Mitochondria
Mitochondria are life sustaining organelles that convert the oxygen we breathe and the food we eat into energy and signals that power and orchestrate all mind–body processes (1). Unlike traditional biomarkers with singular functions, mitochondria are multifunctional, performing a wide range functions and that vary across different cell types (2-4). In response to psychological stress, mitochondria both drive physiological changes underlying adaptation (driver of stress responses), and also undergo structural, molecular, and functional recalibrations (target of stress responses), making them potential mediators of stress resilience.
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Background
Mitochondria are multifaceted organelles whose biology can be defined as molecular and morphological features, activities, functions, and behaviors (5). Emerging evidence highlights mitochondria as critical mediators of the stress response at the cellular level. Both acute and chronic stress can influence multiple domains of mitochondrial biology and cellular bioenergetics (6-10).
Animal studies suggest that mitochondrial health impacts stress reactivity and behaviors related to social interaction, anxiety, and depression (11-20; reviewed in 21). In humans, cross-sectional studies have linked variations in mitochondrial respiration in immune cells or muscle tissues with mood (22), childhood adversity (23-25) and depression (26-30), among others (31). Post-mortem brain proteomics data further suggest that well-being in late life correlates with higher levels of mitochondrial oxidative phosphorylation (OxPhos) proteins (particularly complex I), whereas negative mood related to lower OxPhos protein content (32).
Collectively, these findings support the idea that mitochondrial biology is intimately linked to stress and health, making it a promising avenue for research on stress biomarkers.
Collection and Measurement
Mitochondria are dynamic, multifunctional organelles that can be studied using various techniques ranging from molecular markers to functional assays (5,33).
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1. Mitochondrial DNA Copy Number (mtDNAcn)
Mitochondria possess their own genome, the mitochondrial DNA (mtDNA). The number of mtDNA copies per cell (mtDNA copy number; mtDNAcn) has been proposed to reflect mitochondrial health since mtDNA is needed for the expression mitochondrial respiratory chain proteins. mtDNAcn has been widely used as an outcome measure mostly because it is easy to obtain from any genomic material. However, its interpretation is challenging since both increases and decreases in mtDNAcn may indicate abnormal mitochondrial bioenergetics (34). As such, it is best used in conjunction with other measures (22).
2. Respirometry and Enzymatic Activity Assays
Respirometry is a technique that measures oxygen consumption as a proxy for mitochondrial energy transformation capacity, reflecting the ability of mitochondria to transform energy through oxidative phosphorylation (23). Under basal conditions where cells are monitored without perturbation, respirometry assesses how much energy the cell consumes as transformed by mitochondria. To assess maximal capacity for energy transformation, the cells are disrupted (e.g., permeabilized) and the activity of specific enzymes monitored using respiration as a readout (25). Complementary to respirometry, enzymatic activity assays, often performed on frozen cells or tissues, quantify the activity of mitochondrial respiratory chain complexes involved in ATP synthesis as well as markers of mitochondrial content. Using a combination of approaches, e.g. by integrating enzymatic assays results with molecular markers of mitochondrial content (mtDNAcn) (22,35), can provide a more reliable picture of mitochondrial biology.
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3. Omics Approaches
High-throughput omics techniques, such as transcriptomics (RNA sequencing), enable the analysis of mitochondrial pathways (MitoPathways) by grouping and scoring multiple functionally related genes (32,36). Such pathway-based approaches can be applied to omics data derived from a variety of tissues (e.g., immune, brain. etc) and provide more biologically interpretable and more robust indices compared to single-gene based approaches. These approaches open the door to building systems-level understanding of mitochondrial recalibrations in the context of acute or chronic stress exposure.
4. Circulating Markers: cf-mtDNA and GDF15
Biofluids such as blood-derived plasma and serum and saliva can be used to measure signaling markers related to mitochondria biology such as cell-free mitochondrial DNA (cf-mtDNA) and growth differentiation factor 15 (GDF15).
Cell-free mitochondrial DNA (cf-mtDNA): Found in biofluids such as blood, saliva, urine and others, cf-mtDNA is a promising marker of mitochondrial health. Elevated cf-mtDNA levels have been observed in various diseases (37,38), including psychiatric conditions such as depression (39; e.g. 26,40), and increase in response to acute psychological stress (41-44). Recent work showed a several-fold increase in saliva cf-mtDNA within 5-20 minutes following social-evaluative stress, relative to smaller magnitude and delayed response in blood (44), suggesting that cf-mtDNA in different biofluids may reflect different psychobiological processes. Plasma and serum also show different cf-mtDNA levels and dynamics, calling for attention to collection tube type used. To standardize cf-mtDNA measurements across studies, harmonized pre-processing methodologies are required (39).
Growth Differentiation Factor 15 (GDF15): GDF15 is a cytokine that signals energetic stress to the brain, influencing behavior and energy expenditure 45-49. Elevated blood GDF15 levels are associated with mitochondrial defects 50-(52, 53,54) and in many aging-related diseases (53,55-62). GDF15 is also elevated in psychiatric conditions such as depression and schizophrenia (57,63-66). GDF15 is also the protein most strongly associated with social isolation and loneliness (67), further highlights its relevance for stress and well-being research.
​Author(s) and Reviewer(s):
Prepared by Caroline Trumpff and Martin Picard, Ph.D.
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Version July 2025. Waiting for Review.
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References:
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