Biology subjects

Picard, M.

Publications and source records attributed to Picard, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Circulating colorectal tumor cells remodel their surfaceome to increase their viability and metastatic potential in the bloodstream

Circulating tumor cells (CTCs) are the potential seeds of distant metastases; however, little is known about how they survive in the bloodstream. Using a large cohort of colorectal cancer (CRC) patients, we found that the pseudokinase receptor PTK7 is highly expressed in primary tumors and metastatic lesions. Consistent with previous reports, high PTK7 expression is associated with reduced disease-free survival and increased metastatic dissemination. Surprisingly, PTK7 is absent from most CTCs and undergoes a cell-autonomous ONtumor/OFFCTC/ONmetastasis switch that can be recapitulated in a xenografted mouse model, in in vitro systems, and a fluidic platform. PTK7-negative cancer cells exhibit increased expression of YAP1-driven genes, senescence-like features, and enhanced resistance to hemodynamic stress following loss of cell-cell and cell-matrix adhesion. This adaptive phenotype depends on metalloproteases, notably ADAM17, whose cleavage activity remodels the CTCs surfaceome. Functionally, the PTK7 OFFCTC state confers enhanced metastatic potential in vivo, and can be pharmacologically suppressed using metalloprotease inhibitors. Collectively, our findings identify a reversible, cell-autonomous, protease-driven surfaceome remodeling program that enables metastatic adaptation during hematogenous dissemination. Highlights / statement of significanceBy investigating potential markers for circulating colorectal tumor cells with strong metastatic potential, we describe a reversible and cell-autonomous remodeling of the circulating tumor cell surfaceome in patients that confers resistance to anoikis and stress induced by entry into the bloodstream. One Sentence SummaryThe dynamic regulation of PTK7 serves as a surrogate marker for tumor cell plasticity, aggressiveness, survival in the bloodstream, and efficiency in forming metastases. Trial registrationCTC colon Cohort: registered on https://ClinicalTrials.gov identifier NCT03256084; date of registration 2017-07-17 B-Org cohort: registered on https://ClinicalTrials.gov NCT05384184; date of registration 2019-06-06 Ethics statement for animal experimentsStudies on animals were conducted in accordance with the current ethical standards of the European Community (Directive 2010/63/EU), the Ethics Committee for Animal Experimentation (CEEA#14) and the French Ministry of Higher Education and Research, which approved and authorized the entire procedure described in this paper (project number APAFIS #35294).

cancer biology↗

bioRxiv2026

The Energetic Cost of Adrenergic Signaling in Primary Human Fibroblasts

Stress involves the activation of cellular, physiological, and emotional processes that cost energy--nothing is free in biology. In mammals, the stress response involves hormone release, including norepinephrine (NE), which increases energy expenditure. To quantify the energetic cost of NE signaling in a simple cellular system, we interrogated the dose (0 - 10 M NE) and time-dependent (up to 10 hours) effects of adrenergic signaling in primary human fibroblasts. Oxygen consumption rates (OCR, reflecting ATP generated by mitochondria) and extracellular acidification rate (ECAR, reflecting ATP generated by glycolysis) were measured continuously using extracellular flux analysis, allowing us to estimate the ATP turnover rates, and thus cellular energy expenditure. Within the first 18 minutes (early phase), glycolysis increases up to 47% whereas respiration decreased 2-5%. Both parameters normalized within 1-2 hours for low NE concentrations. This was followed by an increase in oxidative phosphorylation (OxPhos), peaking around 9-12% by 2-6 hours (mid or late-phase). These minutes-to-hours data reveal the temporal dynamics whereby NE increases cellular energy expenditure in fibroblasts. Blocking OxPhos with oligomycin or piericidin A abolished OxPhos changes post-NE addition while conserving the glycolytic response. Withdrawal of glucose from the media significantly dampened the absolute rise in ECAR in response to NE, and instead increased OxPhos, revealing the metabolic flexibility in fibroblasts. Finally, cells with genetic defects impairing OxPhos exhibited a 50% blunted NE-driven metabolic response, consistent with the existence of an energy constraint in mitochondrial diseases. In summary, we have resolved the dynamics and flexible bioenergetic recalibrations associated with NE-driven hypermetabolism in primary human fibroblasts. Mapping the nature and magnitude of these recalibrations in humans would advance our understanding of the potential energetic forces underlying the damage to health by chronic stress.

cell biology↗

bioRxiv2026

Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.

