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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

Reactive oxygen species (ROS) regulate cellular stress responses by redox regulation of transcription factors, phosphatases/kinases and chromatin structure that control nuclear gene networks to maintain cellular homeostasis and health as described in the text. Most intracellular ROS is produced inside mitochondria by the electron transport chain (ETC). The NADPH oxidases (NOX) and the xanthine oxidase (XO) also contribute to cellular ROS production. Superoxide (·O2−) is the main initial free radical species, which can be converted to other ROS and reactive nitrogen species as described in the text. Abbreviations are: GPxs; gluthathion peroxidases, Prxs; peroxiredoxines, HO-1; hemeoxygenase-1, and SOD; superoxide dismutase
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Fig1: Reactive oxygen species (ROS) regulate cellular stress responses by redox regulation of transcription factors, phosphatases/kinases and chromatin structure that control nuclear gene networks to maintain cellular homeostasis and health as described in the text. Most intracellular ROS is produced inside mitochondria by the electron transport chain (ETC). The NADPH oxidases (NOX) and the xanthine oxidase (XO) also contribute to cellular ROS production. Superoxide (·O2−) is the main initial free radical species, which can be converted to other ROS and reactive nitrogen species as described in the text. Abbreviations are: GPxs; gluthathion peroxidases, Prxs; peroxiredoxines, HO-1; hemeoxygenase-1, and SOD; superoxide dismutase

Mentions: Although ROS are generated from many sources, including the Nox family of NADPH oxidases, cytochrome P450 enzymes and xanthine oxidase, over 90 % of intracellular ROS is produced inside mitochondria. ROS, in the form of superoxide radical anions (O2.-) are produced by incomplete reduction of oxygen or by leak of electrons from the respiratory chain, mostly complex I and III. However, also other mitochondrial enzymes like complex II, the electron transfer flavoprotein (ETF) and its ubiquinone oxidoreductase (ETF:QO), α-ketogluterate dehydrogenase and glycerol-3-phosphate dehydrogenase have been implicated in ROS production (Dröse and Brandt 2012; Goncalves et al 2015). Whereas all these mitochondrial enzymes release superoxide in the matrix, complex III releases superoxide both in the matrix and the intermembrane space. Superoxide is highly reactive and in toxic levels can oxidize and damage the structure and function of other molecules in the cell or react with nitric oxide (·NO) that leads to the formation of the highly deleterious peroxynitrite species (ONOO−). To prevent these harmful reactions, superoxide is rapidly converted into hydrogen peroxide (H2O2) by the superoxide dismutases (SOD). In the presence of transition metals such as iron or cupper, hydrogen peroxide can be further reduced to the highly reactive hydroxyl radical (.OH) by the Fenton reaction, or be detoxified to water by peroxiredoxins (Prxs), glutathione peroxidases (GPxs) or catalase. All these ROS scavenger enzymes function to limit ROS or reactive nitrogen species (RNS) induced oxidative damage, but important for the content of this review, also to buffer cellular ROS species (especially H2O2), and bring them to a level at which they function as signalling molecules between mitochondrial function and redox activation of cell stress protective pathways (Bolisetty and Jaimes 2013) (Fig. 1).Fig. 1


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

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

Reactive oxygen species (ROS) regulate cellular stress responses by redox regulation of transcription factors, phosphatases/kinases and chromatin structure that control nuclear gene networks to maintain cellular homeostasis and health as described in the text. Most intracellular ROS is produced inside mitochondria by the electron transport chain (ETC). The NADPH oxidases (NOX) and the xanthine oxidase (XO) also contribute to cellular ROS production. Superoxide (·O2−) is the main initial free radical species, which can be converted to other ROS and reactive nitrogen species as described in the text. Abbreviations are: GPxs; gluthathion peroxidases, Prxs; peroxiredoxines, HO-1; hemeoxygenase-1, and SOD; superoxide dismutase
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4493798&req=5

Fig1: Reactive oxygen species (ROS) regulate cellular stress responses by redox regulation of transcription factors, phosphatases/kinases and chromatin structure that control nuclear gene networks to maintain cellular homeostasis and health as described in the text. Most intracellular ROS is produced inside mitochondria by the electron transport chain (ETC). The NADPH oxidases (NOX) and the xanthine oxidase (XO) also contribute to cellular ROS production. Superoxide (·O2−) is the main initial free radical species, which can be converted to other ROS and reactive nitrogen species as described in the text. Abbreviations are: GPxs; gluthathion peroxidases, Prxs; peroxiredoxines, HO-1; hemeoxygenase-1, and SOD; superoxide dismutase
Mentions: Although ROS are generated from many sources, including the Nox family of NADPH oxidases, cytochrome P450 enzymes and xanthine oxidase, over 90 % of intracellular ROS is produced inside mitochondria. ROS, in the form of superoxide radical anions (O2.-) are produced by incomplete reduction of oxygen or by leak of electrons from the respiratory chain, mostly complex I and III. However, also other mitochondrial enzymes like complex II, the electron transfer flavoprotein (ETF) and its ubiquinone oxidoreductase (ETF:QO), α-ketogluterate dehydrogenase and glycerol-3-phosphate dehydrogenase have been implicated in ROS production (Dröse and Brandt 2012; Goncalves et al 2015). Whereas all these mitochondrial enzymes release superoxide in the matrix, complex III releases superoxide both in the matrix and the intermembrane space. Superoxide is highly reactive and in toxic levels can oxidize and damage the structure and function of other molecules in the cell or react with nitric oxide (·NO) that leads to the formation of the highly deleterious peroxynitrite species (ONOO−). To prevent these harmful reactions, superoxide is rapidly converted into hydrogen peroxide (H2O2) by the superoxide dismutases (SOD). In the presence of transition metals such as iron or cupper, hydrogen peroxide can be further reduced to the highly reactive hydroxyl radical (.OH) by the Fenton reaction, or be detoxified to water by peroxiredoxins (Prxs), glutathione peroxidases (GPxs) or catalase. All these ROS scavenger enzymes function to limit ROS or reactive nitrogen species (RNS) induced oxidative damage, but important for the content of this review, also to buffer cellular ROS species (especially H2O2), and bring them to a level at which they function as signalling molecules between mitochondrial function and redox activation of cell stress protective pathways (Bolisetty and Jaimes 2013) (Fig. 1).Fig. 1

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