The Experts below are selected from a list of 222 Experts worldwide ranked by ideXlab platform
Vineta Fellman - One of the best experts on this subject based on the ideXlab platform.
-
cox7a2l scafi and pre complex iii modify respiratory chain supercomplex formation in different mouse strains with a BCS1L mutation
PLOS ONE, 2016Co-Authors: Mina Davoudi, Heike Kotarsky, Vineta Fellman, Eva Hansson, Jukka KallijarviAbstract:The COX7A2L (Supercomplex Assembly Factor I, SCAFI) protein has been proposed to be a mitochondrial supercomplex assembly factor required for respirasome (supercomplex containing complexes I, III, and IV) formation. In the C57BL/6 mouse strain a homozygous in-frame 6-base-pair deletion in the COX7a2l/SCAF1 gene resulting in unstable protein and suggesting loss of function was previously identified. The loss of SCAFI was shown to impede respirasome formation, a major concern for the use of C57BL mouse strains in mitochondrial research. In contradiction, another recent study suggested that supercomplex formation is independent of SCAFI isoforms. We investigated whether SCAFI isoform status affected the disease severity and supercomplex formation in the liver of BCS1Lc.232A>G knock-in mice with incomplete complex III assembly. In homozygotes (BCS1LG/G) of mixed (C57BL/6:129/Sv) genetic background, the lifespan was similar in mice with wild-type SCAFI allele and in those homozygous (SCAFIshort/short) for the deleted SCAF1 variant (34±3 days; n = 6 vs. 32±2 days; n = 7, respectively). SCAFI heterozygosity (SCAFIlong/short) resulted in decreased SCAFI protein but respirasome assembly was unaffected. Congenic (C57BL/6) mice were of the genotype SCAFIshort/short and had no detectable SCAFI protein. In their liver mitochondria, respirasome composition was altered as compared to mixed background mice. Complex IV was mainly present as monomers and dimers, and only low amounts were found in combination with complex I and complex III or with precomplex III. The main supercomplex in the liver mitochondria of C57BL/6 mice comprised only complexes I and III. In conclusion, in liver mitochondria of C57BL/6 mice, supercomplexes had markedly reduced amount of, but were not completely depleted of, complex IV, supporting a role for COX7A2L/SCAFI in supercomplex assembly. However, the disease progression of the BCS1L mutant mice was unrelated to SCAFI isoforms and supercomplex composition, suggesting that other genetic factors contribute to the different survival in the different genetic backgrounds.
-
a turkish BCS1L mutation causes gracile like disorder
Turkish Journal of Pediatrics, 2016Co-Authors: Esra Serdaroglu, Heike Kotarsky, Sahin Takci, Onur Cil, Eda Utine, Sule Yigit, Vineta FellmanAbstract:A full-term growth-restricted female newborn (1790 g), presented with lactic acidosis (12.5 mmol/L) after birth. She had renal tubulopathy, cholestasis and elevated serum ferritin concentration (2819 ng/ml). Two similarly affected sisters had died before 3 months of age. Mitochondrial disorder was suspected since the disease resembled the Finnish GRACILE syndrome, caused by a homozygous mutation (c.232A>G) in BCS1L. Thus, we sequenced the BCS1L gene, encoding the assembly factor for respiratory chain complex III. The patient had a homozygous mutation (c.296C>T; p.P99L), for which both parents were heterozygous. In four previously published patients of Turkish origin, the same homozygous mutation resulted in complex III deficiency, tubulopathy, encephalopathy, and liver failure. The p.P99L mutation seems to be specific to Turkish population and leads to GRACILE-like or Leigh-like condition. Assembly defects in complex III should be investigated in the affected tissues, since fibroblasts may not exhibit the deficiency. (Less)
-
complex i function and supercomplex formation are preserved in liver mitochondria despite progressive complex iii deficiency
