- Research article
- Open Access
Mitochondrial oxidative phosphorylation in autosomal dominant optic atrophy
© Mayorov et al; licensee BioMed Central Ltd. 2008
- Received: 29 April 2008
- Accepted: 10 September 2008
- Published: 10 September 2008
Autosomal dominant optic atrophy (ADOA), a form of progressive bilateral blindness due to loss of retinal ganglion cells and optic nerve deterioration, arises predominantly from mutations in the nuclear gene for the mitochondrial GTPase, OPA1. OPA1 localizes to mitochondrial cristae in the inner membrane where electron transport chain complexes are enriched. While OPA1 has been characterized for its role in mitochondrial cristae structure and organelle fusion, possible effects of OPA1 on mitochondrial function have not been determined.
Mitochondria from six ADOA patients bearing OPA1 mutations and ten ADOA patients with unidentified gene mutations were studied for respiratory capacity and electron transport complex function. Results suggest that the nuclear DNA mutations that give rise to ADOA in our patient population do not alter mitochondrial electron transport.
We conclude that the pathophysiology of ADOA likely stems from the role of OPA1 in mitochondrial structure or fusion and not from OPA1 support of oxidative phosphorylation.
- Lymphoblast Cell Line
- Nonsense Mediate mRNA Decay
- Autosomal Dominant Optic Atrophy
- Electron Transport Chain Complex
- Gene OPA1
Autosomal dominant optic atrophy (ADOA) is a progressive form of bilateral blindness that shares the end-stage clinical characteristics of retinal gangln cell (RGC) death and optic nerve atrophy with the mitochondrial disease, Leber's hereditary optic neuropathy (LHON) . ADOA, also referred to as Kjer's disease (OMIM 165500), has an earlier onset than LHON, with patients presenting mainly during childhood or adolescence. Unlike LHON, which results from mutations in mitochondrial DNA (mtDNA)-encoded complex I subunits, ADOA disease results primarily from mutations in two nuclear genes, OPA1 at 3q28 and OPA4 at 18q12, and displays incomplete penetrance and variable expressivity in families [2–7]. OPA1 mutations are responsible for the majority of reported ADOA cases and nearly half of the reported disease mutations give rise to a truncated OPA1 protein . OPA1 encodes a 960 amino acid mitochondrial dynamin-related GTPase that resides in the inner membrane cristae and plays an essential role in cristae structure and mitochondrial fusion [8–16]. However, the relationship between these roles for OPA1 and the relationship of either function to cellular energy production remain to be elucidated.
While OPA1 is critical for optic nerve function, the mechanism by which OPA1 mutations lead to blindness is unknown . A few studies have found ADOA patient OPA1 defects to be associated with diminished ATP synthesis and aberrant mitochondrial architecture at the tissue and cellular level [17–19]. Since cellular structure and nuclear gene expression differs between neurons and most cell types used for analysis of ATP production in ADOA, OPA1 mutations may reduce cellular ATP synthesis by different molecular mechanisms in each cell type . Without an analysis of isolated mitochondria from ADOA patients harboring OPA1 mutations, it remains unclear whether the reduced ATP production in cells arises from a biochemical defect in respiratory function or is secondary to a frank disruption of mitochondrial membrane morphology or mitochondrial biogenesis [17, 20, 21]. Due to its location in the cristae of the inner membrane, the OPA1 protein may support OXPHOS through interactions with electron transport chain complexes, by maintaining a membrane topology conducive to efficient electron transfer, or by facilitating the fusion of mitochondria into networks that are more responsive to cellular ATP demand. Haploinsufficiency for OPA1 has been suggested as the primary cause of heterozygote phenotypes based on the finding that a downregulation of OPA1 results in cristae disorganization and mitochondrial aggregation, however the level of OPA1 found in some ADOA patient cell lysates was near that of controls [19, 20, 22, 23]. In our study, we examined mitochondria from patients harboring ADOA OPA1 mutations to determine whether the protein defects alter mitochondrial respiration.
