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 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.

miR‐181a/b downregulation exerts a protective action on mitochondrial disease models

“…MLS is a neurodevelopmental disorder characterized by microphthalmia, brain abnormalities, and skin defects in heterozygous females and in utero lethality in hemizygous males (Indrieri & Franco, ). The disease is due to mutations in key players of the MRC, such as the holocytochrome c‐type synthase ( HCCS ), involved in complex III function (Bernard et al , ; Wimplinger et al , ; Indrieri et al , ), and COX7B, the 7B subunit of cytochrome c oxidase (MRC complex IV) (Indrieri et al , ). We previously generated two medakafish ( Oryzias latipes ) models of MLS by knocking down, using a Morpholino(MO)‐based approach, hccs or cox7B expression (Indrieri et al , , ).…”

Whole exome sequence analysis of Peters anomaly

“…Deletions of HCCS are common in MLS, however, missense and a nonsense variant have also been reported (Wimplinger et al 2006). Involvement of HCCS in the Peters anomaly phenotype may relate to its role in promoting apoptosis (Indrieri et al 2013) which is thought to play a role in the separation of the lens vesicle from the overlying surface ectoderm.…”

Mitochondrial cytochrome c biogenesis: no longer an enigma

“…Likewise, an HCCS E159A variant in domain II displays a property similar to domain I alanine substitutions with an increase in cyt c release relative to WT (biosynthesized) [42]. This contrasts with the domain II MLS variant HCCS E159K, which shows a decrease in both heme binding and in released cyt c, thus resulting in a cyt c biogenesis defect seen in yeast, recombinant E. coli , and in humans [42, 50, 84]. The HCCS Glu159 results suggests that changes to the opposite charge (Glu to Lys) impact interactions with heme differently than a neutral substitution (Glu to Ala).…”