OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
12 01 2023
12 01 2023
Historique:
received:
08
09
2022
accepted:
26
11
2022
entrez:
12
1
2023
pubmed:
13
1
2023
medline:
17
1
2023
Statut:
epublish
Résumé
Patients with primary mitochondrial oxidative phosphorylation (OxPhos) defects present with fatigue and multi-system disorders, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. By integrating data from 17 cohorts of patients with mitochondrial diseases (n = 690) we find evidence that these disorders increase resting energy expenditure, a state termed hypermetabolism. We examine this phenomenon longitudinally in patient-derived fibroblasts from multiple donors. Genetically or pharmacologically disrupting OxPhos approximately doubles cellular energy expenditure. This cell-autonomous state of hypermetabolism occurs despite near-normal OxPhos coupling efficiency, excluding uncoupling as a general mechanism. Instead, hypermetabolism is associated with mitochondrial DNA instability, activation of the integrated stress response (ISR), and increased extracellular secretion of age-related cytokines and metabokines including GDF15. In parallel, OxPhos defects accelerate telomere erosion and epigenetic aging per cell division, consistent with evidence that excess energy expenditure accelerates biological aging. To explore potential mechanisms for these effects, we generate a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations. Taken together, these findings highlight the need to understand how OxPhos defects influence the energetic cost of living, and the link between hypermetabolism and aging in cells and patients with mitochondrial diseases.
Identifiants
pubmed: 36635485
doi: 10.1038/s42003-022-04303-x
pii: 10.1038/s42003-022-04303-x
pmc: PMC9837150
doi:
Substances chimiques
DNA, Mitochondrial
0
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
22Subventions
Organisme : NHLBI NIH HHS
ID : R35 HL155670
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG066828
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R01 GM123771
Pays : United States
Informations de copyright
© 2023. The Author(s).
Références
Science. 2005 Jan 21;307(5708):384-7
pubmed: 15662004
J Gerontol A Biol Sci Med Sci. 2008 Jul;63(7):698-706
pubmed: 18693224
Psychoneuroendocrinology. 2022 Oct 8;146:105951
pubmed: 36302295
N Engl J Med. 2022 Oct 13;387(15):1395-1403
pubmed: 36239646
Elife. 2017 Nov 14;6:
pubmed: 29132502
N Engl J Med. 1992 Apr 9;326(15):983-7
pubmed: 1545851
J Appl Physiol (1985). 2016 Sep 1;121(3):699-708
pubmed: 27445303
Orphanet J Rare Dis. 2021 Mar 11;16(1):127
pubmed: 33706792
Sci Adv. 2021 May 26;7(22):
pubmed: 34039602
Nat Cell Biol. 2003 Aug;5(8):741-7
pubmed: 12855956
Sci Rep. 2016 Jan 05;6:18722
pubmed: 26729469
JIMD Rep. 2016;26:103-13
pubmed: 26354038
Nat Rev Genet. 2018 Jun;19(6):371-384
pubmed: 29643443
Biochem J. 1995 Nov 15;312 ( Pt 1):163-7
pubmed: 7492307
Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):2705-2710
pubmed: 28223503
PLoS Biol. 2018 Apr 18;16(4):e2005707
pubmed: 29668680
Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18435-18444
