ISSN 00062979, Biochemistry (Moscow), 2014, Vol. 79, No. 8, pp. 750760. © Pleiades Publishing, Ltd., 2014. Published in Russian in Biokhimiya, 2014, Vol. 79, No. 8, pp. 944956.
REVIEW
Mechanisms of Sensing and Adaptive Responses to Low Oxygen Conditions in Mammals and Yeasts T. A. Trendeleva1*, D. A. Aliverdieva2, and R. A. Zvyagilskaya1 1
Bach Institute of Biochemistry, Russian Academy of Sciences, Leninsky pr. 33/2, 119071 Moscow, Russia; fax: +7 (495) 9542732; Email: [email protected] 2 Caspian Institute of Biological Resources, Russian Academy of Sciences, ul. M. Gadzhieva 45, 367025 Makhachkala, Russia; fax: +7 (8722) 675905; Email: [email protected] Received April 14, 2014 Abstract—Oxygen is required for effective production of ATP and plays a key role in the maintenance of life for all organ isms, excepting strict anaerobes. The ability of aerobic organisms to sense and respond to changes in oxygen level is a basic requirement for their survival. Eukaryotes have developed adaptive mechanisms to sense and respond to decreased oxygen concentrations (hypoxia) through adjustment of oxygen homeostasis by upregulating hypoxic and downregulating aerobic nuclear genes. This review summarizes recent data on mechanisms of cells sensing and responding to changes in oxygen availability in mammals and in yeasts. In the first part of the review, prominence is given to functional regulation and stabi lization of hypoxiainducible factors (HIFs), HIFmediated regulation of electron transport flux and repression of lipoge nesis, as well as to hypoxiainduced mitochondrial permeability transition (pore) opening, cell death, and autophagy. In the second part of the review emphasis is placed on oxygen sensing in nonpathogenic yeasts by heme, unsaturated fatty acids, and sterols, as well as on responses to hypoxia in fungal pathogens. DOI: 10.1134/S0006297914080033 Key words: hypoxia, yeasts, HIF, FIH, Hap1p, SREBP, mPTP
HYPOXIC RESPONSE IN MAMMALS Hypoxia, the reduction of oxygen below its physio logical level, is usually considered pernicious, especially to tissues with high oxygen requirements. Thus, acute oxygen starvation, even for a brief period, can be danger ous. Under natural conditions hypoxia occurs at high altitudes, as a result of intense exercise, and in various respiratory diseases [1, 2]. The fact that cells survive stressful hypoxic condi tions suggests that these responses are mobilized for adap tive compensation of oxygen deficiency [2]. Thus, at the molecular level, a turning point in the evolution of multi Abbreviations: FAS, fatty acid synthase; FIH, factor inhibiting HIF; HIF, hypoxiainducible factor; mPTP, mitochondrial per meability transition pore; ODD, oxygendependent degrada tion domain; PDH, pyruvate dehydrogenase; PHD, prolyl4 hyrdoxylase domain enzymes; ROS, reactive oxygen species; SCAP, SREBP cleavageacting protein; SREBP, sterol regula tory element binding protein; TAD, terminal transactivation domain. * To whom correspondence should be addressed.
cellular organisms was the emergence of transcription factors that regulate gene expression in response to changes in oxygen availability. Such regulation of gene expression alters metabolism, resulting in the predomi nance of anaerobic glycolysis (glycolytic through activa tion of enzymes and glucose transporters) and normaliza tion of mitochondrial respiration.
