PMID- 36635485
OWN - NLM
STAT- MEDLINE
DCOM- 20230116
LR  - 20240404
IS  - 2399-3642 (Electronic)
IS  - 2399-3642 (Linking)
VI  - 6
IP  - 1
DP  - 2023 Jan 12
TI  - OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients 
      with mitochondrial diseases.
PG  - 22
LID - 10.1038/s42003-022-04303-x [doi]
LID - 22
AB  - 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.
CI  - (c) 2023. The Author(s).
FAU - Sturm, Gabriel
AU  - Sturm G
AUID- ORCID: 0000-0002-7280-4310
AD  - Department of Psychiatry, Division of Behavioral Medicine, Columbia University 
      Irving Medical Center, New York, NY, USA.
AD  - Department of Biochemistry and Biophysics, University of California, San 
      Francisco, CA, USA.
FAU - Karan, Kalpita R
AU  - Karan KR
AD  - Department of Psychiatry, Division of Behavioral Medicine, Columbia University 
      Irving Medical Center, New York, NY, USA.
FAU - Monzel, Anna S
AU  - Monzel AS
AD  - Department of Psychiatry, Division of Behavioral Medicine, Columbia University 
      Irving Medical Center, New York, NY, USA.
FAU - Santhanam, Balaji
AU  - Santhanam B
AD  - Departments of Biological Sciences, Systems Biology, and Biochemistry and 
      Molecular Biophysics, Institute for Cancer Dynamics, Columbia University, New 
      York, NY, USA.
FAU - Taivassalo, Tanja
AU  - Taivassalo T
AD  - Department of Physiology and Functional Genomics, Clinical and Translational 
      Research Building, University of Florida, Gainesville, FL, USA.
FAU - Bris, Celine
AU  - Bris C
AD  - Department of Genetics and Neurology, Angers Hospital, Angers, France.
AD  - UMR CNRS 6015, INSERM U1083, MITOVASC, SFR ICAT, Universite d'Angers, Angers, 
      France.
FAU - Ware, Sarah A
AU  - Ware SA
AD  - Department of Medicine, Vascular Medicine Institute and Center for Metabolic and 
      Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Cross, Marissa
AU  - Cross M
AD  - Department of Psychiatry, Division of Behavioral Medicine, Columbia University 
      Irving Medical Center, New York, NY, USA.
FAU - Towheed, Atif
AU  - Towheed A
AD  - Department of Psychiatry, Division of Behavioral Medicine, Columbia University 
      Irving Medical Center, New York, NY, USA.
AD  - Internal Medicine-Pediatrics Residency Program, University of Pittsburgh Medical 
      Centre, Pittsburgh, PA, USA.
FAU - Higgins-Chen, Albert
AU  - Higgins-Chen A
AUID- ORCID: 0000-0003-2904-2741
AD  - Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
FAU - McManus, Meagan J
AU  - McManus MJ
AD  - Department of Anesthesiology and Critical Care Medicine, The Children's Hospital 
      of Philadelphia, Philadelphia, PA, USA.
AD  - Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of 
      Philadelphia, Philadelphia, PA, USA.
FAU - Cardenas, Andres
AU  - Cardenas A
AUID- ORCID: 0000-0003-2284-3298
AD  - Department of Epidemiology and Population Health, Stanford University, Stanford, 
      CA, USA.
FAU - Lin, Jue
AU  - Lin J
AD  - Department of Biochemistry and Biophysics, University of California, San 
      Francisco, CA, USA.
FAU - Epel, Elissa S
AU  - Epel ES
AD  - Department of Psychiatry and Behavioral Sciences, University of California, San 
      Francisco, CA, USA.
FAU - Rahman, Shamima
AU  - Rahman S
AUID- ORCID: 0000-0003-2088-730X
AD  - Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, 
      and Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation 
      Trust, London, UK.
FAU - Vissing, John
AU  - Vissing J
AD  - Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, 
      University of Copenhagen, Copenhagen, Denmark.
FAU - Grassi, Bruno
AU  - Grassi B
AD  - Department of Medicine, University of Udine, Udine, Italy.
FAU - Levine, Morgan
AU  - Levine M
AUID- ORCID: 0000-0001-9890-9324
AD  - Altos Labs, San Diego, CA, USA.
FAU - Horvath, Steve
AU  - Horvath S
AUID- ORCID: 0000-0002-4110-3589
AD  - Altos Labs, San Diego, CA, USA.
