Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases

GDF15 (growth differentiation factor 15) is a marker of cellular energetic stress linked to physical-mental illness, aging, and mortality. However, questions remain about its dynamic properties and measurability in human biofluids other than blood. Here, we examine the natural dynamics and psychobiological regulation of plasma and saliva GDF15 in four human studies representing 4,749 samples from 188 individuals. We show that GDF15 protein is detectable in saliva (8% of plasma concentration), likely produced by salivary glands secretory duct cells. Using a brief laboratory socio-evaluative stressor paradigm, we find that psychosocial stress increases plasma (+3.5-5.9%) and saliva GDF15 (+43%) with distinct kinetics, within minutes. Moreover, saliva GDF15 exhibits a robust awakening response, declining by ∼40-89% within 30-45 minutes from its peak level at the time of waking up. Clinically, individuals with genetic mitochondrial OxPhos diseases show elevated baseline plasma and saliva GDF15, and post-stress GDF15 levels in both biofluids correlate with multi-system disease severity, exercise intolerance, and the subjective experience of fatigue. Taken together, our data establish that saliva GDF15 is dynamic, sensitive to psychological states, a clinically relevant endocrine marker of mitochondrial diseases. These findings also point to a shared psychobiological pathway integrating metabolic and mental stress.