PLOS ONE, 2014Co-Authors: Mina Davoudi, Heike Kotarsky, Vineta Fellman, Eva Ekvall HanssonAbstract:Functional oxidative phosphorylation requires appropriately assembled mitochondrial respiratory complexes and their supercomplexes formed mainly of complexes I, III and IV. BCS1L is the chaperone needed to incorporate the catalytic subunit, Rieske iron-sulfur protein, into complex III at the final stage of its assembly. In cell culture studies, this subunit has been considered necessary for supercomplex formation and for maintaining the stability of complex I. Our aim was to assess the importance of fully assembled complex III for supercomplex formation in intact liver tissue. We used our transgenic mouse model with a homozygous c.232A>G mutation in BCS1L leading to decreased expression of BCS1L and progressive decrease of Rieske iron-sulfur protein in complex III, resulting in hepatopathy. We studied supercomplex formation at different ages using blue native gel electrophoresis and complex activity using high-resolution respirometry. In isolated liver mitochondria of young and healthy homozygous mutant mice, we found similar supercomplexes as in wild type. In homozygotes aged 27–29 days with liver disorder, complex III was predominantly a pre-complex lacking Rieske iron-sulfur protein. However, the main supercomplex was clearly detected and contained complex III mainly in the pre-complex form. Oxygen consumption of complex IV was similar and that of complex I was twofold compared with controls. These complexes in free form were more abundant in homozygotes than in controls, and the mRNA of complex I subunits were upregulated. In conclusion, when complex III assembly is deficient, the pre-complex without Rieske iron-sulfur protein can participate with available fully assembled complex III in supercomplex formation, complex I function is preserved, and respiratory chain stability is maintained.
-
1036 gracile syndrome in a turkish newborn infant caused by a homozygous mutation p99l in complex iii assembly factor BCS1L
Archives of Disease in Childhood, 2012Co-Authors: Erkin Serdaroglu, Heike Kotarsky, Vineta Fellman, Sahin Takci, Onur Cil, Eda Utine, Sule YigitAbstract:Background and Aim GRACILE syndrome, a neonatal, autosomally recessive disorder found in Finland, featuring growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death, is caused by a homozygous mutation (S78G) in BCS1L, the assembly factor for respiratory chain complex III. We investigated a newborn Turkish girl with similar symptoms. Her two sisters with low birth weight, metabolic acidosis, cholestasis and renal Fanconi syndrome, had died at 18 and 105 days age, respectively. Methods and results The girl was born to healthy nonconsanguineous parents. She was growth retarded (1789 g at term), developed tachypnea and metabolic acidosis on day one. Lactic acidosis, jaundice with direct hyperbilirubinemia, nonspecific aminoaciduria, high phosphaturia, proteinuria and glucosuria were detected. Serum iron (190 mcg/dl), ferritin (2819 ng/ml) and transferrin saturation (99.4%) were increased. Metabolic, cardiologic and sonographic workup were otherwise normal. Because of similarities with GRACILE syndrome, the BCS1L gene was investigated. The Finnish SNP was not found, but gene sequencing revealed a homozygous mutation resulting in an amino acid exchange (P99L) in the protein. Conclusions The studied infant had a GRACILE-like disorder caused by a different mutation than that in newborns of Finnish ancestors. Most likely the two diseased siblings had the same homozygous BCS1L mutation that previously has been published in three other newborns or Turkish origin. We proposed that P99L-mutation in BCS1L is a Turkish genotype resulting in GRACILE syndrome phenotype, and should be investigated in Turkish newborns with the typical clinical features.
