OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion
1Dipartimento di Biologia Evoluzionistica Sperimentale, Università di Bologna, Italy, 2Biochemistry Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 3Molecular Genetics Laboratory, University Eye Hospital, Tuebingen, Germany, 4Dipartimento di Scienze Biomediche, Sezione di Patologia Generale, Università di Modena e Reggio Emilia and 5Dipartimento di Scienze Neurologiche, Università di Bologna, Italy
Correspondence to: Dr Claudia Zanna, Dipartimento di Biologia Evoluzionistica Sperimentale, Università di Bologna, Via Irnerio 42, 40126 Bologna, Italy E-mail: zanna{at}alma.unibo.it
Dominant optic atrophy (DOA) is characterized by retinal ganglion cell degeneration leading to optic neuropathy. A subset of DOA is caused by mutations in the OPA1 gene, encoding for a dynamin-related GTPase required for mitochondrial fusion. The functional consequences of OPA1 mutations in DOA patients are still poorly understood. This study investigated the effect of five different OPA1 pathogenic mutations on the energetic efficiency and mitochondrial network dynamics of skin fibroblasts from patients. Although DOA fibroblasts maintained their ATP levels and grew in galactose medium, i.e. under forced oxidative metabolism, a significant impairment in mitochondrial ATP synthesis driven by complex I substrates was found. Furthermore, balloon-like structures in the mitochondrial reticulum were observed in galactose medium and mitochondrial fusion was completely inhibited in about 50% of DOA fibroblasts, but not in control cells. Respiratory complex assembly and the expression level of complex I subunits were similar in control and DOA fibroblasts. Co-immunoprecipitation experiments revealed that OPA1 directly interacts with subunits of complexes I, II and III, but not IV and with apoptosis inducing factor. The results disclose a novel link between OPA1, apoptosis inducing factor and the respiratory complexes that may shed some light on the pathogenic mechanism of DOA.
Key Words: OPA1; DOA; oxidative phosphorylation; mitochondrial fusion; AIF
Abbreviations: AIF, apoptosis inducing factor; DMEM, Dulbecco's modified Eagle's medium; mito-PAGFP, mitochondrial matrix-targeted photoactivable green fluorescent protein; mtDNA, mitochondrial DNA; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide; RGC, retinal ganglion cell
.
Received July 27, 2007. Revised December 18, 2007. Accepted December 19, 2007.
*These authors contributed equally to this work.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Verburg and P. J. Hollenbeck Mitochondrial Membrane Potential in Axons Increases with Local Nerve Growth Factor or Semaphorin Signaling J. Neurosci., August 13, 2008; 28(33): 8306 - 8315. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zeviani OPA1 mutations and mitochondrial DNA damage: keeping the magic circle in shape Brain, February 1, 2008; 131(2): 314 - 317. [Full Text] [PDF]
|
|