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The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes.

Indrieri A, Conte I, Chesi G, Romano A, Quartararo J, Tatè R, Ghezzi D, Zeviani M, Goffrini P, Ferrero I, Bovolenta P, Franco B - EMBO Mol Med (2013)

Bottom Line: Mitochondrial-dependent (intrinsic) programmed cell death (PCD) is an essential homoeostatic mechanism that selects bioenergetically proficient cells suitable for tissue/organ development.By taking advantage of a medaka model that recapitulates the MLS phenotype we demonstrate that downregulation of hccs, an essential player of the mitochondrial respiratory chain (MRC), causes increased cell death via an apoptosome-independent caspase-9 activation in brain and eyes.We also show that the unconventional activation of caspase-9 occurs in the mitochondria and is triggered by MRC impairment and overproduction of reactive oxygen species (ROS).

View Article: PubMed Central - PubMed

Affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.

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Model for apoptosome-independent, ROS-dependent, mitochondrial caspase-9 activation in the absence of HCCSThe mitochondrial electron transfer system, complexes I–V (CI-CV), is illustrated. Red arrows indicate an increase (upward) or decrease (downward) in each physiological parameter. Bar-headed lines indicate inhibition. OMM, outer mitochondrial membrane; IMS, intermembrane space; IMM, inner mitochondrial membrane.Canonical mitochondrial-dependent cell death pathway. In the presence of HCCS, upon apoptotic stimuli, holo-Cytc is released from mitochondria and binds Apaf1 and Pro-caspase-9 in the cytoplasm inducing the formation of the apoptosome and the sequential activation of caspase-9.In HCCS deficient condition the lack of holo-Cytc leads to inhibition of the MRC with the subsequent increase of ROS levels, which results in Apaf1-independent caspase-9 activation into mitochondria.
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fig07: Model for apoptosome-independent, ROS-dependent, mitochondrial caspase-9 activation in the absence of HCCSThe mitochondrial electron transfer system, complexes I–V (CI-CV), is illustrated. Red arrows indicate an increase (upward) or decrease (downward) in each physiological parameter. Bar-headed lines indicate inhibition. OMM, outer mitochondrial membrane; IMS, intermembrane space; IMM, inner mitochondrial membrane.Canonical mitochondrial-dependent cell death pathway. In the presence of HCCS, upon apoptotic stimuli, holo-Cytc is released from mitochondria and binds Apaf1 and Pro-caspase-9 in the cytoplasm inducing the formation of the apoptosome and the sequential activation of caspase-9.In HCCS deficient condition the lack of holo-Cytc leads to inhibition of the MRC with the subsequent increase of ROS levels, which results in Apaf1-independent caspase-9 activation into mitochondria.

Mentions: Besides their role in energy production, mitochondria are also key regulators of PCD through the mitochondrial-dependent pathway. According to previous studies, in the absence of hccs, cells should not activate the canonical intrinsic apoptotic pathway owing to the absence of Cytc (Li et al, 2000; Fig 7A). However, our results provide the experimental evidence that hccs deficiency induces a non-canonical caspase-9 activation that is independent from apoptosome formation and occur into mitochondria. We hypothesized that hccs deficiency might induce caspase activation and cell death by MRC impairment and overproduction of ROS, mostly derived from complex III (St-Pierre et al, 2002). Interestingly, antioxidant treatment significantly ameliorated the phenotype of hccs-morphants indicating that enhanced levels of ROS due to MRC impairment triggers PCD, ultimately leading to the CNS abnormalities observed in morphants. Therefore, we conclude that hccs, besides driving Cytc synthesis, is endowed with a previously unknown role in a novel start-up of non-canonical cell death pathway (Fig 7B). The correct regulation of this pathway can be crucial for the proper development of the brain and the eyes. Our data strongly support a role for mitochondrial caspase-9 activation in pathological conditions. ROS seem to act as cell signalling molecules with a central role in physiological cellular responses (Miki & Funato, 2012). Therefore, the non-canonical cell death pathway we described here may likely operate in different physiological context that we hope to elucidate in the future.


The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes.

