Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

OxPhos Dysfunction Causes Hypermetabolism and Reduces Lifespan in Cells and in Patients with Mitochondrial Diseases

View ORCID ProfileGabriel Sturm, View ORCID ProfileKalpita R Karan, View ORCID ProfileAnna Monzel, Balaji S Santhanam, Tanja Taivassalo, Céline Bris, Sarah A Duplaga, Marissa Cross, View ORCID ProfileAtif Towheed, Albert Higgins-Chen, Meagan J McManus, View ORCID ProfileAndres Cardenas, Jue Lin, Elissa S Epel, Shamima Rahman, View ORCID ProfileJohn Vissing, Bruno Grassi, View ORCID ProfileMorgan Levine, View ORCID ProfileSteve Horvath, Ronald G Haller, View ORCID ProfileGuy Lanaers, View ORCID ProfileDouglas C Wallace, View ORCID ProfileSaeed Tavazoie, View ORCID ProfileVincent Procaccio, View ORCID ProfileBrett A Kaufman, View ORCID ProfileErin L Seifert, View ORCID ProfileMichio Hirano, View ORCID ProfileMartin Picard
doi: https://doi.org/10.1101/2021.11.29.470428
Gabriel Sturm
1Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Gabriel Sturm
Kalpita R Karan
1Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Kalpita R Karan
Anna Monzel
1Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Anna Monzel
Balaji S Santhanam
2Departments of Biological Sciences, Systems Biology, and Biochemistry and Molecular Biophysics, Institute for Cancer Dynamics, Columbia University, New York, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tanja Taivassalo
3Department of Physiology and Functional Genomics, Clinical and Translational Research Building, University of Florida, Gainesville, FL, United states
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Céline Bris
4Department of Genetics, Angers Hospital, Angers, France
5Angers University, MitoLab team, UMR CNRS 6015 - INSERM U1083, MitoVasc Institute, Angers, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sarah A Duplaga
6Department of Medicine, Vascular Medicine Institute and Center for Metabolic and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marissa Cross
1Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Atif Towheed
1Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, United States
7Touro College of Osteopathic Medicine, Middletown, NY, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Atif Towheed
Albert Higgins-Chen
8Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Meagan J McManus
9Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
10Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andres Cardenas
11Department of Environmental Health Sciences and Center for Computational Biology, University of California Berkeley, Berkeley, CA, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Andres Cardenas
Jue Lin
12Department of Biochemistry and Biophysics, University of California, San Francisco, CA, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elissa S Epel
13Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shamima Rahman
14Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, and Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John Vissing
15Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for John Vissing
Bruno Grassi
16Department of Medicine, University of Udine, Udine, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Morgan Levine
17Department of Pathology, Yale University School of Medicine, New Haven, CT, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Morgan Levine
Steve Horvath
18Human Genetics, David Geffen School of Medicine, University of California, Los Angeles CA, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Steve Horvath
Ronald G Haller
19Neuromuscular Center, Institute for Exercise and Environmental Medicine of Texas Health Resources and Department of Neurology, University of Texas Southwestern Medical Center, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Guy Lanaers
4Department of Genetics, Angers Hospital, Angers, France
5Angers University, MitoLab team, UMR CNRS 6015 - INSERM U1083, MitoVasc Institute, Angers, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Guy Lanaers
Douglas C Wallace
10Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Douglas C Wallace
Saeed Tavazoie
2Departments of Biological Sciences, Systems Biology, and Biochemistry and Molecular Biophysics, Institute for Cancer Dynamics, Columbia University, New York, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Saeed Tavazoie
Vincent Procaccio
4Department of Genetics, Angers Hospital, Angers, France
5Angers University, MitoLab team, UMR CNRS 6015 - INSERM U1083, MitoVasc Institute, Angers, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Vincent Procaccio
Brett A Kaufman
6Department of Medicine, Vascular Medicine Institute and Center for Metabolic and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Brett A Kaufman
Erin L Seifert
21Thomas Jefferson University, Department of Pathology, Anatomy and Cell Biology and MitoCare Center, Philadelphia, PA, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Erin L Seifert
Michio Hirano
22Department of Neurology, H. Houston Merritt Center, Columbia Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, NY, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Michio Hirano
Martin Picard
1Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, United States
22Department of Neurology, H. Houston Merritt Center, Columbia Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, NY, United States
23New York State Psychiatric Institute, New York, NY, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Martin Picard
  • For correspondence: martin.picard@columbia.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Data/Code
  • Preview PDF
Loading