FAU - Haller, Ronald G
AU  - Haller RG
AD  - Neuromuscular Center, Institute for Exercise and Environmental Medicine of Texas 
      Health Resources and Department of Neurology, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Lenaers, Guy
AU  - Lenaers G
AD  - Department of Genetics and Neurology, Angers Hospital, Angers, France.
AD  - UMR CNRS 6015, INSERM U1083, MITOVASC, SFR ICAT, Universite d'Angers, Angers, 
      France.
FAU - Wallace, Douglas C
AU  - Wallace DC
AUID- ORCID: 0000-0002-7480-8278
AD  - Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of 
      Philadelphia, Philadelphia, PA, USA.
FAU - St-Onge, Marie-Pierre
AU  - St-Onge MP
AD  - Center of Excellence for Sleep & Circadian Research and Division of General 
      Medicine, Department of Medicine, Columbia University Irving Medical Center, New 
      York, NY, USA.
FAU - Tavazoie, Saeed
AU  - Tavazoie S
AD  - Departments of Biological Sciences, Systems Biology, and Biochemistry and 
      Molecular Biophysics, Institute for Cancer Dynamics, Columbia University, New 
      York, NY, USA.
FAU - Procaccio, Vincent
AU  - Procaccio V
AD  - Department of Genetics and Neurology, Angers Hospital, Angers, France.
AD  - UMR CNRS 6015, INSERM U1083, MITOVASC, SFR ICAT, Universite d'Angers, Angers, 
      France.
FAU - Kaufman, Brett A
AU  - Kaufman BA
AD  - Department of Medicine, Vascular Medicine Institute and Center for Metabolic and 
      Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Seifert, Erin L
AU  - Seifert EL
AD  - Department of Pathology and Genomic Medicine, and MitoCare Center, Thomas 
      Jefferson University, Philadelphia, PA, USA.
FAU - Hirano, Michio
AU  - Hirano M
AD  - Department of Neurology, H. Houston Merritt Center, Columbia Translational 
      Neuroscience Initiative, Columbia University Irving Medical Center, New York, NY, 
      USA.
FAU - Picard, Martin
AU  - Picard M
AUID- ORCID: 0000-0003-2835-0478
AD  - Department of Psychiatry, Division of Behavioral Medicine, Columbia University 
      Irving Medical Center, New York, NY, USA. martin.picard@columbia.edu.
AD  - Department of Neurology, H. Houston Merritt Center, Columbia Translational 
      Neuroscience Initiative, Columbia University Irving Medical Center, New York, NY, 
      USA. martin.picard@columbia.edu.
AD  - New York State Psychiatric Institute, New York, NY, USA. 
      martin.picard@columbia.edu.
LA  - eng
GR  - R35 HL155670/HL/NHLBI NIH HHS/United States
GR  - R01 AG066828/AG/NIA NIH HHS/United States
GR  - R01 AG065403/AG/NIA NIH HHS/United States
GR  - P50 HD105354/HD/NICHD NIH HHS/United States
GR  - WT_/Wellcome Trust/United Kingdom
GR  - R01 GM123771/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230112
PL  - England
TA  - Commun Biol
JT  - Communications biology
JID - 101719179
RN  - 0 (DNA, Mitochondrial)
SB  - IM
MH  - Humans
MH  - *Oxidative Phosphorylation
MH  - Longevity
MH  - *Mitochondrial Diseases/genetics/metabolism
MH  - Mitochondria/genetics/metabolism
MH  - DNA, Mitochondrial/genetics/metabolism
PMC - PMC9837150
COIS- The authors declare no competing interests.
EDAT- 2023/01/13 06:00
MHDA- 2023/01/17 06:00
PMCR- 2023/01/12
CRDT- 2023/01/12 23:25
PHST- 2022/09/08 00:00 [received]
PHST- 2022/11/26 00:00 [accepted]
PHST- 2023/01/12 23:25 [entrez]
PHST- 2023/01/13 06:00 [pubmed]
PHST- 2023/01/17 06:00 [medline]
PHST- 2023/01/12 00:00 [pmc-release]
AID - 10.1038/s42003-022-04303-x [pii]
AID - 4303 [pii]
AID - 10.1038/s42003-022-04303-x [doi]
PST - epublish
SO  - Commun Biol. 2023 Jan 12;6(1):22. doi: 10.1038/s42003-022-04303-x.