OPA1 mutations in OPA1-positive ADOA patients
Patient Cell Lines
All patients in this study were examined by two experienced neuro-ophthalmologists (NJN, VB) and had clinical symptoms, age of onset, and family histories typical for ADOA, as described previously . Informed consent was obtained from each study participant using an institutional IRB approved consent form. OPA1 exons and intron/exon junctions were sequenced for all patients and a complete characterization of the ADOA-associated OPA1 variants have been described in detail in . None harbored known LHON mtDNA mutations. Lymphoblast cell lines were established by EBV transformation of leukocytes isolated from whole blood by Ficoll-Hypaque gradient . Lymphoblastoid cell lines were maintained in RPMI 1640 medium (Bio-Whitaker, Walkersville, MD) supplemented with 15% (v/v) heat-inactivated fetal bovine serum (Life Technologies, Inc., Grand Isle, NY).
Mitochondrial Isolation, Polarography, and Enzymology
All procedures for mitochondrial isolation, polarographic respiration analysis and respiratory chain enzymology have been previously described [25–27]. Briefly, for respiration studies, electrons were entered at either complex I (using either malate + pyruvate or glutamate + malate as substrate) or complex II (using succinate as the substrate) using intact whole mitochondria. Two polarographic runs were performed for each substrate and each run included two additions of ADP (125 nmole for complex I substrates and 75 nmole for succinate) to stimulate state III and subsequent state IV respiration. Each run was concluded by the addition of the OXPHOS uncoupler, 2,4-dinitrophenol (DNP) to assess maximal respiration rates. All runs were performed with 250 – 500 μg of mitochondrial protein.
OXPHOS specific enzyme activities in submitochondrial particles were measured using a Varian Cary 300 Bio UV/Vis spectrophotometer [25–27]. Briefly, mitochondrial protein was prepared by sonication of isolated organelles. Complex I activity was monitored in triplicate samples as the reduction of 10 μM decylubiquinone at 272 nm by 30 μg of mitochondrial protein with 30 μM NADH. Using this method, 90–100% of the total complex I activity is sensitive to rotenone inhibition. Complex III and complex IV activities were determined at 550 nm in duplicate samples containing 7.5 μg mitochondrial protein and appropriate substrates. Complex III activity was assayed as the antimycin A-sensitive oxidation of reduced decylubiquinone by cytochrome c. Using this method, complex III activity is 75 – 100% antimycin A sensitive. Complex IV activity was determined by the cyanide-sensitive oxidation of cytochrome c. Citrate synthase was assayed at 412 nm in duplicate samples containing 15 μg of mitochondrial protein.
For all samples, mitochondrial protein concentration was determined using the modified Lowry assay and mitochondrial preparations were not used for biochemical analysis if the protein concentration was below 2 mg/ml. Further, all mitochondrial preparations exhibited a respiratory control ratio of ≥ 4, indicative of a high quality mitochondrial isolation as evidenced by well-coupled mitochondria upon polarographic analysis (data not shown) [25, 28]. Statistical significance for all data (p < 0.05) was determined by the Mann-Whitney unpaired, two-tailed test using Instat Graphpad Software [25, 29].
Polarographic analysis of ADOA patient and control mitochondria
Mean respiration rates and ADP/O with substrates indicated a
nmol O/min/mg mitochondrial protein
Malate + Pyruvate
Glutamate + Malate
b OPA1+ (n = 6)
Mean ± SD
259 ± 62
45 ± 8
344 ± 70
284 ± 77
41 ± 9
350 ± 76
364 ± 94
70 ± 16
439 ± 112
b OPA1- (n = 10)
Mean ± SD
230 ± 64
38 ± 13
309 ± 99
270 ± 88
39 ± 18
312 ± 145
301 ± 83
58 ± 22
356 ± 124
Control (n = 10)
Mean ± SD
300 ± 37
49 ± 12
370 ± 73
312 ± 38
45 ± 12
328 ± 98
376 ± 66
66 ± 18
421 ± 63
Specific enzyme analysis of ADOA patient and control mitochondria
Mean specific enzyme activities
nmol/min/mg mitochondrial protein
a OPA1+ (n = 6)
Mean ± SD
152 ± 105
1036 ± 162
872 ± 162
1327 ± 488
a OPA1- (n = 10)
Mean ± SD
190 ± 144
945 ± 174
810 ± 204
1154 ± 650
Control (n = 10)
Mean ± SD
170 ± 64
886 ± 179
893 ± 271
1304 ± 364
For our OPA1-positive patients, two (P2 and P3) harbored pathogenic missense mutations and four (P4, P6-8) contained protein-truncating variants (Table 1). Since the protein terminating mutations may be considered potentially more severe than the missense mutations, we examined our data to see if this was the case from a functional perspective. Although our sample size is low, we found no significant differences between OPA1-positive patients with missense or frameshift/nonsense mutations. Further, patient P2 is a compound heterozygote, harboring both the c.239A>G exon 2 missense mutation and the c.2883A>C exon 28 variant that changes the OPA1 stop codon to a tyrosine and extends the OPA1 polypeptide 3 additional amino acids. As indicated in Tables 2 and 3 for OPA1-positive patient P2, both respiration and specific enzyme activities do not differ significantly when compared to the other OPA1-positive patients, suggesting that the combined presence of these two deleterious OPA1 variants does not cause greater functional impairment.
