The article challenges the prevailing model of mitochondrial disease pathogenesis, which is based on the central dogma of DNA–RNA–protein function, suggesting that ATP deficiency is the primary driver. Instead, it argues that oxidative phosphorylation (OxPhos) defects trigger maladaptive stress responses that consume excess energy, leading to chronic hypermetabolism. This hypermetabolism imposes energetic constraints, causing mitochondrial disease pathophysiology. The authors review evidence from in vitro, animal, and clinical studies to support their hypothesis. They highlight that patients with OxPhos defects exhibit elevated resting metabolic rates, increased tissue-specific energy expenditure, and hyperkinetic cardiorespiratory responses. These conditions are accompanied by upregulated stress responses, such as the integrated stress response (ISR), which increases the secretion of cytokines and metabokines like GDF15 and FGF21. Despite reduced division rates, OxPhos-deficient cells show marked hyperactivity and stress pathway upregulation, leading to increased energy costs. The article proposes two hypotheses to explain how hypermetabolism causes disease manifestations: increased molecular entropy and energetic trade-offs. Hypermetabolism increases chronic resting energy flux, leading to faster accumulation of molecular damage and tissue stress. Additionally, the body's finite resources are reallocated from longevity-promoting processes to maintain short-term vital functions, resulting in accelerated ageing and physiological decline. The authors suggest three potential therapeutic avenues: improving sleep quality, implementing psychological and behavioral interventions to reduce stress, and developing molecular therapies to target the ISR and metabokine signaling. They emphasize the need for interdisciplinary research to understand and treat mitochondrial disorders effectively.The article challenges the prevailing model of mitochondrial disease pathogenesis, which is based on the central dogma of DNA–RNA–protein function, suggesting that ATP deficiency is the primary driver. Instead, it argues that oxidative phosphorylation (OxPhos) defects trigger maladaptive stress responses that consume excess energy, leading to chronic hypermetabolism. This hypermetabolism imposes energetic constraints, causing mitochondrial disease pathophysiology. The authors review evidence from in vitro, animal, and clinical studies to support their hypothesis. They highlight that patients with OxPhos defects exhibit elevated resting metabolic rates, increased tissue-specific energy expenditure, and hyperkinetic cardiorespiratory responses. These conditions are accompanied by upregulated stress responses, such as the integrated stress response (ISR), which increases the secretion of cytokines and metabokines like GDF15 and FGF21. Despite reduced division rates, OxPhos-deficient cells show marked hyperactivity and stress pathway upregulation, leading to increased energy costs. The article proposes two hypotheses to explain how hypermetabolism causes disease manifestations: increased molecular entropy and energetic trade-offs. Hypermetabolism increases chronic resting energy flux, leading to faster accumulation of molecular damage and tissue stress. Additionally, the body's finite resources are reallocated from longevity-promoting processes to maintain short-term vital functions, resulting in accelerated ageing and physiological decline. The authors suggest three potential therapeutic avenues: improving sleep quality, implementing psychological and behavioral interventions to reduce stress, and developing molecular therapies to target the ISR and metabokine signaling. They emphasize the need for interdisciplinary research to understand and treat mitochondrial disorders effectively.