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: The spatio-temporal distribution of developmental cell death has been well characterized in medaka CNS (Iijima & Yokoyama, 2007). In good agreement with this report, in the retina of control embryos we detected the highest peak of TUNEL-positive cells at st24, whereas only occasional apoptotic cells were detected thereafter (Fig 4A and G). In contrast, the retinas of hccs-morphants not only displayed a significant increase in the number of TUNEL-positive cells at st24, but were also characterized by a sustained apoptosis at later stages of development coinciding with the onset of a visible microphthalmia (Fig 4A–D and G).
Affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.