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EMBO Mol Med. 2013 Feb;5(2):280-93. doi: 10.1002/emmm.201201739. Epub 2013 Jan 22.

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

Author information

1
Telethon Institute of Genetics and Medicine, Naples, Italy.

Erratum in

  • EMBO Mol Med. 2014 Jun;6(6):849.

Abstract

Mitochondrial-dependent (intrinsic) programmed cell death (PCD) is an essential homoeostatic mechanism that selects bioenergetically proficient cells suitable for tissue/organ development. However, the link between mitochondrial dysfunction, intrinsic apoptosis and developmental anomalies has not been demonstrated to date. Now we provide the evidence that non-canonical mitochondrial dependent apoptosis explains the phenotype of microphthalmia with linear skin lesions (MLS), an X-linked developmental disorder caused by mutations in the holocytochrome c-type synthase (HCCS)gene [corrected]. 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). We thus propose that HCCS plays a key role in central nervous system (CNS) development by modulating a novel non-canonical start-up of cell death and provide the first experimental evidence for a mechanistic link between mitochondrial dysfunction, intrinsic apoptosis and developmental disorders.

PMID:
23239471
PMCID:
PMC3569643
DOI:
10.1002/emmm.201201739
[Indexed for MEDLINE]
Free PMC Article

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