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Massimo Zeviani - One of the best experts on this subject based on the ideXlab platform.
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Data on cytochrome c oxidase assembly in mice and human fibroblasts or tissues induced by SURF1 defect
Data in Brief, 2016Co-Authors: Nikola Kovářová, Massimo Zeviani, Petr Pecina, Hana Nůsková, Marek Vrbacký, Tomáš Mráček, Carlo Viscomi, Josef HouštěkAbstract:This paper describes data related to a research article entitled “Tissue- and species-specific differences in cytochrome c oxidase assembly induced by SURF1 defects” [1]. This paper includes data of the quantitative analysis of individual forms of respiratory chain complexes I, III and IV present in SURF1 knockout (SURF1−/−) and control (SURF1+/+) mouse fibroblasts and tissues and in fibroblasts of human control and patients with SURF1 gene mutation. Also it includes data demonstrating response of complex IV, cytochrome c oxidase (COX), to reversible inhibition of mitochondrial translation in SURF1−/− mouse and SURF1 patient fibroblast cell lines.
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Tissue- and species-specific differences in cytochrome c oxidase assembly induced by SURF1 defects.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2016Co-Authors: Nikola Kovářová, Massimo Zeviani, Petr Pecina, Hana Nůsková, Marek Vrbacký, Tomáš Mráček, Carlo Viscomi, Josef HouštěkAbstract:Mitochondrial protein SURF1 is a specific assembly factor of cytochrome c oxidase (COX), but its function is poorly understood. SURF1 gene mutations cause a severe COX deficiency manifesting as the Leigh syndrome in humans, whereas in mice SURF1−/− knockout leads only to a mild COX defect. We used SURF1−/− mouse model for detailed analysis of disturbed COX assembly and COX ability to incorporate into respiratory supercomplexes (SCs) in different tissues and fibroblasts. Furthermore, we compared fibroblasts from SURF1−/− mouse and SURF1 patients to reveal interspecies differences in kinetics of COX biogenesis using 2D electrophoresis, immunodetection, arrest of mitochondrial proteosynthesis and pulse-chase metabolic labeling. The crucial differences observed are an accumulation of abundant COX1 assembly intermediates, low content of COX monomer and preferential recruitment of COX into I–III2–IVn SCs in SURF1 patient fibroblasts, whereas SURF1−/− mouse fibroblasts were characterized by low content of COX1 assembly intermediates and milder decrease in COX monomer, which appeared more stable. This pattern was even less pronounced in SURF1−/− mouse liver and brain. Both the control and SURF1−/− mice revealed only negligible formation of the I–III2–IVn SCs and marked tissue differences in the contents of COX dimer and III2–IV SCs, also less noticeable in liver and brain than in heart and muscle. Our studies support the view that COX assembly is much more dependent on SURF1 in humans than in mice. We also demonstrate markedly lower ability of mouse COX to form I–III2–IVn supercomplexes, pointing to tissue-specific and species-specific differences in COX biogenesis.
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Leigh Syndrome in Drosophila melanogaster morphological and biochemical characterization of SURF1 post-transcriptional silencing
Journal of Biological Chemistry, 2014Co-Authors: Sophia Von Stockum, Massimo Zeviani, Alberto Biscontin, Caterina Millino, Paola Cisotto, Mauro Agostino Zordan, Paolo Bernardi, Cristiano De Pittà, Rodolfo CostaAbstract:Abstract Leigh Syndrome (LS) is the most common early-onset, progressive mitochondrial encephalopathy usually leading to early death. The single most prevalent cause of LS is occurrence of mutations in the SURF1 gene, and LSSURF1 patients show a ubiquitous and specific decrease in the activity of mitochondrial respiratory chain complex IV (cytochrome c oxidase, COX). SURF1 encodes an inner membrane mitochondrial protein involved in COX assembly. We established a Drosophila melanogaster model of LS based on the post-transcriptional silencing of CG9943, the Drosophila homolog of SURF1. Knockdown of SURF1 was induced ubiquitously in larvae and adults, which led to lethality; in the mesodermal derivatives, which led to pupal lethality; or in the central nervous system, which allowed survival. A biochemical characterization was carried out in knockdown individuals, which revealed that larvae unexpectedly displayed defects in all complexes of the mitochondrial respiratory chain and in the F-ATP synthase, while adults had a COX-selective impairment. Silencing of SURF1 expression in Drosophila S2R+ cells led to selective loss of COX activity associated with decreased oxygen consumption and respiratory reserve. We conclude that SURF1 is essential for COX activity and mitochondrial function in D. melanogaster, thus providing a new tool that may help clarify the pathogenic mechanisms of LS.