-
metabolite profiles reveal energy failure and impaired beta oxidation in liver of mice with complex iii deficiency due to a BCS1L mutation
PLOS ONE, 2012Co-Authors: Heike Kotarsky, Vineta Fellman, Mina Davoudi, Riitta Karikoski, Matthias Keller, Per Leveen, David P EnotAbstract:AIMS: Liver is a target organ in many mitochondrial disorders, especially if the complex III assembly factor BCS1L is mutated. To reveal disease mechanism due to such mutations, we have produced a transgenic mouse model with c.232A>G mutation in BCS1L, the causative mutation for GRACILE syndrome. The homozygous mice develop mitochondrial hepatopathy with steatosis and fibrosis after weaning. Our aim was to assess cellular mechanisms for disease onset and progression using metabolomics. METHODS: With mass spectrometry we analyzed metabolite patterns in liver samples obtained from homozygotes and littermate controls of three ages. As oxidative stress might be a mechanism for mitochondrial hepatopathy, we also assessed H(2)O(2) production and expression of antioxidants. RESULTS: Homozygotes had a similar metabolic profile at 14 days of age as controls, with the exception of slightly decreased AMP. At 24 days, when hepatocytes display first histopathological signs, increases in succinate, fumarate and AMP were found associated with impaired glucose turnover and beta-oxidation. At end stage disease after 30 days, these changes were pronounced with decreased carbohydrates, high levels of acylcarnitines and amino acids, and elevated biogenic amines, especially putrescine. Signs of oxidative stress were present in end-stage disease. CONCLUSIONS: The findings suggest an early Krebs cycle defect with increases of its intermediates, which might play a role in disease onset. During disease progression, carbohydrate and fatty acid metabolism deteriorate leading to a starvation-like condition. The mouse model is valuable for further investigations on mechanisms in mitochondrial hepatopathy and for interventions. (Less)
Heike Kotarsky - One of the best experts on this subject based on the ideXlab platform.
-
cox7a2l scafi and pre complex iii modify respiratory chain supercomplex formation in different mouse strains with a BCS1L mutation
PLOS ONE, 2016Co-Authors: Mina Davoudi, Heike Kotarsky, Vineta Fellman, Eva Hansson, Jukka KallijarviAbstract:The COX7A2L (Supercomplex Assembly Factor I, SCAFI) protein has been proposed to be a mitochondrial supercomplex assembly factor required for respirasome (supercomplex containing complexes I, III, and IV) formation. In the C57BL/6 mouse strain a homozygous in-frame 6-base-pair deletion in the COX7a2l/SCAF1 gene resulting in unstable protein and suggesting loss of function was previously identified. The loss of SCAFI was shown to impede respirasome formation, a major concern for the use of C57BL mouse strains in mitochondrial research. In contradiction, another recent study suggested that supercomplex formation is independent of SCAFI isoforms. We investigated whether SCAFI isoform status affected the disease severity and supercomplex formation in the liver of BCS1Lc.232A>G knock-in mice with incomplete complex III assembly. In homozygotes (BCS1LG/G) of mixed (C57BL/6:129/Sv) genetic background, the lifespan was similar in mice with wild-type SCAFI allele and in those homozygous (SCAFIshort/short) for the deleted SCAF1 variant (34±3 days; n = 6 vs. 32±2 days; n = 7, respectively). SCAFI heterozygosity (SCAFIlong/short) resulted in decreased SCAFI protein but respirasome assembly was unaffected. Congenic (C57BL/6) mice were of the genotype SCAFIshort/short and had no detectable SCAFI protein. In their liver mitochondria, respirasome composition was altered as compared to mixed background mice. Complex IV was mainly present as monomers and dimers, and only low amounts were found in combination with complex I and complex III or with precomplex III. The main supercomplex in the liver mitochondria of C57BL/6 mice comprised only complexes I and III. In conclusion, in liver mitochondria of C57BL/6 mice, supercomplexes had markedly reduced amount of, but were not completely depleted of, complex IV, supporting a role for COX7A2L/SCAFI in supercomplex assembly. However, the disease progression of the BCS1L mutant mice was unrelated to SCAFI isoforms and supercomplex composition, suggesting that other genetic factors contribute to the different survival in the different genetic backgrounds.
