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Redox signalling and mitochondrial stress responses; lessons from inborn errors of metabolism.

Olsen RK, Cornelius N, Gregersen N - J. Inherit. Metab. Dis. (2015)

Bottom Line: Based on our own and other's studies we re-introduce the ROS triangle model and discuss how inborn errors of mitochondrial metabolism, by production of pathological amounts of ROS, may cause disturbed redox signalling and induce chronic cell stress with non-resolving or compromised cell repair responses and increased susceptibility to cell stress induced cell death.We suggest that this model may have important implications for those inborn errors of metabolism, where mitochondrial dysfunction plays a major role, as it allows the explanation of oxidative stress, metabolic reprogramming and altered signalling growth pathways that have been reported in many of the diseases.It is our hope that the model may facilitate novel ideas and directions that can be tested experimentally and used in the design of future new approaches for pre-symptomatic diagnosis and prognosis and perhaps more effective treatments of inborn errors of metabolism.

View Article: PubMed Central - PubMed

Affiliation: Research Unit for Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark, rikke.olsen@clin.au.dk.

ABSTRACT
Mitochondria play a key role in overall cell physiology and health by integrating cellular metabolism with cellular defense and repair mechanisms in response to physiological or environmental changes or stresses. In fact, dysregulation of mitochondrial stress responses and its consequences in the form of oxidative stress, has been linked to a wide variety of diseases including inborn errors of metabolism. In this review we will summarize how the functional state of mitochondria -- and especially the concentration of reactive oxygen species (ROS), produced in connection with the respiratory chain -- regulates cellular stress responses by redox regulation of nuclear gene networks involved in repair systems to maintain cellular homeostasis and health. Based on our own and other's studies we re-introduce the ROS triangle model and discuss how inborn errors of mitochondrial metabolism, by production of pathological amounts of ROS, may cause disturbed redox signalling and induce chronic cell stress with non-resolving or compromised cell repair responses and increased susceptibility to cell stress induced cell death. We suggest that this model may have important implications for those inborn errors of metabolism, where mitochondrial dysfunction plays a major role, as it allows the explanation of oxidative stress, metabolic reprogramming and altered signalling growth pathways that have been reported in many of the diseases. It is our hope that the model may facilitate novel ideas and directions that can be tested experimentally and used in the design of future new approaches for pre-symptomatic diagnosis and prognosis and perhaps more effective treatments of inborn errors of metabolism.

No MeSH data available.


