mammalian cells. NIX and BNIP3 are outer mitochondrial membrane proteins that interact with LC3 through LIR motifs in their N-terminal region. Upon hypoxia, NIX and BNIP3 are transcriptionally induced in a HIF-α-dependent manner. Phosphorylation of BNIP3 promotes its binding to LC3 and subsequent mitophagy. The kinase for BNIP3 phosphorylation is unknown. (C) FUNDC1-mediated mitophagy in mammalian cells. FUNDC1 is an outer mitochondrial membrane protein that interacts with LC3 through a LIR domain at its cytosol-exposed N-terminus. Under normal physiological conditions, FUNDC1 is phosphorylated by SRC and CK2, thereby preventing LC3 binding. Upon hypoxia or loss of mitochondrial membrane potential (Δψm), the expression of SRC is strongly suppressed and PGAM5 dephosphorylates FUNDC1. Dephosphorylation of FUNDC1 enhances the interaction between FUNDC1 and LC3 and promotes mitophagy. Phosphorylation of FUNDC1 by ULK1 enhances its binding to LC3.
Mentions: Although mitophagy has been extensively studied in mammals, mitophagy-specific factors still remain controversial. In yeast Atg32 has been identified as receptor protein for mitophagy (Kanki et al., 2009, 2015; Okamoto et al., 2009). Atg32 localizes to the OMM, harbors a classical LIR consensus sequence and interacts with Atg8 and the scaffold protein Atg11 to enable the assembly of the core autophagy machinery around the cargo (Figure 3A). Casein kinase 2 (CK2) regulates mitophagy by phosphorylating Atg32, which stabilizes the Atg32-Atg11 interaction and promotes mitophagy. So far no mammalian homolog has been identified for Atg32.

Bottom Line: We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability.HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders.We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Institute of Molecular Health Sciences ETH Zurich, Zurich, Switzerland.

ABSTRACT
Oxygen (O2) is an essential substrate in cellular metabolism, bioenergetics, and signaling and as such linked to the survival and normal function of all metazoans. Low O2 tension (hypoxia) is a fundamental feature of physiological processes as well as pathophysiological conditions such as cancer and ischemic diseases. Central to the molecular mechanisms underlying O2 homeostasis are the hypoxia-inducible factors-1 and -2 alpha (HIF-1α and EPAS1/HIF-2α) that function as master regulators of the adaptive response to hypoxia. HIF-induced genes promote characteristic tumor behaviors, including angiogenesis and metabolic reprogramming. The aim of this review is to critically explore current knowledge of how HIF-α signaling regulates the abundance and function of major O2-consuming organelles. Abundant evidence suggests key roles for HIF-1α in the regulation of mitochondrial homeostasis. An essential adaptation to sustained hypoxia is repression of mitochondrial respiration and induction of glycolysis. HIF-1α activates several genes that trigger mitophagy and represses regulators of mitochondrial biogenesis. Several lines of evidence point to a strong relationship between hypoxia, the accumulation of misfolded proteins in the endoplasmic reticulum, and activation of the unfolded protein response. Surprisingly, although peroxisomes depend highly on molecular O2 for their function, there has been no evidence linking HIF signaling to peroxisomes. We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability. HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders. We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health.

No MeSH data available.


Related in: MedlinePlus