The HIF Family The family of hypoxiainducible transcriptional fac tors (HIFs) is responsible for the activation of the vast majority of genes involved in adaptive responses of cells to hypoxia [1, 36]. HIF was discovered by Semenza and colleagues and identified as an oxygendependent tran scription factor that is regulated posttranscriptionally at the level of protein stability [7]. HIF is a heterodimeric transcription factor consist ing of an oxygensensitive HIFα subunit and a constitu tive HIFβ subunit, also known as ARNT (aryl hydrocar bon receptor nuclear translocator). Both HIF subunits
750
MECHANISMS OF SENSING AND RESPONSES TO HYPOXIA are members of the family of transcription factors carry ing the PAS domain (periodicaryl hydrocarbon recep torsingleminded), which contains helixloophelix (bHLH). Each subunit contains two PAS domains desig nated as PASA and PASB. The PAS domains typically comprise 100120 amino acid residues folding into a five stranded antiparallel βsheet flanked by several αhelices [8]. There are three HIFα proteins in higher multicellu lar organisms: HIF1α, HIF2α (also known as EPAS1 (endothelial PAS domain protein 1)), the most similar in structure and the best characterized, encoded by inde pendent genes and presumably equally regulated by oxy gen, and also HIF3α. HIF3α, also known as inhibitory PAS domain protein (IPAS), exists in a variety of splice variants, some of which inhibit HIF1α and HIF2α activity in a dominantnegative manner. HIF1α is ubiq uitously expressed in mammalian cells, while HIF2α and HIF3α are selectively expressed in certain tissues, such as vascular endothelial cells, pneumocytes of type II, renal interstitial cells, liver parenchymal cells, and cells of myeloid lineage [9]. Both HIF1α and HIF2α comprise two independ ent ODD domains (oxygendependent degradation) (N ODD and CODD), and two transactivation domains, NTAD (Nterminal transactivation domain) and CTAD (Cterminal transactivation domain). The ODD domain is required for cleavage HIF1α by the ubiquitin–protea some pathway. The NTAD domain contains the bHLH/PAS domains and the nuclear localization signal, and the CTAD comprises two transactivation domains [10, 11]. Transcriptional activation of target genes by HIF1 is a result of binding to the core DNA sequence 5′ RCGTG3′ (where R is G or A) within cisacting hypo xiaresponse elements and recruiting the transacting coactivators p300 and CBP (cAMPresponseelement binding proteinbinding protein) [1, 12]. HIF stabilization. The active synthesis of HIFα pro tein occurs in cells under hypoxia. However, under aero bic conditions it is rapidly degraded by the ubiquitin– proteasome system, whose activity is suppressed immedi ately during a shortage of oxygen, contributing to the rapid accumulation of HIFα [6, 7, 12]. Regulation of the activities of the three HIFα iso forms (HIF1α, HIF2α, and HIF3α) by oxygen is believed to be similar and controlled via fusion, degrada tion, or intracellular localization of the α subunit [1, 5]. Degradation of HIF1α under aerobic conditions is regulated by the oxygendependent activity of a class of proteins called PHDs (prolyl hydroxylase domain enzymes), also known as EGLNs (EGLnine homologs), and factor inhibiting HIF (FIH). There are three known independent PHD (or EGLN) enzymes – EGLN1, 2, and 3 (PHD2, 1, and 3, respectively). Interestingly, these enzymes exhibit substrate specificity: whereas EGLN1 BIOCHEMISTRY (Moscow) Vol. 79 No. 8 2014
751
and 2 are capable of hydroxylating both proline residues of HIFα (Pro402 and Pro564 in human HIF1α) within the ODD domain, EGLN3 cannot interact with the N terminal radical (P402 in human HIF1α). Apparently, EGLN1 is the main HIF prolyl hydroxylase, which has the highest HIF prolyl hydroxylase activity under aerobic conditions, and as a result it sets the HIF1α level under normal conditions [1, 1315]. PHDdependent hydroxylation of the HIF1α sub unit facilitates the binding of HIF1α to the E3 ligase complex of pVHL protein (von Hippel–Lindau tumor suppressor) (a key factor in the cellular response to oxy gen level required for oxygendependent proteolysis of HIFα), mediating polyubiquitination of HIF1α with its subsequent 26Sproteasomal degradation [16]. It should be noted that for full activity of PHD and FIH, the enzymes require the availability of oxygen in addition to iron and the tricarboxylicacidcycle intermediate 2 oxoglutarate for full activity [6, 17]. The asparagine hydroxylase activity of FIH prevents interaction of HIF with transcriptional coactivators, such as CBP/p300, effectively inhibiting the transcriptional activity of HIF1α by hydroxylation of an asparagine residue within CTAD. HIF2α, compared to HIF1α, is relatively resistant to FIH1mediated inactivation. FIH 1 remains active even at low oxygen concentrations com pared to PHDs. As a result, the interaction with pVHL