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Complex IV Deficient SURF1−/− Mice Initiate Mitochondrial Stress Responses
Biochemical Journal, 2014Co-Authors: Daniel Pulliam, Carlo Viscomi, Sathyaseelan S. Deepa, Shauna Hill, Yun Shi, Lauren B. Sloane, Ai-ling Lin, Yuhong Liu, Arunabh Bhattacharya, Massimo ZevianiAbstract:Mutations in SURF1 (surfeit locus protein 1) COX (cytochrome c oxidase) assembly protein are associated with Leigh's syndrome, a human mitochondrial disorder that manifests as severe mitochondrial phenotypes and early lethality. In contrast, mice lacking the SURF1 protein ( SURF1 −/−) are viable and were previously shown to have enhanced longevity and a greater than 50% reduction in COX activity. We measured mitochondrial function in heart and skeletal muscle, and despite the significant reduction in COX activity, we found little or no difference in ROS (reactive oxygen species) generation, membrane potential, ATP production or respiration in isolated mitochondria from SURF1−/− mice compared with wild-type. However, blood lactate levels were elevated and SURF1−/− mice had reduced running endurance, suggesting compromised mitochondrial energy metabolism in vivo . Decreased COX activity in SURF1−/− mice is associated with increased markers of mitochondrial biogenesis [PGC-1α (peroxisome-proliferator-activated receptor γ co-activator 1α) and VDAC (voltage-dependent anion channel)] in both heart and skeletal muscle. Although mitochondrial biogenesis is a common response in the two tissues, skeletal muscle has an up-regulation of the UPRMT (mitochondrial unfolded protein response) and heart exhibits induction of the Nrf2 (nuclear factor-erythroid 2-related factor 2) antioxidant response pathway. These data are the first to show induction of the UPRMT in a mammalian model of decreased COX activity. In addition, the results of the present study suggest that impaired mitochondrial function can lead to induction of mitochondrial stress pathways to confer protective effects on cellular homoeostasis. Abbreviations: ARE, antioxidant response element; CHOP, C/EBP (CCAAT/enhancer-binding protein)-homologous protein; ClpP, caseinolytic peptidase; COX, cytochrome c oxidase; DCIP, dichlorophenol-indophenol; DIPPMPO, 5-(di-isopropoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide; ETC, electron transport chain; 18FDG, 2-[18F]fluoro-2-deoxy-D-glucose; HO-1, haem oxygenase 1; Hsp60, heat-shock protein 60; MURE, mitochondrial unfolded response element; Nrf2, nuclear factor-erythroid 2-related factor 2; PET, positron-emission tomography; PGC-1α, peroxisome-proliferator-activated receptor γ co-activator 1α; RCR, respiratory control ratio; ROS, reactive oxygen species; SOD, superoxide dismutase; SURF1, surfeit locus protein 1; SUV, standardized uptake value; TFAM, mitochondrial transcription factor A; Trx, thioredoxin; UPRMT, mitochondrial unfolded protein response; VDAC, voltage-dependent anion channel
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Improved insulin sensitivity associated with reduced mitochondrial complex IV assembly and activity
The FASEB Journal, 2012Co-Authors: Sathyaseelan S. Deepa, Massimo Zeviani, Daniel Pulliam, Shauna Hill, Yun Shi, Michael E. Walsh, Adam B. Salmon, Lauren B. Sloane, Ning Zhang, Carlo ViscomiAbstract:Mice lacking SURF1, a complex IV assembly protein, have ∼50-70% reduction in cytochrome c oxidase activity in all tissues yet a paradoxical increase in lifespan. Here we report that SURF1−/− mice have lower body (15%) and fat (20%) mass, in association with reduced lipid storage, smaller adipocytes, and elevated indicators of fatty acid oxidation in white adipose tissue (WAT) compared with control mice. The respiratory quotient in the SURF1−/− mice was significantly lower than in the control animals (0.83–0.93 vs. 0.90–0.98), consistent with enhanced fat utilization in SURF1−/− mice. Elevated fat utilization was associated with increased insulin sensitivity measured as insulin-stimulated glucose uptake, as well as an increase in insulin receptor levels (∼2-fold) and glucose transporter type 4 (GLUT4; ∼1.3-fold) levels in WAT in the SURF1−/− mice. The expression of peroxisome proliferator-activated receptor γ-coactivator 1-α (PGC-1α) mRNA and protein was up-regulated by 2.5- and 1.9-fold, respectively, in ...