Related in: MedlinePlus

An integrated gene network links mitochondrial biogenesis to cell repair functions. AMPK and Nrf2 are central players in activating this gene network during oxidative stress, as both proteins are activated by redox modification of critical cysteine residues as described in the text. Nrf2 directly binds to promoters of a number of antioxidant (HO-1, GPxs, Prxs, catalase, SOD), anti-inflammatory proteins (IL10, IL1Ra), as well as autophagy (p62) and proteasomal (PSMB5) proteins, and also to proteins (G6PD, IDH1, ME), needed for synthesis and regeneration of the antioxidant NADPH as described in the text. Sirtuin-1 (SIRT1) activates AMPK via de-acetylation of LKB1, which subsequently triggers AMPK activation by phosphorylation. Activated AMPK phosphorylates downstream targets like PGC-1α, which upon de-acetylation binds to and co-activates transcription factors involved in mitochondrial biogenesis and dynamics such as the nuclear respiratory factors (NRF-1 and NRF-2). NRF-1 in turn binds to and modulates expression of other factors such as mitochondrial DNA polymerase (Polγ) and mitochondrial transcription factor A (Tfam), which regulate mtDNA replication and transcription, and also binds to and activates a number of genes required for oxidative phosphorylation (OXPHOS) through expression of respiratory chain components. PGC-1α can also activate the nuclear estrogen-related receptors (ERRα), which binds to the promoters of fatty acid oxidation enzymes (FAO) and to the promoter of the NAD+-dependent deacetylase, sirtuin-3 (SIRT3), which is required for post-translational activation of a number of metabolic and antioxidant enzymes located inside mitochondria. PGC-1α can also directly activate the expression of antioxidant and FAO enzymes by co-activating PPARs. PPARs comprise three members; PPARα, PPARβ and PPARγ, each responsible for tissue specific activation of FAO and antioxidant proteins, albeit with some overlap. When activated any of the PPARs can induce the expression of PGC-1α. Moreover, AMPK can phosphorylate the FOXO3a upon oxidative stress to promote its nuclear translocation and expression of antioxidants (MnSOD, catalase, Prxs) and autophagy (Atg5, LC3II) proteins. FOXO3a also binds to the promoter of the AMPK-activating protein kinase LKB1, the SIRT1 promoter and to the Nampt gene promoter and induces NAD+ synthesis and further AMPK activation. AMPK also up-regulates glycolysis by increasing fructose-2,6-biphosphate concentrations through phosphorylation of PFK2. Finally, AMPK can phosphorylate tuberous sclerosis complex 2 (TSC2) and thereby inhibit mTOR, which is a negative regulator of authophagy and an activator of HIF-1α. Thus, to sustain energy requiring repair function during cellular stress, AMPK activates mitochondrial biogenesis and inhibits energy-demanding cellular functions, such as cell growth, and immune responses. The inhibitory effects of AMPK on immune responses are likely to be indirect and governed by downstream mediators such as SIRT1 mediated de-acetylation and inactivation of NF-κB. NF-κB signalling is also kept in an inactive state by Nrf2. Nuclear translocation of NF-κB requires activation by an IKKβ kinase, which like Nrf2 is targeted for proteasomal degradation by Keap1. When Nrf2 is released from Keap1 by moderate increases in oxidative stress, there is an increase in unbound Keap1 available for IKKβ binding, thus inhibiting the expression of NF-κB target genes. Abbreviations not explained in the text are: Atg5; autophagy protein 5, G6PD; glucose-6-phosphate dehydrogenase, IDH1; isocitrate dehydrogenase 1, LC3II; the phosphatidylethanolamine form of microtubule-associated protein 1A/1B-light chain 3, ME; malic enzyme, PFK2; phosphofructokinase 2, and PSMB5; proteasome subunit beta type 5. The symbol “¤” indicates that the proteins are inactivated by SIRT1 mediated de-acetylation. Activated proteins are in black and repressed once in grey
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Fig2: An integrated gene network links mitochondrial biogenesis to cell repair functions. AMPK and Nrf2 are central players in activating this gene network during oxidative stress, as both proteins are activated by redox modification of critical cysteine residues as described in the text. Nrf2 directly binds to promoters of a number of antioxidant (HO-1, GPxs, Prxs, catalase, SOD), anti-inflammatory proteins (IL10, IL1Ra), as well as autophagy (p62) and proteasomal (PSMB5) proteins, and also to proteins (G6PD, IDH1, ME), needed for synthesis and regeneration of the antioxidant NADPH as described in the text. Sirtuin-1 (SIRT1) activates AMPK via de-acetylation of LKB1, which subsequently triggers AMPK activation by phosphorylation. Activated AMPK phosphorylates downstream targets like PGC-1α, which upon de-acetylation binds to and co-activates transcription factors involved in mitochondrial biogenesis and dynamics such as the nuclear respiratory factors (NRF-1 and NRF-2). NRF-1 in turn binds to and modulates expression of other factors such as mitochondrial DNA polymerase (Polγ) and mitochondrial transcription factor A (Tfam), which regulate mtDNA replication and transcription, and also binds to and activates a number of genes required for oxidative phosphorylation (OXPHOS) through expression of respiratory chain components. PGC-1α can also activate the nuclear estrogen-related receptors (ERRα), which binds to the promoters of fatty acid oxidation enzymes (FAO) and to the promoter of the NAD+-dependent deacetylase, sirtuin-3 (SIRT3), which is required for post-translational activation of a number of metabolic and antioxidant enzymes located inside mitochondria. PGC-1α can also directly activate the expression of antioxidant and FAO enzymes by co-activating PPARs. PPARs comprise three members; PPARα, PPARβ and PPARγ, each responsible for tissue specific activation of FAO and antioxidant proteins, albeit with some overlap. When activated any of the PPARs can induce the expression of PGC-1α. Moreover, AMPK can phosphorylate the FOXO3a upon oxidative stress to promote its nuclear translocation and expression of antioxidants (MnSOD, catalase, Prxs) and autophagy (Atg5, LC3II) proteins. FOXO3a also binds to the promoter of the AMPK-activating protein kinase LKB1, the SIRT1 promoter and to the Nampt gene promoter and induces NAD+ synthesis and further AMPK activation. AMPK also up-regulates glycolysis by increasing fructose-2,6-biphosphate concentrations through phosphorylation of PFK2. Finally, AMPK can phosphorylate tuberous sclerosis complex 2 (TSC2) and thereby inhibit mTOR, which is a negative regulator of authophagy and an activator of HIF-1α. Thus, to sustain energy requiring repair function during cellular stress, AMPK activates mitochondrial biogenesis and inhibits energy-demanding cellular functions, such as cell growth, and immune responses. The inhibitory effects of AMPK on immune responses are likely to be indirect and governed by downstream mediators such as SIRT1 mediated de-acetylation and inactivation of NF-κB. NF-κB signalling is also kept in an inactive state by Nrf2. Nuclear translocation of NF-κB requires activation by an IKKβ kinase, which like Nrf2 is targeted for proteasomal degradation by Keap1. When Nrf2 is released from Keap1 by moderate increases in oxidative stress, there is an increase in unbound Keap1 available for IKKβ binding, thus inhibiting the expression of NF-κB target genes. Abbreviations not explained in the text are: Atg5; autophagy protein 5, G6PD; glucose-6-phosphate dehydrogenase, IDH1; isocitrate dehydrogenase 1, LC3II; the phosphatidylethanolamine form of microtubule-associated protein 1A/1B-light chain 3, ME; malic enzyme, PFK2; phosphofructokinase 2, and PSMB5; proteasome subunit beta type 5. The symbol “¤” indicates that the proteins are inactivated by SIRT1 mediated de-acetylation. Activated proteins are in black and repressed once in grey