pubmed: 31451640
Proc Natl Acad Sci U S A. 2015 Dec 1;112(48):E6614-23
pubmed: 26627253
Eur J Immunol. 2014 May;44(5):1552-62
pubmed: 24470107
Anal Biochem. 2007 Nov 1;370(1):127-9
pubmed: 17662684
Brief Funct Genomics. 2016 Nov;15(6):485-490
pubmed: 27323952
Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10996-1001
pubmed: 20534480
Innov Aging. 2019 Sep 04;3(4):igz036
pubmed: 31528719
Science. 2021 Aug 13;373(6556):808-812
pubmed: 34385400
Brain. 2009 Sep;132(Pt 9):2317-26
pubmed: 19525327
Nat Med. 2019 Dec;25(12):1843-1850
pubmed: 31806903
Nat Rev Mol Cell Biol. 2018 Feb;19(2):77-92
pubmed: 28792006
Mol Syst Biol. 2009;5:323
pubmed: 19888218
Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):8402-8407
pubmed: 28716914
Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):E4033-42
pubmed: 25192935
Brain. 2003 Feb;126(Pt 2):413-23
pubmed: 12538407
Cell Metab. 2019 Dec 3;30(6):1040-1054.e7
pubmed: 31523008
Nucleic Acids Res. 2021 Jan 8;49(D1):D1541-D1547
pubmed: 33174596
Nat Biotechnol. 2016 May;34(5):525-7
pubmed: 27043002
Am J Clin Nutr. 1998 Nov;68(5):1046-52
pubmed: 9808221
Cell. 2019 Apr 4;177(2):399-413.e12
pubmed: 30853215
J Clin Invest. 1988 Apr;81(4):1137-45
pubmed: 3280601
J Biol Chem. 2020 Nov 13;295(46):15677-15691
pubmed: 32900851
Epigenetics. 2019 Oct;14(10):961-976
pubmed: 31156022
Ann Neurol. 1996 Oct;40(4):655-62
pubmed: 8871586
Nucleic Acids Res. 2002 May 15;30(10):e47
pubmed: 12000852
Am J Physiol Regul Integr Comp Physiol. 2011 Oct;301(4):R873-84
pubmed: 21813873
PLoS One. 2011;6(10):e25823
pubmed: 21991365
J Clin Endocrinol Metab. 2011 Jun;96(6):E972-6
pubmed: 21450984
Neurology. 2011 Nov 29;77(22):1965-71
pubmed: 22094475
Int J Cardiol. 2013 Oct 9;168(4):3599-608
pubmed: 23742928
J Neuromuscul Dis. 2015 Jun 4;2(2):151-155
pubmed: 27858729
PLoS Genet. 2018 Feb 14;14(2):e1007210
pubmed: 29444077
Hum Mol Genet. 2003 Feb 15;12(4):399-413
pubmed: 12566387
Cell Metab. 2019 Jan 8;29(1):78-90.e5
pubmed: 30174309
Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10654-9
pubmed: 25002485
Arch Neurol. 2009 Mar;66(3):365-70
pubmed: 19273755
Cell Rep. 2016 Jan 5;14(1):22-31
pubmed: 26725116
PLoS Biol. 2020 Jan 16;18(1):e3000599
pubmed: 31945054
PLoS One. 2019 Jul 25;14(7):e0219628
pubmed: 31344055
Comp Biochem Physiol A Mol Integr Physiol. 2011 Mar;158(3):287-304
pubmed: 20869457
Genet Med. 2019 Jun;21(6):1407-1416
pubmed: 30393377
PLoS One. 2011;6(7):e22294
pubmed: 21799815
Neurology. 2016 Nov 29;87(22):2290-2299
pubmed: 27794108
Biochem J. 2003 Mar 15;370(Pt 3):751-62
pubmed: 12467494
Sci Data. 2022 Dec 3;9(1):751
pubmed: 36463290
Mol Neurodegener. 2021 Nov 6;16(1):75
pubmed: 34742335
Aging Cell. 2014 Jun;13(3):401-7
pubmed: 24341918
Mol Cell. 2009 Dec 11;36(5):900-11
pubmed: 20005852
Elife. 2020 May 28;9:
pubmed: 32463360
Nucleic Acids Res. 2019 Aug 22;47(14):7430-7443
pubmed: 31147703
Orphanet J Rare Dis. 2013 Jul 05;8:96
pubmed: 23829769
Hum Mol Genet. 1997 Jun;6(6):905-8
pubmed: 9175737
Nat Phys. 2012 May 1;8(5):422-428
pubmed: 22737175
Hum Mol Genet. 2013 Dec 1;22(23):4739-47
pubmed: 23847047
Cell Rep. 2020 Sep 15;32(11):108131
pubmed: 32937126
