A platform to map the mind-mitochondria connection and the hallmarks of psychobiology: the MiSBIE study

Abstract

Health emerges from coordinated psychobiological processes powered by mitochondrial energy transformation. But how do mitochondria regulate the multisystem responses that shape resilience and disease risk across the lifespan? The Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study was established to address this question and determine how mitochondria influence the interconnected neuroendocrine, immune, metabolic, cardiovascular, cognitive, and emotional systems among individuals spanning the spectrum of mitochondrial energy transformation capacity, including participants with rare mitochondrial DNA (mtDNA) lesions causing mitochondrial diseases (MitoDs). This interdisciplinary effort is expected to generate new insights into the pathophysiology of MitoDs, provide a foundation to develop novel biomarkers of human health, and integrate our fragmented knowledge of bioenergetic, brain-body, and mind-mitochondria processes relevant to medicine and public health.

Keywords: allostasis; metabolism; mitochondrial disorders; mtDNA; psychobiology; stress.

Figure 1.. The hallmarks of psychobiology.

(A) The hallmarks of psychobiology, separated for illustrative purposes, functionally interact as a psychobiological network of measurable elements (nodes) and functional connections (edges). Psychosocial factors and behaviors include mental states and attributes of the mind (green nodes). Biological processes (blue nodes) overlap and functionally interact with psychosocial factors in more complex ways than the 2D network illustrates. (B) Mitochondria functionally sit at the interface of psychological and biological processes that together transform exposures into integrated stress responses (left), evolve over time and must therefore be captured dynamically via repeated measures and time-series analyses (middle), and operate across levels of complexity (right). Some figure elements created using BioRender.

Figure 2.. Model of mind–body processes emerging from information flow across the psychobiological network.

(A) An experimental paradigm where a standardized laboratory psychosocial stressor [e.g., Trier Social Stress Test (TSST) speech task] triggers proximal psychological processes that ripple out into diverse brain–body systems functionally interconnected and regulated by mitochondrial oxidative phosphorylation (OxPhos). Pre-existing disturbances (e.g., hunger), disorders (e.g., anxiety), and symptoms (e.g., pain) affecting specific nodes of the psychobiological network not illustrated here also could influence both the perception of the stressor and the nature and magnitude of the response elicited by the stressor. (B) Study design where the mitochondrial OxPhos node is perturbed, as in primary mitochondrial diseases. This leads to cellular and physiological recalibrations that influence how the same stressor as in (A) can produce distinct (exaggerated, blunted, or qualitatively distinct) psychobiological responses. The 2D psychobiological network is a static simplification of the complex dynamical system that is the human organism. Abbreviations: CORT, cortisol; GDF15, growth differentiation factor 15; HR, heart rate; SBP, systolic blood pressure.

Figure 3.. The Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study.

Top: multimodal approach to sample and data collection addressing the hallmarks of psychobiology via clinician-assessed signs and symptoms, self-reported outcomes, rich time series of psychophysiological signals, and diurnal/behavioral rhythms, in parallel with a rich biobanked tissues for every participant. Middle: the MiSBIE group composition includes individuals with two distinct rare, molecularly defined mitochondrial DNA (mtDNA) lesions and a control group recruited from the community. The Mutation and Deletion groups exhibit distinct molecular and clinical phenotypes. Bottom: example outcome measures range from molecular and cellular bioenergetic profiles, single-cell transcriptomics, and neuroimaging to laboratory and home-based tracking of psychological, physiological, behavior, stress reactivity, and recovery. Abbreviation: OxPhos, oxidative phosphorylation. Figure created using BioRender.

Figure I.. Core principles of psychobiology.

The MiSBIE study integrates all core principles of psychobiology.

Figure I.. MiSBIE study components.

MiSBIE assesses all hallmarks and principles of human psychobiology. (top) The three major MiSBIE components include (1) highly controlled laboratory-based baseline measures of biomarkers, mitochondrial biology, and other outcomes, (2) a validated experimental speech delivery stress reactivity paradigm, and (3) home-based data and sample collection.① Baseline measures capture stable traits of individuals along the spectrum of normal and abnormal OxPhos capacity, reflecting the stable state of the organism. ② Stress-reactivity and recovery measures capture the robustness, resilience, and adaptability of the organism to psychosocial stress, deep breathing (DB), standing transition (ST), 30-second sit-to-stand test (SST), and cold pressor (CP), and metabolic rate measurement (MR). Different biomarkers exhibit distinct expected kinetics from which indices of reactivity, recovery, resilience, and elasticity can be computed. ③ Home-based data collection captures daily cycles of sleep and awakening in biological, psychosocial, and behavioral outcomes from four saliva samples per day, two sets of mood-related questionnaires (AM, evening), and continuous wrist actigraphy.Abbreviations: CBC, complete blood count; PBMCs, peripheral blood mononuclear cells.