Prouteau-Angebault 2013 Abstract IOC75

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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

Claire Prouteau-Angebault

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.  

  1. Sarzi E, Angebault C, Seveno M, Gueguen N, Chaix B, Bielicki G, Boddaert N, Mausset-Bonnefont AL, Cazevieille C, Rigau V, Renou JP, Wang J, Delettre C, Brabet P, Puel JL, Hamel CP, Reynier P, Lenaers G (2012) The human OPA1delTTAG mutation induces premature age-related systemic neurodegeneration in mouse. Brain 135: 3599-3613
  2. Acin-Perez R, Fernandez-Silva P, Peleato ML, Perez-Martos A, Enriquez JA (2008) Respiratory active mitochondrial supercomplexes. Molecular cell 32: 529-539
  3. Gohil VM, Hayes P, Matsuyama S, Schagger H, Schlame M, Greenberg ML (2004) Cardiolipin biosynthesis and mitochondrial respiratory chain function are interdependent. J Biol Chem 279: 42612-42618
  4. Schlame M, Ren M, Xu Y, Greenberg ML, Haller I (2005) Molecular symmetry in mitochondrial cardiolipins. Chem Phys Lipid 138: 38-49
  5. Zhong Q, Gohil VM, Ma L, Greenberg ML (2004) Absence of cardiolipin results in temperature sensitivity, respiratory defects, and mitochondrial DNA instability independent of pet56. J Biol Chem 279: 32294-32300

Keywords: Cardiolipin, Cytochrome c oxidase, OPA1

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 




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