-
a turkish BCS1L mutation causes gracile like disorder
Turkish Journal of Pediatrics, 2016Co-Authors: Esra Serdaroglu, Heike Kotarsky, Sahin Takci, Onur Cil, Eda Utine, Sule Yigit, Vineta FellmanAbstract:A full-term growth-restricted female newborn (1790 g), presented with lactic acidosis (12.5 mmol/L) after birth. She had renal tubulopathy, cholestasis and elevated serum ferritin concentration (2819 ng/ml). Two similarly affected sisters had died before 3 months of age. Mitochondrial disorder was suspected since the disease resembled the Finnish GRACILE syndrome, caused by a homozygous mutation (c.232A>G) in BCS1L. Thus, we sequenced the BCS1L gene, encoding the assembly factor for respiratory chain complex III. The patient had a homozygous mutation (c.296C>T; p.P99L), for which both parents were heterozygous. In four previously published patients of Turkish origin, the same homozygous mutation resulted in complex III deficiency, tubulopathy, encephalopathy, and liver failure. The p.P99L mutation seems to be specific to Turkish population and leads to GRACILE-like or Leigh-like condition. Assembly defects in complex III should be investigated in the affected tissues, since fibroblasts may not exhibit the deficiency. (Less)
-
complex i function and supercomplex formation are preserved in liver mitochondria despite progressive complex iii deficiency
PLOS ONE, 2014Co-Authors: Mina Davoudi, Heike Kotarsky, Vineta Fellman, Eva Ekvall HanssonAbstract:Functional oxidative phosphorylation requires appropriately assembled mitochondrial respiratory complexes and their supercomplexes formed mainly of complexes I, III and IV. BCS1L is the chaperone needed to incorporate the catalytic subunit, Rieske iron-sulfur protein, into complex III at the final stage of its assembly. In cell culture studies, this subunit has been considered necessary for supercomplex formation and for maintaining the stability of complex I. Our aim was to assess the importance of fully assembled complex III for supercomplex formation in intact liver tissue. We used our transgenic mouse model with a homozygous c.232A>G mutation in BCS1L leading to decreased expression of BCS1L and progressive decrease of Rieske iron-sulfur protein in complex III, resulting in hepatopathy. We studied supercomplex formation at different ages using blue native gel electrophoresis and complex activity using high-resolution respirometry. In isolated liver mitochondria of young and healthy homozygous mutant mice, we found similar supercomplexes as in wild type. In homozygotes aged 27–29 days with liver disorder, complex III was predominantly a pre-complex lacking Rieske iron-sulfur protein. However, the main supercomplex was clearly detected and contained complex III mainly in the pre-complex form. Oxygen consumption of complex IV was similar and that of complex I was twofold compared with controls. These complexes in free form were more abundant in homozygotes than in controls, and the mRNA of complex I subunits were upregulated. In conclusion, when complex III assembly is deficient, the pre-complex without Rieske iron-sulfur protein can participate with available fully assembled complex III in supercomplex formation, complex I function is preserved, and respiratory chain stability is maintained.
-
1036 gracile syndrome in a turkish newborn infant caused by a homozygous mutation p99l in complex iii assembly factor BCS1L
Archives of Disease in Childhood, 2012Co-Authors: Erkin Serdaroglu, Heike Kotarsky, Vineta Fellman, Sahin Takci, Onur Cil, Eda Utine, Sule YigitAbstract:Background and Aim GRACILE syndrome, a neonatal, autosomally recessive disorder found in Finland, featuring growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death, is caused by a homozygous mutation (S78G) in BCS1L, the assembly factor for respiratory chain complex III. We investigated a newborn Turkish girl with similar symptoms. Her two sisters with low birth weight, metabolic acidosis, cholestasis and renal Fanconi syndrome, had died at 18 and 105 days age, respectively. Methods and results The girl was born to healthy nonconsanguineous parents. She was growth retarded (1789 g at term), developed tachypnea and metabolic acidosis on day one. Lactic acidosis, jaundice with direct hyperbilirubinemia, nonspecific aminoaciduria, high phosphaturia, proteinuria and glucosuria were detected. Serum iron (190 mcg/dl), ferritin (2819 ng/ml) and transferrin saturation (99.4%) were increased. Metabolic, cardiologic and sonographic workup were otherwise normal. Because of similarities with GRACILE syndrome, the BCS1L gene was investigated. The Finnish SNP was not found, but gene sequencing revealed a homozygous mutation resulting in an amino acid exchange (P99L) in the protein. Conclusions The studied infant had a GRACILE-like disorder caused by a different mutation than that in newborns of Finnish ancestors. Most likely the two diseased siblings had the same homozygous BCS1L mutation that previously has been published in three other newborns or Turkish origin. We proposed that P99L-mutation in BCS1L is a Turkish genotype resulting in GRACILE syndrome phenotype, and should be investigated in Turkish newborns with the typical clinical features.
