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The integration of biological, psychological, and social factors in medicine has benefited from increasingly precise stress response biomarkers. Mitochondria, a subcellular organelle with its own genome, produce the energy required for life and generate signals that enable stress adaptation. An emerging concept proposes that mitochondria sense, integrate, and transduce psychosocial and behavioral factors into cellular and molecular modifications. Mitochondrial signaling might in turn contribute to the biological embedding of psychological states.A narrative literature review was conducted to evaluate evidence supporting this model implicating mitochondria in the stress response, and its implementation in behavioral and psychosomatic medicine.Chronically, psychological stress induces metabolic and neuroendocrine mediators that cause structural and functional recalibrations of mitochondria, which constitutes mitochondrial allostatic load. Clinically, primary mitochondrial defects affect the brain, the endocrine system, and the immune systems that play a role in psychosomatic processes, suggesting a shared underlying mechanistic basis. Mitochondrial function and dysfunction also contribute to systemic physiological regulation through the release of mitokines and other metabolites. At the cellular level, mitochondrial signaling influences gene expression and epigenetic modifications, and modulates the rate of cellular aging.This evidence suggests that mitochondrial allostatic load represents a potential subcellular mechanism for transducing psychosocial experiences and the resulting emotional responses—both adverse and positive—into clinically meaningful biological and physiological changes. The associated article in this issue of Psychosomatic Medicine presents a systematic review of the effects of psychological stress on mitochondria. Integrating mitochondria into biobehavioral and psychosomatic research opens new possibilities to investigate how psychosocial factors influence human health and well-being across the life-span.