Personalised modelling of clinical heterogeneity between medium-chain acyl-CoA dehydrogenase patients.
Inborn error of metabolism
Kinetic modelling
Medium-chain acyl-CoA dehydrogenase deficiency
Metabolite partitioning
Mitochondrial fatty acid oxidation
Personalised medicine
Phenotypic heterogeneity
Journal
BMC biology
ISSN: 1741-7007
Titre abrégé: BMC Biol
Pays: England
ID NLM: 101190720
Informations de publication
Date de publication:
04 09 2023
04 09 2023
Historique:
received:
14
11
2022
accepted:
21
06
2023
medline:
6
9
2023
pubmed:
5
9
2023
entrez:
4
9
2023
Statut:
epublish
Résumé
Monogenetic inborn errors of metabolism cause a wide phenotypic heterogeneity that may even differ between family members carrying the same genetic variant. Computational modelling of metabolic networks may identify putative sources of this inter-patient heterogeneity. Here, we mainly focus on medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common inborn error of the mitochondrial fatty acid oxidation (mFAO). It is an enigma why some MCADD patients-if untreated-are at risk to develop severe metabolic decompensations, whereas others remain asymptomatic throughout life. We hypothesised that an ability to maintain an increased free mitochondrial CoA (CoASH) and pathway flux might distinguish asymptomatic from symptomatic patients. We built and experimentally validated, for the first time, a kinetic model of the human liver mFAO. Metabolites were partitioned according to their water solubility between the bulk aqueous matrix and the inner membrane. Enzymes are also either membrane-bound or in the matrix. This metabolite partitioning is a novel model attribute and improved predictions. MCADD substantially reduced pathway flux and CoASH, the latter due to the sequestration of CoA as medium-chain acyl-CoA esters. Analysis of urine from MCADD patients obtained during a metabolic decompensation showed an accumulation of medium- and short-chain acylcarnitines, just like the acyl-CoA pool in the MCADD model. The model suggested some rescues that increased flux and CoASH, notably increasing short-chain acyl-CoA dehydrogenase (SCAD) levels. Proteome analysis of MCADD patient-derived fibroblasts indeed revealed elevated levels of SCAD in a patient with a clinically asymptomatic state. This is a rescue for MCADD that has not been explored before. Personalised models based on these proteomics data confirmed an increased pathway flux and CoASH in the model of an asymptomatic patient compared to those of symptomatic MCADD patients. We present a detailed, validated kinetic model of mFAO in human liver, with solubility-dependent metabolite partitioning. Personalised modelling of individual patients provides a novel explanation for phenotypic heterogeneity among MCADD patients. Further development of personalised metabolic models is a promising direction to improve individualised risk assessment, management and monitoring for inborn errors of metabolism.
Sections du résumé
BACKGROUND
Monogenetic inborn errors of metabolism cause a wide phenotypic heterogeneity that may even differ between family members carrying the same genetic variant. Computational modelling of metabolic networks may identify putative sources of this inter-patient heterogeneity. Here, we mainly focus on medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common inborn error of the mitochondrial fatty acid oxidation (mFAO). It is an enigma why some MCADD patients-if untreated-are at risk to develop severe metabolic decompensations, whereas others remain asymptomatic throughout life. We hypothesised that an ability to maintain an increased free mitochondrial CoA (CoASH) and pathway flux might distinguish asymptomatic from symptomatic patients.
RESULTS
We built and experimentally validated, for the first time, a kinetic model of the human liver mFAO. Metabolites were partitioned according to their water solubility between the bulk aqueous matrix and the inner membrane. Enzymes are also either membrane-bound or in the matrix. This metabolite partitioning is a novel model attribute and improved predictions. MCADD substantially reduced pathway flux and CoASH, the latter due to the sequestration of CoA as medium-chain acyl-CoA esters. Analysis of urine from MCADD patients obtained during a metabolic decompensation showed an accumulation of medium- and short-chain acylcarnitines, just like the acyl-CoA pool in the MCADD model. The model suggested some rescues that increased flux and CoASH, notably increasing short-chain acyl-CoA dehydrogenase (SCAD) levels. Proteome analysis of MCADD patient-derived fibroblasts indeed revealed elevated levels of SCAD in a patient with a clinically asymptomatic state. This is a rescue for MCADD that has not been explored before. Personalised models based on these proteomics data confirmed an increased pathway flux and CoASH in the model of an asymptomatic patient compared to those of symptomatic MCADD patients.
CONCLUSIONS
We present a detailed, validated kinetic model of mFAO in human liver, with solubility-dependent metabolite partitioning. Personalised modelling of individual patients provides a novel explanation for phenotypic heterogeneity among MCADD patients. Further development of personalised metabolic models is a promising direction to improve individualised risk assessment, management and monitoring for inborn errors of metabolism.
