Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK.
AMP-Activated Protein Kinases
/ metabolism
Animals
Cell Line
Humans
Inositol
/ metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria
/ metabolism
Mitochondrial Dynamics
/ physiology
PC-3 Cells
Phosphoric Monoester Hydrolases
/ metabolism
Phosphorylation
Stress, Physiological
/ physiology
AMP
AMPK
IMPA1
energy stress
glucose deprivation
inosiotl sensor
inositol
inositol/AMP ratio
mitochondrial fission
mitocondrial dynamics
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
16 09 2021
16 09 2021
Historique:
received:
01
11
2020
revised:
01
06
2021
accepted:
19
08
2021
entrez:
21
9
2021
pubmed:
22
9
2021
medline:
16
10
2021
Statut:
ppublish
Résumé
Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show that inositol is a critical metabolite directly restricting AMPK-dependent mitochondrial fission independently of its classical mode as a precursor for phosphoinositide generation. Inositol decline by IMPA1/2 deficiency elicits AMPK activation and mitochondrial fission without affecting ATP level, whereas inositol accumulation prevents AMPK-dependent mitochondrial fission. Metabolic stress or mitochondrial damage causes inositol decline in cells and mice to elicit AMPK-dependent mitochondrial fission. Inositol directly binds to AMPKγ and competes with AMP for AMPKγ binding, leading to restriction of AMPK activation and mitochondrial fission. Our study suggests that the AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model in which AMPK activation requires inositol decline to release AMPKγ for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission.
Identifiants
pubmed: 34547240
pii: S1097-2765(21)00692-4
doi: 10.1016/j.molcel.2021.08.025
pmc: PMC8462099
mid: NIHMS1737151
pii:
doi:
Substances chimiques
Inositol
4L6452S749
AMP-Activated Protein Kinases
EC 2.7.11.31
Phosphoric Monoester Hydrolases
EC 3.1.3.2
myo-inositol-1 (or 4)-monophosphatase
EC 3.1.3.25
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
3803-3819.e7Subventions
Organisme : NCI NIH HHS
ID : P30 CA012197
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA182424
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193813
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA248037
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
J Neurosci Methods. 2016 Mar 15;262:56-65
pubmed: 26777473
Cell Metab. 2013 Oct 1;18(4):556-66
pubmed: 24093679
Exp Eye Res. 2011 Oct;93(4):460-74
pubmed: 21722635
J Biol Chem. 1980 Dec 25;255(24):11710-2
pubmed: 7002927
Hepatology. 2011 Aug;54(2):452-62
pubmed: 21488074
Eur Rev Med Pharmacol Sci. 2011 Feb;15(2):129-34
pubmed: 21434479
Biochem Soc Trans. 2009 Oct;37(Pt 5):1099-103
pubmed: 19754460
Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5924-8
pubmed: 8392181
Science. 2012 Aug 10;337(6095):653-4
pubmed: 22879491
Eur J Obstet Gynecol Reprod Biol. 2011 Dec;159(2):267-72
pubmed: 21835536
Nat Rev Drug Discov. 2019 Jul;18(7):527-551
pubmed: 30867601
Dementia. 1993 Mar-Apr;4(2):81-6
pubmed: 8395284
