Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice.
Animals
Astrocytes
/ metabolism
Brain
/ metabolism
Brain Mapping
Cells, Cultured
Cellular Reprogramming
/ physiology
Disease Models, Animal
Disease Susceptibility
/ pathology
Glucose
/ metabolism
Huntingtin Protein
/ genetics
Huntington Disease
/ genetics
Male
Metabolism
/ genetics
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurons
/ metabolism
Organ Specificity
Oxidation-Reduction
Reactive Oxygen Species
/ metabolism
DNA repair
Huntington disease
astrocytes
double-strand break repair
fatty acids
metabolism
mitochondria
neurodegeneration
neurons
reprogramming
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
04 06 2019
04 06 2019
Historique:
received:
07
05
2018
revised:
25
10
2018
accepted:
05
03
2019
pubmed:
2
4
2019
medline:
15
8
2020
entrez:
2
4
2019
Statut:
ppublish
Résumé
The basis for region-specific neuronal toxicity in Huntington disease is unknown. Here, we show that region-specific neuronal vulnerability is a substrate-driven response in astrocytes. Glucose is low in HdhQ(150/150) animals, and astrocytes in each brain region adapt by metabolically reprogramming their mitochondria to use endogenous, non-glycolytic metabolites as an alternative fuel. Each region is characterized by distinct metabolic pools, and astrocytes adapt accordingly. The vulnerable striatum is enriched in fatty acids, and mitochondria reprogram by oxidizing them as an energy source but at the cost of escalating reactive oxygen species (ROS)-induced damage. The cerebellum is replete with amino acids, which are precursors for glucose regeneration through the pentose phosphate shunt or gluconeogenesis pathways. ROS is not elevated, and this region sustains little damage. While mhtt expression imposes disease stress throughout the brain, sensitivity or resistance arises from an adaptive stress response, which is inherently region specific. Metabolic reprogramming may have relevance to other diseases.
Identifiants
pubmed: 30930170
pii: S1550-4131(19)30132-9
doi: 10.1016/j.cmet.2019.03.004
pmc: PMC6583797
mid: NIHMS1023637
pii:
doi:
Substances chimiques
Htt protein, mouse
0
Huntingtin Protein
0
Reactive Oxygen Species
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1258-1273.e11Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM119161
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA092584
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM076516
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS105158
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM103540
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK078775
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM066359
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS060115
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019. Published by Elsevier Inc.
Références
Biochim Biophys Acta. 2011 Jun;1807(6):726-34
pubmed: 21692241
Nature. 2007 Jan 11;445(7124):168-76
pubmed: 17151600
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
Eur J Nucl Med Mol Imaging. 2016 Nov;43(12):2183-2189
pubmed: 27349245
Free Radic Biol Med. 2010 Apr 15;48(8):983-1001
pubmed: 20116425
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
J Neurochem. 2005 Jun;93(6):1361-70
pubmed: 15935052
Brain Res. 2005 Jan 7;1031(1):82-9
pubmed: 15621015
J Cereb Blood Flow Metab. 2013 Oct;33(10):1493-9
pubmed: 23921897
J Lipid Res. 2003 Feb;44(2):415-23
pubmed: 12576524
Proc Natl Acad Sci U S A. 1988 Aug;85(15):5733-7
pubmed: 2456581
J Neurol. 2005 Jan;252(1):36-41
pubmed: 15672208
Sci Rep. 2016 Oct 07;6:34755
pubmed: 27713486
Mech Ageing Dev. 2017 Jan;161(Pt A):181-197
pubmed: 27634555
J Biol Chem. 2008 Nov 21;283(47):32492-9
pubmed: 18809674
J Neurosci Res. 2000 Jun 15;60(6):779-82
pubmed: 10861790
Sci Rep. 2016 Feb 11;6:20681
pubmed: 26864449
J Neurochem. 2009 May;109(4):1179-91