Identifiants
pubmed: 37667308
doi: 10.1186/s12915-023-01652-9
pii: 10.1186/s12915-023-01652-9
pmc: PMC10478272
doi:
Substances chimiques
Acyl-CoA Dehydrogenase
EC 1.3.8.7
Coenzyme A
SAA04E81UX
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
184Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
J Biol Chem. 2019 Aug 16;294(33):12380-12391
pubmed: 31235473
Toxicol In Vitro. 2006 Dec;20(8):1582-6
pubmed: 16930941
Acta Biochim Pol. 1990;37(1):135-9
pubmed: 2087902
Biosystems. 2006 Feb-Mar;83(2-3):81-90
pubmed: 16426740
J Biol Chem. 2019 Dec 13;294(50):19034-19047
pubmed: 31676684
BMC Biol. 2016 Dec 7;14(1):107
pubmed: 27927213
J Inherit Metab Dis. 2021 Jan;44(1):164-177
pubmed: 33340416
JCI Insight. 2019 Apr 23;5:
pubmed: 31012869
J Biol Chem. 1977 Jan 25;252(2):542-7
pubmed: 833142
Cell Metab. 2016 Jan 12;23(1):13-26
pubmed: 26712461
FEBS Lett. 1976 Oct 15;69(1):265-71
pubmed: 992036
J Biol Chem. 1995 May 19;270(20):12177-83
pubmed: 7744868
Eur J Biochem. 1997 Feb 15;244(1):1-14
pubmed: 9063439
Arch Biochem Biophys. 1992 Nov 1;298(2):527-31
pubmed: 1416981
Biochem Biophys Res Commun. 1992 Mar 16;183(2):443-8
pubmed: 1550553
Diabetes. 1968 Apr;17(4):194-208
pubmed: 4296238
J Inherit Metab Dis. 1998 Jun;21(4):391-9
pubmed: 9700596
Ann Neurol. 1996 Oct;40(4):597-602
pubmed: 8871579
J Biol Chem. 2010 Sep 24;285(39):29834-41
pubmed: 20663895
Nat Rev Genet. 2006 Jun;7(6):449-60
pubmed: 16708072
Cell Metab. 2017 Mar 7;25(3):749-756
pubmed: 28111213
Nucleic Acids Res. 2021 Jan 8;49(D1):D1388-D1395
pubmed: 33151290
J Pediatr. 2016 Feb;169:208-13.e2
pubmed: 26602010
Bioinformatics. 2017 May 15;33(10):1589-1590
pubmed: 28130238
Biochemistry. 1964 Mar;3:338-45
pubmed: 14155095
Biochem J. 1984 Mar 1;218(2):511-20
pubmed: 6712627
Mol Aspects Med. 2011 Aug;32(4-6):223-33
pubmed: 22020112
Biochem J. 1982 May 15;204(2):399-403
pubmed: 7115336
Mol Genet Metab. 2001 May;73(1):46-54
pubmed: 11350182
J Biol Chem. 1997 Feb 7;272(6):3207-15
pubmed: 9013556
Mol Genet Metab. 2019 Aug;127(4):327-335
pubmed: 31279622
Biochem J. 1987 Dec 15;248(3):727-33
pubmed: 3435481
J Biol Chem. 1988 Dec 5;263(34):18036-42
pubmed: 3056937
Nucleic Acids Res. 2018 Jan 4;46(D1):D1271-D1281
pubmed: 29106664
Biochem Soc Trans. 2001 May;29(Pt 2):279-82
pubmed: 11356167
Biochim Biophys Acta. 1991 Nov 13;1071(3):291-312
pubmed: 1958691
Biochem J. 1994 Apr 1;299 ( Pt 1):165-70
pubmed: 8166635
Mol Genet Metab. 2007 Jun;91(2):138-47
pubmed: 17374501
PLoS One. 2017 Dec 28;12(12):e0190366
pubmed: 29284039
Syst Biol (Stevenage). 2006 Sep;153(5):338-41
pubmed: 16986312
J Hepatol. 2019 Jun;70(6):1145-1158
pubmed: 30630011
JCI Insight. 2017 Sep 7;2(17):
pubmed: 28878125
Biochem J. 1967 Aug;104(2):510-8
pubmed: 6069132
J Biol Chem. 1995 Jan 13;270(2):530-5
pubmed: 7822275
Biochemistry. 1999 May 4;38(18):5786-98
pubmed: 10231530
Acta Crystallogr D Biol Crystallogr. 2014 Dec 1;70(Pt 12):3212-25
