Mitochondrial Signaling, Stress, and Sleep in Children with Internalizing Disorders - Project Summary Psychosocial stress in childhood is a prominent risk factor in the development, severity, and outcomes of internalizing disorders. Stress may impact pediatric mental health by disrupting homeostatic pathways, such as sleep and energy metabolism that can be indexed using mitochondrial biomarkers. Mitochondria, with broad roles in cellular energy and metabolic homeostasis, may contribute to stress-associated physiological wear and tear and serve as a target for intervention in children with internalizing disorders. Mitochondrial DNA (mtDNA) contains unique inflammatory and cell-signaling properties and is actively released as cell-free mtDNA (cf- mtDNA) in response to psychosocial stressors, promoting inflammation and oxidative damage. Levels of cf- mtDNA appear to fluctuate across days and throughout the day and may have a circadian rhythm. Importantly, pervasive disturbances in sleep are observed in both severe stress and mental health disorders and sleep impairment interferes with mitochondrial maintenance. Recent preclinical work indicates that sleep is required for homeostatic oxidative recovery of mitochondria and emerging clinical research demonstrates that circadian disruption is associated with dysregulation of cf-mtDNA. Taken together, this work suggests that stress- induced changes in mitochondrial signaling may contribute to physiological dysfunction and symptoms, potentially due in part to stress effects on sleep. Quantification of cf-mtDNA is now accessible through saliva and may hold promise as a robust biomarker of the dynamic effects of stress and behavior on psychiatric symptoms. The proposed study will recruit N=60 children ages 9-12 with internalizing disorders from a day hospital program. At the time of admission, children and caregivers will each provide baseline assessments of cumulative stress history, sleep disturbances and behavioral health symptoms over the past month, and assessment of a range of internalizing and externalizing symptoms. Following recruitment, children and caregivers will provide daily diary assessments of stress exposure, sleep, and symptoms, and salivary samples assessed for cf-mtDNA across two weeks. This study will 1) characterize baseline cross-sectional associations of levels of cf-mtDNA with cumulative early life stress, baseline sleep disturbances, and baseline internalizing symptom severity and 2) examine daily fluctuations of cf-mtDNA in association with daily stressors (type, severity, and timing), sleep (duration, timing, regularity and quality), and mental health symptoms. By investigating stress-associated mitochondrial processes and sleep in children with psychopathology, this study will yield clinically relevant information, consistent with NIMH Strategic Plan Strategy 2.2, to identify mechanisms of risk to guide the development of novel treatment targets for children with acute psychiatric pathology. Further, data from this study will be used to inform an R01 application investigating cf-mtDNA and additional mitochondrial indices and inflammatory targets in a larger, more definitive study of children with internalizing disorders.