Alessandro Agostino - One of the best experts on this subject based on the ideXlab platform.
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Increased longevity and refractoriness to Ca2+-dependent neurodegeneration in SURF1 knockout mice
Human Molecular Genetics, 2007Co-Authors: Carlotta Dell'agnello, Alessandro Agostino, Cecilia Tiveron, Alessandro Prelle, Sara Leo, Gyorgy Szabadkai, Alessandra Zulian, Pierre L. Roubertoux, Rosario Rizzuto, Massimo ZevianiAbstract:Leigh syndrome associated with cytochrome c oxidase (COX) deficiency is a mitochondrial disorder usually caused by mutations of SURF1, a gene encoding a putative COX assembly factor. We present here a SURF1-/- recombinant mouse obtained by inserting a loxP sequence in the open reading frame of the gene. The frequency of -/-, +/+ and +/- genotypes in newborn mice followed a mendelian distribution, indicating that the ablation of SURF1 is compatible with postnatal survival. The biochemical and assembly COX defect was present in SURF1(loxP)-/- mice, but milder than in humans. Surprisingly, not only these animals failed to show spontaneous neurodegeneration at any age, but they also displayed markedly prolonged lifespan, and complete protection from Ca(2+)-dependent neurotoxicity induced by kainic acid. Experiments on primary neuronal cultures showed markedly reduced rise of cytosolic and mitochondrial Ca(2+) in SURF1(loxP)-/- neurons, and reduced mortality, compared to controls. The mitochondrial membrane potential was unchanged in KO versus wild-type neurons, suggesting that the effects of the ablation of SURF1 on Ca(2+) homeostasis, and possibly on longevity, may be independent, at least in part, from those on COX assembly and mitochondrial bioenergetics.
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Post-transcriptional silencing and functional characterization of the Drosophila melanogaster homolog of human SURF1.
Genetics, 2005Co-Authors: Mauro Agostino Zordan, Alessandro Agostino, Paola Cisotto, Clara Benna, Giorgia Rizzo, Alberto Piccin, Mirko Pegoraro, Federica Sandrelli, G Perini, Giuseppe TognonAbstract:Mutations in SURF1, a human gene involved in the assembly of cytochrome c oxidase (COX), cause Leigh syndrome, the most common infantile mitochondrial encephalopathy, characterized by a specific COX deficiency. We report the generation and characterization of functional knockdown (KD) lines for SURF1 in Drosophila. KD was produced by post-transcriptional silencing employing a transgene encoding a dsRNA fragment of the Drosophila homolog of human SURF1, activated by the UAS transcriptional activator. Two alternative drivers, Actin5C–GAL4 or elav–GAL4, were used to induce silencing ubiquitously or in the CNS, respectively. Actin5C–GAL4 KD produced 100% egg-to-adult lethality. Most individuals died as larvae, which were sluggish and small. The few larvae reaching the pupal stage died as early imagos. Electron microscopy of larval muscles showed severely altered mitochondria. elav–GAL4-driven KD individuals developed to adulthood, although cephalic sections revealed low COX-specific activity. Behavioral and electrophysiological abnormalities were detected, including reduced photoresponsiveness in KD larvae using either driver, reduced locomotor speed in Actin5C–GAL4 KD larvae, and impaired optomotor response as well as abnormal electroretinograms in elav–GAL4 KD flies. These results indicate important functions for SURF1 specifically related to COX activity and suggest a crucial role of mitochondrial energy pathways in organogenesis and CNS development and function.
