Prouteau-Angebault 2013 Abstract IOC75
Prouteau-Angebault C (2013) Are cardiolipins involved in the mitochondrial respiratory chain defect in OPA1 mouse model? Mitochondr Physiol Network 18.03. |
Link: IOC75 Open Access
Prouteau-Angebault C, Sarzi E, Seveno M, Gueguen N, Hamel CP, Reynier P, Lenaers G (2013)
Event: IOC75
Autosomal Dominant Optic Atrophy (ADOA) is a mitochondrial blinding disease caused by mutation in the OPA1 gene. This pathology, first described as isolated, is today commonly associated with ataxia, sensorineural deafness, sensory-motor neuropathy and myopathy in syndromic forms. Although the specific loss of retinal ganglion cells has already been addressed, the in-depth pathophysiology and the tissue-specificity remain to be understood. We generated and characterized an Opa1 mouse model carrying the mutation c.2708delTTAG and showed that it presents a syndromic clinical presentation including optic atrophy, deafness, encephalomyopathy, peripheral neuropathy, ataxia and cardiopathy. At cellular level, we observed axonal and myelin degenerations, increase of autophagy and mitophagy. Associated with these morphological changes, we observed a tissue-dependent mitochondrial dysfunction in primary affected tissues: retina, optic nerve and glycolytic muscles [1]. Further investigations in glycolytic muscle show that the COX defect is not related to a reduction of COX subunit amounts, nor to abnormal assembly of holoenzyme, but to a premature age-related decrease in the stability of mitochondrial supercomplexes (SC), leading to the accumulation of isolated monomers, which have lower efficiency in transferring electrons along the mitochondrial respiratory chain than when assembled into SC [2]. Interestingly, we know that cardiolipins (CL), which are specific phospholipid components of the mitochondrial inner membrane, play a key role in the COX assembly and activity, which in turn regulate CL biosynthesis [3]. CL contents vary among cell types, conferring more stability to the respiratory chain in oxidative tissues [4], and their abundance is also correlated to mtDNA content modifications [5]. We hypothesize that Opa1 dysfunction could alter CL availability and consequently modify in a tissue-specific way, the COX-related SC stability, and consequently the mitochondrial respiratory chain activities, which require further in depth characterizations. β
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β’ Keywords: Cardiolipin, Cytochrome c oxidase, OPA1
β’ O2k-Network Lab: FR Angers Gueguen N, FR Montpellier Prouteau-Angebault C
Labels: MiParea: Respiration Pathology: Neurodegenerative
Organism: Mouse Tissue;cell: Skeletal muscle, Nervous system Preparation: Permeabilized cells, Homogenate, Isolated mitochondria Enzyme: Complex IV;cytochrome c oxidase Regulation: Redox state Coupling state: OXPHOS Pathway: N, S, CIV HRR: Oxygraph-2k