-
metabolite profiles reveal energy failure and impaired beta oxidation in liver of mice with complex iii deficiency due to a BCS1L mutation
PLOS ONE, 2012Co-Authors: Heike Kotarsky, Vineta Fellman, Mina Davoudi, Riitta Karikoski, Matthias Keller, Per Leveen, David P EnotAbstract:AIMS: Liver is a target organ in many mitochondrial disorders, especially if the complex III assembly factor BCS1L is mutated. To reveal disease mechanism due to such mutations, we have produced a transgenic mouse model with c.232A>G mutation in BCS1L, the causative mutation for GRACILE syndrome. The homozygous mice develop mitochondrial hepatopathy with steatosis and fibrosis after weaning. Our aim was to assess cellular mechanisms for disease onset and progression using metabolomics. METHODS: With mass spectrometry we analyzed metabolite patterns in liver samples obtained from homozygotes and littermate controls of three ages. As oxidative stress might be a mechanism for mitochondrial hepatopathy, we also assessed H(2)O(2) production and expression of antioxidants. RESULTS: Homozygotes had a similar metabolic profile at 14 days of age as controls, with the exception of slightly decreased AMP. At 24 days, when hepatocytes display first histopathological signs, increases in succinate, fumarate and AMP were found associated with impaired glucose turnover and beta-oxidation. At end stage disease after 30 days, these changes were pronounced with decreased carbohydrates, high levels of acylcarnitines and amino acids, and elevated biogenic amines, especially putrescine. Signs of oxidative stress were present in end-stage disease. CONCLUSIONS: The findings suggest an early Krebs cycle defect with increases of its intermediates, which might play a role in disease onset. During disease progression, carbohydrate and fatty acid metabolism deteriorate leading to a starvation-like condition. The mouse model is valuable for further investigations on mechanisms in mitochondrial hepatopathy and for interventions. (Less)
Mina Davoudi - One of the best experts on this subject based on the ideXlab platform.
-
cox7a2l scafi and pre complex iii modify respiratory chain supercomplex formation in different mouse strains with a BCS1L mutation
PLOS ONE, 2016Co-Authors: Mina Davoudi, Heike Kotarsky, Vineta Fellman, Eva Hansson, Jukka KallijarviAbstract:The COX7A2L (Supercomplex Assembly Factor I, SCAFI) protein has been proposed to be a mitochondrial supercomplex assembly factor required for respirasome (supercomplex containing complexes I, III, and IV) formation. In the C57BL/6 mouse strain a homozygous in-frame 6-base-pair deletion in the COX7a2l/SCAF1 gene resulting in unstable protein and suggesting loss of function was previously identified. The loss of SCAFI was shown to impede respirasome formation, a major concern for the use of C57BL mouse strains in mitochondrial research. In contradiction, another recent study suggested that supercomplex formation is independent of SCAFI isoforms. We investigated whether SCAFI isoform status affected the disease severity and supercomplex formation in the liver of BCS1Lc.232A>G knock-in mice with incomplete complex III assembly. In homozygotes (BCS1LG/G) of mixed (C57BL/6:129/Sv) genetic background, the lifespan was similar in mice with wild-type SCAFI allele and in those homozygous (SCAFIshort/short) for the deleted SCAF1 variant (34±3 days; n = 6 vs. 32±2 days; n = 7, respectively). SCAFI heterozygosity (SCAFIlong/short) resulted in decreased SCAFI protein but respirasome assembly was unaffected. Congenic (C57BL/6) mice were of the genotype SCAFIshort/short and had no detectable SCAFI protein. In their liver mitochondria, respirasome composition was altered as compared to mixed background mice. Complex IV was mainly present as monomers and dimers, and only low amounts were found in combination with complex I and complex III or with precomplex III. The main supercomplex in the liver mitochondria of C57BL/6 mice comprised only complexes I and III. In conclusion, in liver mitochondria of C57BL/6 mice, supercomplexes had markedly reduced amount of, but were not completely depleted of, complex IV, supporting a role for COX7A2L/SCAFI in supercomplex assembly. However, the disease progression of the BCS1L mutant mice was unrelated to SCAFI isoforms and supercomplex composition, suggesting that other genetic factors contribute to the different survival in the different genetic backgrounds.