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Constitutive knockout of SURF1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice
Human Molecular Genetics, 2003Co-Authors: Alessandro Agostino, Federica Invernizzi, Cecilia Tiveron, Gigliola Fagiolari, Alessandro Prelle, Eleonora Lamantea, Alessio Giavazzi, Giorgio Battaglia, Laura Tatangelo, Valeria TirantiAbstract:We report here the creation of a constitutive knockout mouse for SURF1, a gene encoding one of the assembly proteins involved in the formation of cytochrome c oxidase (COX). Loss-of-function mutations of SURF1 cause Leigh syndrome associated with an isolated and generalized COX deficiency in humans. The murine phenotype is characterized by the following hallmarks: (1) high post-implantation embryonic lethality, affecting approximately 90% of the SURF1(-/-) individuals; (2) early-onset mortality of post-natal individuals; (3) highly significant deficit in muscle strength and motor performance; (4) profound and isolated defect of COX activity in skeletal muscle and liver, and, to a lesser extent, heart and brain; (5) morphological abnormalities of skeletal muscle, characterized by reduced histochemical reaction to COX and mitochondrial proliferation; (6) no obvious abnormalities in brain morphology, reflecting the virtual absence of overt neurological symptoms. These results indicate a function for murine SURF1 protein (SURF1p) specifically related to COX and recapitulate, at least in part, the human phenotype. This is the first mammalian model for a nuclear disease gene of a human mitochondrial disorder. Our model constitutes a useful tool to investigate the function of SURF1p, help understand the pathogenesis of SURF1p deficiency in vivo, and evaluate the efficacy of treatment.
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new splicing site mutations in the SURF1 gene in leigh syndrome patients
Journal of Biological Chemistry, 2001Co-Authors: Marie O. Péquignot, Alessandro Agostino, Massimo Zeviani, Isabelle Desguerre, Marzia Tartari, C. Benelli, Françoise Fouque, Runu Dey, Carina Pripbuus, Dominique MarchantAbstract:The gene SURF1 encodes a factor involved in the biogenesis of cytochrome c oxidase, the last complex in the respiratory chain. Mutations of the SURF1 gene result in Leigh syndrome and severe cytochrome c oxidase deficiency. Analysis of seven unrelated patients with cytochrome c oxidase deficiency and typical Leigh syndrome revealed different SURF1 mutations in four of them. Only these four cases had associated demyelinating neuropathy. Three mutations were novel splicing-site mutations that lead to the excision of exon 6. Two different novel heterozygous mutations were found at the same guanine residue at the donor splice site of intron 6; one was a deletion, whereas the other was a transition [588+1G>A]. The third novel splicing-site mutation was a homozygous [516-2_516-1delAG] in intron 5. One patient only had a homozygous polymorphism in the middle of the intron 8 [835+25C>T]. Western blot analysis showed that SURF1 protein was absent in all four patients harboring mutations. Our studies confirm that the SURF1 gene is an important nuclear gene involved in the cytochrome c oxidase deficiency. We also show that SURF1 protein is not implicated in the assembly of other respiratory chain complexes or the pyruvate dehydrogenase complex.
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New Splicing-site Mutations in the SURF1Gene in Leigh Syndrome Patients
Journal of Biological Chemistry, 2001Co-Authors: Marie O. Péquignot, Alessandro Agostino, Massimo Zeviani, Isabelle Desguerre, Marzia Tartari, C. Benelli, Françoise Fouque, Carina Prip-buus, Dominique MarchantAbstract:Abstract The gene SURF1 encodes a factor involved in the biogenesis of cytochrome c oxidase, the last complex in the respiratory chain. Mutations of theSURF1 gene result in Leigh syndrome and severe cytochromec oxidase deficiency. Analysis of seven unrelated patients with cytochrome c oxidase deficiency and typical Leigh syndrome revealed different SURF1 mutations in four of them. Only these four cases had associated demyelinating neuropathy. Three mutations were novel splicing-site mutations that lead to the excision of exon 6. Two different novel heterozygous mutations were found at the same guanine residue at the donor splice site of intron 6; one was a deletion, whereas the other was a transition [588+1G>A]. The third novel splicing-site mutation was a homozygous [516–2_516–1delAG] in intron 5. One patient only had a homozygous polymorphism in the middle of the intron 8 [835+25C>T]. Western blot analysis showed that SURF1 protein was absent in all four patients harboring mutations. Our studies confirm that theSURF1 gene is an important nuclear gene involved in the cytochrome c oxidase deficiency. We also show that SURF1 protein is not implicated in the assembly of other respiratory chain complexes or the pyruvate dehydrogenase complex.
Josef Houštěk - One of the best experts on this subject based on the ideXlab platform.
