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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

Mitochondria are present in most tissues, and decline in mitochondrial function and signalling is a common finding in many chronic diseases and ageing. As such, we suggest that comorbidity is clinical expression of mitochondrial dysfunction, and that research in chronic disease development and prevention should be directed towards targeting mitochondrial signalling and pathways
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Fig5: Mitochondria are present in most tissues, and decline in mitochondrial function and signalling is a common finding in many chronic diseases and ageing. As such, we suggest that comorbidity is clinical expression of mitochondrial dysfunction, and that research in chronic disease development and prevention should be directed towards targeting mitochondrial signalling and pathways

Mentions: A recent special issue of Science celebrated a resumed interest in metabolism and discussed a new metabolic paradigm for disease (Ray 2010). The increasing use of system biological approaches has driven this new understanding for disease development with a realization that altered nutrient-sensing signalling growth pathways and metabolic reprogramming, towards a more glycolytic metabolism, drives the initiation or progression of most diseases, like cancer, diabetes, neurodegenerative diseases, cardiovascular diseases and IEM. As discussed in the present review, mitochondria are absolutely central for this metabolic paradigm for disease as these organelles do not only provide the cell with energy and biosynthetic intermediates for cell growth, but also for support of ROS- and energy-dependent mechanisms like those involved in cell defense and the repair of cell and tissue damage (Fig. 5). Therefore, to move present knowledge towards clinical applicability will require scientists to incorporate mitochondrial stress responses and the principle of the ROS triangle model into understanding the altered nutrient-sensing signalling growth pathway and metabolic reprogramming revealed in many chronic diseases during the last decade.Fig. 5


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

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

Mitochondria are present in most tissues, and decline in mitochondrial function and signalling is a common finding in many chronic diseases and ageing. As such, we suggest that comorbidity is clinical expression of mitochondrial dysfunction, and that research in chronic disease development and prevention should be directed towards targeting mitochondrial signalling and pathways
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig5: Mitochondria are present in most tissues, and decline in mitochondrial function and signalling is a common finding in many chronic diseases and ageing. As such, we suggest that comorbidity is clinical expression of mitochondrial dysfunction, and that research in chronic disease development and prevention should be directed towards targeting mitochondrial signalling and pathways
Mentions: A recent special issue of Science celebrated a resumed interest in metabolism and discussed a new metabolic paradigm for disease (Ray 2010). The increasing use of system biological approaches has driven this new understanding for disease development with a realization that altered nutrient-sensing signalling growth pathways and metabolic reprogramming, towards a more glycolytic metabolism, drives the initiation or progression of most diseases, like cancer, diabetes, neurodegenerative diseases, cardiovascular diseases and IEM. As discussed in the present review, mitochondria are absolutely central for this metabolic paradigm for disease as these organelles do not only provide the cell with energy and biosynthetic intermediates for cell growth, but also for support of ROS- and energy-dependent mechanisms like those involved in cell defense and the repair of cell and tissue damage (Fig. 5). Therefore, to move present knowledge towards clinical applicability will require scientists to incorporate mitochondrial stress responses and the principle of the ROS triangle model into understanding the altered nutrient-sensing signalling growth pathway and metabolic reprogramming revealed in many chronic diseases during the last decade.Fig. 5

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