Skip to main content
Erschienen in: Journal of Inherited Metabolic Disease 2/2018

20.11.2017 | Original Article

Propionyl-CoA carboxylase pcca-1 and pccb-1 gene deletions in Caenorhabditis elegans globally impair mitochondrial energy metabolism

verfasst von: Kimberly A. Chapman, Julian Ostrovsky, Meera Rao, Stephen D. Dingley, Erzsebet Polyak, Marc Yudkoff, Rui Xiao, Michael J. Bennett, Marni J. Falk

Erschienen in: Journal of Inherited Metabolic Disease | Ausgabe 2/2018

Einloggen, um Zugang zu erhalten

Abstract

Propionic acidemia (PA) is a classical inborn error of metabolism with high morbidity that results from the inability of the propionyl-CoA carboxylase (PCC) enzyme to convert propionyl-CoA to methylmalonyl-CoA. PA is inherited in an autosomal recessive fashion due to functional loss of both alleles of either PCCA or PCCB. These genes are highly conserved across evolutionarily diverse species and share extensive similarity with pcca-1 and pccb-1 in the nematode, Caenorhabditis elegans. Here, we report the global metabolic effects of deletion in a single PCC gene, either pcca-1 or pccb-1, in C. elegans. Animal lifespan was significantly reduced relative to wild-type worms in both mutant strains, although to a greater degree in pcca-1. Mitochondrial oxidative phosphorylation (OXPHOS) capacity and efficiency as determined by direct polarography of isolated mitochondria were also significantly reduced in both mutant strains. While in vivo quantitation of mitochondrial physiology was normal in pccb-1 mutants, pcca-1 deletion mutants had significantly increased mitochondrial matrix oxidant burden as well as significantly decreased mitochondrial membrane potential and mitochondrial content. Whole worm steady-state free amino acid profiling by UPLC revealed reduced levels in both mutant strains of the glutathione precursor cysteine, possibly suggestive of increased oxidative stress. Intermediary metabolic flux analysis by GC/MS with 1,6-13C2-glucose further showed both PCC deletion strains had decreased accumulation of a distal tricarboxylic acid (TCA) cycle metabolic intermediate (+1 malate), isotopic enrichment in a proximal TCA cycle intermediate (+1 citrate), and increased +1 lactate accumulation. GC/MS analysis further revealed accumulation in the PCC mutants of a small amount of 3-hydroxypropionate, which appeared to be metabolized in C. elegans to oxalate through a unique metabolic pathway. Collectively, these detailed metabolic investigations in translational PA model animals with genetic-based PCC deficiency reveal their significantly dysregulated energy metabolism at multiple levels, including reduced mitochondrial OXPHOS capacity, increased oxidative stress, and inhibition of distal TCA cycle flux, culminating in reduced animal lifespan. These findings demonstrate that the pathophysiology of PA extends well beyond what has classically been understood as a single PCC enzyme deficiency with toxic precursor accumulation, and suggest that therapeutically targeting the globally disrupted energy metabolism may offer novel treatment opportunities for PA. Summary: Two C. elegans model animals of propionic acidemia with single-gene pcca-1 or pccb-1 deletions have reduced lifespan with significantly reduced mitochondrial energy metabolism and increased oxidative stress, reflecting the disease’s broader pathophysiology beyond a single enzyme deficiency with toxic precursor accumulation.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
Zurück zum Zitat Baumgartner MR, Horster F, Dionisi-Vici C et al (2014) Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis 9:130CrossRefPubMedPubMedCentral Baumgartner MR, Horster F, Dionisi-Vici C et al (2014) Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis 9:130CrossRefPubMedPubMedCentral
