Defects in mitochondrial respiratory chain (RC) are linked to many neurodegenerative disorders, and specifically to rare
mitochondrial diseases, such as Complex III (CIII) deficiency. Symptoms of CIII deficiency include encephalopathy, optic atrophy and muscle weakness. Genetic defects preventing the incorporation of the Rieske iron sulfur protein (RISP) in the mitochondrial CIII lead to CIII deficiency. Loss of RISP function has been shown to trigger oxidative-stress dependent neurodegeneration in mice, however the underlying molecular mechanisms are unknown. Degenerating neurons often exhibit apoptotic (caspase dependent) and necrotic (caspase independent) hallmarks. While a lot is known on apoptosis, much less is understood on necrotic pathways and their regulation. In addition, the distinct contribution of these forms of cell death to neurodegeneration is still unclear.
Using the Drosophila RISP mutant, we have established a genetic model of necrosis to dissect the pathways of necrotic cell death and their role in the pathogenesis of disorders due to RC defects. RISPmutant photoreceptor neurons showed progressive degeneration with necrotic morphology, and no apparent developmental defect. In situ analysis of caspase activity suggests that necrotic pathways are predominant in our model. Through genetic and biochemical approaches, we have identified candidate pathways of necrosis in the RISP mutant. We are currently dissecting these pathways, and analyzing their interaction with apoptosis and with potential neuroprotective mechanisms, such as autophagy and oxidative stress response.
Clarifying the multiplicity of cell death mechanisms will provide potential therapeutic strategies for effective cytoprotection in human diseases due to mitochondrial dysfunction.