is lost, leading to stabilization of HIF [1, 1315, 18, 19]. Under sustained hypoxia, degradation of the HIFα subunit is inhibited, this allowing the protein to accumu late, heterodimerize, and translocate to the nucleus, where it forms a complex with HIF1β and CBP/p300, thereby upregulating the transcription of various genes of hypoxia [16]. Amplification of hypoxic gene transcription occurs as a consequence of HIFα subunit binding to a specific region of HRE (hypoxia response element), which are consensus sequences in DNA [7, 12]. HIF stabilization and reactive oxygen/nitrogen species. Although the stabilization of HIF1α is probably mainly determined by the concentration of oxygen, regu lating the activity of PHDs, there is a considerable body of evidence that free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) can change the function and/or activity of HIF [2023]. However, hydrogen peroxide, but not superoxide, is required for HIF1α protein stabilization [24]. ROS formed in mitochondria during hypoxia act as signaling agents that trigger different functional responses, includ ing activation of gene expression by stabilization of the HIFα [24, 25]. ROS, especially NO compounds (such as peroxyni trite), can stabilize HIF1α as a result of significant changes in PHDs, such as nitrosylation or changes in the redox state of bivalent iron. However, this stabilization might be a twostep process in which a ROSdependent mechanism that takes place at low oxygen conditions is
752
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gradually substituted by inactivation of PHDs, related to lack of oxygen under hypoxic conditions. An increase in oxidative stress due to hypoxia is required for hypoxiainduced transcription of genes [24, 26]. It should be noted that HIF2α, the homolog of HIF1α, also can be regulated by this mechanism. FIH is significantly more sensitive to ROSdependent inactiva tion [17]. HIFmediated regulation of pyruvate dehydrogenase activity and electron transport flux. The key point of the glycolytic pathway is the formation of pyruvate, which under hypoxic conditions in mammals is converted to lactate, and under normal conditions by pyruvate dehy drogenase (PDH) to acetyl coenzyme A (acetylCoA), the first step of the tricarboxylic acid cycle [2729]. PDH activity is controlled by two enzymes: pyruvate dehydrogenase kinase (PDK), which phosphorylates and inactivates the enzyme, and pyruvate dehydrogenase phosphatase, which dephosphorylates the enzyme to the active form [30]. Conversion of pyruvate to acetylCoA by the action of PDH is vital, linking glycolysis and the Krebs cycle [31]. The activity of lactate dehydrogenase A and mono carboxylate transporters is also increased due to HIF1 during hypoxia, coupled with inability of cells to convert pyruvate into acetylCoA by activating of PDK1, which leads to an increase in lactate level [32]. Lactate may strengthen and support activation of HIF by inhibition of prolyl hydroxylases [33]. Thus, during hypoxia the metabolism of pyruvate changes dramatically as a result of coordinate stimulation of lactate dehydrogenase A and inhibition of PDH. As a result, pyruvate is exported from the mitochondria, inhibiting the flux through the tricarboxylic acid cycle and thereby decreasing the delivery of reducing equiva lents to the electrontransport chain [12]. HIF represses lipogenesis. Lipogenesis is an ATP dependent anabolic process that encompasses the processes of conversion of glucose into triglyceride by the action of lipogenic enzymes. It is known that hypoxia inhibits genes of the fatty acid synthase (FAS) and of SREBP (sterol regulatory element binding protein). FAS is the main lipogenic enzyme responsible for the synthesis of endogenous fatty acids. SREBP is a major transactivator for some lipogenic enzymes, particularly FAS [34]. SREBP contains two transmembrane segments and is inserted into membranes of the endoplasmic reticulum (ER) in a hairpin fashion, such that the N and Ctermi nal ends of the protein are in the cytosol. SREBP is syn thesized as an inactive, membranebound precursor, which forms a complex with the SCAP (SREBP cleavage acting protein), a widespread membrane protein that is a component of the sterol sensor. HIF suppresses SREBP by inducing Stra13/DEC1 and its isoforms DEC2, which are bHLH homodimeric
transcriptional repressors. Both Stra13 and DEC2 can react with other types of bHLH proteins including a SREBP. Both suppress SREBPinduced transcription as a result of competition for binding to the Ebox (cisact ing site) in promoters of SREBP. This suggests that the protein–protein interaction between SREBP and Stra13 also prevents SREBP from binding to its potential promoter. During acute oxygen deficiency mRNA expression of DEC2 increases rapidly and systematically, whereas Stra13 level increases during prolonged hypoxia.