pubmed: 19519782
Hum Mol Genet. 2016 May 1;25(9):1792-802
pubmed: 26908614
Mol Neurodegener. 2013 Dec 11;8:45
pubmed: 24330821
J Proteomics. 2016 Jan 30;132:155-66
pubmed: 26581643
Hum Mol Genet. 2013 Oct 1;22(19):3869-82
pubmed: 23720495
J Neurosci. 2016 Mar 23;36(12):3453-70
pubmed: 27013675
Biophys J. 2008 Jan 15;94(2):L14-6
pubmed: 17981902
Nat Struct Mol Biol. 2004 Jun;11(6):567-73
pubmed: 15122347
Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5727-32
pubmed: 15824309
Science. 2008 Feb 8;319(5864):810-3
pubmed: 18174397
PLoS One. 2013 Nov 26;8(11):e81528
pubmed: 24303051
PLoS Genet. 2010 Feb 05;6(2):e1000838
pubmed: 20140187
Mol Neurobiol. 2016 Jul;53(5):2944-2953
pubmed: 25941077
Curr Protoc Mol Biol. 2016 Apr 01;114:30.4.1-30.4.32
pubmed: 27038389
Glia. 2017 Jan;65(1):50-61
pubmed: 27615381
Adv Exp Med Biol. 2012;748:65-106
pubmed: 22729855
J Neurochem. 2007 Apr;101(1):241-9
pubmed: 17394466
Best Pract Res Clin Endocrinol Metab. 2012 Dec;26(6):711-23
pubmed: 23168274
Sci Rep. 2017 Sep 7;7(1):10779
pubmed: 28883484
Science. 2013 Jan 25;339(6118):452-6
pubmed: 23239625
Acta Neuropathol. 2016 Mar;131(3):323-45
pubmed: 26671410
Cell Rep. 2012 Nov 29;2(5):1137-42
pubmed: 23122961
J Cereb Blood Flow Metab. 2014 Sep;34(9):1500-10
pubmed: 24938402
Free Radic Biol Med. 2015 Dec;89:1085-96
pubmed: 26456058
Physiol Rev. 2014 Jul;94(3):909-50
pubmed: 24987008
Cell Rep. 2015 Jan 13;10(2):266-79
pubmed: 25578732
Curr Protoc Neurosci. 2010 Jul;Chapter 7:Unit 7.22
pubmed: 20578034
Biochem Biophys Res Commun. 2017 Feb 19;483(4):1084-1095
pubmed: 27639641
Expert Rev Neurother. 2015;15(8):867-84
pubmed: 26092668
Nat Neurosci. 2002 Aug;5(8):731-6
pubmed: 12089530
Nat Neurosci. 2014 May;17(5):694-703
pubmed: 24686787
J Neurosci. 2003 Jun 15;23(12):4858-67
pubmed: 12832508
BMC Bioinformatics. 2012 May 16;13:99
pubmed: 22591066
Curr Neuropharmacol. 2016;14(2):143-54
pubmed: 26903445
Cell Metab. 2011 Dec 7;14(6):724-38
pubmed: 22152301
J Nucl Med. 2006 Feb;47(2):215-22
pubmed: 16455626
PLoS One. 2015 Aug 21;10(8):e0134465
pubmed: 26295712
EMBO Mol Med. 2015 Aug 12;7(10):1307-26
pubmed: 26268247
Nucleic Acids Res. 2018 Jul 2;46(W1):W486-W494
pubmed: 29762782
Nat Cell Biol. 2009 Jun;11(6):747-52
pubmed: 19448625
Handb Clin Neurol. 2017;144:15-28
pubmed: 28947113
PLoS One. 2012;7(11):e48014
pubmed: 23144844
J Neuropathol Exp Neurol. 1985 Nov;44(6):559-77
pubmed: 2932539
BMC Bioinformatics. 2011 Aug 04;12:321
pubmed: 21816034
J Clin Invest. 2011 Feb;121(2):493-9
pubmed: 21285522
Hum Mol Genet. 2016 Jul 1;25(13):2762-2775
pubmed: 27131346
J Cereb Blood Flow Metab. 2017 Jun;37(6):1927-1943
pubmed: 28276944
FEBS J. 2008 Oct;275(19):4740-55
pubmed: 18721135
Sci Rep. 2015 May 20;5:9848
pubmed: 25993434
Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1271-5
pubmed: 1741380
J Comp Neurol. 2016 Dec 15;524(18):3865-3895
pubmed: 27187682
Hum Mol Genet. 2015 Sep 1;24(17):4862-78
pubmed: 26041817
Hum Mol Genet. 2001 Jan 15;10(2):137-44
pubmed: 11152661
J Biol Chem. 1999 Nov 19;274(47):33426-32
pubmed: 10559224
J Biol Chem. 2017 Mar 17;292(11):4727-4742
pubmed: 28167533
Curr Protoc Neurosci. 2014 Apr 10;67:9.48.1-9.48.14
pubmed: 24723322
Cell Death Differ. 2015 Apr;22(4):690-702
pubmed: 25301063
Nat Methods. 2006 Oct;3(10):793-5
pubmed: 16896339
Arch Biochem Biophys. 1991 Sep;289(2):329-36
pubmed: 1654856
J Neurosci. 2017 Apr 19;37(16):4231-4242
pubmed: 28314814
PLoS One. 2016 Jan 08;11(1):e0146480
pubmed: 26744893
Hum Mol Genet. 2003 Mar 1;12(5):497-508
pubmed: 12588797
PLoS One. 2015 Mar 11;10(3):e0118765
pubmed: 25761110
J Biol Chem. 2011 Jul 8;286(27):23637-43
pubmed: 21566124
Cell. 2015 Jan 15;160(1-2):177-90
pubmed: 25594180
BMC Bioinformatics. 2010 Jul 23;11:395
pubmed: 20650010
PLoS One. 2013 Jul 17;8(7):e68831
pubmed: 23874783
J Neurol Neurosurg Psychiatry. 1997 Feb;62(2):169-76
pubmed: 9048718