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2015 ; 38
(4
): 703-19
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Redox signalling and mitochondrial stress responses; lessons from inborn errors
of metabolism
#MMPMID26025548
Olsen RK
; Cornelius N
; Gregersen N
J Inherit Metab Dis
2015[Jul]; 38
(4
): 703-19
PMID26025548
show ga
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.