HypoxiaInduced Mitochondrial Permeability Transition Pore Opening On the occurrence of stress conditions, mitochon dria respond by induction of the Ca2+/Pidependent mitochondrial permeability transition pore (mPTP) and by releasing a series of proapoptotic proteins from the intermembrane space. The mPTP is a megachannel with diameter of 2.62.9 nm, hence it is permeable for free molecules
REVIEW
Mechanisms of Sensing and Adaptive Responses to Low Oxygen Conditions in Mammals and Yeasts T. A. Trendeleva1*, D. A. Aliverdieva2, and R. A. Zvyagilskaya1 1
Bach Institute of Biochemistry, Russian Academy of Sciences, Leninsky pr. 33/2, 119071 Moscow, Russia; fax: +7 (495) 9542732; Email: [email protected] 2 Caspian Institute of Biological Resources, Russian Academy of Sciences, ul. M. Gadzhieva 45, 367025 Makhachkala, Russia; fax: +7 (8722) 675905; Email: [email protected] Received April 14, 2014 Abstract—Oxygen is required for effective production of ATP and plays a key role in the maintenance of life for all organ isms, excepting strict anaerobes. The ability of aerobic organisms to sense and respond to changes in oxygen level is a basic requirement for their survival. Eukaryotes have developed adaptive mechanisms to sense and respond to decreased oxygen concentrations (hypoxia) through adjustment of oxygen homeostasis by upregulating hypoxic and downregulating aerobic nuclear genes. This review summarizes recent data on mechanisms of cells sensing and responding to changes in oxygen availability in mammals and in yeasts. In the first part of the review, prominence is given to functional regulation and stabi lization of hypoxiainducible factors (HIFs), HIFmediated regulation of electron transport flux and repression of lipoge nesis, as well as to hypoxiainduced mitochondrial permeability transition (pore) opening, cell death, and autophagy. In the second part of the review emphasis is placed on oxygen sensing in nonpathogenic yeasts by heme, unsaturated fatty acids, and sterols, as well as on responses to hypoxia in fungal pathogens. DOI: 10.1134/S0006297914080033 Key words: hypoxia, yeasts, HIF, FIH, Hap1p, SREBP, mPTP
HYPOXIC RESPONSE IN MAMMALS Hypoxia, the reduction of oxygen below its physio logical level, is usually considered pernicious, especially to tissues with high oxygen requirements. Thus, acute oxygen starvation, even for a brief period, can be danger ous. Under natural conditions hypoxia occurs at high altitudes, as a result of intense exercise, and in various respiratory diseases [1, 2]. The fact that cells survive stressful hypoxic condi tions suggests that these responses are mobilized for adap tive compensation of oxygen deficiency [2]. Thus, at the molecular level, a turning point in the evolution of multi Abbreviations: FAS, fatty acid synthase; FIH, factor inhibiting HIF; HIF, hypoxiainducible factor; mPTP, mitochondrial per meability transition pore; ODD, oxygendependent degrada tion domain; PDH, pyruvate dehydrogenase; PHD, prolyl4 hyrdoxylase domain enzymes; ROS, reactive oxygen species; SCAP, SREBP cleavageacting protein; SREBP, sterol regula tory element binding protein; TAD, terminal transactivation domain. * To whom correspondence should be addressed.
cellular organisms was the emergence of transcription factors that regulate gene expression in response to changes in oxygen availability. Such regulation of gene expression alters metabolism, resulting in the predomi nance of anaerobic glycolysis (glycolytic through activa tion of enzymes and glucose transporters) and normaliza tion of mitochondrial respiration.