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Data on cytochrome c oxidase assembly in mice and human fibroblasts or tissues induced by SURF1 defect
Data in Brief, 2016Co-Authors: Nikola Kovářová, Massimo Zeviani, Petr Pecina, Hana Nůsková, Marek Vrbacký, Tomáš Mráček, Carlo Viscomi, Josef HouštěkAbstract:This paper describes data related to a research article entitled “Tissue- and species-specific differences in cytochrome c oxidase assembly induced by SURF1 defects” [1]. This paper includes data of the quantitative analysis of individual forms of respiratory chain complexes I, III and IV present in SURF1 knockout (SURF1−/−) and control (SURF1+/+) mouse fibroblasts and tissues and in fibroblasts of human control and patients with SURF1 gene mutation. Also it includes data demonstrating response of complex IV, cytochrome c oxidase (COX), to reversible inhibition of mitochondrial translation in SURF1−/− mouse and SURF1 patient fibroblast cell lines.
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Tissue- and species-specific differences in cytochrome c oxidase assembly induced by SURF1 defects.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2016Co-Authors: Nikola Kovářová, Massimo Zeviani, Petr Pecina, Hana Nůsková, Marek Vrbacký, Tomáš Mráček, Carlo Viscomi, Josef HouštěkAbstract:Mitochondrial protein SURF1 is a specific assembly factor of cytochrome c oxidase (COX), but its function is poorly understood. SURF1 gene mutations cause a severe COX deficiency manifesting as the Leigh syndrome in humans, whereas in mice SURF1−/− knockout leads only to a mild COX defect. We used SURF1−/− mouse model for detailed analysis of disturbed COX assembly and COX ability to incorporate into respiratory supercomplexes (SCs) in different tissues and fibroblasts. Furthermore, we compared fibroblasts from SURF1−/− mouse and SURF1 patients to reveal interspecies differences in kinetics of COX biogenesis using 2D electrophoresis, immunodetection, arrest of mitochondrial proteosynthesis and pulse-chase metabolic labeling. The crucial differences observed are an accumulation of abundant COX1 assembly intermediates, low content of COX monomer and preferential recruitment of COX into I–III2–IVn SCs in SURF1 patient fibroblasts, whereas SURF1−/− mouse fibroblasts were characterized by low content of COX1 assembly intermediates and milder decrease in COX monomer, which appeared more stable. This pattern was even less pronounced in SURF1−/− mouse liver and brain. Both the control and SURF1−/− mice revealed only negligible formation of the I–III2–IVn SCs and marked tissue differences in the contents of COX dimer and III2–IV SCs, also less noticeable in liver and brain than in heart and muscle. Our studies support the view that COX assembly is much more dependent on SURF1 in humans than in mice. We also demonstrate markedly lower ability of mouse COX to form I–III2–IVn supercomplexes, pointing to tissue-specific and species-specific differences in COX biogenesis.
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Adaptation of respiratory chain biogenesis to cytochrome c oxidase deficiency caused by SURF1 gene mutations.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2012Co-Authors: Nikola Kovářová, Petr Pecina, Ewa Pronicka, Alena Vrbacká, Viktor Stránecký, Stanislav Kmoch, Josef HouštěkAbstract:Abstract The loss of SURF1 protein leads to a severe COX deficiency manifested as a fatal neurodegenerative disorder, the Leigh syndrome (LS COX ). SURF1 appears to be involved in the early step of COX assembly but its function remains unknown. The aim of the study was to find out how SURF1 gene mutations influence expression of OXPHOS and other pro-mitochondrial genes and to further characterize the altered COX assembly. Analysis of fibroblast cell lines from 9 patients with SURF1 mutations revealed a 70% decrease of the COX complex content to be associated with 32–54% upregulation of respiratory chain complexes I, III and V and accumulation of Cox5a subunit. Whole genome expression profiling showed a general decrease of transcriptional activity in LS COX cells and indicated that the adaptive changes in OXPHOS complexes are due to a posttranscriptional compensatory mechanism. Electrophoretic and WB analysis showed that in mitochondria of LS COX cells compared to controls, the assembled COX is present entirely in a supercomplex form, as I–III 2 –IV supercomplex but not as larger supercomplexes. The lack of COX also caused an accumulation of I–III 2 supercomplex. The accumulated Cox5a was mainly present as a free subunit. We have found out that the major COX assembly subcomplexes accumulated due to SURF1 mutations range in size between approximately 85–140 kDa. In addition to the originally proposed S2 intermediate they might also represent Cox1-containing complexes lacking other COX subunits. Unlike the assembled COX, subcomplexes are unable to associate with complexes I and III.