pubmed: 25478839
J Biochem. 1986 May;99(5):1345-52
pubmed: 3711067
J Nutr. 2000 Feb;130(2S Suppl):294S-298S
pubmed: 10721891
Biochem J. 1982 Jul 1;205(1):123-7
pubmed: 7126172
Biochim Biophys Acta. 2014 Apr;1837(4):408-17
pubmed: 24183692
J Biol Chem. 2001 Jun 8;276(23):20182-5
pubmed: 11274214
Biochem Med Metab Biol. 1987 Apr;37(2):133-41
pubmed: 3593587
Biochemistry. 1992 Jan 21;31(2):557-67
pubmed: 1731912
J Biochem. 1981 Aug;90(2):511-9
pubmed: 6117552
Biochemistry. 1985 Jul 16;24(15):3922-5
pubmed: 2996585
Sci Rep. 2019 Oct 10;9(1):14539
pubmed: 31601874
Biochem Med Metab Biol. 1993 Aug;50(1):103-10
pubmed: 8373630
J Pharm Sci. 2004 Dec;93(12):3103-10
pubmed: 15514985
Biochem J. 1975 Jul;150(1):77-88
pubmed: 1201010
Biochem J. 2018 Mar 9;475(5):959-976
pubmed: 29438065
Trends Genet. 1999 Jul;15(7):267-72
pubmed: 10390625
J Inherit Metab Dis. 2009 Apr;32(2):214-7
pubmed: 19255872
PLoS Comput Biol. 2021 Aug 12;17(8):e1009259
pubmed: 34383741
FEBS Lett. 1990 Nov 12;274(1-2):163-6
pubmed: 2174799
J Pers Med. 2021 Jul 29;11(8):
pubmed: 34442389
Cell Res. 2019 Dec;29(12):1009-1026
pubmed: 31628434
Orphanet J Rare Dis. 2012 May 25;7:30
pubmed: 22630369
Biochem J. 1992 Sep 1;286 ( Pt 2):313-30
pubmed: 1530563
J Pediatr. 2000 Aug;137(2):257-9
pubmed: 10931422
Pediatr Res. 2005 Jun;57(6):755-9
pubmed: 15845636
Annu Rev Physiol. 2016;78:23-44
pubmed: 26474213
Life Sci Alliance. 2019 Mar 28;2(2):
pubmed: 30923191
Biochemistry. 2002 Sep 17;41(37):11126-33
pubmed: 12220177
J Proteome Res. 2016 Sep 2;15(9):3204-13
pubmed: 27447838
FEBS J. 2015 Apr;282(8):1481-511
pubmed: 25693925
Biochim Biophys Acta. 2001 Mar 9;1546(1):21-43
pubmed: 11257506
Eur J Biochem. 1981 Jul;117(2):425-30
pubmed: 6115749
Mol Genet Metab. 2001 Sep-Oct;74(1-2):45-50
pubmed: 11592802
Expert Rev Mol Diagn. 2019 Jun;19(6):499-515
pubmed: 31057016
J Biol Chem. 1992 Jan 15;267(2):1034-41
pubmed: 1730633
J Inherit Metab Dis. 2019 Sep;42(5):890-897
pubmed: 31012112
J Biol Chem. 1978 Mar 25;253(6):1827-31
pubmed: 344310
J Pediatr. 1994 Mar;124(3):409-15
pubmed: 8120710
Prog Lipid Res. 2002 May;41(3):197-239
pubmed: 11814524
Hum Mutat. 1992;1(4):271-9
pubmed: 1363805
Mol Cell Biochem. 1988 Jan;79(1):25-30
pubmed: 3374476
Eur J Biochem. 2000 Sep;267(17):5313-29
pubmed: 10951190
J Biol Chem. 1992 Jan 15;267(2):1027-33
pubmed: 1730632
Biochemistry. 2009 Feb 17;48(6):1293-304
pubmed: 19170545
Front Oncol. 2017 Feb 20;7:13
pubmed: 28265552
Hum Mol Genet. 2013 Dec 20;22(25):5249-61
pubmed: 23933733
Curr Top Membr. 2014;73:289-320
pubmed: 24745987
Arch Dis Child. 1999 May;80(5):459-62
pubmed: 10208954
J Clin Invest. 1994 Apr;93(4):1740-7
pubmed: 8163672
Biochem J. 1998 Jan 15;329 ( Pt 2):225-9
pubmed: 9425103
Biochemistry. 2010 Oct 5;49(39):8608-17
pubmed: 20825197
J Biochem. 1981 Dec;90(6):1739-50
pubmed: 7334008
J Inherit Metab Dis. 2008 Feb;31(1):88-96
pubmed: 18188679
