Fig. 1: Meta-analysis of human studies reveals increased energy expenditure and shortened lifespan in primary mitochondrial diseases.

a Overall conceptual model linking mtDNA- and nDNA-related OxPhos defects to impaired metabolic efficiency at the cellular level, impacting whole-body resting energy expenditure and clinical outcomes. b Skeletal muscle biopsy with individual muscle fibers stained with cytochrome c oxidase/succinate dehydrogenase (COX/SDH) histochemistry to reveal functional (brown) and respiratory chain deficient (blue) mitochondria. In the affected cell (middle), three sub-regions showing low, intermediate, and high mtDNA mutation load were captured by laser capture microdissection and subjected to quantitative PCR analysis as in ref. ¹¹⁷. Subcellular regions with high mtDNA mutation load show elevated mtDNA density, which is predicted to increase the energetic cost due to mitochondrial biogenesis and turnover processes. WT, wild type. c Meta-analysis of human mitochondrial disease cohorts showing elevated resting heart rate (n = 104 controls, 111 patients), d catecholamines (urinary-Cohort 3 and blood-Cohort 6) at rest or during fixed-intensity exercise (n = 38 controls, 19 patients), e whole-body oxygen consumption measured by indirect calorimetry at rest or during the response to mild exercise challenge; one before training, two after training. Slope refers to the rate of increase in VO₂ relative to work rate, where a higher slope indicates increased energetic cost for a given work rate (n = 56 controls, 78 patients). f Body mass index (BMI) across mitochondrial disease cohorts and compared to relevant national averages (USA, UK, and Italy combined) (n = 285 controls, 174 patients). g Average life expectancy in individuals with mitochondrial diseases relative to the national average (n = 301 patients). Data are means ± SEM, with % difference between mitochondrial disease and control group were available. h Mortality (age at death) over 10 years (2010–2020) in Cohort 17 compared to national averages for women and men (n = 109 patients). See Table 1 for cohort details. Total n = 225 healthy controls, 690 patients. Only aggregate group means (with or without a measure of variance) were available for some cohorts, so individual participant data is not shown. Standardized effect sizes are quantified as Hedges’ g (g). Overall group comparisons were performed by paired t tests (c and f) or one-sample t tests (d and e), *p < 0.05, **p < 0.01, ****p < 0.0001.