The analysis of six ADOA patient lymphoblastoid cell lines with mutations in the nuclear gene OPA1 indicates that OPA1 has no direct role in mitochondrial respiratory chain function. These data represent the first report on in vitro OXPHOS function using isolated mitochondria from patients with ADOA. No significant effects on respiratory capacity or specific electron transport chain enzyme activity were observed in mitochondria from OPA1-positive or OPA1-negative ADOA patients suggesting that ADOA-related gene defects alter mitochondrial function primarily by disruption of inner mitochondrial membrane topography. This is intriguing as the bilateral vision loss experienced by ADOA patients is clinically similar to that observed in LHON patients harboring primary complex I mtDNA variants that directly impair mitochondrial biochemistry [25, 28]. Overall, it appears that RGC function is sensitive to different mechanisms of mitochondrial perturbation.
The study of OPA1 in the physiological context of ADOA is limited by the inability to culture patient RGCs. Similar to previous studies of LHON complex I mutations, our study of mitochondrial respiratory capacity of isolated ADOA patient organelles was an attempt to elucidate the pathological role of OPA1 at the biochemical level and enhance knowledge gained through several human cell models [17–19]. OPA1 is expressed as eight, tissue-specific transcripts resulting from alternative splicing in the gene region encompassing exons 4 through 5b [8, 13]. OPA1 transcripts 1, 4 and 7 expressed in retina are also found in leukocytes, therefore the results obtained here with patient lymphoblast mitochondria should reflect any mitochondrial impairments due to the ADOA OPA1 mutations affecting protein isoforms in RGCs . The protein products of OPA1 transcripts 1, 2, 4 and 7 support mitochondrial fusion activity to a greater extent than other OPA1 isoforms . The OPA1 protein encoded by each transcript is cleaved by proteases within the mitochondrial matrix at sequences translated from exons 5 and 5b [13, 30, 31]. This activity removes the N-terminal, membrane-anchored region of the full-length protein generating one or more short, matrix isoforms. Both the long and short OPA1 gene products are required for mitochondrial fusion activity, and proteolysis is in part stimulated by loss of mitochondrial membrane potential [13, 30].
The ADOA OPA1 mutations in our patient lymphoblasts alter key functional domains that are present in all OPA1 proteins and lie outside of the proteolytic sites of the OPA1 protein (Table 1). The mutations would affect both long and short isoforms and should disrupt OPA1-mediated networking of mitochondria that may be required for the high level of ATP production in RGCs [3, 8–10, 12, 13, 15, 16, 19, 30]. Surprisingly, none of the OPA1 mutations evaluated here diminished OXPHOS to a significant extent, even though the c.2708delTTAG mutation has been associated with decreased ATP synthesis in fibroblasts and OPA1 appears to interact with AIF, a stability factor for electron transport chain complex I . Although ADOA shares many clinical hallmarks of LHON, defects in OPA1 do not compromise mitochondrial respiratory capacity. These results suggest that OPA1 may not be required for maintaining the electron transport chain for OXPHOS and may function primarily at the level of mitochondrial morphology within RGCs. Indeed, OPA1 function in the control of morphology may require alterations in membrane potential or cellular signals not induced in the context of cell culture, thereby limiting our ability to observe OPA1 effects in isolated mitochondria.
