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Emmanuelle Sarzi, Allel Chabli, Marie Seveno, Christian P Hamel, Agnes Müller, Guy Lenaers, Cecile Delettre; Retinal cardiolipin metabolism is altered in a mouse model of Dominant Optic Atrophy.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3321.
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© ARVO (1962-2015); The Authors (2016-present)
OPA1 mutations are responsible for Autosomal Dominant Optic Atrophy (ADOA), one of the most frequent hereditary optic neuropathies, characterized by retinal ganglion cell degeneration, the underlying mechanisms of which are poorly understood. We previously described the existence of a mitochondrial complex IV defect due to respiratory chain supercomplex instability in retina of the Opa1delTTAG mouse model, contributing to ADOA pathophysiology. Thus, here we tested the hypothesis of retinal cardiolipin metabolism modification in mitochondria responsible for these respiratory chain alterations. Indeed, cardiolipins are specific phospholipids of the inner mitochondrial membrane which have a key role in the stabilization of respiratory chain supercomplexes and in particular mitochondrial complex IV.
Using the mouse model carrying the human recurrent OPA1 mutation, we quantifiedin retina (n=3-5) cardiolipins and cardiolipin precursors, monolysocardiolipins (MLCL) by LC-MS/MS. Quantification of these compounds is crucial to assess the quality and efficiency of cardiolipin synthesis and remodeling.
Although the total amount of cardiolipin was unchanged, we disclosed in retinal samples increased amount of the major specie of cardiolipins, i.e. cardiolipins containing 18-carbon fatty alkyl chains with two unsaturated bonds on each of them (0.213±0.015 vs 0.405±0.13). We also found a significant increase in MLCL (0.059±0.012 vs 0.100±0.009) in these retinal samples.
Thus, our results showed that Opa1 haploinsufficiency impacts cardiolipin metabolism in the retina. Considering that cardiolipins and MLCL amounts are modified, our results pointed to the alteration of both synthesis and remodelling of cardiolipins. In consequence, cardiolipin quality and quantity are modified in Opa1 mouse retinas leading to mitochondrial inner membrane structural modification and promoting mitochondrial complex IV defect.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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