Mentions: The distinct actors of the repair systems — such as antioxidant enzymes, DNA repair enzymes, chaperones and proteases — require energy and other mitochondrial products like NAD+ for their functional activity. Therefore, the cell needs to adapt or expand its mitochondrial population during episodes of cell damage by the induction of mitochondrial biogenesis (Piantadosi and Suliman 2012). Mitochondria exist as a tubular network in the cells, and they are not generated de novo. Rather, healthy mitochondria in the network are stimulated to proliferate, while defective mitochondria are selected and removed by mitophagy (Youle and van der Bliek 2012; Archer 2013). The peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α protein (PGC-1α) is a major upstream regulator of the gene network that controls mitochondrial biogenesis. PGC-1α is activated and regulated by a multitude of mechanisms (Scarpulla et al 2012; Suliman and Piantadosi 2014). For the present discussion, we will focus on its potential activation during oxidative conditions (Fig. 2).Fig. 2


Redox signalling and mitochondrial stress responses; lessons from inborn errors of metabolism.

Olsen RK, Cornelius N, Gregersen N - J. Inherit. Metab. Dis. (2015)

An integrated gene network links mitochondrial biogenesis to cell repair functions. AMPK and Nrf2 are central players in activating this gene network during oxidative stress, as both proteins are activated by redox modification of critical cysteine residues as described in the text. Nrf2 directly binds to promoters of a number of antioxidant (HO-1, GPxs, Prxs, catalase, SOD), anti-inflammatory proteins (IL10, IL1Ra), as well as autophagy (p62) and proteasomal (PSMB5) proteins, and also to proteins (G6PD, IDH1, ME), needed for synthesis and regeneration of the antioxidant NADPH as described in the text. Sirtuin-1 (SIRT1) activates AMPK via de-acetylation of LKB1, which subsequently triggers AMPK activation by phosphorylation. Activated AMPK phosphorylates downstream targets like PGC-1α, which upon de-acetylation binds to and co-activates transcription factors involved in mitochondrial biogenesis and dynamics such as the nuclear respiratory factors (NRF-1 and NRF-2). NRF-1 in turn binds to and modulates expression of other factors such as mitochondrial DNA polymerase (Polγ) and mitochondrial transcription factor A (Tfam), which regulate mtDNA replication and transcription, and also binds to and activates a number of genes required for oxidative phosphorylation (OXPHOS) through expression of respiratory chain components. PGC-1α can also activate the nuclear estrogen-related receptors (ERRα), which binds to the promoters of fatty acid oxidation enzymes (FAO) and to the promoter of the NAD+-dependent deacetylase, sirtuin-3 (SIRT3), which is required for post-translational activation of a number of metabolic and antioxidant enzymes located inside mitochondria. PGC-1α can also directly activate the expression of antioxidant and FAO enzymes by co-activating PPARs. PPARs comprise three members; PPARα, PPARβ and PPARγ, each responsible for tissue specific activation of FAO and antioxidant proteins, albeit with some overlap. When activated any of the PPARs can induce the expression of PGC-1α. Moreover, AMPK can phosphorylate the FOXO3a upon oxidative stress to promote its nuclear translocation and expression of antioxidants (MnSOD, catalase, Prxs) and autophagy (Atg5, LC3II) proteins. FOXO3a also binds to the promoter of the AMPK-activating protein kinase LKB1, the SIRT1 promoter and to the Nampt gene promoter and induces NAD+ synthesis and further AMPK activation. AMPK also up-regulates glycolysis by increasing fructose-2,6-biphosphate concentrations through phosphorylation of PFK2. Finally, AMPK can phosphorylate tuberous sclerosis complex 2 (TSC2) and thereby inhibit mTOR, which is a negative regulator of authophagy and an activator of HIF-1α. Thus, to sustain energy requiring repair function during cellular stress, AMPK activates mitochondrial biogenesis and inhibits energy-demanding cellular functions, such as cell growth, and immune responses. The inhibitory effects of AMPK on immune responses are likely to be indirect and governed by downstream mediators such as SIRT1 mediated de-acetylation and inactivation of NF-κB. NF-κB signalling is also kept in an inactive state by Nrf2. Nuclear translocation of NF-κB requires activation by an IKKβ kinase, which like Nrf2 is targeted for proteasomal degradation by Keap1. When Nrf2 is released from Keap1 by moderate increases in oxidative stress, there is an increase in unbound Keap1 available for IKKβ binding, thus inhibiting the expression of NF-κB target genes. Abbreviations not explained in the text are: Atg5; autophagy protein 5, G6PD; glucose-6-phosphate dehydrogenase, IDH1; isocitrate dehydrogenase 1, LC3II; the phosphatidylethanolamine form of microtubule-associated protein 1A/1B-light chain 3, ME; malic enzyme, PFK2; phosphofructokinase 2, and PSMB5; proteasome subunit beta type 5. The symbol “¤” indicates that the proteins are inactivated by SIRT1 mediated de-acetylation. Activated proteins are in black and repressed once in grey