A recent report by Schimpf et al. suggests that OPA1 mutations that would produce large C-terminal truncations in OPA1 protein may lead to message degradation by nonsense mediated mRNA decay (NMD) [32, 33]. The net effect of NMD would be expression of protein only from the functional OPA1 allele, thereby creating a haploinsufficiency for OPA1. This mechanism may be the underlying cause of RGC death and disease in our OPA1-positive ADOA patients with two exceptions, patient P2 and patient P3. Patient P2 is a compound heterozygote harboring two mutant alleles, a mitochondrial targeting sequence mutation in exon 2 and a Stop961Tyr in exon 28, which extends the C-terminus by 3 amino acids. The exon 2 mutation should prevent mitochondrial localization of the gene product, resulting in a downregulation of functional protein expression and haploinsufficiency. The three amino acid extension of OPA1 is not expected to alter protein function, however a small effect on protein activity may be detrimental in the context of diminished levels mitochondrial OPA1. The OPA1 genotype of patient P3 is more intriguing, as the single base change results in an amino acid substitution, Tyr841Cys, that lies outside of known functional domains in the C-terminal region. The Tyr841Cys OPA1 protein should be expressed and targeted to the mitochondria where it conceivably may compete in molecular interactions with both the long and short isoforms of protein expressed from the normal allele. While no significance was found for the average mitochondrial respiration and specific activity data for the ADOA OPA1-positive mitochondria compared to controls, mitochondria from P3 lymphoblasts displayed notably higher respiration, slightly elevated complex I activity, and substantially lower complex IV activity. This suggests that the Tyr841 may mediate regulatory or stabilizing interactions with complexes I and IV within the mitochondrial membrane [18, 19, 34]. A more detailed analysis of the C-terminus of OPA1 may uncover critical interactions with the electron transport chain in the cristae of the mitochondria.
From this study we conclude that OPA1 is not directly involved in maintaining electron transport efficiency for OXPHOS. The OPA1 mutations causing ADOA most likely result in a cellular haploinsufficiency for OPA1 protein in mitochondrial network formation and total cellular energy production. The results obtained for mitochondria bearing an OPA1 protein with a Tyr841Cys change in the C-terminus indicate that this domain of OPA1 could be responsible for stabilizing electron transport chain complexes and suggest that functional interactions for OPA1 may exist within the inner membrane. However, the apparent cause of ADOA pathology is the loss of OPA1 control of mitochondrial morphology in RGCs.
We thank the patients and their families for their contributions, the National Eye Institute for support through grant award EY014393 (M.D.B./S.D.C.), and Research to Prevent Blindness (New York, NY) for an unrestricted grant to the Emory University School of Medicine Department of Ophthalmology.
- Carelli V, La Morgia C, Iommarini L, Carroccia R, Mattiazzi M, Sangiorgi S, Farne S, Maresca A, Foscarini B, Lanzi L, Amadori M, Bellan M, Valentino ML: Mitochondrial Optic Neuropathies: How Two Genomes may Kill the Same Cell Type?. Biosci Rep. 2007, 27 (1–3): 173-184.View ArticlePubMedGoogle Scholar
- Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P, Pelloquin L, Grosgeorge J, Turc-Carel C, Perret E, Astarie-Dequeker C, Lasquellec L, Arnaud B, Ducommun B, Kaplan J, Hamel CP: Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet. 2000, 26 (2): 207-210.View ArticlePubMedGoogle Scholar