Mitochondria support the bioenergetic processes that enable brain function and cognition, but we have lacked a label-free, non-invasive approach to explore how brain mitochondria are linked to ageing, disease, and cognition in humans. A recently introduced MitoBrainMap neuroimaging framework predicts mitochondrial features from magnetic resonance data alone, potentially bridging cellular biology with macroscale brain organization. Here, we tested whether this framework captures meaningful age- and pathology-related mitochondrial variation. Consistent with existing literature, we find that MR-predicted mitochondrial density and tissue respiratory capacity consistently declined with age, whereas mitochondrial respiratory capacity-an index of mitochondrial quality-was relatively preserved across the lifespan. Moreover, the relations among specific mitochondrial features predicted from our algorithm were consistent with their biological organization, supporting preliminary construct validity for MR-predicted mitochondrial features. In patients with rare mitochondrial diseases, predicted maps revealed region-specific alterations in mitochondrial density and respiratory chain components, particularly the expected compensatory upregulation of complex II, but not of other mitochondrial genome-encoded components. Finally, the MR-based mitochondrial features were associated with the energetic stress marker GDF15 measured in blood, as well as with cognitive performance measures, linking the novel predictions of brain mitochondria to systemic stress and behavior. These findings introduce a first-generation, label-free, neuroimaging-based mitochondrial mapping as a non-invasive window into living human brain mitochondria.

neuroscience↗

bioRxiv2026

Multiomic dissection of HR+/HER2- invasive lobular breast carcinoma reveals mobilized yet dysfunctional anti-tumor immunity shaped by tumor-stroma crosstalk and impaired antigen presentation

ContextImmunotherapy based on immune checkpoint inhibitors (ICI) revolutionized the treatment of triple-negative (TN) breast carcinomas (BC), but remains more challenging in HR+/HER2- BCs. Because invasive lobular carcinomas (ILC) generally exhibit low immune infiltration, ICIs were largely overlooked in this pathological type. The only clinical trial of ICIs dedicated to ILCs showed disappointing results, notably in HR+/HER2- cases. The immune landscape of HR+/HER2- ILCs has been poorly described. High level of tumor-infiltrating lymphocytes (TIL) was associated with worse prognosis in HR+/HER2- ILCs. A better characterization of the immune landscape of HR+/HER2- ILCs could clarify the poor efficiency of ICIs and the negative prognostic value of TILs, and reveal complementary targets able to increase immunotherapy efficiency. MethodWe comprehensively characterized the immune landscape of HR+/HER2- ILCs, comparatively to HR+/HER2- invasive ductal carcinomas (IDC), by applying multi-omics and multi-scale analysis (gene expression at the bulk and single-cell levels, and protein-based spatial analysis) to clinical samples. ResultsWhile the overall level of immune infiltration was comparable between both pathological types, the quality of immune infiltrate differed markedly. Comparatively to HR+/HER2- IDCs, HR+/HER2- ILCs were enriched in immune cells and tertiary lymphoid structures with anti-tumor potential, presented more spatial proximity between cancer cells and CD8+ cytotoxic T cells, and stronger theorical vulnerability to ICIs. However, in HR+/HER2- ILCs, anti-tumor response was defective; CD8+ cytotoxic T cells failed to fully unleash their cytotoxic function and CD4+ helper T cells evidenced a pro-tumoral and naive phenotype. Furthermore, antigen-presenting compartment was defective, altogether embedded in a stronger immunosuppressive environment, enriched in immunoregulatory cancer-associated fibroblasts (iCAF). ConclusionThis study contributes to explain the lesser efficiency of PD-1/PD-L1-based ICIs in HR+/HER2-ILCs by comparison with HR+/HER2- IDCs, by shedding light on a complex ecosystem where tumor cells shape a distinctive stroma that contribute to prevent anti-tumor immune response activation. Altogether, our findings further support the rationale for combining iCAF-targeting strategy with an ad hoc immunotherapy (such as an anti-VTCN1/B7-H4 antibody-drug conjugates for example). Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/728418v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1dfbc7eorg.highwire.dtl.DTLVardef@1d030a7org.highwire.dtl.DTLVardef@12a3e84org.highwire.dtl.DTLVardef@6e6139_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_ST_ABSWHAT IS ALREADY KNOWN ON THIS TOPICC_ST_ABSO_LIImmune cells infiltrate both HR+/HER2- IDC and HR+/HER2- ILC tumors, but current ICIs are less effective in HR+/HER2- ILCs than HR+/HER2- IDCs. C_LI WHAT THIS STUDY ADDSO_LIThe anti-tumor immune response is mobilized but not effective in HR+/HER2- ILCs. C_LIO_LIA complex ecosystem - composed of immunoregulatory cancer-associated fibroblasts, high levels of TGFa, prostaglandin, acidosis, and a lack of antigen-presenting cells - prevents anti-tumor CD8+ cytotoxic T cell activation in HR+/HER2- ILCs. C_LI HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICYO_LITargeting the PD-1/PD-L1 axis is not the appropriate therapeutic strategy for HR+/HER2- ILCs. A more complex approach should be considered, notably those combining other immune-based strategies and iCAF targeting, which may offer a better chance to eradicate HR+/HER2- ILC tumor cells. C_LI

