RT Journal Article
SR Electronic
T1 OxPhos Dysfunction Causes Hypermetabolism and Reduces Lifespan in Cells and in Patients with Mitochondrial Diseases
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.11.29.470428
DO 10.1101/2021.11.29.470428
A1 Gabriel Sturm
A1 Kalpita R Karan
A1 Anna Monzel
A1 Balaji S Santhanam
A1 Tanja Taivassalo
A1 Céline Bris
A1 Sarah A Duplaga
A1 Marissa Cross
A1 Atif Towheed
A1 Albert Higgins-Chen
A1 Meagan J McManus
A1 Andres Cardenas
A1 Jue Lin
A1 Elissa S Epel
A1 Shamima Rahman
A1 John Vissing
A1 Bruno Grassi
A1 Morgan Levine
A1 Steve Horvath
A1 Ronald G Haller
A1 Guy Lenaers
A1 Douglas C Wallace
A1 Saeed Tavazoie
A1 Vincent Procaccio
A1 Brett A Kaufman
A1 Erin L Seifert
A1 Michio Hirano
A1 Martin Picard
YR 2021
UL http://biorxiv.org/content/early/2021/11/30/2021.11.29.470428.1.abstract
AB 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 StatementThe authors have declared no competing interest.