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

Alessia Indrieri, Ivan Conte, Giancarlo Chesi, Alessia Romano, Jade Quartararo, Rosarita Tatè, Daniele Ghezzi, Massimo Zeviani, Paola Goffrini, Ileana Ferrero, Paola Bovolenta, Brunella Franco

Research output: Contribution to journalArticle

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 holo-cytochrome c-type synthase (HCCS) gene. 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. The X-linked disorder microphtalmia with skin lesions (MLS) is caused by HCCS gene mutations. The disease phenotype is now be explained by the increased non-conventional caspase-9 -mediated cell death in the brain and eyes due to HCCS impairment.

Original languageEnglish
Pages (from-to)280-293
Number of pages14
JournalEMBO Molecular Medicine
Volume5
Issue number2
DOIs
Publication statusPublished - Feb 2013

Keywords

  • Apoptosis
  • Eye development
  • Holo-cytochrome c-type synthase
  • Mitochondrial diseases
  • MLS syndrome

ASJC Scopus subject areas

  • Molecular Medicine

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  • Cite this

    Indrieri, A., Conte, I., Chesi, G., Romano, A., Quartararo, J., Tatè, R., Ghezzi, D., Zeviani, M., Goffrini, P., Ferrero, I., Bovolenta, P., & Franco, B. (2013). The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes. EMBO Molecular Medicine, 5(2), 280-293. https://doi.org/10.1002/emmm.201201739