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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

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)
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Fig3: 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)

Mentions: Mild and transient oxidative stress conditions or energy demanding processes, such as exercise and caloric restriction, can induce mitochondrial biogenesis with its integrated repair gene networks, and thereby produce a larger and healthier population of mitochondria (Lopez-Lluch et al 2006; Safdar et al 2011; Milisav et al 2012; Piantadosi and Suliman 2012; Aquilano et al 2013; Rodell et al 2013). Such cells are more adapted to handle a subsequent event of energy crisis or damaging ROS levels, as for example in connection with an infection or ischemia. This concept that low levels of a mitochondrial damaging agent improve systemic defense mechanisms by inducing an adaptive response has been named mitochondrial hormesis or mitohormesis (Demirovic and Rattan 2013; Ristow and Schmeisser 2014). Thus, in healthy cells mitochondrial biogenesis, in combination with a basal level of mitophagy, is a beneficial and essential process that maintains or improves healthy cell stress responses (Baldelli et al 2014). However, when mitochondria accumulate oxidative damage — for example under pathological conditions in cells with inborn errors of metabolism — the fine-tuned redox regulation of integrated mitochondrial biogenesis and repair systems may be disturbed, and contribute to the accumulation of oxidative stress and cell damage as illustrated in Fig. 3a and b and further discussed below.Fig. 3


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

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

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)
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Related In: Results  -  Collection

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Fig3: 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)
Mentions: Mild and transient oxidative stress conditions or energy demanding processes, such as exercise and caloric restriction, can induce mitochondrial biogenesis with its integrated repair gene networks, and thereby produce a larger and healthier population of mitochondria (Lopez-Lluch et al 2006; Safdar et al 2011; Milisav et al 2012; Piantadosi and Suliman 2012; Aquilano et al 2013; Rodell et al 2013). Such cells are more adapted to handle a subsequent event of energy crisis or damaging ROS levels, as for example in connection with an infection or ischemia. This concept that low levels of a mitochondrial damaging agent improve systemic defense mechanisms by inducing an adaptive response has been named mitochondrial hormesis or mitohormesis (Demirovic and Rattan 2013; Ristow and Schmeisser 2014). Thus, in healthy cells mitochondrial biogenesis, in combination with a basal level of mitophagy, is a beneficial and essential process that maintains or improves healthy cell stress responses (Baldelli et al 2014). However, when mitochondria accumulate oxidative damage — for example under pathological conditions in cells with inborn errors of metabolism — the fine-tuned redox regulation of integrated mitochondrial biogenesis and repair systems may be disturbed, and contribute to the accumulation of oxidative stress and cell damage as illustrated in Fig. 3a and b and further discussed below.Fig. 3

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