-
complex i function and supercomplex formation are preserved in liver mitochondria despite progressive complex iii deficiency
PLOS ONE, 2014Co-Authors: Mina Davoudi, Heike Kotarsky, Vineta Fellman, Eva Ekvall HanssonAbstract:Functional oxidative phosphorylation requires appropriately assembled mitochondrial respiratory complexes and their supercomplexes formed mainly of complexes I, III and IV. BCS1L is the chaperone needed to incorporate the catalytic subunit, Rieske iron-sulfur protein, into complex III at the final stage of its assembly. In cell culture studies, this subunit has been considered necessary for supercomplex formation and for maintaining the stability of complex I. Our aim was to assess the importance of fully assembled complex III for supercomplex formation in intact liver tissue. We used our transgenic mouse model with a homozygous c.232A>G mutation in BCS1L leading to decreased expression of BCS1L and progressive decrease of Rieske iron-sulfur protein in complex III, resulting in hepatopathy. We studied supercomplex formation at different ages using blue native gel electrophoresis and complex activity using high-resolution respirometry. In isolated liver mitochondria of young and healthy homozygous mutant mice, we found similar supercomplexes as in wild type. In homozygotes aged 27–29 days with liver disorder, complex III was predominantly a pre-complex lacking Rieske iron-sulfur protein. However, the main supercomplex was clearly detected and contained complex III mainly in the pre-complex form. Oxygen consumption of complex IV was similar and that of complex I was twofold compared with controls. These complexes in free form were more abundant in homozygotes than in controls, and the mRNA of complex I subunits were upregulated. In conclusion, when complex III assembly is deficient, the pre-complex without Rieske iron-sulfur protein can participate with available fully assembled complex III in supercomplex formation, complex I function is preserved, and respiratory chain stability is maintained.
-
metabolite profiles reveal energy failure and impaired beta oxidation in liver of mice with complex iii deficiency due to a BCS1L mutation
PLOS ONE, 2012Co-Authors: Heike Kotarsky, Vineta Fellman, Mina Davoudi, Riitta Karikoski, Matthias Keller, Per Leveen, David P EnotAbstract:AIMS: Liver is a target organ in many mitochondrial disorders, especially if the complex III assembly factor BCS1L is mutated. To reveal disease mechanism due to such mutations, we have produced a transgenic mouse model with c.232A>G mutation in BCS1L, the causative mutation for GRACILE syndrome. The homozygous mice develop mitochondrial hepatopathy with steatosis and fibrosis after weaning. Our aim was to assess cellular mechanisms for disease onset and progression using metabolomics. METHODS: With mass spectrometry we analyzed metabolite patterns in liver samples obtained from homozygotes and littermate controls of three ages. As oxidative stress might be a mechanism for mitochondrial hepatopathy, we also assessed H(2)O(2) production and expression of antioxidants. RESULTS: Homozygotes had a similar metabolic profile at 14 days of age as controls, with the exception of slightly decreased AMP. At 24 days, when hepatocytes display first histopathological signs, increases in succinate, fumarate and AMP were found associated with impaired glucose turnover and beta-oxidation. At end stage disease after 30 days, these changes were pronounced with decreased carbohydrates, high levels of acylcarnitines and amino acids, and elevated biogenic amines, especially putrescine. Signs of oxidative stress were present in end-stage disease. CONCLUSIONS: The findings suggest an early Krebs cycle defect with increases of its intermediates, which might play a role in disease onset. During disease progression, carbohydrate and fatty acid metabolism deteriorate leading to a starvation-like condition. The mouse model is valuable for further investigations on mechanisms in mitochondrial hepatopathy and for interventions. (Less)
Kathryn J Wahl - One of the best experts on this subject based on the ideXlab platform.
