OPA1 cleavage mediates impaired mitochondrial dynamics in an experimental model of Parkinsonism.

ALAIMO, A; GOROJOD R.; SAPIENZA C; KOTLER M.L.

Huerta Grande, Provincia de Córdoba, Argentina

Congreso; II Reunión conjunta Taller Argentino de Neurociencias-Sociedad Argentina de Investigación en Neurociencias; 2010

Sociedad Argentina de Neurociencia

Neurotoxicity due to excessive manganese (Mn) accumulation in the brain leads to Manganism, a neurodegenerative pathology, whose symptoms resemble tho­se of Idiopathic Parkinson’s Disease. Mn is mainly accumulated in astrocyte´s mi­tochondria which continuously undergo fusion/fission events to form a dynamic tubular network (DTN). OPA1 is a fusion GTPase involved in cristae remodeling and maintenance; its cleavage and complexes disassembly lead to DTN disinte­gration and cell death. Previously, we have reported mitochondrial morphology alterations and OPA1 processing in astrocytoma C6 cells Mn- induced apoptosis, an experimental model of Parkinsonism. The present work demonstrates that mitochondrial membrane potential collapse, and consequent opening of mPTP by Mn, has drastic consequences on DTN integrity. Cyclosporin A (mPTP inhibi­tor) nearly avoided mitochondria fragmentation and OPA1 cleavage. Moreover, C6 cells transiently transfected either WT or Q297V (disassembly-resistant mutant) OPA1 cDNA3 resulted in cell viability protection, reduced number of apoptotic nuclei and maintenance of DTN integrity. Our results suggest that OPA1 has a bi­functional role, promoting mitochondrial fusion, and regulating apoptosis by pla­ying as an anti-apoptotic protein.