Fig. 2: SURF1 defects decrease metabolic efficiency and cause hypermetabolism without affecting coupling efficiency.

a Schematic of the study design with primary human fibroblasts, coupled with repeated, longitudinal measures of cellular, bioenergetic, and molecular profiling across the lifespan. Three Control and three SURF1 donors (one female, two males in each group) were used for all experiments. b Example oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) obtained from Seahorse measurements of Control and SURF1 cells. c Comparison of average OCR and ECAR values across the cellular lifespan. The specificity of the ECAR signal for glycolysis was verified (see Methods for details). d Lifespan trajectories of ATP production rates (J_ATP) derived from glycolysis (J_ATP-Glyc), oxidative phosphorylation (J_ATP-OxPhos), and total ATP (J_ATP-Total: Glycolytic- + OxPhos-derived rates) over up to 150 days. Percentages show the average difference between SURF1 and Control across the lifespan. e Lifespan average energy expenditure (EE) by cell line and f corrected for cell volume. g Balance of J_ATP derived from OxPhos and glycolysis and h quantified SURF1-induced metabolic shift. Dotted lines in (h) denote the range in control cells. i Lifespan trajectory of mtDNAcn and average mtDNAcn at the first 3 time points (early life, days 5–40) and peak value across the lifespan. j Lifespan trajectories and averages of proton leak and k coupling efficiency estimated from extracellular flux measurements of ATP-coupled and uncoupled respiration. n = 3 individuals per group, 7–9 timepoints per individual. Data are means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, mixed effects model (fixed effect of control/SURF1 group and days grown, random effects of the donor or cell line).