Reduced mitochondrial fission and impaired energy metabolism in human primary skeletal muscle cells of Megaconial Congenital Muscular Dystrophy.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
13 09 2021
13 09 2021
Historique:
received:
06
03
2021
accepted:
13
08
2021
entrez:
14
9
2021
pubmed:
15
9
2021
medline:
15
12
2021
Statut:
epublish
Résumé
Megaconial Congenital Muscular Dystrophy (CMD) is a rare autosomal recessive disorder characterized by enlarged mitochondria located mainly at the periphery of muscle fibers and caused by mutations in the Choline Kinase Beta (CHKB) gene. Although the pathogenesis of this disease is not well understood, there is accumulating evidence for the presence of mitochondrial dysfunction. In this study, we aimed to investigate whether imbalanced mitochondrial dynamics affects mitochondrial function and bioenergetic efficiency in skeletal muscle cells of Megaconial CMD. Immunofluorescence, confocal and transmission electron microscopy studies revealed impaired mitochondrial network, morphology, and localization in primary skeletal muscle cells of Megaconial CMD. The organelle disruption was specific only to skeletal muscle cells grown in culture. The expression levels of mitochondrial fission proteins (DRP1, MFF, FIS1) were found to be decreased significantly in both primary skeletal muscle cells and tissue sections of Megaconial CMD by Western blotting and/or immunofluorescence analysis. The metabolomic and fluxomic analysis, which were performed in Megaconial CMD for the first time, revealed decreased levels of phosphonucleotides, Krebs cycle intermediates, ATP, and altered energy metabolism pathways. Our results indicate that reduced mitochondrial fission and altered mitochondrial energy metabolism contribute to mitochondrial dysmorphology and dysfunction in the pathogenesis of Megaconial CMD.
Identifiants
pubmed: 34518586
doi: 10.1038/s41598-021-97294-4
pii: 10.1038/s41598-021-97294-4
pmc: PMC8438035
doi:
Substances chimiques
Mitochondrial Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
18161Subventions
Organisme : Department of Health
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
Références
Front Genet. 2015 Feb 03;6:3
pubmed: 25691889
Genome Med. 2009 Mar 25;1(3):32
pubmed: 19341503
Mol Biol Cell. 2001 Aug;12(8):2245-56
pubmed: 11514614
Sci Rep. 2020 Jul 16;10(1):11824
pubmed: 32678274
Am J Hum Genet. 2011 Jun 10;88(6):845-851
pubmed: 21665002
N Engl J Med. 2013 Dec 5;369(23):2236-51
pubmed: 24304053
PLoS One. 2006 Dec 20;1:e107
pubmed: 17205111
Curr Opin Neurol. 2013 Oct;26(5):536-43
pubmed: 23945283
Graefes Arch Clin Exp Ophthalmol. 2007 Oct;245(10):1533-41
pubmed: 17522883
Mol Biol Cell. 2004 Nov;15(11):5001-11
pubmed: 15356267
Mol Biol Cell. 1999 Dec;10(12):4403-17
pubmed: 10588666
Nat Genet. 2003 Dec;35(4):367-71
pubmed: 14625552
J Hum Genet. 2015 Jun;60(6):305-12
pubmed: 25740612
J Cell Biol. 2003 Jan 20;160(2):189-200
pubmed: 12527753
J Cell Biol. 1986 Jan;102(1):97-103
pubmed: 2867101
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43
pubmed: 18230723
Brain Dev. 2016 Jan;38(1):167-72
pubmed: 26006750
Pediatr Neurol. 2016 Jan;54:49-54
pubmed: 26548592
Cancer Lett. 2020 Jan 28;469:186-194
pubmed: 31669517
Mitochondrion. 2016 Mar;27:32-8
pubmed: 26855408
Hum Mol Genet. 2011 Oct 1;20(19):3841-51
pubmed: 21750112
Mol Cell Biol. 2003 Aug;23(15):5409-20
pubmed: 12861026
Am J Hum Genet. 2010 Jul 9;87(1):52-9
pubmed: 20598274
J Cell Biol. 2012 May 14;197(4):535-51
pubmed: 22564413
J Biol Chem. 2006 Feb 24;281(8):4938-48
pubmed: 16371353
Ophthalmic Plast Reconstr Surg. 2020 Jul/Aug;36(4):380-384
pubmed: 31913207
Muscle Nerve. 1998 Jan;21(1):40-7
pubmed: 9427222
Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15927-32
pubmed: 15509649
Mol Biol Cell. 2013 Mar;24(5):659-67
pubmed: 23283981
J Neurosci. 2007 Nov 7;27(45):12413-8
pubmed: 17989306
Cold Spring Harb Perspect Biol. 2013 Jun 01;5(6):
pubmed: 23732471
Muscles Ligaments Tendons J. 2014 Feb 24;3(4):281-6
pubmed: 24596691
Physiol Genomics. 2012 Apr 2;44(7):386-402
pubmed: 22234996
Muscle Nerve. 2016 Oct;54(4):806-8
pubmed: 27169979
Arch Neurol. 2012 May;69(5):657-61
pubmed: 22782513
Biomed Res Int. 2016;2016:3128735
pubmed: 27123443
Trends Biochem Sci. 2012 Jul;37(7):284-92
pubmed: 22410198
J Med Genet. 2013 Jul;50(7):437-43
pubmed: 23687351
Mitochondrion. 2019 Jul;47:24-29
pubmed: 30986505
PLoS One. 2014 Dec 26;9(12):e115763
pubmed: 25541951
Microsc Res Tech. 1994 Feb 15;27(3):198-219
pubmed: 8204911
J Vasc Res. 2013;50(5):357-71
pubmed: 23887139
J Biol Chem. 2016 May 27;291(22):11928-38
pubmed: 27036942
Neuromuscul Disord. 2016 Feb;26(2):160-4
pubmed: 26782016
Cells. 2018 Nov 23;7(12):
pubmed: 30477120
Sci Rep. 2019 Jul 11;9(1):10070
pubmed: 31296900
Cell Death Differ. 2017 Feb;24(2):330-342
pubmed: 27834955
PLoS One. 2015 Sep 17;10(9):e0136556
pubmed: 26378442
Neuromuscul Disord. 2020 Jan;30(1):47-53
pubmed: 31926838
Autophagy. 2011 Dec;7(12):1559-61
pubmed: 22024749
Neuromuscul Disord. 2013 Jul;23(7):549-56
pubmed: 23692895
Cell Death Differ. 2007 Jun;14(6):1086-94
pubmed: 17332775
Am J Physiol Endocrinol Metab. 2020 Feb 1;318(2):E87-E101
pubmed: 31846372
Anal Chim Acta. 2021 Apr 15;1154:338325
pubmed: 33736808
J Inherit Metab Dis. 2015 Nov;38(6):1099-108
pubmed: 26067811
Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):378-83
pubmed: 19966284
Muscle Nerve. 2015 Jan;51(1):140-3
pubmed: 25187204
J Med Genet. 2007 Mar;44(3):173-80
pubmed: 17056637
Acta Neuropathol Suppl. 1981;7:279-82
pubmed: 6452787
J Alzheimers Dis. 2007 Mar;11(1):45-51
pubmed: 17361034
Eur J Paediatr Neurol. 2014 Nov;18(6):796-800
pubmed: 24997086
Biochim Biophys Acta. 2003 May 2;1612(1):1-40
pubmed: 12729927