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Decreased affinity for oxygen of cytochrome-c oxidase in Leigh syndrome caused by SURF1 mutations.
American Journal of Physiology-Cell Physiology, 2004Co-Authors: Petr Pecina, Ewa Pronicka, Jiří Zeman, Erich Gnaiger, Josef HouštěkAbstract:Mutations in the gene SURF1 prevent synthesis of cytochrome-c oxidase (COX)-specific assembly protein and result in a fatal neurological disorder, Leigh syndrome. Because this severe COX deficiency...
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A novel mutation in SURF1 causes skipping of exon 8 in a patient with cytochrome c oxidase-deficient Leigh syndrome and hypertrichosis
Molecular Genetics and Metabolism, 2001Co-Authors: Sion Llewelyn Williams, Jan-willem Taanman, Hana Hansíková, Houst'ková H, Subir K. Roy Chowdhury, Jiří Zeman, Josef HouštěkAbstract:Abstract Leigh syndrome is a rare pediatric neurodegenerative disorder attributed to impaired mitochondrial energy metabolism. Mutations in SURF1 have been described in several patients with Leigh syndrome associated with cytochrome c oxidase deficiency. We report a new 18-bp deletion (821del18), spanning the splice donor junction of exon 8 of SURF1, in an infant presenting with cytochrome c oxidase-deficient Leigh syndrome and hypertrichosis. cDNA sequencing demonstrated that this deletion results in a messenger lacking exon 8. RT-PCR experiments suggested a rapid degradation of the aberrant mRNA species from the 5′-end.
Anne Chun-hui Tsai - One of the best experts on this subject based on the ideXlab platform.
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Novel SURF1 mutation in a child with subacute encephalopathy and without the radiological features of Leigh Syndrome.
American journal of medical genetics. Part A, 2004Co-Authors: Leonardo Salviati, Sabrina Sacconi, Salvatore Dimauro, Cindy Freehauf, Janet Thoma, Anne Chun-hui TsaiAbstract:Mutations in SURF1, a gene involved in cytochrome-c oxidase (COX) assembly, cause COX deficiency and Leigh Syndrome (LS). Typical presentation is in the first year of life, with failure to thrive, psychomotor regression, ataxia, signs of brainstem dysfunction, and peripheral neuropathy. Progression is rapid and patients usually die of respiratory failure before 2 years of age. LS is characterized by symmetrical bilateral lesions in the brainstem and basal ganglia, revealed premortem as signal hyperintensities in T2-weighted MRI imaging. Here, we describe a 10-year-old boy with a novel mutation in SURF1 associated with an unusually mild clinical course. At 39 months, there were no MRI lesions, and a follow-up MRI at 8 years of age showed only brainstem and cerebellar involvement without lesions in the basal ganglia or subthalamic nuclei. These data confirm that the spectrum of MRI findings in LS is variable and that SURF1 mutations should be considered in patients with encephalomyopathy and COX deficiency even when early MRI findings are negative.
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Novel SURF1 mutation in a child with subacute encephalopathy and without the radiological features of Leigh Syndrome.
American Journal of Medical Genetics Part A, 2004Co-Authors: Leonardo Salviati, Sabrina Sacconi, Salvatore Dimauro, Cindy Freehauf, Janet Thoma, Anne Chun-hui TsaiAbstract:Mutations in SURF1, a gene involved in cytochrome-c oxidase (COX) assembly, cause COX deficiency and Leigh Syndrome (LS). Typical presentation is in the first year of life, with failure to thrive, psychomotor regression, ataxia, signs of brainstem dysfunction, and peripheral neuropathy. Progression is rapid and patients usually die of respiratory failure before 2 years of age. LS is characterized by symmetrical bilateral lesions in the brainstem and basal ganglia, revealed premortem as signal hyperintensities in T2-weighted MRI imaging. Here, we describe a 10-year-old boy with a novel mutation in SURF1 associated with an unusually mild clinical course. At 39 months, there were no MRI lesions, and a follow-up MRI at 8 years of age showed only brainstem and cerebellar involvement without lesions in the basal ganglia or subthalamic nuclei. These data confirm that the spectrum of MRI findings in LS is variable and that SURF1 mutations should be considered in patients with encephalomyopathy and COX deficiency even when early MRI findings are negative. © 2004 Wiley-Liss, Inc.