Zurück zum Zitat Chandler RJ, Aswani V, Tsai MS et al (2006) Propionyl-CoA and adenosylcobalamin metabolism in Caenorhabditis elegans: evidence for a role of methylmalonyl-CoA epimerase in intermediary metabolism. Mol Genet Metab 89:64–73CrossRefPubMedPubMedCentral Chandler RJ, Aswani V, Tsai MS et al (2006) Propionyl-CoA and adenosylcobalamin metabolism in Caenorhabditis elegans: evidence for a role of methylmalonyl-CoA epimerase in intermediary metabolism. Mol Genet Metab 89:64–73CrossRefPubMedPubMedCentral
Zurück zum Zitat Chemelli AP, Schocke M, Sperl W, Trieb T, Aichner F, Felber S (2000) Magnetic resonance spectroscopy (MRS) in five patients with treated propionic acidemia. J Magn Reson Imaging 11:596–600CrossRefPubMed Chemelli AP, Schocke M, Sperl W, Trieb T, Aichner F, Felber S (2000) Magnetic resonance spectroscopy (MRS) in five patients with treated propionic acidemia. J Magn Reson Imaging 11:596–600CrossRefPubMed
Zurück zum Zitat Clarke C, Xiao R, Place E et al (2013) Mitochondrial respiratory chain disease discrimination by retrospective cohort analysis of blood metabolites. Mol Genet Metab 110:145–152CrossRefPubMed Clarke C, Xiao R, Place E et al (2013) Mitochondrial respiratory chain disease discrimination by retrospective cohort analysis of blood metabolites. Mol Genet Metab 110:145–152CrossRefPubMed
Zurück zum Zitat de Keyzer Y, Valayannopoulos V, Benoist JF et al (2009) Multiple OXPHOS deficiency in the liver, kidney, heart, and skeletal muscle of patients with methylmalonic aciduria and propionic aciduria. Pediatr Res 66:91–95CrossRefPubMed de Keyzer Y, Valayannopoulos V, Benoist JF et al (2009) Multiple OXPHOS deficiency in the liver, kidney, heart, and skeletal muscle of patients with methylmalonic aciduria and propionic aciduria. Pediatr Res 66:91–95CrossRefPubMed
Zurück zum Zitat DiDonato S (2009) Multisystem manifestations of mitochondrial disorders. J Neurol 256:693–710CrossRef DiDonato S (2009) Multisystem manifestations of mitochondrial disorders. J Neurol 256:693–710CrossRef
Zurück zum Zitat Dingley S, Polyak E, Lightfoot R et al (2010) Mitochondrial respiratory chain dysfunction variably increases oxidant stress in Caenorhabditis elegans. Mitochondrion 10:125–136CrossRefPubMed Dingley S, Polyak E, Lightfoot R et al (2010) Mitochondrial respiratory chain dysfunction variably increases oxidant stress in Caenorhabditis elegans. Mitochondrion 10:125–136CrossRefPubMed
Zurück zum Zitat Falk MJ, Kayser EB, Morgan PG, Sedensky MM (2006) Mitochondrial complex I function modulates volatile anesthetic sensitivity in C. elegans. Curr Biol 16:1641–1645CrossRefPubMedPubMedCentral Falk MJ, Kayser EB, Morgan PG, Sedensky MM (2006) Mitochondrial complex I function modulates volatile anesthetic sensitivity in C. elegans. Curr Biol 16:1641–1645CrossRefPubMedPubMedCentral
Zurück zum Zitat Falk MJ, Rao M, Ostrovsky J, Daikhin E, Nissim I, Yudkoff M (2011) Stable isotopic profiling of intermediary metabolic flux in developing and adult stage Caenorhabditis elegans. J Vis Exp48:2288 Falk MJ, Rao M, Ostrovsky J, Daikhin E, Nissim I, Yudkoff M (2011) Stable isotopic profiling of intermediary metabolic flux in developing and adult stage Caenorhabditis elegans. J Vis Exp48:2288
Zurück zum Zitat Falk MJ, Zhang Z, Rosenjack JR et al (2008) Metabolic pathway profiling of mitochondrial respiratory chain mutants in C. elegans. Mol Genet Metab 93:388–397CrossRefPubMed Falk MJ, Zhang Z, Rosenjack JR et al (2008) Metabolic pathway profiling of mitochondrial respiratory chain mutants in C. elegans. Mol Genet Metab 93:388–397CrossRefPubMed
