OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases

Gabriel Sturm, Kalpita R. Karan, Anna S. Monzel, Balaji Santhanam, Tanja Taivassalo, Céline Bris, Sarah A. Ware, 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. HallerGuy Lenaers, Douglas C. Wallace, Marie Pierre St-Onge, Saeed Tavazoie, Vincent Procaccio, Brett A. Kaufman, Erin L. Seifert, Michio Hirano, Martin Picard*

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

38 Citationer (Scopus)
6 Downloads (Pure)

Abstract

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.
OriginalsprogEngelsk
Artikelnummer22
TidsskriftCommunications Biology
Vol/bind6
Udgave nummer1
Antal sider22
ISSN2399-3642
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We are grateful to Jane Newman, Renae Stefanetti, Robert W Taylor, and Gráinne S Gorman (Wellcome Center for Mitochondrial Research) for contributing data for Cohort 2, Rohit Sharma and Vamsi Mootha (Massachusetts General Hospital) for contributing data for Cohort 4, Robert McFarland (Wellcome Center for Mitochondrial Research) for contributing data for Cohort 17, and other investigators whose work contributed to the meta-analysis in Fig. 1. We thank Marlon McGill for technical assistance with parts of this project and Herman Pontzer for analytical advice. The cellular studies and analyses were supported by NIH grant R01AG066828 and the Baszucki Brain Research Fund to M.P., the J. Willard and Alice S. Marriott Foundation, Muscular Dystrophy Association, Nicholas Nunno Foundation, JDF Fund for Mitochondrial Research, and Shuman Mitochondrial Disease Fund to M.H. Further support was provided by NIH grants R01GM123771 and R35HL155670 awarded to E.L.S. and M-P.S-O., respectively. All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIH, NHS, the NIHR, or the Department of Health.

Publisher Copyright:
© 2023, The Author(s).

Citationsformater