Pediatr Dev Pathol. 1999 Jul-Aug;2(4):337-45
pubmed: 10347277
Nat Biotechnol. 2015 Aug;33(8):845-852
pubmed: 26167629
Mol Cell Biochem. 2014 Sep;394(1-2):307-14
pubmed: 24898781
Biochem J. 1993 Sep 15;294 ( Pt 3):645-51
pubmed: 8379919
Pediatr Res. 2001 Jan;49(1):18-23
pubmed: 11134486
J Biol Chem. 1985 Jan 25;260(2):1311-25
pubmed: 3968063
Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6069-6074
pubmed: 30850536
Mol Genet Metab. 2008 May;94(1):4-15
pubmed: 18337138
J Biochem. 1999 Dec;126(6):1013-9
pubmed: 10578051
Eur J Biochem. 1994 Mar 15;220(3):671-81
pubmed: 8143722
Biochemistry. 1990 May 8;29(18):4326-34
pubmed: 2350540
J Hepatol. 2016 Dec;65(6):1198-1208
pubmed: 27312946
Am J Physiol. 1990 Mar;258(3 Pt 1):E519-28
pubmed: 2316645
J Biol Chem. 1984 Feb 10;259(3):1789-97
pubmed: 6546382
J Biol Chem. 1986 Jun 15;261(17):7733-41
pubmed: 3711105
Biochem Med (Zagreb). 2015 Jun 05;25(2):279-84
pubmed: 26110041
J Biol Chem. 1971 Feb 25;246(4):1149-59
pubmed: 5543682
Trends Endocrinol Metab. 2012 Sep;23(9):420-8
pubmed: 22819213
Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1494-9
pubmed: 17242360
Biochem Soc Trans. 1994 May;22(2):441-6
pubmed: 7958342
J Biol Chem. 1986 Oct 25;261(30):14209-13
pubmed: 3771531
FEBS Lett. 2010 May 3;584(9):1931-9
pubmed: 19861126
Mol Cell Biochem. 1983;57(1):3-15
pubmed: 6358858
J Biol Chem. 1988 Dec 5;263(34):18160-7
pubmed: 3192530
Biochim Biophys Acta. 2013 Sep;1831(9):1467-74
pubmed: 23850792
Biochim Biophys Acta. 1989 Mar 23;973(3):355-82
pubmed: 2647140
Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8429-33
pubmed: 1528846
Ann Biomed Eng. 1983;11(5):361-84
pubmed: 6592996
Biochemistry. 1996 Sep 24;35(38):12402-11
pubmed: 8823175
J Inherit Metab Dis. 2010 Oct;33(5):555-61
pubmed: 20830526
Mol Genet Metab. 2007 Jan;90(1):24-9
pubmed: 16935015
J Biol Chem. 1992 Jan 5;267(1):119-25
pubmed: 1730577
Biochim Biophys Acta. 1990 Oct 24;1020(1):81-6
pubmed: 2223786
Biochem Soc Trans. 2000 Feb;28(2):177-82
pubmed: 10816122
Science. 2010 Feb 19;327(5968):1000-4
pubmed: 20167786
Methods Enzymol. 1982;87:366-9
pubmed: 7176921
Nucleic Acids Res. 2012 Jan;40(Database issue):D790-6
pubmed: 22102587
Arch Biochem Biophys. 1986 Jan;244(1):357-60
pubmed: 3947067
Biochim Biophys Acta. 2009 Aug;1791(8):806-15
pubmed: 19465148
Eur J Biochem. 1990 May 20;189(3):539-46
pubmed: 2351134
Nucleic Acids Res. 2012 Jan;40(Database issue):D770-5
pubmed: 22064852
FEBS Lett. 1995 Jan 2;357(1):75-8
pubmed: 8001684
Biochem Soc Trans. 2019 Feb 28;47(1):149-155
pubmed: 30626707
Cell. 2018 Nov 29;175(6):1591-1606.e19
pubmed: 30500538
Orphanet J Rare Dis. 2016 Feb 03;11:12
pubmed: 26841949
Trends Biochem Sci. 2003 Jul;28(7):343-6
pubmed: 12877997
Prog Lipid Res. 2010 Oct;49(4):366-77
pubmed: 20470824
Nat Commun. 2022 Jun 30;13(1):3766
pubmed: 35773252
J Inherit Metab Dis. 2008 Oct;31(5):619-29
pubmed: 18836848
J Clin Invest. 1995 Jun;95(6):2465-73
