The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes.
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).
Affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.Show MeSH
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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.
Affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.