Zurück zum Zitat Fenton WA, Gravel RA, Rosenblatt DS (2001) Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudert AL, Sly WS, Valle D (eds) The Metabolic & molecular basis of inherited disease. McGraw-Hill, New York, pp 2165–2193 Fenton WA, Gravel RA, Rosenblatt DS (2001) Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudert AL, Sly WS, Valle D (eds) The Metabolic & molecular basis of inherited disease. McGraw-Hill, New York, pp 2165–2193
Zurück zum Zitat Gallego-Villar L, Rivera-Barahona A, Cuevas-Martin C et al (2016) In vivo evidence of mitochondrial dysfunction and altered redox homeostasis in a genetic mouse model of propionic acidemia: implications for the pathophysiology of this disorder. Free Radic Biol Med 96:1–12CrossRefPubMed Gallego-Villar L, Rivera-Barahona A, Cuevas-Martin C et al (2016) In vivo evidence of mitochondrial dysfunction and altered redox homeostasis in a genetic mouse model of propionic acidemia: implications for the pathophysiology of this disorder. Free Radic Biol Med 96:1–12CrossRefPubMed
Zurück zum Zitat Gregersen N (1981) The specific inhibition of the pyruvate dehydrogenase complex from pig kidney by propionyl-CoA and isovaleryl-Co-A. Biochemical Med 26:20–27CrossRef Gregersen N (1981) The specific inhibition of the pyruvate dehydrogenase complex from pig kidney by propionyl-CoA and isovaleryl-Co-A. Biochemical Med 26:20–27CrossRef
Zurück zum Zitat Grunert SC, Mullerleile S, de Silva L et al (2013) Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent patients. Orphanet J Rare Dis 8:6CrossRefPubMedPubMedCentral Grunert SC, Mullerleile S, de Silva L et al (2013) Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent patients. Orphanet J Rare Dis 8:6CrossRefPubMedPubMedCentral
Zurück zum Zitat Haas RH, Parikh S, Falk MJ et al (2007) Mitochondrial disease: a practical approach for primary care physicians. Pediatrics 120:1326–1333CrossRefPubMed Haas RH, Parikh S, Falk MJ et al (2007) Mitochondrial disease: a practical approach for primary care physicians. Pediatrics 120:1326–1333CrossRefPubMed
Zurück zum Zitat Hope LA (1999) C. elegans: a practical approach. The practical approach series. Oxford University Press, New York Hope LA (1999) C. elegans: a practical approach. The practical approach series. Oxford University Press, New York
Zurück zum Zitat Huang CS, Sadre-Bazzaz K, Shen Y, Deng B, Zhou ZH, Tong L (2010) Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme a carboxylase. Nature 466:1001–1005CrossRefPubMedPubMedCentral Huang CS, Sadre-Bazzaz K, Shen Y, Deng B, Zhou ZH, Tong L (2010) Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme a carboxylase. Nature 466:1001–1005CrossRefPubMedPubMedCentral
Zurück zum Zitat Kayser EB, Hoppel CL, Morgan PG, Sedensky MM (2003) A mutation in mitochondrial complex I increases ethanol sensitivity in Caenorhabditis elegans. Alcohol Clin Exp Res 27:584–592CrossRefPubMed Kayser EB, Hoppel CL, Morgan PG, Sedensky MM (2003) A mutation in mitochondrial complex I increases ethanol sensitivity in Caenorhabditis elegans. Alcohol Clin Exp Res 27:584–592CrossRefPubMed
Zurück zum Zitat Kraus JP, Spector E, Venezia S et al (2012) Mutation analysis in 54 propionic acidemia patients. J Inherit Metab Dis 35:51–63CrossRefPubMed Kraus JP, Spector E, Venezia S et al (2012) Mutation analysis in 54 propionic acidemia patients. J Inherit Metab Dis 35:51–63CrossRefPubMed
Zurück zum Zitat Lee SH, Davis EJ (1979) Carboxylation and decarboxylation reactions. Anaplerotic flux and removal of citrate cycle intermediates in skeletal muscle. J Biol Chem 254:420–430PubMed Lee SH, Davis EJ (1979) Carboxylation and decarboxylation reactions. Anaplerotic flux and removal of citrate cycle intermediates in skeletal muscle. J Biol Chem 254:420–430PubMed