Abstract

Patients with primary mitochondrial diseases present with fatigue and multi-system disease, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. Integrating data from 17 cohorts of patients with mitochondrial diseases (n=690), we find that clinical mitochondrial disorders increase resting energy expenditure, a state termed hypermetabolism. In a longitudinal cellular model of primary patient-derived fibroblasts from multiple donors, we show that genetic and pharmacological disruptions of oxidative phosphorylation (OxPhos) similarly trigger increased energy consumption in a cell-autonomous manner, despite near-normal OxPhos coupling efficiency. Hypermetabolism was associated with mtDNA instability, activation of the integrated stress response, increased extracellular secretion of age-related cytokines and metabokines including GDF15, as well as an accelerated rate of telomere erosion and epigenetic aging, and a reduced Hayflick limit. Finally, we generate a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations to OxPhos dysfunction. Hypermetabolism, or the increased energetic cost of living in mitochondrial diseases, has important biological and clinical implications.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE179849

  • https://columbia-picard.shinyapps.io/shinyapp-Lifespan_Study/

  • https://www.biorxiv.org/content/10.1101/2021.11.12.468448v3

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted November 30, 2021.
Download PDF

Supplementary Material

Data/Code
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
OxPhos Dysfunction Causes Hypermetabolism and Reduces Lifespan in Cells and in Patients with Mitochondrial Diseases
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
OxPhos Dysfunction Causes Hypermetabolism and Reduces Lifespan in Cells and in Patients with Mitochondrial Diseases
Gabriel Sturm, Kalpita R Karan, Anna Monzel, Balaji S Santhanam, Tanja Taivassalo, Céline Bris, Sarah A Duplaga, Marissa Cross, Atif Towheed, Albert Higgins-Chen, Meagan J McManus, Andres Cardenas, Jue Lin, Elissa S Epel, Shamima Rahman, John Vissing, Bruno Grassi, Morgan Levine, Steve Horvath, Ronald G Haller, Guy Lanaers, Douglas C Wallace, Saeed Tavazoie, Vincent Procaccio, Brett A Kaufman, Erin L Seifert, Michio Hirano, Martin Picard
bioRxiv 2021.11.29.470428; doi: https://doi.org/10.1101/2021.11.29.470428
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
OxPhos Dysfunction Causes Hypermetabolism and Reduces Lifespan in Cells and in Patients with Mitochondrial Diseases
Gabriel Sturm, Kalpita R Karan, Anna Monzel, Balaji S Santhanam, Tanja Taivassalo, Céline Bris, Sarah A Duplaga, Marissa Cross, Atif Towheed, Albert Higgins-Chen, Meagan J McManus, Andres Cardenas, Jue Lin, Elissa S Epel, Shamima Rahman, John Vissing, Bruno Grassi, Morgan Levine, Steve Horvath, Ronald G Haller, Guy Lanaers, Douglas C Wallace, Saeed Tavazoie, Vincent Procaccio, Brett A Kaufman, Erin L Seifert, Michio Hirano, Martin Picard
bioRxiv 2021.11.29.470428; doi: https://doi.org/10.1101/2021.11.29.470428

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cell Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3484)
  • Biochemistry (7336)
  • Bioengineering (5308)
  • Bioinformatics (20225)
  • Biophysics (9991)
  • Cancer Biology (7717)
  • Cell Biology (11280)
  • Clinical Trials (138)
  • Developmental Biology (6426)
  • Ecology (9930)
  • Epidemiology (2065)
  • Evolutionary Biology (13298)
  • Genetics (9354)
  • Genomics (12566)
  • Immunology (7687)
  • Microbiology (18979)
  • Molecular Biology (7428)
  • Neuroscience (40944)
  • Paleontology (300)
  • Pathology (1226)
  • Pharmacology and Toxicology (2132)
  • Physiology (3146)
  • Plant Biology (6850)
  • Scientific Communication and Education (1272)
  • Synthetic Biology (1893)
  • Systems Biology (5306)
  • Zoology (1087)