The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes.
Bottom Line: Mitochondrial-dependent (intrinsic) programmed cell death (PCD) is an essential homoeostatic mechanism that selects bioenergetically proficient cells suitable for tissue/organ development.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).
Affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.Show MeSH
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Mentions: When the respiratory chain is inhibited downstream of complex III, electrons coming from succinate oxidation can lead to ROS generation by reverse electron transport from complex II to complex I (Lambert & Brand, 2004; St-Pierre et al, 2002). ROS production can also increase when electron transport is reduced as a consequence of low respiratory rates (Korshunov et al, 1997) or in pathological situations associated to MRC defects (Wallace, 2005). Accordingly, H2O2-induced growth inhibition was markedly increased in the B-8025-Δcyc3 strain defective for heme lyase function (Supporting Information Fig S8), as were ROS levels in hccs-morphants as determined by accumulation of oxidized CM-H2DCFDA (Fig 6A). Notably, in vitro experimental evidence suggested that ROS could directly mediate mitochondrial caspase-9 auto-activation, inducing cell death via an apoptosome-independent pathway (Katoh et al, 2008, 2004). We thus hypothesized that caspase-dependent cell death induced by hccs deficiency could be linked to MRC impairment and ROS overproduction. Indeed, detection of mitochondrial superoxide by MitoSOX staining revealed a specific increase of mitochondrial ROS levels in the CNS of alive morphants compared to controls (Supporting Information Fig S9).
Affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.