Zurück zum Zitat Lehnert W, Sperl W, Suormala T, Baumgartner ER (1994) Propionic acidaemia: clinical, biochemical and therapeutic aspects. Experience in 30 patients. Eur J Pediatr 153:S68–S80CrossRefPubMed Lehnert W, Sperl W, Suormala T, Baumgartner ER (1994) Propionic acidaemia: clinical, biochemical and therapeutic aspects. Experience in 30 patients. Eur J Pediatr 153:S68–S80CrossRefPubMed
Zurück zum Zitat Mardach R, Verity MA, Cederbaum SD (2005) Clinical, pathological, and biochemical studies in a patient with propionic acidemia and fatal cardiomyopathy. Mol Genet Metab 85:286–290CrossRefPubMed Mardach R, Verity MA, Cederbaum SD (2005) Clinical, pathological, and biochemical studies in a patient with propionic acidemia and fatal cardiomyopathy. Mol Genet Metab 85:286–290CrossRefPubMed
Zurück zum Zitat Murfitt RR, Vogel K, Sanadi DR (1976) Characterization of the mitochondria of the free-living nematode, Caenorhabditis elegans. Comp Biochem Physiol B 53:423–430CrossRefPubMed Murfitt RR, Vogel K, Sanadi DR (1976) Characterization of the mitochondria of the free-living nematode, Caenorhabditis elegans. Comp Biochem Physiol B 53:423–430CrossRefPubMed
Zurück zum Zitat Muro S, Perez B, Desviat LR et al (2001) Effect of PCCB gene mutations on the heteromeric and homomeric assembly of propionyl-CoA carboxylase. Mol Genet Metab 74:476–483CrossRefPubMed Muro S, Perez B, Desviat LR et al (2001) Effect of PCCB gene mutations on the heteromeric and homomeric assembly of propionyl-CoA carboxylase. Mol Genet Metab 74:476–483CrossRefPubMed
Zurück zum Zitat Narayan SB, Ditewig-Meyers G, Graham KS, Scott R, Bennett MJ (2011) Measurement of plasma amino acids by Ultraperformance(R) liquid chromatography. Clin Chem Lab Med 49:1177–1185CrossRefPubMed Narayan SB, Ditewig-Meyers G, Graham KS, Scott R, Bennett MJ (2011) Measurement of plasma amino acids by Ultraperformance(R) liquid chromatography. Clin Chem Lab Med 49:1177–1185CrossRefPubMed
Zurück zum Zitat Ohura T, Kraus JP, Rosenberg LE (1989) Unequal synthesis and differential degradation of propionyl CoA carboxylase subunits in cells from normal and propionic acidemia patients. Am J Hum Genet 45:33–40PubMedPubMedCentral Ohura T, Kraus JP, Rosenberg LE (1989) Unequal synthesis and differential degradation of propionyl CoA carboxylase subunits in cells from normal and propionic acidemia patients. Am J Hum Genet 45:33–40PubMedPubMedCentral
Zurück zum Zitat O'Riordan VB, Burnell AM (1989) Intermediary metabolism in the dauer larva of the nematode Caenorhabditis elegans-- 1. Glycolysis, gluconeogenesis, oxidative phosphorylation and the tricarboxylic acid cycle. Comp Biochem Physiol B: Comp Biochem 92:233–238CrossRef O'Riordan VB, Burnell AM (1989) Intermediary metabolism in the dauer larva of the nematode Caenorhabditis elegans-- 1. Glycolysis, gluconeogenesis, oxidative phosphorylation and the tricarboxylic acid cycle. Comp Biochem Physiol B: Comp Biochem 92:233–238CrossRef
Zurück zum Zitat Patel TB, DeBuysere MS, Olson MS (1983) The effect of propionate on the regulation of the pyruvate dehydrogenase complex in the rat liver. Arch Biochem Biophys 220:405–414CrossRefPubMed Patel TB, DeBuysere MS, Olson MS (1983) The effect of propionate on the regulation of the pyruvate dehydrogenase complex in the rat liver. Arch Biochem Biophys 220:405–414CrossRefPubMed
Zurück zum Zitat Perez-Cerda C, Merinero B, Rodriguez-Pombo P et al (2000) Potential relationship between genotype and clinical outcome in propionic acidaemia patients. Eur J Hum Genet 8:187–194CrossRefPubMed Perez-Cerda C, Merinero B, Rodriguez-Pombo P et al (2000) Potential relationship between genotype and clinical outcome in propionic acidaemia patients. Eur J Hum Genet 8:187–194CrossRefPubMed