J Am Geriatr Soc. 2014 Apr;62(4):667-72
pubmed: 24635835
J Clin Invest. 1962 Sep;41:1776-804
pubmed: 14467237
Am J Hum Genet. 1998 Dec;63(6):1609-21
pubmed: 9837813
Exp Cell Res. 2016 Jul 15;345(2):239-46
pubmed: 27339653
Cell Metab. 2017 Aug 1;26(2):419-428.e5
pubmed: 28768179
Nat Metab. 2019 Oct;1(10):958-965
pubmed: 32694840
Nature. 2016 Jul 28;535(7613):561-5
pubmed: 27383793
PLoS Comput Biol. 2019 Jun 26;15(6):e1007023
pubmed: 31242175
Hum Mol Genet. 2010 Aug 1;19(15):3043-52
pubmed: 20484224
Physiology (Bethesda). 2018 Nov 1;33(6):384-393
pubmed: 30303776
J Immunol Methods. 2010 Jan 31;352(1-2):71-80
pubmed: 19837074
Bioinformatics. 2020 Apr 15;36(8):2628-2629
pubmed: 31882993
Nat Commun. 2020 Jan 2;11(1):68
pubmed: 31896772
Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):16994-9
pubmed: 18952839
Clin Nutr. 2015 Feb;34(1):151-5
pubmed: 24636151
Biochem J. 2011 Apr 15;435(2):297-312
pubmed: 21726199
Nat Aging. 2022 Jul;2(7):644-661
pubmed: 36277076
Med Sci Sports Exerc. 2009 Dec;41(12):2120-7
pubmed: 19915508
Essays Biochem. 2018 Jul 20;62(3):423-442
pubmed: 29980629
Nat Commun. 2021 Mar 26;12(1):1929
pubmed: 33771987
Am J Respir Crit Care Med. 2012 Dec 1;186(11):1140-9
pubmed: 23024021
Nature. 2020 Mar;579(7799):427-432
pubmed: 32132707
J Clin Invest. 2021 Jan 19;131(2):
pubmed: 33463549
Nat Genet. 1992 Aug;1(5):359-67
pubmed: 1284549
J Cell Biol. 2017 Jan 2;216(1):149-165
pubmed: 27986797
J Mol Med (Berl). 2020 Oct;98(10):1467-1478
pubmed: 32851462
Science. 2005 Jul 15;309(5733):481-4
pubmed: 16020738
J Biol Chem. 2017 Apr 28;292(17):7189-7207
pubmed: 28270511
Cell Metab. 2016 Feb 9;23(2):303-14
pubmed: 26686024
Neuromuscul Disord. 2015 Jul;25(7):563-6
pubmed: 26031904
Muscle Nerve. 2007 Apr;35(4):510-20
pubmed: 17143893
Nat Phys. 2015 Sep;11(9):772-778
pubmed: 26566392
Biochim Biophys Acta Mol Basis Dis. 2018 Jun;1864(6 Pt A):2131-2142
pubmed: 29601977
Neuromuscul Disord. 2013 Aug;23(8):629-36
pubmed: 23838278
Genet Med. 2021 Sep;23(9):1769-1778
pubmed: 34040194
J Biol Chem. 2021 Oct;297(4):101140
pubmed: 34461088
Aging Cell. 2018 Oct;17(5):e12799
pubmed: 29992704
Nature. 2015 Dec 3;528(7580):99-104
pubmed: 26632588
J Neurol. 2014 Jan;261(1):73-82
pubmed: 24150688
Proc Natl Acad Sci U S A. 2021 Jun 29;118(26):
pubmed: 34140336
Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3453-8
pubmed: 23401503
Mitochondrion. 2015 Mar;21:19-26
pubmed: 25575636
Nat Rev Dis Primers. 2016 Oct 20;2:16080
pubmed: 27775730
EMBO Rep. 2018 May;19(5):
pubmed: 29588285
Brain Behav Immun Health. 2020 May;5:
pubmed: 33073254
J Pathol. 2018 Nov;246(3):261-265
pubmed: 30058194
Pediatr Neurol. 2017 Jan;66:82-88
pubmed: 27843091
Ann Neurol. 2018 Aug;84(2):289-301
pubmed: 30014514
J Cell Biol. 2017 Jul 3;216(7):2027-2045
pubmed: 28566324
Science. 2016 Apr 1;352(6281):54-61
pubmed: 26917594
Arch Neurol. 2009 Jan;66(1):85-91
pubmed: 19139304
Cell Rep. 2019 May 14;27(7):2050-2062.e6
pubmed: 31091445
Exp Cell Res. 1961 Dec;25:585-621
pubmed: 13905658
Nature. 2004 May 27;429(6990):417-23
pubmed: 15164064
Genet Med. 2021 Dec;23(12):2415-2425
pubmed: 34400813
Sci Rep. 2016 Apr 28;6:25186
pubmed: 27122135