The prevailing model of mitochondrial disease pathogenesis, based on the central dogma of DNA–RNA–protein function, assumes that mitochondrial diseases arise from ATP deficiency. However, recent evidence challenges this view, suggesting that oxidative phosphorylation (OxPhos) defects trigger maladaptive stress responses that consume excess energy, leading to chronic hypermetabolism. This hypermetabolism imposes energetic constraints, contributing to mitochondrial disease pathophysiology. OxPhos defects do not downregulate biological processes but instead activate compensatory responses, increasing energy demand and causing hypermetabolism. This state of elevated energy expenditure is associated with clinical signs such as fatigue, increased resting ventilation and heart rate, and elevated levels of certain hormones and metabolites. In humans with OxPhos defects, energy expenditure is significantly higher than in healthy controls, indicating a hypermetabolic state. Animal models also show similar hypermetabolic effects, with OxPhos-deficient mice exhibiting increased energy expenditure and resistance to obesity. At the cellular level, OxPhos-deficient cells show increased mitochondrial biogenesis, activation of the integrated stress response (ISR), and secretion of cytokines and metabokines, all of which consume energy. Hypermetabolism may drive accelerated ageing and physiological decline by increasing molecular entropy and overwhelming repair mechanisms. This model is consistent with genomic instability and accelerated telomere shortening in OxPhos-deficient cells. Therapeutic approaches may include improving sleep, implementing psychological and behavioural interventions, and developing molecular therapies targeting the ISR and metabokines GDF15 and FGF21. These strategies could help mitigate hypermetabolism and improve outcomes in patients with mitochondrial diseases. The current model of mitochondrial disorders needs to be revised to account for the hyperactive molecular, cellular, physiological, and whole-body energy expenditure phenotypes of OxPhos deficiency. Understanding and treating inherited and acquired mitochondrial disorders requires a multidisciplinary approach that integrates molecular biology with human energetics and patient experiences.The prevailing model of mitochondrial disease pathogenesis, based on the central dogma of DNA–RNA–protein function, assumes that mitochondrial diseases arise from ATP deficiency. However, recent evidence challenges this view, suggesting that oxidative phosphorylation (OxPhos) defects trigger maladaptive stress responses that consume excess energy, leading to chronic hypermetabolism. This hypermetabolism imposes energetic constraints, contributing to mitochondrial disease pathophysiology. OxPhos defects do not downregulate biological processes but instead activate compensatory responses, increasing energy demand and causing hypermetabolism. This state of elevated energy expenditure is associated with clinical signs such as fatigue, increased resting ventilation and heart rate, and elevated levels of certain hormones and metabolites. In humans with OxPhos defects, energy expenditure is significantly higher than in healthy controls, indicating a hypermetabolic state. Animal models also show similar hypermetabolic effects, with OxPhos-deficient mice exhibiting increased energy expenditure and resistance to obesity. At the cellular level, OxPhos-deficient cells show increased mitochondrial biogenesis, activation of the integrated stress response (ISR), and secretion of cytokines and metabokines, all of which consume energy. Hypermetabolism may drive accelerated ageing and physiological decline by increasing molecular entropy and overwhelming repair mechanisms. This model is consistent with genomic instability and accelerated telomere shortening in OxPhos-deficient cells. Therapeutic approaches may include improving sleep, implementing psychological and behavioural interventions, and developing molecular therapies targeting the ISR and metabokines GDF15 and FGF21. These strategies could help mitigate hypermetabolism and improve outcomes in patients with mitochondrial diseases. The current model of mitochondrial disorders needs to be revised to account for the hyperactive molecular, cellular, physiological, and whole-body energy expenditure phenotypes of OxPhos deficiency. Understanding and treating inherited and acquired mitochondrial disorders requires a multidisciplinary approach that integrates molecular biology with human energetics and patient experiences.