-
Barnacle Balanus amphitrite Adheres by a Stepwise Cementing Process
2016Co-Authors: Daniel K. Burden, Daniel E Barlow, Christopher M Spillmann, Beatriz Orihuela, Dan Rittschof, Richard K Everett, Kathryn J WahlAbstract:Barnacles adhere permanently to surfaces by secreting and curing a thin interfacial adhesive underwater. Here, we show that the acorn barnacle Balanus amphitrite adheres by a two-step fluid secretion process, both contributing to adhesion. We found that, as barnacles grow, the first barnacle cement secretion (BCS1) is released at the periphery of the expanding base plate. Subsequently, a second, autofluorescent fluid (BCS2) is released. We show that secretion of BCS2 into the interface results, on average, in a 2-fold increase in adhesive strength over adhesion by BCS1 alone. The two secretions are distinguishable both spatially and temporally, and differ in morphology, protein conformation, and chemical functionality. The short time window for BCS2 secretion relative to the overall area increase demonstrates that it has a disproportionate, surprisingly powerful, impact on adhesion. The dramatic change in adhesion occurs without measurable changes in interface thickness and total protein content. A fracture mechanics analysis suggests the interfacial material’s modulus or work of adhesion, or both, were substantially increased after BCS2 secretion. Addition of BCS2 into the interface generates highly networked amyloid-like fibrils and enhanced phenolic content. Both intertwined fibers and phenolic chemistries may contribute to mechanical stability of the interface through physically or chemically anchoring interface proteins to the substrate and intermolecular interactions. Our experiments point to the need to reexamine the role of phenolic components in barnacle adhesion, long discounted despite their prevalence in structural membranes of arthropods and crustaceans, as they may contribute to chemical processes that strengthen adhesion through intermolecular cross-linking
-
barnacle balanus amphitrite adheres by a stepwise cementing process
Langmuir, 2012Co-Authors: Daniel K Burden, Daniel E Barlow, Christopher M Spillmann, Beatriz Orihuela, Dan Rittschof, Richard K Everett, Kathryn J WahlAbstract:Barnacles adhere permanently to surfaces by secreting and curing a thin interfacial adhesive underwater. Here, we show that the acorn barnacle Balanus amphitrite adheres by a two-step fluid secretion process, both contributing to adhesion. We found that, as barnacles grow, the first barnacle cement secretion (BCS1) is released at the periphery of the expanding base plate. Subsequently, a second, autofluorescent fluid (BCS2) is released. We show that secretion of BCS2 into the interface results, on average, in a 2-fold increase in adhesive strength over adhesion by BCS1 alone. The two secretions are distinguishable both spatially and temporally, and differ in morphology, protein conformation, and chemical functionality. The short time window for BCS2 secretion relative to the overall area increase demonstrates that it has a disproportionate, surprisingly powerful, impact on adhesion. The dramatic change in adhesion occurs without measurable changes in interface thickness and total protein content. A fractu...
Paola Goffrini - One of the best experts on this subject based on the ideXlab platform.