cancer biology↗

bioRxiv2026

Mitochondrial Permeability Transition in Skeletal Muscle Phenocopies Muscle Alterations seen in Cancer Cachexia and other Wasting Conditions

Skeletal muscle in wasting conditions often exhibits atrophy, mitochondrial respiratory dysfunction, and fragmentation of the acetylcholine receptor (AChR) cluster at the endplate. The accompanying alterations of mitochondrial morphology suggest mitochondria may be involved in muscle pathology in these conditions. To address this gap, we tested an established pathological mechanism in ischemia-reperfusion injury and neurodegeneration but poorly studied in skeletal muscle: mitochondrial permeability transition (mPT). We tested if mPT recapitulated phenotypes common in wasting conditions, whether tumor-conditioned media (TCM) could promote mPT, and compared differentially expressed genes (DEGs) induced by mPT with DEGs observed in a mouse model of pancreatic cancer cachexia. Inducing mPT in mouse skeletal muscle bundles progressively altered mitochondrial cristae morphology, culminating in breach of the outer mitochondrial membrane. Inducing mPT in mouse muscle fibers increased mROS and Caspase 3 activity and caused atrophy. Inducing mPT caused a complex I mitochondrial respiratory impairment, increased lysosome-mitochondrion co-localization, and fragmented the AChR cluster at the muscle endplate. The Ca2+ threshold for mPT, mitochondrial calcein colocalization and mitochondrial membrane potential were reduced by TCM in skeletal muscle or C2C12 myoblasts, respectively. Knockout of the mPT-regulating protein CypD attenuated the reduction in Ca2+ threshold for mPT by TCM. Inhibitors of mPT attenuated atrophy with TCM in C2C12 and human primary myotubes. Finally, there was overlap between the DEGs of mPT and diaphragm muscle in a mouse model of pancreatic cancer cachexia during the muscle wasting phase. We conclude that mPT should be explored as a therapeutic target in muscle wasting disorders.

physiology↗

bioRxiv2025

Electroconvulsive Therapy Induces Dopaminergic Axon Regeneration, Corticostriatal Remodeling, and Restoration of Motor Function in Parkinsonian Mice

