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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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Analysis of cell proliferation in hccs-morphant embryosA–D. Immunohistochemistry with α-pHH3. Embryos injected with control-MO (A, B) and with hccs-MO (C, D). Scale bars: 20 µm.E. Number of pHH3-positive cells normalized for area (mm2). At st24 and st30 morphant embryos do not show abnormalities in cell proliferation (n ≥ 5 embryos/stage, error bars are SEM).
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fig03: Analysis of cell proliferation in hccs-morphant embryosA–D. Immunohistochemistry with α-pHH3. Embryos injected with control-MO (A, B) and with hccs-MO (C, D). Scale bars: 20 µm.E. Number of pHH3-positive cells normalized for area (mm2). At st24 and st30 morphant embryos do not show abnormalities in cell proliferation (n ≥ 5 embryos/stage, error bars are SEM).

Mentions: Heart-specific Hccs inactivation delays cardiomyocyte proliferation in the mouse (Drenckhahn et al, 2008), and HCCS and Cytc have been implicated in caspase-dependent PCD (Jiang & Wang, 2004; Kiryu-Seo et al, 2006). Thus, we determined whether alterations in proliferation and/or apoptosis in hccs-morphants could account for the microphthalmia and the other observed CNS abnormalities. Immunostaining for phosphorylated histone H3 (pHH3), a specific marker for cells in M-phase, revealed no significant differences between the number of proliferating cells in the neural retina and RPE of morphants versus control embryos neither at st24, when the ocular phenotype can first be detected, nor at st30 (Fig 3A–E) when the microphthalmic phenotype is evident.


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)

Analysis of cell proliferation in hccs-morphant embryosA–D. Immunohistochemistry with α-pHH3. Embryos injected with control-MO (A, B) and with hccs-MO (C, D). Scale bars: 20 µm.E. Number of pHH3-positive cells normalized for area (mm2). At st24 and st30 morphant embryos do not show abnormalities in cell proliferation (n ≥ 5 embryos/stage, error bars are SEM).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig03: Analysis of cell proliferation in hccs-morphant embryosA–D. Immunohistochemistry with α-pHH3. Embryos injected with control-MO (A, B) and with hccs-MO (C, D). Scale bars: 20 µm.E. Number of pHH3-positive cells normalized for area (mm2). At st24 and st30 morphant embryos do not show abnormalities in cell proliferation (n ≥ 5 embryos/stage, error bars are SEM).
Mentions: Heart-specific Hccs inactivation delays cardiomyocyte proliferation in the mouse (Drenckhahn et al, 2008), and HCCS and Cytc have been implicated in caspase-dependent PCD (Jiang & Wang, 2004; Kiryu-Seo et al, 2006). Thus, we determined whether alterations in proliferation and/or apoptosis in hccs-morphants could account for the microphthalmia and the other observed CNS abnormalities. Immunostaining for phosphorylated histone H3 (pHH3), a specific marker for cells in M-phase, revealed no significant differences between the number of proliferating cells in the neural retina and RPE of morphants versus control embryos neither at st24, when the ocular phenotype can first be detected, nor at st30 (Fig 3A–E) when the microphthalmic phenotype is evident.

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