-
molecular genetic investigations identify new clinical phenotypes associated with BCS1L related mitochondrial disease
Human Molecular Genetics, 2019Co-Authors: Monika Olahova, Camilla Ceccatelli Berti, Jack J Collier, Charlotte L Alston, Elisabeth Jameson, Simon Jones, Noel Edwards, Patrick F Chinnery, Rita Horvath, Paola GoffriniAbstract:BCS1L encodes a homolog of the Saccharomyces cerevisiae bcs1 protein, which has a known role in the assembly of Complex III of the mitochondrial respiratory chain. Phenotypes reported in association with pathogenic BCS1L variants include growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death (GRACILE syndrome), and Bjornstad syndrome, characterized by abnormal flattening and twisting of hair shafts (pili torti) and hearing problems. Here we describe two patients harbouring biallelic variants in BCS1L; the first with a heterozygous variant c.166C>T, p.(Arg56*) together with a novel heterozygous variant c.205C>T, p.(Arg69Cys) and a second patient with a novel homozygous c.325C>T, p.(Arg109Trp) variant. The two patients presented with different phenotypes; the first patient presented as an adult with aminoaciduria, seizures, bilateral sensorineural deafness and learning difficulties. The second patient was an infant who presented with a classical GRACILE syndrome leading to death at 4 months of age. A decrease in BCS1L protein levels was seen in both patients, and biochemical analysis of Complex III revealed normal respiratory chain enzyme activities in the muscle of both patients. A decrease in Complex III assembly was detected in the adult patient's muscle, whilst the paediatric patient displayed a combined mitochondrial respiratory chain defect in cultured fibroblasts. Yeast complementation studies indicate that the two missense variants, c.205C>T, p.(Arg69Cys) and c.325C>T, p.(Arg109Trp), impair the respiratory capacity of the cell. Together, these data support the pathogenicity of the novel BCS1L variants identified in our patients.
-
long term survival of neonatal mitochondrial complex iii deficiency associated with a novel BCS1L gene mutation
Molecular Genetics and Metabolism, 2010Co-Authors: Helen A L Tuppen, Rita Horvath, Paola Goffrini, Iliana Ferrero, Janev Fehmi, Birgit Czermin, Francesca Meloni, Emma L Blakely, Robert Mcfarland, Douglass M TurnbullAbstract:Mutations of the BCS1L gene are a recognised cause of isolated respiratory chain complex III deficiency and underlie several fatal, neonatal mitochondrial diseases. Here we describe a 20-year-old Kenyan woman who initially presented as a floppy infant but whose condition progressed during childhood and adolescence with increasing muscle weakness, focal motor seizures and optic atrophy. Muscle biopsy demonstrated complex III deficiency and the pathogenicity of a novel, homozygous BCS1L mutation was confirmed by yeast complementation studies. Our data indicate that BCS1L mutations can cause a variable, neurological course which is not always fatal in childhood.
-
impaired complex iii assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy
Human Molecular Genetics, 2007Co-Authors: Erika Fernandezvizarra, Paola Goffrini, Marianna Bugiani, Franco Carrara, Laura Farina, Elena Procopio, Alice Donati, Graziella Uziel, Iliana Ferrero, Massimo ZevianiAbstract:We investigated two unrelated children with an isolated defect of mitochondrial complex III activity. The clinical picture was characterized by a progressive encephalopathy featuring early-onset developmental delay, spasticity, seizures, lactic acidosis, brain atrophy and MRI signal changes in the basal ganglia. Both children were compound heterozygotes for novel mutations in the human bc1 synthesis like (BCS1L) gene, which encodes an AAA mitochondrial protein putatively involved in both iron homeostasis and complex III assembly. The pathogenic role of the mutations was confirmed by complementation assays, using a DeltaBcs1 strain of Saccharomyces cerevisiae. By investigating complex III assembly and the structural features of the BCS1L gene product in skeletal muscle, cultured fibroblasts and lymphoblastoid cell lines from our patients, we have demonstrated, for the first time in a mammalian system, that a major function of BCS1L is to promote the maturation of complex III and, more specifically, the incorporation of the Rieske iron-sulfur protein into the nascent complex. Defective BCS1L leads to the formation of a catalytically inactive, structurally unstable complex III. We have also shown that BCS1L is contained within a high-molecular-weight supramolecular complex which is clearly distinct from complex III intermediates.