Carlo Viscomi - One of the best experts on this subject based on the ideXlab platform.
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Data on cytochrome c oxidase assembly in mice and human fibroblasts or tissues induced by SURF1 defect
Data in Brief, 2016Co-Authors: Nikola Kovářová, Massimo Zeviani, Petr Pecina, Hana Nůsková, Marek Vrbacký, Tomáš Mráček, Carlo Viscomi, Josef HouštěkAbstract:This paper describes data related to a research article entitled “Tissue- and species-specific differences in cytochrome c oxidase assembly induced by SURF1 defects” [1]. This paper includes data of the quantitative analysis of individual forms of respiratory chain complexes I, III and IV present in SURF1 knockout (SURF1−/−) and control (SURF1+/+) mouse fibroblasts and tissues and in fibroblasts of human control and patients with SURF1 gene mutation. Also it includes data demonstrating response of complex IV, cytochrome c oxidase (COX), to reversible inhibition of mitochondrial translation in SURF1−/− mouse and SURF1 patient fibroblast cell lines.
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Tissue- and species-specific differences in cytochrome c oxidase assembly induced by SURF1 defects.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2016Co-Authors: Nikola Kovářová, Massimo Zeviani, Petr Pecina, Hana Nůsková, Marek Vrbacký, Tomáš Mráček, Carlo Viscomi, Josef HouštěkAbstract:Mitochondrial protein SURF1 is a specific assembly factor of cytochrome c oxidase (COX), but its function is poorly understood. SURF1 gene mutations cause a severe COX deficiency manifesting as the Leigh syndrome in humans, whereas in mice SURF1−/− knockout leads only to a mild COX defect. We used SURF1−/− mouse model for detailed analysis of disturbed COX assembly and COX ability to incorporate into respiratory supercomplexes (SCs) in different tissues and fibroblasts. Furthermore, we compared fibroblasts from SURF1−/− mouse and SURF1 patients to reveal interspecies differences in kinetics of COX biogenesis using 2D electrophoresis, immunodetection, arrest of mitochondrial proteosynthesis and pulse-chase metabolic labeling. The crucial differences observed are an accumulation of abundant COX1 assembly intermediates, low content of COX monomer and preferential recruitment of COX into I–III2–IVn SCs in SURF1 patient fibroblasts, whereas SURF1−/− mouse fibroblasts were characterized by low content of COX1 assembly intermediates and milder decrease in COX monomer, which appeared more stable. This pattern was even less pronounced in SURF1−/− mouse liver and brain. Both the control and SURF1−/− mice revealed only negligible formation of the I–III2–IVn SCs and marked tissue differences in the contents of COX dimer and III2–IV SCs, also less noticeable in liver and brain than in heart and muscle. Our studies support the view that COX assembly is much more dependent on SURF1 in humans than in mice. We also demonstrate markedly lower ability of mouse COX to form I–III2–IVn supercomplexes, pointing to tissue-specific and species-specific differences in COX biogenesis.
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Complex IV Deficient SURF1−/− Mice Initiate Mitochondrial Stress Responses
Biochemical Journal, 2014Co-Authors: Daniel Pulliam, Carlo Viscomi, Sathyaseelan S. Deepa, Shauna Hill, Yun Shi, Lauren B. Sloane, Ai-ling Lin, Yuhong Liu, Arunabh Bhattacharya, Massimo ZevianiAbstract:Mutations in SURF1 (surfeit locus protein 1) COX (cytochrome c oxidase) assembly protein are associated with Leigh's syndrome, a human mitochondrial disorder that manifests as severe mitochondrial phenotypes and early lethality. In contrast, mice lacking the SURF1 protein ( SURF1 −/−) are viable and were previously shown to have enhanced longevity and a greater than 50% reduction in COX activity. We measured mitochondrial function in heart and skeletal muscle, and despite the significant reduction in COX activity, we found little or no difference in ROS (reactive oxygen species) generation, membrane potential, ATP production or respiration in isolated mitochondria from SURF1−/− mice compared with wild-type. However, blood lactate levels were elevated and SURF1−/− mice had reduced running endurance, suggesting compromised mitochondrial energy metabolism in vivo . Decreased COX activity in SURF1−/− mice is associated with increased markers of