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig2: An integrated gene network links mitochondrial biogenesis to cell repair functions. AMPK and Nrf2 are central players in activating this gene network during oxidative stress, as both proteins are activated by redox modification of critical cysteine residues as described in the text. Nrf2 directly binds to promoters of a number of antioxidant (HO-1, GPxs, Prxs, catalase, SOD), anti-inflammatory proteins (IL10, IL1Ra), as well as autophagy (p62) and proteasomal (PSMB5) proteins, and also to proteins (G6PD, IDH1, ME), needed for synthesis and regeneration of the antioxidant NADPH as described in the text. Sirtuin-1 (SIRT1) activates AMPK via de-acetylation of LKB1, which subsequently triggers AMPK activation by phosphorylation. Activated AMPK phosphorylates downstream targets like PGC-1α, which upon de-acetylation binds to and co-activates transcription factors involved in mitochondrial biogenesis and dynamics such as the nuclear respiratory factors (NRF-1 and NRF-2). NRF-1 in turn binds to and modulates expression of other factors such as mitochondrial DNA polymerase (Polγ) and mitochondrial transcription factor A (Tfam), which regulate mtDNA replication and transcription, and also binds to and activates a number of genes required for oxidative phosphorylation (OXPHOS) through expression of respiratory chain components. PGC-1α can also activate the nuclear estrogen-related receptors (ERRα), which binds to the promoters of fatty acid oxidation enzymes (FAO) and to the promoter of the NAD+-dependent deacetylase, sirtuin-3 (SIRT3), which is required for post-translational activation of a number of metabolic and antioxidant enzymes located inside mitochondria. PGC-1α can also directly activate the expression of antioxidant and FAO enzymes by co-activating PPARs. PPARs comprise three members; PPARα, PPARβ and PPARγ, each responsible for tissue specific activation of FAO and antioxidant proteins, albeit with some overlap. When activated any of the PPARs can induce the expression of PGC-1α. Moreover, AMPK can phosphorylate the FOXO3a upon oxidative stress to promote its nuclear translocation and expression of antioxidants (MnSOD, catalase, Prxs) and autophagy (Atg5, LC3II) proteins. FOXO3a also binds to the promoter of the AMPK-activating protein kinase LKB1, the SIRT1 promoter and to the Nampt gene promoter and induces NAD+ synthesis and further AMPK activation. AMPK also up-regulates glycolysis by increasing fructose-2,6-biphosphate concentrations through phosphorylation of PFK2. Finally, AMPK can phosphorylate tuberous sclerosis complex 2 (TSC2) and thereby inhibit mTOR, which is a negative regulator of authophagy and an activator of HIF-1α. Thus, to sustain energy requiring repair function during cellular stress, AMPK activates mitochondrial biogenesis and inhibits energy-demanding cellular functions, such as cell growth, and immune responses. The inhibitory effects of AMPK on immune responses are likely to be indirect and governed by downstream mediators such as SIRT1 mediated de-acetylation and inactivation of NF-κB. NF-κB signalling is also kept in an inactive state by Nrf2. Nuclear translocation of NF-κB requires activation by an IKKβ kinase, which like Nrf2 is targeted for proteasomal degradation by Keap1. When Nrf2 is released from Keap1 by moderate increases in oxidative stress, there is an increase in unbound Keap1 available for IKKβ binding, thus inhibiting the expression of NF-κB target genes. Abbreviations not explained in the text are: Atg5; autophagy protein 5, G6PD; glucose-6-phosphate dehydrogenase, IDH1; isocitrate dehydrogenase 1, LC3II; the phosphatidylethanolamine form of microtubule-associated protein 1A/1B-light chain 3, ME; malic enzyme, PFK2; phosphofructokinase 2, and PSMB5; proteasome subunit beta type 5. The symbol “¤” indicates that the proteins are inactivated by SIRT1 mediated de-acetylation. Activated proteins are in black and repressed once in grey
Mentions: The distinct actors of the repair systems — such as antioxidant enzymes, DNA repair enzymes, chaperones and proteases — require energy and other mitochondrial products like NAD+ for their functional activity. Therefore, the cell needs to adapt or expand its mitochondrial population during episodes of cell damage by the induction of mitochondrial biogenesis (Piantadosi and Suliman 2012). Mitochondria exist as a tubular network in the cells, and they are not generated de novo. Rather, healthy mitochondria in the network are stimulated to proliferate, while defective mitochondria are selected and removed by mitophagy (Youle and van der Bliek 2012; Archer 2013). The peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α protein (PGC-1α) is a major upstream regulator of the gene network that controls mitochondrial biogenesis. PGC-1α is activated and regulated by a multitude of mechanisms (Scarpulla et al 2012; Suliman and Piantadosi 2014). For the present discussion, we will focus on its potential activation during oxidative conditions (Fig. 2).Fig. 2

