Fig. 9: Conceptual model including potential sources of hypermetabolism in cells and patients with mitochondrial diseases.

OxPhos defects trigger mtDNA instability and cell-autonomous stress responses associated with the hypersecretory phenotype, recapitulating findings in plasma of patients with elevated metabokine and cell-free mitochondrial DNA (cf-mtDNA) levels. These responses are linked to the upregulation of multiple energy-dependent transcriptional programs, including the integrated stress response (ISR). We propose that these processes collectively increase energy consumption, leading to hypermetabolism in patient-derived fibroblasts, and physiological hypermetabolism in affected patients. In dividing human fibroblasts, hypermetabolism-causing OxPhos defects curtail lifespan and accelerate canonical cellular senescence and aging markers, namely telomere length, epigenetic aging, as well as secreted and transcriptional markers.