Parkinsons disease (PD) is characterized by the progressive degeneration of midbrain dopaminergic neurons with loss of axonal dopamine neurotransmission in the dorsal striatum, leading to striatal circuit dysfunction and debilitating motor symptoms. Current therapies provide symptomatic relief but do not restore lost neuronal function. Decades of clinical observations have reported the unexpected observation that electroconvulsive therapy (ECT), a standard treatment for refractory neuropsychiatric disorders, can incidentally alleviate motor symptoms in PD patients, yet the underlying mechanisms remain unknown. Here, we report that in the unilateral 6-hydroxydopamine (6-OHDA) mouse model of PD, two weeks of repeated ECT produced robust and sustained motor recovery, with improvements in locomotion and sensorimotor asymmetry persisting for at least 30 days post-treatment. Remarkably, ECT induced dopaminergic axonal sprouting from surviving dopaminergic neurons with cell bodies located at the substantia nigra-ventral tegmental border, leading to a partial recovery of striatal dopaminergic axonal reinnervation. In striatal direct pathway spiny projection neurons (dSPNs), which exhibit pathological hyperexcitability and spine loss following dopamine depletion, ECT normalized both corticostriatal synaptic responses and spine density. Consistently, ECT upregulated gene transcripts involved in cytoskeletal remodeling while downregulating those associated with glutamatergic signaling and neuronal excitability. These changes were accompanied by a coordinated transcriptional shift toward enhanced mitochondrial anabolic capacity and energy production, including increased expression of genes involved in ATP and Coenzyme Q biosynthesis. Together, these findings demonstrate that ECT can partially restore basal ganglia circuitry following dopamine depletion and provide a basis for further study of its potential as a noninvasive, disease-modifying intervention for PD.

neuroscience↗

bioRxiv2025

Aberrant development of glutamatergic inputs to PV and SOM interneurons shape amygdala excitability and oscillatory dynamics after early life stress

Early-life stress (ELS) induces persistent amygdala dysfunction and affects amygdala-related emotional behaviors, yet the developmental and physiological mechanisms driving these effects remain poorly understood. Here, we provide a comprehensive electrophysiological characterization of the effects of ELS on parvalbumin and somatostatin interneurons (INs) as well as principal neurons (PNs) in the mouse lateral amygdala (LA) across development. Additionally, we correlate these findings to activity of the LA circuitry in vivo, using Neuropixels recordings in awake mice. In preweaning juveniles, the effects of ELS were remarkably similar in males and females, involving reduced IN excitability, elevated glutamatergic input to INs and shift in the PN E/I balance. While IN function was largely normalized in adult females, males developed a distinct pathological phenotype characterized by reduced glutamatergic input to INs, impaired recruitment of INs and hyperexcitability of PNs. This male-specific dysfunction correlated with aberrant LA oscillatory dynamics in awake mice and deficits in fear processing. Our data suggest that the impaired glutamatergic wiring of interneurons is a key mechanism underlying the aberrant circuit dynamics in the LA after ELS exposure and contribute to the ELS-induced defects in fear processing. These findings highlight sex-specific developmental trajectories of interneuron connectivity as a potential factor contributing to ELS-induced psychiatric vulnerability.

neuroscience↗

bioRxiv2025

Multi-omic analysis of colorectal adenocarcinoma identifies a new subtype of myofibroblastic cancer-associated fibroblast expressing high level of B7-H3 and with poor prognosis value.