pubmed: 7769092
Public Health Genomics. 2011;14(3):173-7
pubmed: 21178328
J Lipid Res. 2014 Dec;55(12):2458-70
pubmed: 25114170
Biochim Biophys Acta. 1980 Jul 14;619(1):90-7
pubmed: 7417471
Biochem J. 1997 Apr 1;323 ( Pt 1):1-12
pubmed: 9173866
Mol Genet Metab. 2006 Mar;87(3):233-42
pubmed: 16376132
J Biochem. 1996 Apr;119(4):775-82
pubmed: 8743581
Curr Opin Biotechnol. 2005 Jun;16(3):336-43
pubmed: 15922580
Cell. 2007 Nov 30;131(5):861-72
pubmed: 18035408
BMC Med Genet. 2018 Apr 20;19(1):64
pubmed: 29678161
Orphanet J Rare Dis. 2015 Jun 18;10:79
pubmed: 26081110
Mol Cell Proteomics. 2021;20:100165
pubmed: 34673283
FEBS J. 2012 Aug;279(16):2810-22
pubmed: 22712534
Biochemistry. 1993 Oct 5;32(39):10436-43
pubmed: 8399188
Nat Biotechnol. 2018 Mar;36(3):272-281
pubmed: 29457794
Eur J Biochem. 1992 Feb 15;204(1):257-66
pubmed: 1740137
Biochem Biophys Res Commun. 1995 Sep 5;214(1):247-53
pubmed: 7669045
Biochim Biophys Acta. 2016 Oct;1863(10):2379-93
pubmed: 27001633
Mitochondrion. 2019 May;46:73-90
pubmed: 29551309
Biochim Biophys Acta. 1984 Mar 30;764(3):272-82
pubmed: 6704385
Mol Syst Biol. 2010 Sep 7;6:411
pubmed: 20823849
Nat Protoc. 2013 Nov;8(11):2281-2308
pubmed: 24157548
J Biochem. 1983 Feb;93(2):439-51
pubmed: 6404901
J Biol Chem. 1987 Jun 15;262(17):7982-9
pubmed: 3597357
J Proteomics. 2016 Mar 16;136:234-47
pubmed: 26825538
Biochim Biophys Acta. 1993 Feb 13;1156(2):135-43
pubmed: 8427872
Am J Physiol Endocrinol Metab. 2019 Apr 1;316(4):E578-E589
pubmed: 30694691
Bioinformatics. 2012 Aug 1;28(15):2037-44
pubmed: 22645166
Biochem Biophys Rep. 2016 Sep 17;8:333-339
pubmed: 28955973
J Inherit Metab Dis. 2012 Mar;35(2):269-77
pubmed: 21932095
Prog Lipid Res. 2015 Jul;59:1-25
pubmed: 25898985
FEBS Lett. 2003 Sep 25;552(2-3):253-8
pubmed: 14527695
J Biochem. 1996 Sep;120(3):624-32
pubmed: 8902629
FEBS J. 2018 Jun;285(12):2193-2204
pubmed: 29498804
Biophys J. 2012 Apr 18;102(8):1703-11
pubmed: 22768925
Eur J Biochem. 1978 Jan 16;82(2):373-84
pubmed: 624277
J Pediatr. 2003 Sep;143(3):335-42
pubmed: 14517516
Proc Natl Acad Sci U S A. 2018 Jul 3;115(27):7039-7044
pubmed: 29915090
Biochemistry. 1995 Nov 14;34(45):14942-53
pubmed: 7578106
PLoS Comput Biol. 2017 Apr 3;13(4):e1005461
pubmed: 28369071
Am J Hum Genet. 2000 Jun;66(6):1729-35
pubmed: 10793008
BMC Syst Biol. 2009 Jan 06;3:2
pubmed: 19126203
Ann N Y Acad Sci. 2004 Nov;1033:1-16
pubmed: 15590999
Biochem Soc Trans. 1994 May;22(2):427-31
pubmed: 7958339
J Inherit Metab Dis. 2010 Oct;33(5):513-20
pubmed: 20532824
Epilepsy Behav Rep. 2019 Oct 25;12:100336
pubmed: 31754660
Cell. 2007 Sep 21;130(6):1095-107
pubmed: 17889652
Methods. 2004 Jun;33(2):95-103
pubmed: 15121163
PLoS Comput Biol. 2013;9(8):e1003186
pubmed: 23966849
Eur J Pediatr. 2007 Jan;166(1):5-11
pubmed: 16788829
J Neurol Neurosurg Psychiatry. 1997 Feb;62(2):169-76
pubmed: 9048718
J Pediatr. 2006 May;148(5):665-670
pubmed: 16737882