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.  

[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(Pt 12):3599-613.

[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. The Journal of biological chemistry 279: 42612-42618.

[4] Schlame M, Ren M, Xu Y, Greenberg ML, Haller I. 2005. Molecular symmetry in mitochondrial cardiolipins. Chemistry and physics of lipids 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. The Journal of biological chemistry 279: 32294-32300.

• Keywords: cardiolipin, cytochrome c oxidase, OPA1

Labels:

Stress:Mitochondrial Disease; Degenerative Disease and Defect"Mitochondrial Disease; Degenerative Disease and Defect" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property.  Organism: Mouse  Tissue;cell: Skeletal muscle, Nervous system  Preparation: Permeabilized cells, Homogenate, Isolated Mitochondria"Isolated Mitochondria" is not in the list (Intact organism, Intact organ, Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, SMP, Chloroplasts, Enzyme, Oxidase;biochemical oxidation, ...) of allowed values for the "Preparation" property.  Enzyme: Complex IV; Cytochrome c Oxidase"Complex IV; Cytochrome c Oxidase" is not in the list (Adenine nucleotide translocase, Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Inner mt-membrane transporter, Marker enzyme, Supercomplex, TCA cycle and matrix dehydrogenases, ...) of allowed values for the "Enzyme" property.  Regulation: Redox State"Redox State" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property.  Coupling state: OXPHOS 

HRR: Oxygraph-2k, Spectrophotometry"Spectrophotometry" is not in the list (Oxygraph-2k, TIP2k, O2k-Fluorometer, pH, NO, TPP, Ca, O2k-Spectrophotometer, O2k-Manual, O2k-Protocol, ...) of allowed values for the "Instrument and method" property. 

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