- Ferre M, Amati-Bonneau P, Tourmen Y, Malthiery Y, Reynier P: eOPA1: an online database for OPA1 mutations. Hum Mutat. 2005, 25 (5): 423-428.View ArticlePubMedGoogle Scholar
- Toomes C, Marchbank NJ, Mackey DA, Craig JE, Newbury-Ecob RA, Bennett CP, Vize CJ, Desai SP, Black GC, Patel N, Teimory M, Markham AF, Inglehearn CF, Churchill AJ: Spectrum, frequency and penetrance of OPA1 mutations in dominant optic atrophy. Hum Mol Genet. 2001, 10 (13): 1369-1378.View ArticlePubMedGoogle Scholar
- Pesch UE, Leo-Kottler B, Mayer S, Jurklies B, Kellner U, Apfelstedt-Sylla E, Zrenner E, Alexander C, Wissinger B: OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance. Hum Mol Genet. 2001, 10 (13): 1359-1368.View ArticlePubMedGoogle Scholar
- Thiselton DL, Alexander C, Taanman JW, Brooks S, Rosenberg T, Eiberg H, Andreasson S, Van Regemorter N, Munier FL, Moore AT, Bhattacharya SS, Votruba M: A comprehensive survey of mutations in the OPA1 gene in patients with autosomal dominant optic atrophy. Invest Ophthalmol Vis Sci. 2002, 43 (6): 1715-1724.PubMedGoogle Scholar
- Puomila A, Huoponen K, Mantyjarvi M, Hamalainen P, Paananen R, Sankila EM, Savontaus ML, Somer M, Nikoskelainen E: Dominant optic atrophy: correlation between clinical and molecular genetic studies. Acta Ophthalmol Scand. 2005, 83 (3): 337-346.View ArticlePubMedGoogle Scholar
- Delettre C, Griffoin JM, Kaplan J, Dollfus H, Lorenz B, Faivre L, Lenaers G, Belenguer P, Hamel CP: Mutation spectrum and splicing variants in the OPA1 gene. Hum Genet. 2001, 109 (6): 584-591.View ArticlePubMedGoogle Scholar
- Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A, Rodriguez M, Kellner U, Leo-Kottler B, Auburger G, Bhattacharya SS, Wissinger B: OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet. 2000, 26 (2): 211-215.View ArticlePubMedGoogle Scholar
- Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L: OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci USA. 2004, 101 (45): 15927-15932.PubMed CentralView ArticlePubMedGoogle Scholar
- Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ: Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell. 2004, 15 (11): 5001-5011.PubMed CentralView ArticlePubMedGoogle Scholar
- Chen H, Chan DC: Emerging functions of mammalian mitochondrial fusion and fission. Hum Mol Genet. 2005, 14 (Spec No. 2): R283-289.View ArticlePubMedGoogle Scholar
- Ishihara N, Fujita Y, Oka T, Mihara K: Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. Embo J. 2006, 25 (13): 2966-2977.PubMed CentralView ArticlePubMedGoogle Scholar
- Meeusen S, DeVay R, Block J, Cassidy-Stone A, Wayson S, McCaffery JM, Nunnari J: Mitochondrial inner-membrane fusion and crista maintenance requires the dynamin-related GTPase Mgm1. Cell. 2006, 127 (2): 383-395.View ArticlePubMedGoogle Scholar
- Chan DC: Dissecting mitochondrial fusion. Dev Cell. 2006, 11 (5): 592-594.View ArticlePubMedGoogle Scholar
- Hoppins S, Lackner L, Nunnari J: The machines that divide and fuse mitochondria. Annu Rev Biochem. 2007, 76: 751-780.View ArticlePubMedGoogle Scholar
- Lodi R, Tonon C, Valentino ML, Iotti S, Clementi V, Malucelli E, Barboni P, Longanesi L, Schimpf S, Wissinger B, Baruzzi A, Barbiroli B, Carelli V: Deficit of in vivo mitochondrial ATP production in OPA1-related dominant optic atrophy. Ann Neurol. 2004, 56 (5): 719-723.View ArticlePubMedGoogle Scholar
- Amati-Bonneau P, Valentino ML, Reynier P, Gallardo ME, Bornstein B, Boissiere A, Campos Y, Rivera H, de la Aleja JG, Carroccia R, Iommarini L, Labauge P, Figarella-Branger D, Marcorelles P, Furby A, Beauvais K, Letournel F, Liguori R, La Morgia C, Montagna P, Liguori M, Zanna C, Rugolo M, Cossarizza A, Wissinger B, Verny C, Schwarzenbacher R, Martin MA, Arenas J, Ayuso C, Garesse R, Lenaers G, Bonneau D, Carelli V: OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes. Brain. 2008, 131 (Pt 2): 338-351.View ArticlePubMedGoogle Scholar