The HIF Family The family of hypoxiainducible transcriptional fac tors (HIFs) is responsible for the activation of the vast majority of genes involved in adaptive responses of cells to hypoxia [1, 36]. HIF was discovered by Semenza and colleagues and identified as an oxygendependent tran scription factor that is regulated posttranscriptionally at the level of protein stability [7]. HIF is a heterodimeric transcription factor consist ing of an oxygensensitive HIFα subunit and a constitu tive HIFβ subunit, also known as ARNT (aryl hydrocar bon receptor nuclear translocator). Both HIF subunits
750
MECHANISMS OF SENSING AND RESPONSES TO HYPOXIA are members of the family of transcription factors carry ing the PAS domain (periodicaryl hydrocarbon recep torsingleminded), which contains helixloophelix (bHLH). Each subunit contains two PAS domains desig nated as PASA and PASB. The PAS domains typically comprise 100120 amino acid residues folding into a five stranded antiparallel βsheet flanked by several αhelices [8]. There are three HIFα proteins in higher multicellu lar organisms: HIF1α, HIF2α (also known as EPAS1 (endothelial PAS domain protein 1)), the most similar in structure and the best characterized, encoded by inde pendent genes and presumably equally regulated by oxy gen, and also HIF3α. HIF3α, also known as inhibitory PAS domain protein (IPAS), exists in a variety of splice variants, some of which inhibit HIF1α and HIF2α activity in a dominantnegative manner. HIF1α is ubiq uitously expressed in mammalian cells, while HIF2α and HIF3α are selectively expressed in certain tissues, such as vascular endothelial cells, pneumocytes of type II, renal interstitial cells, liver parenchymal cells, and cells of myeloid lineage [9]. Both HIF1α and HIF2α comprise two independ ent ODD domains (oxygendependent degradation) (N ODD and CODD), and two transactivation domains, NTAD (Nterminal transactivation domain) and CTAD (Cterminal transactivation domain). The ODD domain is required for cleavage HIF1α by the ubiquitin–protea some pathway. The NTAD domain contains the bHLH/PAS domains and the nuclear localization signal, and the CTAD comprises two transactivation domains [10, 11]. Transcriptional activation of target genes by HIF1 is a result of binding to the core DNA sequence 5′ RCGTG3′ (where R is G or A) within cisacting hypo xiaresponse elements and recruiting the transacting coactivators p300 and CBP (cAMPresponseelement binding proteinbinding protein) [1, 12]. HIF stabilization. The active synthesis of HIFα pro tein occurs in cells under hypoxia. However, under aero bic conditions it is rapidly degraded by the ubiquitin– proteasome system, whose activity is suppressed immedi ately during a shortage of oxygen, contributing to the rapid accumulation of HIFα [6, 7, 12]. Regulation of the activities of the three HIFα iso forms (HIF1α, HIF2α, and HIF3α) by oxygen is believed to be similar and controlled via fusion, degrada tion, or intracellular localization of the α subunit [1, 5]. Degradation of HIF1α under aerobic conditions is regulated by the oxygendependent activity of a class of proteins called PHDs (prolyl hydroxylase domain enzymes), also known as EGLNs (EGLnine homologs), and factor inhibiting HIF (FIH). There are three known independent PHD (or EGLN) enzymes – EGLN1, 2, and 3 (PHD2, 1, and 3, respectively). Interestingly, these enzymes exhibit substrate specificity: whereas EGLN1 BIOCHEMISTRY (Moscow) Vol. 79 No. 8 2014
751
and 2 are capable of hydroxylating both proline residues of HIFα (Pro402 and Pro564 in human HIF1α) within the ODD domain, EGLN3 cannot interact with the N terminal radical (P402 in human HIF1α). Apparently, EGLN1 is the main HIF prolyl hydroxylase, which has the highest HIF prolyl hydroxylase activity under aerobic conditions, and as a result it sets the HIF1α level under normal conditions [1, 1315]. PHDdependent hydroxylation of the HIF1α sub unit facilitates the binding of HIF1α to the E3 ligase complex of pVHL protein (von Hippel–Lindau tumor suppressor) (a key factor in the cellular response to oxy gen level required for oxygendependent proteolysis of HIFα), mediating polyubiquitination of HIF1α with its subsequent 26Sproteasomal degradation [16]. It should be noted that for full activity of PHD and FIH, the enzymes require the availability of oxygen in addition to iron and the tricarboxylicacidcycle intermediate 2 oxoglutarate for full activity [6, 17]. The asparagine hydroxylase activity of FIH prevents interaction of HIF with transcriptional coactivators, such as CBP/p300, effectively inhibiting the transcriptional activity of HIF1α by hydroxylation of an asparagine residue within CTAD. HIF2α, compared to HIF1α, is relatively resistant to FIH1mediated inactivation. FIH 1 remains active even at low oxygen concentrations com pared to PHDs. As a result, the interaction with pVHL is lost, leading to stabilization of HIF [1, 1315, 18, 19]. Under sustained hypoxia, degradation of the HIFα subunit is inhibited, this allowing the protein to accumu late, heterodimerize, and translocate to the nucleus, where it forms a complex with HIF1β and CBP/p300, thereby upregulating the transcription of various genes of hypoxia [16]. Amplification of hypoxic gene transcription occurs as a consequence of HIFα subunit binding to a specific region of HRE (hypoxia response element), which are consensus sequences in DNA [7, 12]. HIF stabilization and reactive oxygen/nitrogen species. Although the stabilization of HIF1α is probably mainly determined by the concentration of oxygen, regu lating the activity of PHDs, there is a considerable body of evidence that free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) can change the function and/or activity of HIF [2023]. However, hydrogen peroxide, but not superoxide, is required for HIF1α protein stabilization [24]. ROS formed in mitochondria during hypoxia act as signaling agents that trigger different functional responses, includ ing activation of gene expression by stabilization of the HIFα [24, 25]. ROS, especially NO compounds (such as peroxyni trite), can stabilize HIF1α as a result of significant changes in PHDs, such as nitrosylation or changes in the redox state of bivalent iron. However, this stabilization might be a twostep process in which a ROSdependent mechanism that takes place at low oxygen conditions is
752
TRENDELEVA et al.
