Sanja Medenica

Cellular stress is not inherently detrimental; its biological consequences depend on intensity, duration, context, and the capacity for recovery. This narrative review proposes the Burn-ON/Burn-OUT paradigm as a hypothesis-generating framework describing the transition from adaptive cellular activation to progressive loss of cellular resilience. A structured literature search was conducted for English-language articles published between 2021 and 2026 in PubMed, Web of Science, and Scopus, focusing on cellular stress adaptation, mitochondrial dysfunction, integrated stress response, autophagy and mitophagy, redox signaling, inflammasome activation, metabolic flexibility, senescence, and nutritional modulation. In the proposed model, Burn-ON represents a state of increased cellular demand in which mitochondrial adaptation, stress-response signaling, autophagic quality control, redox homeostasis, and metabolic flexibility remain sufficiently preserved to sustain function and allow recovery. With persistent or repetitive stress, these adaptive mechanisms may progressively lose reversibility, defining a potential tipping point toward Burn-OUT. Burn-OUT is characterized conceptually by impaired mitochondrial quality control, reduced energetic reserve, defective autophagic flux, persistent inflammatory signaling, redox imbalance, metabolic inflexibility, and loss of functional recovery, with senescence or regulated cell death representing possible downstream outcomes. Nutrition and lifestyle may modulate this continuum by influencing nutrient sensing, substrate load, mitochondrial metabolism, autophagy, and inflammatory pathways. The Burn-ON/Burn-OUT model frames cellular stress as a double-edged biological process, in which adaptation and dysfunction represent different positions along a dynamic continuum. Longitudinal studies are needed to determine whether recovery kinetics and multidimensional biomarker profiles can distinguish these proposed states.