- Zanna C, Ghelli A, Porcelli AM, Karbowski M, Youle RJ, Schimpf S, Wissinger B, Pinti M, Cossarizza A, Vidoni S, Valentino ML, Rugolo M, Carelli V: OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion. Brain. 2008, 131 (Pt 2): 352-367.View ArticlePubMedGoogle Scholar
- Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P, Lenaers G: Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem. 2003, 278 (10): 7743-7746.View ArticlePubMedGoogle Scholar
- Griparic L, Wel van der NN, Orozco IJ, Peters PJ, Bliek van der AM: Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria. J Biol Chem. 2004, 279 (18): 18792-18798.View ArticlePubMedGoogle Scholar
- Griparic L, Bliek van der AM: The many shapes of mitochondrial membranes. Traffic. 2001, 2 (4): 235-244.View ArticlePubMedGoogle Scholar
- Kamei S, Chen-Kuo-Chang M, Cazevieille C, Lenaers G, Olichon A, Belenguer P, Roussignol G, Renard N, Eybalin M, Michelin A, Delettre C, Brabet P, Hamel CP: Expression of the Opa1 mitochondrial protein in retinal ganglion cells: its downregulation causes aggregation of the mitochondrial network. Invest Ophthalmol Vis Sci. 2005, 46 (11): 4288-4294.View ArticlePubMedGoogle Scholar
- Han J, Thompson-Lowrey AJ, Reiss A, Mayorov V, Jia H, Biousse V, Newman NJ, Brown MD: OPA1 mutations and mitochondrial DNA haplotypes in autosomal dominant optic atrophy. Genet Med. 2006, 8 (4): 217-225.View ArticlePubMedGoogle Scholar
- Brown MD, Trounce IA, Jun AS, Allen JC, Wallace DC: Functional analysis of lymphoblast and cybrid mitochondria containing the 11778, or 14484 Leber's hereditary optic neuropathy mitochondrial DNA mutation. J Biol Chem. 3460, 275 (51): 39831-39836.View ArticleGoogle Scholar
- Trounce IA, Kim YL, Jun AS, Wallace DC: Assessment of mitochondrial oxidative phosphorylation in patient muscle biopsies, lymphoblasts, and transmitochondrial cell lines. Methods Enzymol. 1996, 264: 484-509.View ArticlePubMedGoogle Scholar
- Brown MD, Starikovskaya E, Derbeneva O, Hosseini S, Allen JC, Mikhailovskaya IE, Sukernik RI, Wallace DC: The role of mtDNA background in disease expression: a new primary LHON mutation associated with Western Eurasian haplogroup J. Hum Genet. 2002, 110 (2): 130-138.View ArticlePubMedGoogle Scholar
- Brown MD, Allen JC, Van Stavern GP, Newman NJ, Wallace DC: Clinical, genetic, and biochemical characterization of a Leber hereditary optic neuropathy family containing both the 11778 and 14484 primary mutations. Am J Med Genet. 2001, 104 (4): 331-338.View ArticlePubMedGoogle Scholar
- Jun AS, Trounce IA, Brown MD, Shoffner JM, Wallace DC: Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia. Mol Cell Biol. 1996, 16 (3): 771-777.PubMed CentralView ArticlePubMedGoogle Scholar
- Song Z, Chen H, Fiket M, Alexander C, Chan DC: OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol. 2007, 178 (5): 749-755.PubMed CentralView ArticlePubMedGoogle Scholar
- Gottlieb E: OPA1 and PARL keep a lid on apoptosis. Cell. 2006, 126 (1): 27-29.View ArticlePubMedGoogle Scholar
- Frischmeyer PA, Dietz HC: Nonsense-mediated mRNA decay in health and disease. Hum Mol Genet. 1999, 8 (10): 1893-1900.View ArticlePubMedGoogle Scholar
- Schimpf S, Fuhrmann N, Schaich S, Wissinger B: Comprehensive cDNA study and quantitative transcript analysis of mutant OPA1 transcripts containing premature termination codons. Hum Mutat. 2008, 29 (1): 106-112.View ArticlePubMedGoogle Scholar
- Zhang M, Mileykovskaya E, Dowhan W: Gluing the respiratory chain together. Cardiolipin is required for supercomplex formation in the inner mitochondrial membrane. J Biol Chem. 2002, 277 (46): 43553-43556.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.