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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

Molecular mechanisms of chronic disease progression in which persistent or increased ROS/damage load and/or decreased levels of NAD+ drive the transition from AMPK/PGC-1α/FOXO3a-linked repair responses towards pro-inflammatory responses controlled by the mTOR/HIF-1α/NF-κB axis. See text for further explanation
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Fig4: Molecular mechanisms of chronic disease progression in which persistent or increased ROS/damage load and/or decreased levels of NAD+ drive the transition from AMPK/PGC-1α/FOXO3a-linked repair responses towards pro-inflammatory responses controlled by the mTOR/HIF-1α/NF-κB axis. See text for further explanation

Mentions: The ROS triangle model links increasing ROS and damage to chronic stress adaptation with non-resolving repair responses (green graphic), or compromised repair responses that drive a more pro-inflammatory environment (orange graphic). The antagonistic cell stress responses are linked to distinct cellular metabolism through redox-sensitive nutrient-sensing signalling growth pathways that control a Warburg-like shift from mitochondrial respiration (AMPK/PGC-1α) towards mostly cytosolic glycolysis (mTOR/HIF-1α). ROS, but also NAD+, are the most important mitochondrial signalling molecules that drive the transition from one stage of the triangle to another as discussed in the text and illustrated in Fig. 4. When oxidative stress becomes too high to allow cell stress adaptive redox signalling, apoptosis and cell death are induced (red graphic) (a). In the sick cell, chronic non-resolving repair responses or inflammatory responses will dominate depending on the duration and/or level of ROS load. In the healthy cell, well-controlled physiological levels of ROS allow healthy redox signalling and dynamic cell stress responses to ensure that inflammatory and damaging cell responses are followed by repair responses to restore homeostasis. The ROS range, at which dynamic healthy redox signalling is taking place, to regulate transient physiological changes or stressors like cell growth/differentiation and inflammation/repair, is called the homeodynamic space. Mild and transient oxidative stress, such as exercise and caloric restriction, increases the homeodynamic space by boosting repair responses, and prevent chronic disease development. IEM and other persistent ROS-inducers decrease the homeodynamic space, making the cells more prone to chronic disease development (b)


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

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

Molecular mechanisms of chronic disease progression in which persistent or increased ROS/damage load and/or decreased levels of NAD+ drive the transition from AMPK/PGC-1α/FOXO3a-linked repair responses towards pro-inflammatory responses controlled by the mTOR/HIF-1α/NF-κB axis. See text for further explanation
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Molecular mechanisms of chronic disease progression in which persistent or increased ROS/damage load and/or decreased levels of NAD+ drive the transition from AMPK/PGC-1α/FOXO3a-linked repair responses towards pro-inflammatory responses controlled by the mTOR/HIF-1α/NF-κB axis. See text for further explanation
Mentions: The ROS triangle model links increasing ROS and damage to chronic stress adaptation with non-resolving repair responses (green graphic), or compromised repair responses that drive a more pro-inflammatory environment (orange graphic). The antagonistic cell stress responses are linked to distinct cellular metabolism through redox-sensitive nutrient-sensing signalling growth pathways that control a Warburg-like shift from mitochondrial respiration (AMPK/PGC-1α) towards mostly cytosolic glycolysis (mTOR/HIF-1α). ROS, but also NAD+, are the most important mitochondrial signalling molecules that drive the transition from one stage of the triangle to another as discussed in the text and illustrated in Fig. 4. When oxidative stress becomes too high to allow cell stress adaptive redox signalling, apoptosis and cell death are induced (red graphic) (a). In the sick cell, chronic non-resolving repair responses or inflammatory responses will dominate depending on the duration and/or level of ROS load. In the healthy cell, well-controlled physiological levels of ROS allow healthy redox signalling and dynamic cell stress responses to ensure that inflammatory and damaging cell responses are followed by repair responses to restore homeostasis. The ROS range, at which dynamic healthy redox signalling is taking place, to regulate transient physiological changes or stressors like cell growth/differentiation and inflammation/repair, is called the homeodynamic space. Mild and transient oxidative stress, such as exercise and caloric restriction, increases the homeodynamic space by boosting repair responses, and prevent chronic disease development. IEM and other persistent ROS-inducers decrease the homeodynamic space, making the cells more prone to chronic disease development (b)

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