The mitochondrial disease biomarker GDF15 is quantifiable in saliva, exhibits dynamic properties, and correlates with disease severity

Circulating growth differentiation factor 15 (GDF15) is a biomarker of mitochondrial diseases and aging, but its natural dynamics and response to acute stress in blood and other biofluids have not been well defined. Using extensively sampled participants from the MiSBIE study, we examined GDF15 biology in 290 plasma and 860 saliva samples from 40 patients with rare mitochondrial diseases (MitoD) and compared them to a reference control group. We first confirm that individuals with the m.3243A>G mutation (n=25) or with single, large-scale mtDNA deletions (n=15) exhibit elevated GDF15 (p<0.0001) in both blood and saliva. To examine the basis for GDF15 in saliva, we profiled GDF15 expression in 48 tissues from the GTEx dataset and discovered high GDF15 expression in salivary gland secretory cells. Despite being chronically elevated in MitoD, saliva GDF15 further increased in response to an experimental laboratory mental stress alone (without physical exertion), whereas the stress-induced plasma GDF15 reactivity was blunted in MitoD compared to controls. Using a home-based saliva collection protocol, we show that similar to other stress-related metabolic hormones saliva GDF15 is highest at the time of waking up and declines rapidly within 30-45 minutes in both control and MitoD groups. Elevated saliva GDF15 levels persisted throughout the day in MitoD. Clinically, both plasma and saliva GDF15 were correlated with neurological symptoms, fatigue, and functional capacity. Importantly, stress-evoked GDF15 levels did not yield noisier associations with disease severity, but in fact consistently increased the effects sizes for the GDF15-symptoms connection, pointing to converging biology for mental stress and OxPhos defects. These results open the door to exploring saliva GDF15 as a non-invasive monitoring approach for mitochondrial diseases, calling for further studies examining the psychobiological processes linking mitochondria and GDF15 biology.