mitochondrial biogenesis [PGC-1α (peroxisome-proliferator-activated receptor γ co-activator 1α) and VDAC (voltage-dependent anion channel)] in both heart and skeletal muscle. Although mitochondrial biogenesis is a common response in the two tissues, skeletal muscle has an up-regulation of the UPRMT (mitochondrial unfolded protein response) and heart exhibits induction of the Nrf2 (nuclear factor-erythroid 2-related factor 2) antioxidant response pathway. These data are the first to show induction of the UPRMT in a mammalian model of decreased COX activity. In addition, the results of the present study suggest that impaired mitochondrial function can lead to induction of mitochondrial stress pathways to confer protective effects on cellular homoeostasis. Abbreviations: ARE, antioxidant response element; CHOP, C/EBP (CCAAT/enhancer-binding protein)-homologous protein; ClpP, caseinolytic peptidase; COX, cytochrome c oxidase; DCIP, dichlorophenol-indophenol; DIPPMPO, 5-(di-isopropoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide; ETC, electron transport chain; 18FDG, 2-[18F]fluoro-2-deoxy-D-glucose; HO-1, haem oxygenase 1; Hsp60, heat-shock protein 60; MURE, mitochondrial unfolded response element; Nrf2, nuclear factor-erythroid 2-related factor 2; PET, positron-emission tomography; PGC-1α, peroxisome-proliferator-activated receptor γ co-activator 1α; RCR, respiratory control ratio; ROS, reactive oxygen species; SOD, superoxide dismutase; SURF1, surfeit locus protein 1; SUV, standardized uptake value; TFAM, mitochondrial transcription factor A; Trx, thioredoxin; UPRMT, mitochondrial unfolded protein response; VDAC, voltage-dependent anion channel
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Improved insulin sensitivity associated with reduced mitochondrial complex IV assembly and activity
The FASEB Journal, 2012Co-Authors: Sathyaseelan S. Deepa, Massimo Zeviani, Daniel Pulliam, Shauna Hill, Yun Shi, Michael E. Walsh, Adam B. Salmon, Lauren B. Sloane, Ning Zhang, Carlo ViscomiAbstract:Mice lacking SURF1, a complex IV assembly protein, have ∼50-70% reduction in cytochrome c oxidase activity in all tissues yet a paradoxical increase in lifespan. Here we report that SURF1−/− mice have lower body (15%) and fat (20%) mass, in association with reduced lipid storage, smaller adipocytes, and elevated indicators of fatty acid oxidation in white adipose tissue (WAT) compared with control mice. The respiratory quotient in the SURF1−/− mice was significantly lower than in the control animals (0.83–0.93 vs. 0.90–0.98), consistent with enhanced fat utilization in SURF1−/− mice. Elevated fat utilization was associated with increased insulin sensitivity measured as insulin-stimulated glucose uptake, as well as an increase in insulin receptor levels (∼2-fold) and glucose transporter type 4 (GLUT4; ∼1.3-fold) levels in WAT in the SURF1−/− mice. The expression of peroxisome proliferator-activated receptor γ-coactivator 1-α (PGC-1α) mRNA and protein was up-regulated by 2.5- and 1.9-fold, respectively, in ...
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Hypoxic and hypercapnic challenges unveil respiratory vulnerability of SURF1 knockout mice, an animal model of Leigh syndrome.
Mitochondrion, 2011Co-Authors: Georg M. Stettner, Massimo Zeviani, Carlo Viscomi, Ekkehard Wilichowski, Mathias DutschmannAbstract:SURF1 gene mutations were detected as a main cause for Leigh syndrome (LS), also known as infantile subacute necrotizing encephalomyelopathy. This syndrome which is commonly associated with systemic cytochrome c oxidase (COX) deficiency manifests in early childhood and has an invariable poor prognosis. Progressive disturbances of the respiratory function, for which both the metabolic condition and necrotizing brainstem lesions contribute, belong to the major symptoms of LS. A constitutive knockout (KO) mouse for SURF1 enables invasive investigations of distinct aspects of LS. In the present study the respiratory function was analyzed applying an arterially perfused brainstem preparation. Compared to wild type (WT) preparations SURF1 KO preparations had a higher baseline respiratory frequency and abnormal responses to hypoxia and hypercapnia that involved both respiratory frequency and motor nerve discharge pattern. These data suggest that COX deficiency impairs peripheral and/or central chemoreceptor function.