Indrieri A, Conte I, Chesi G, Romano A, Quartararo J, Tatè R, Ghezzi D, Zeviani M, Goffrini P, Ferrero I, Bovolenta P, Franco B - EMBO Mol Med (2013)

Model for apoptosome-independent, ROS-dependent, mitochondrial caspase-9 activation in the absence of HCCSThe mitochondrial electron transfer system, complexes I–V (CI-CV), is illustrated. Red arrows indicate an increase (upward) or decrease (downward) in each physiological parameter. Bar-headed lines indicate inhibition. OMM, outer mitochondrial membrane; IMS, intermembrane space; IMM, inner mitochondrial membrane.Canonical mitochondrial-dependent cell death pathway. In the presence of HCCS, upon apoptotic stimuli, holo-Cytc is released from mitochondria and binds Apaf1 and Pro-caspase-9 in the cytoplasm inducing the formation of the apoptosome and the sequential activation of caspase-9.In HCCS deficient condition the lack of holo-Cytc leads to inhibition of the MRC with the subsequent increase of ROS levels, which results in Apaf1-independent caspase-9 activation into mitochondria.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569643&req=5

fig07: Model for apoptosome-independent, ROS-dependent, mitochondrial caspase-9 activation in the absence of HCCSThe mitochondrial electron transfer system, complexes I–V (CI-CV), is illustrated. Red arrows indicate an increase (upward) or decrease (downward) in each physiological parameter. Bar-headed lines indicate inhibition. OMM, outer mitochondrial membrane; IMS, intermembrane space; IMM, inner mitochondrial membrane.Canonical mitochondrial-dependent cell death pathway. In the presence of HCCS, upon apoptotic stimuli, holo-Cytc is released from mitochondria and binds Apaf1 and Pro-caspase-9 in the cytoplasm inducing the formation of the apoptosome and the sequential activation of caspase-9.In HCCS deficient condition the lack of holo-Cytc leads to inhibition of the MRC with the subsequent increase of ROS levels, which results in Apaf1-independent caspase-9 activation into mitochondria.
Mentions: Besides their role in energy production, mitochondria are also key regulators of PCD through the mitochondrial-dependent pathway. According to previous studies, in the absence of hccs, cells should not activate the canonical intrinsic apoptotic pathway owing to the absence of Cytc (Li et al, 2000; Fig 7A). However, our results provide the experimental evidence that hccs deficiency induces a non-canonical caspase-9 activation that is independent from apoptosome formation and occur into mitochondria. We hypothesized that hccs deficiency might induce caspase activation and cell death by MRC impairment and overproduction of ROS, mostly derived from complex III (St-Pierre et al, 2002). Interestingly, antioxidant treatment significantly ameliorated the phenotype of hccs-morphants indicating that enhanced levels of ROS due to MRC impairment triggers PCD, ultimately leading to the CNS abnormalities observed in morphants. Therefore, we conclude that hccs, besides driving Cytc synthesis, is endowed with a previously unknown role in a novel start-up of non-canonical cell death pathway (Fig 7B). The correct regulation of this pathway can be crucial for the proper development of the brain and the eyes. Our data strongly support a role for mitochondrial caspase-9 activation in pathological conditions. ROS seem to act as cell signalling molecules with a central role in physiological cellular responses (Miki & Funato, 2012). Therefore, the non-canonical cell death pathway we described here may likely operate in different physiological context that we hope to elucidate in the future.

Bottom Line: Mitochondrial-dependent (intrinsic) programmed cell death (PCD) is an essential homoeostatic mechanism that selects bioenergetically proficient cells suitable for tissue/organ development.By taking advantage of a medaka model that recapitulates the MLS phenotype we demonstrate that downregulation of hccs, an essential player of the mitochondrial respiratory chain (MRC), causes increased cell death via an apoptosome-independent caspase-9 activation in brain and eyes.We also show that the unconventional activation of caspase-9 occurs in the mitochondria and is triggered by MRC impairment and overproduction of reactive oxygen species (ROS).

View Article: PubMed Central - PubMed

Affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.

Show MeSH
Related in: MedlinePlus