Project Details
Projekt
Single-cell profiling of immune responses to acute psychosocial stress in mitochondrial disease
Applicant
Dr. Deniz Yildirim Dogan
Subject Area
Biological Psychiatry
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 584812408
Acute psychosocial stress initiates coordinated neuroendocrine and immune reactions that are energetically costly and depend on rapid cellular adaptation. Mitochondria play a central role in these processes by integrating metabolic and signaling pathways that support immune activation. Although mitochondrial dysfunction has been associated with blunted immune responses, it remains unknown how such defects shape stress-induced immune regulation at the level of individual cell types in humans. This project addresses this gap by providing a single-cell–resolved characterization of immune responses to acute psychosocial stress in individuals with primary mitochondrial disease (MitoD), including both the m.3243A>G mutation and single large-scale mtDNA deletions, using peripheral blood mononuclear cells (PBMCs) as an accessible model of immune function. A key rationale for this work is that mitochondrial diseases provide a naturally occurring model of energetic constraint. Patients exhibit chronic metabolic stress and altered immune signaling, yet their cell type-specific stress adaptability has not been systematically investigated. Using samples from the NIH-funded MiSBIE study, PBMCs from healthy controls and genetically defined MitoD carriers were collected across several timepoints before and after a modified Trier Social Stress Test (TSST), a standardized paradigm involving anticipatory stress, a mock interview, and mental arithmetic, optimized to elicit robust cortisol and autonomic responses. These samples allow for a detailed temporal characterization of immune stress dynamics. Using single-cell RNA sequencing (scRNA-seq), the project will quantify stress-induced transcriptional changes across immune subsets. Stress- and cytokine-response transcriptional modules, together with pathway-level metabolic scores (e.g., glycolysis, oxidative phosphorylation), will be used to capture alterations in activation and metabolic states. Longitudinal and pseudotime analyses will characterize transcriptional trajectories within and between groups, testing the hypothesis that mtDNA defects reduce the flexibility and magnitude of immune stress responses. An optional complementary aim uses in vitro glucocorticoid stimulation with dexamethasone to model acute stress signaling under controlled conditions, enabling mechanistic validation of in vivo patterns and assessment of glucocorticoid sensitivity in mtDNA-deficient cells. Expected outcomes include the identification of baseline mitochondrial and immune alterations in MitoD PBMCs, discovery of cell type-specific transcriptional responses to psychosocial stress, and clarification of altered stress- and glucocorticoid-induced signaling in mtDNA-deficient immune cells. Together, these findings will provide the first high-resolution map of how mitochondrial dysfunction shapes human immune adaptation to acute psychosocial stress.
DFG Programme
Fellowship
International Connection
USA
