Unknown

Dataset Information

0

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


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.

SUBMITTER: Indrieri A 

PROVIDER: S-EPMC3569643 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Indrieri Alessia A   Conte Ivan I   Chesi Giancarlo G   Romano Alessia A   Quartararo Jade J   Tatè Rosarita R   Ghezzi Daniele D   Zeviani Massimo M   Goffrini Paola P   Ferrero Ileana I   Bovolenta Paola P   Franco Brunella B  

EMBO molecular medicine 20130122 2


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 developme  ...[more]

Similar Datasets

| S-EPMC4021606 | biostudies-literature
| S-EPMC7658709 | biostudies-literature
| S-EPMC6168390 | biostudies-literature
| S-EPMC6477508 | biostudies-literature
2022-10-10 | GSE185542 | GEO
| S-EPMC3841111 | biostudies-literature
2019-12-04 | PXD013821 | Pride
| S-EPMC5859474 | biostudies-literature
2024-05-15 | GSE248792 | GEO
| S-EPMC3104026 | biostudies-literature