Bottom Line: Based on our own and other's studies we re-introduce the ROS triangle model and discuss how inborn errors of mitochondrial metabolism, by production of pathological amounts of ROS, may cause disturbed redox signalling and induce chronic cell stress with non-resolving or compromised cell repair responses and increased susceptibility to cell stress induced cell death.We suggest that this model may have important implications for those inborn errors of metabolism, where mitochondrial dysfunction plays a major role, as it allows the explanation of oxidative stress, metabolic reprogramming and altered signalling growth pathways that have been reported in many of the diseases.It is our hope that the model may facilitate novel ideas and directions that can be tested experimentally and used in the design of future new approaches for pre-symptomatic diagnosis and prognosis and perhaps more effective treatments of inborn errors of metabolism.

View Article: PubMed Central - PubMed

Affiliation: Research Unit for Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark, rikke.olsen@clin.au.dk.

ABSTRACT
Mitochondria play a key role in overall cell physiology and health by integrating cellular metabolism with cellular defense and repair mechanisms in response to physiological or environmental changes or stresses. In fact, dysregulation of mitochondrial stress responses and its consequences in the form of oxidative stress, has been linked to a wide variety of diseases including inborn errors of metabolism. In this review we will summarize how the functional state of mitochondria -- and especially the concentration of reactive oxygen species (ROS), produced in connection with the respiratory chain -- regulates cellular stress responses by redox regulation of nuclear gene networks involved in repair systems to maintain cellular homeostasis and health. Based on our own and other's studies we re-introduce the ROS triangle model and discuss how inborn errors of mitochondrial metabolism, by production of pathological amounts of ROS, may cause disturbed redox signalling and induce chronic cell stress with non-resolving or compromised cell repair responses and increased susceptibility to cell stress induced cell death. We suggest that this model may have important implications for those inborn errors of metabolism, where mitochondrial dysfunction plays a major role, as it allows the explanation of oxidative stress, metabolic reprogramming and altered signalling growth pathways that have been reported in many of the diseases. It is our hope that the model may facilitate novel ideas and directions that can be tested experimentally and used in the design of future new approaches for pre-symptomatic diagnosis and prognosis and perhaps more effective treatments of inborn errors of metabolism.

No MeSH data available.


Related in: MedlinePlus