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 impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes / A., Indrieri; I., Conte; G., Chesi; A., Romano; Quartararo, Jade; R., Tatè; D., Ghezzi; M., Zeviani; Goffrini, Paola; FERRERO FORTUNATI, Iliana; P., Bovolenta; B., Franco. - In: EMBO MOLECULAR MEDICINE. - ISSN 1757-4676. - 5:2(2013), pp. 280-293. [10.1002/emmm.201201739]

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

QUARTARARO, Jade;GOFFRINI, Paola;FERRERO FORTUNATI, Iliana;
2013-01-01

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.
2013
The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes / A., Indrieri; I., Conte; G., Chesi; A., Romano; Quartararo, Jade; R., Tatè; D., Ghezzi; M., Zeviani; Goffrini, Paola; FERRERO FORTUNATI, Iliana; P., Bovolenta; B., Franco. - In: EMBO MOLECULAR MEDICINE. - ISSN 1757-4676. - 5:2(2013), pp. 280-293. [10.1002/emmm.201201739]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2560044
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