gradually substituted by inactivation of PHDs, related to lack of oxygen under hypoxic conditions. An increase in oxidative stress due to hypoxia is required for hypoxiainduced transcription of genes [24, 26]. It should be noted that HIF2α, the homolog of HIF1α, also can be regulated by this mechanism. FIH is significantly more sensitive to ROSdependent inactiva tion [17]. HIFmediated regulation of pyruvate dehydrogenase activity and electron transport flux. The key point of the glycolytic pathway is the formation of pyruvate, which under hypoxic conditions in mammals is converted to lactate, and under normal conditions by pyruvate dehy drogenase (PDH) to acetyl coenzyme A (acetylCoA), the first step of the tricarboxylic acid cycle [2729]. PDH activity is controlled by two enzymes: pyruvate dehydrogenase kinase (PDK), which phosphorylates and inactivates the enzyme, and pyruvate dehydrogenase phosphatase, which dephosphorylates the enzyme to the active form [30]. Conversion of pyruvate to acetylCoA by the action of PDH is vital, linking glycolysis and the Krebs cycle [31]. The activity of lactate dehydrogenase A and mono carboxylate transporters is also increased due to HIF1 during hypoxia, coupled with inability of cells to convert pyruvate into acetylCoA by activating of PDK1, which leads to an increase in lactate level [32]. Lactate may strengthen and support activation of HIF by inhibition of prolyl hydroxylases [33]. Thus, during hypoxia the metabolism of pyruvate changes dramatically as a result of coordinate stimulation of lactate dehydrogenase A and inhibition of PDH. As a result, pyruvate is exported from the mitochondria, inhibiting the flux through the tricarboxylic acid cycle and thereby decreasing the delivery of reducing equiva lents to the electrontransport chain [12]. HIF represses lipogenesis. Lipogenesis is an ATP dependent anabolic process that encompasses the processes of conversion of glucose into triglyceride by the action of lipogenic enzymes. It is known that hypoxia inhibits genes of the fatty acid synthase (FAS) and of SREBP (sterol regulatory element binding protein). FAS is the main lipogenic enzyme responsible for the synthesis of endogenous fatty acids. SREBP is a major transactivator for some lipogenic enzymes, particularly FAS [34]. SREBP contains two transmembrane segments and is inserted into membranes of the endoplasmic reticulum (ER) in a hairpin fashion, such that the N and Ctermi nal ends of the protein are in the cytosol. SREBP is syn thesized as an inactive, membranebound precursor, which forms a complex with the SCAP (SREBP cleavage acting protein), a widespread membrane protein that is a component of the sterol sensor. HIF suppresses SREBP by inducing Stra13/DEC1 and its isoforms DEC2, which are bHLH homodimeric
transcriptional repressors. Both Stra13 and DEC2 can react with other types of bHLH proteins including a SREBP. Both suppress SREBPinduced transcription as a result of competition for binding to the Ebox (cisact ing site) in promoters of SREBP. This suggests that the protein–protein interaction between SREBP and Stra13 also prevents SREBP from binding to its potential promoter. During acute oxygen deficiency mRNA expression of DEC2 increases rapidly and systematically, whereas Stra13 level increases during prolonged hypoxia.
HypoxiaInduced Mitochondrial Permeability Transition Pore Opening On the occurrence of stress conditions, mitochon dria respond by induction of the Ca2+/Pidependent mitochondrial permeability transition pore (mPTP) and by releasing a series of proapoptotic proteins from the intermembrane space. The mPTP is a megachannel with diameter of 2.62.9 nm, hence it is permeable for free molecules