Zurück zum Zitat Rea SL, Graham BH, Nakamaru-Ogiso E, Kar A, Falk MJ (2010) Bacteria, yeast, worms, and flies: exploiting simple model organisms to investigate human mitochondrial diseases. Dev Disabil Res Rev 16:200–218CrossRefPubMedPubMedCentral Rea SL, Graham BH, Nakamaru-Ogiso E, Kar A, Falk MJ (2010) Bacteria, yeast, worms, and flies: exploiting simple model organisms to investigate human mitochondrial diseases. Dev Disabil Res Rev 16:200–218CrossRefPubMedPubMedCentral
Zurück zum Zitat Schrier VS, Rao M, McCormack S et al (2014) In vivo metabolic flux profiling with stable isotopes discriminates sites and quantifies effects of mitochondrial dysfunction in C. elegans. Mol Genet Metab 111:331–341CrossRef Schrier VS, Rao M, McCormack S et al (2014) In vivo metabolic flux profiling with stable isotopes discriminates sites and quantifies effects of mitochondrial dysfunction in C. elegans. Mol Genet Metab 111:331–341CrossRef
Zurück zum Zitat Schwab MA, Sauer SW, Okun JG et al (2006) Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins. Biochem J 398:107–112CrossRefPubMedPubMedCentral Schwab MA, Sauer SW, Okun JG et al (2006) Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins. Biochem J 398:107–112CrossRefPubMedPubMedCentral
Zurück zum Zitat Sutton VR, Chapman KA, Gropman AL et al (2012) Chronic management and health supervision of individuals with propionic acidemia. Mol Genet Metab 105:26–33CrossRefPubMed Sutton VR, Chapman KA, Gropman AL et al (2012) Chronic management and health supervision of individuals with propionic acidemia. Mol Genet Metab 105:26–33CrossRefPubMed
Zurück zum Zitat Wadsworth WG, Riddle DL (1989) Developmental regulation of energy metabolism in Caenorhabditis elegans. Dev Biol 132:167–173CrossRefPubMed Wadsworth WG, Riddle DL (1989) Developmental regulation of energy metabolism in Caenorhabditis elegans. Dev Biol 132:167–173CrossRefPubMed
Zurück zum Zitat Watson E, MacNeil LT, Arda HE, Zhu LJ, Walhout AJ (2013) Integration of metabolic and gene regulatory networks modulates the C. elegans dietary response. Cell 153:253–266CrossRefPubMed Watson E, MacNeil LT, Arda HE, Zhu LJ, Walhout AJ (2013) Integration of metabolic and gene regulatory networks modulates the C. elegans dietary response. Cell 153:253–266CrossRefPubMed
Zurück zum Zitat Watson E, Olin-Sandoval V, Hoy MJ, et al (2016) Metabolic network rewiring of propionate flux compensates vitamin B12 deficiency in C. elegans. eLife 5.pii:e17670. doi: 10.7554/eLife.17670. Watson E, Olin-Sandoval V, Hoy MJ, et al (2016) Metabolic network rewiring of propionate flux compensates vitamin B12 deficiency in C. elegans. eLife 5.pii:e17670. doi: 10.7554/eLife.17670.
Zurück zum Zitat Wendel U (2006) Branched-chain organic Acidemia. In: Fernandez J, Saudubray JM, van den Berghe G, Walter JH (eds.) Inborn metabolic diseases. Springer, Wurzberg Wendel U (2006) Branched-chain organic Acidemia. In: Fernandez J, Saudubray JM, van den Berghe G, Walter JH (eds.) Inborn metabolic diseases. Springer, Wurzberg
Metadaten
Titel
Propionyl-CoA carboxylase pcca-1 and pccb-1 gene deletions in Caenorhabditis elegans globally impair mitochondrial energy metabolism
verfasst von
Kimberly A. Chapman
Julian Ostrovsky
Meera Rao
Stephen D. Dingley
Erzsebet Polyak
Marc Yudkoff
Rui Xiao
Michael J. Bennett
Marni J. Falk
Publikationsdatum
20.11.2017
Verlag
Springer Netherlands
Erschienen in
Journal of Inherited Metabolic Disease / Ausgabe 2/2018
Print ISSN: 0141-8955
Elektronische ISSN: 1573-2665
DOI
https://doi.org/10.1007/s10545-017-0111-x

Weitere Artikel der Ausgabe 2/2018

Journal of Inherited Metabolic Disease 2/2018 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.