J Biol Chem. 1967 Apr 10;242(7):1375-82
pubmed: 4290245
Biochim Biophys Acta. 2008 Sep;1777(9):1092-7
pubmed: 18519024
Gynecol Endocrinol. 2012 Jul;28(7):509-15
pubmed: 22296306
Science. 2012 Aug 10;337(6095):727-30
pubmed: 22722250
J Cell Biol. 2009 Dec 28;187(7):959-66
pubmed: 20038677
Annu Rev Nutr. 1986;6:563-97
pubmed: 2425833
J Clin Invest. 1995 Feb;95(2):542-6
pubmed: 7860736
Neuropsychopharmacology. 2008 Feb;33(3):674-84
pubmed: 17460611
Science. 2012 Aug 31;337(6098):1062-5
pubmed: 22936770
Cancer Cell. 2015 Feb 9;27(2):271-85
pubmed: 25640402
Cell. 2016 Jul 28;166(3):555-566
pubmed: 27471965
J Proteome Res. 2020 Jun 5;19(6):2367-2378
pubmed: 32397718
EMBO Rep. 2007 Oct;8(10):939-44
pubmed: 17721437
Cell. 2010 Jul 23;142(2):270-83
pubmed: 20655468
J Cell Biol. 2014 Feb 17;204(4):477-86
pubmed: 24515348
Science. 2016 Jan 15;351(6270):275-281
pubmed: 26816379
Nature. 2007 Sep 27;449(7161):496-500
pubmed: 17851531
Cell Res. 2018 Mar;28(3):265-280
pubmed: 29219147
J Cell Biol. 2010 Dec 13;191(6):1141-58
pubmed: 21149567
Genes Dev. 2011 Sep 15;25(18):1895-908
pubmed: 21937710
Mol Biol Cell. 2013 Mar;24(5):659-67
pubmed: 23283981
Semin Cancer Biol. 2021 Apr 17;:
pubmed: 33862221
ACS Omega. 2018 Oct 31;3(10):13876-13881
pubmed: 30411052
J Biol Chem. 2007 Jul 27;282(30):21583-7
pubmed: 17553808
Cell. 2019 Jun 27;178(1):176-189.e15
pubmed: 31155231
J Biol Chem. 2003 Mar 21;278(12):10602-12
pubmed: 12525476
Biochim Biophys Acta. 1997 Sep 4;1348(1-2):245-56
pubmed: 9370339
Cell Metab. 2012 Jul 3;16(1):9-17
pubmed: 22768835
Clin Cancer Res. 2019 Nov 1;25(21):6452-6462
pubmed: 31533931
J Cell Biol. 2016 Feb 15;212(4):379-87
pubmed: 26858267
Eur Rev Med Pharmacol Sci. 2011 May;15(5):509-14
pubmed: 21744744
Neuropsychopharmacology. 2014 Jan;39(2):319-28
pubmed: 23924600
Nat Cell Biol. 2011 Sep 02;13(9):1016-23
pubmed: 21892142
J Neurosci. 2011 Nov 2;31(44):15716-26
pubmed: 22049414
Cancer Lett. 2019 Oct 28;463:11-26
pubmed: 31404613
Mol Cell. 2015 Feb 5;57(3):537-51
pubmed: 25658205
J Biol Chem. 2014 Feb 28;289(9):6028-40
pubmed: 24429282
Nature. 2006 Oct 12;443(7112):651-7
pubmed: 17035995
Mol Psychiatry. 2016 Aug;21(8):1125-9
pubmed: 26416544
Trends Biochem Sci. 1992 Oct;17(10):414-7
pubmed: 1455509
J Biol Chem. 2014 Apr 11;289(15):10785-10796
pubmed: 24554717
Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8745-50
pubmed: 10411946
Cell Signal. 2015 May;27(5):978-88
pubmed: 25683918
Nat Rev Mol Cell Biol. 2005 Aug;6(8):657-63
pubmed: 16025099
Science. 1994 Aug 5;265(5173):813-5
pubmed: 8047889
Nature. 2015 Feb 19;518(7539):413-6
pubmed: 25487152
J Biol Chem. 2009 May 15;284(20):13843-13855
pubmed: 19279012
Nat Protoc. 2013 Nov;8(11):2281-2308
pubmed: 24157548
EMBO J. 2006 Jul 12;25(13):2966-77
pubmed: 16778770
N Engl J Med. 2013 Dec 5;369(23):2236-51
pubmed: 24304053
Mol Cell. 2005 Apr 29;18(3):283-93
pubmed: 15866171
Antioxid Redox Signal. 2011 May 15;14(10):1939-51
pubmed: 21128700
Annu Rev Biophys Biomol Struct. 2002;31:151-75
pubmed: 11988466
Cell. 2013 Sep 26;155(1):160-71
pubmed: 24055366