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: Non-canonical apoptosome-independent caspase-9 activation has been observed in few specific conditions (Hao et al, 2005; Ho et al, 2004; Katoh et al, 2008; Manns et al, 2011; Mills et al, 2006). To determine the mechanism of caspase-9 activation in hccs-morphants, we thus co-injected hccs-MO with a MO designed against Apaf1 (Apaf1-MO). Apaf1 down-regulation protected the embryos from staurosporine induced PCD but failed to rescue PCD in hccs-morphants. At st30, the large majority of co-injected embryos were in fact morphologically undistinguishable from hccs-morphants with a similar number of apoptotic cells (Fig 5A–C and G and Supporting Information Table S1). These data clearly involve non-canonical, apoptosome-independent caspase-9 activation in the pathogenesis of microphthalmia.
Affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.