The high mortality rate of colorectal cancer (CRC) combined with the lack of non-toxic and efficient personalized treatments makes it urgent to develop new targeted therapies for this disease. B7-H3 appears to be a good target as it is overexpressed in tumor tissue compared to normal tissue. However, B7-H3 is a molecule with ambivalent functions and is expressed by different cell types. This complexity contributed to the delay in identifying cell subtypes that express B7-H3 and their potential role in colorectal oncogenesis. In this study, we used in silico bulk, single-cell, and spatial transcriptomic data to investigate the clinical and biological characteristics of tumors with high B7-H3 expression, the precise nature of cells expressing high level of B7-H3, and their temporal appearance during colorectal oncogenesis. We found that tumors with high B7-H3 expression corresponded to tumors with a predominant stroma composed mainly of fibroblasts. Among them, two subtypes of ecm-myCAF fibroblasts and pro-fibrotic pericytes specifically expressed high levels of B7-H3, the former being an independent factor for poor prognosis in CRC. Finally, by examining precancerous lesions, we report that fibroblast subtypes with high levels of B7-H3 appear early during oncogenesis, especially at the inflamed stage. We also shed light on the fact that anti-B7-H3 immunotherapies might therefore preferentially target cells from the microenvironment rather than the tumor cells. This is particularly important to understand the mode of action of the anti-B7-H3 antibody-drug conjugate, which is currently being tested in clinical trials in several solid tumors. HighlightsO_LIHigh level of B7-H3 expression is associated with poor prognosis in colorectal cancer C_LIO_LIB7-H3 is recurrently found expressed by two subtypes of cancer-associated fibroblasts (CAF): pro-fibrotic pericytes and ecm-myCAF C_LIO_LIB7-H3high ecm-myCAF subtype is an independent poor prognosis for survival C_LIO_LIB7-H3high ecm-myCAF is detectable in pre-cancerous inflamed colonic tissues C_LI

cancer biology↗

bioRxiv2025

Mitochondrial Energy Transformation Capacity Influences Brain Activation During Sensory, Affective, and Cognitive Tasks

Mitochondria supply the energy required for brain function, but how energetic capacity constrains human brain activity remains unclear. We compared patients with genetically defined mitochondrial disease to matched controls, testing whether bioenergetic stress selectively limits neural processes assessed with functional magnetic resonance imaging during rest and during tasks probing working memory, sensory perception, and affective responses (cold pain). We report impairment in working memory performance and reduced activation of associated brain networks in a subset of patients with the largest clinical and cognitive impairments. A resilient subgroup showed higher working-memory-related BOLD responses, which were associated with preserved task performance. Neural and behavioral effects scaled with the circulating markers of energetic stress growth differentiation factor 15 (GDF15). Brain activity related to sensory and affective responses and resting-state connectivity were comparable for patients and controls. These findings support an energy-hierarchy model in which complex cognition fails first, while sensory processes remain largely preserved under energetic stress.

neuroscience↗

bioRxiv2025

Biopsychosocial Correlates of Resting and Stress-Reactive Salivary GDF15: Preliminary Findings

Growth differentiation factor 15 (GDF15) is a biomarker of energetic stress related to aging, disease, and mitochondrial defects. We recently showed that GDF15 is quantifiable in saliva and acutely inducible by psychosocial stress. To date, the associations between GDF15 and biopsychosocial factors and individual characteristics remain unknown. Here, in a sample of healthy working adults (n = 198, 70% females), we first confirmed that salivary GDF15 reacts to acute psychosocial stress, peaking 10 min following a socio-evaluative stress paradigm (+28.3%, g = 0.50, p < 0.0001). We then explored associations between i) baseline GDF15 and ii) GDF15 stress reactivity and a variety of trait- and state-level biopsychosocial factors including sex and gender characteristics; measures of mental health, stress, and burnout; physical health and health behaviors; and anthropometric and blood-based metabolic biomarkers. Baseline salivary GDF15 was higher in men than in women and was positively correlated with testosterone, while negatively correlated with estrogen and traditionally feminine gender roles. Of the psychosocial factors examined, we found that work-related stress variables were most consistently related to GDF15, with work-related cynicism, burnout, and emotional exhaustion predicting higher GDF15 reactivity, while job-related autonomy and utilization of competence predicted smaller GDF15 responses. Consistent with GDF15s induction in metabolic and renal diseases, baseline GDF15 was also positively correlated with indirect markers of metabolic disease including waist-to-hip ratio, creatinine, and albumin. Finally, participants with greater GDF15 reactivity also exhibited greater cortisol reactivity, consistent with the role of GDF15 in stress regulation and energy mobilization. Together, this exploratory analysis of salivary GDF15 suggest new biological and psychosocial correlates, calling for large-scale studies connecting human experiences with biological markers of energetic stress.

physiology↗

bioRxiv2025

Novel Pipelines to Extract Differences in Proteome Dynamics Based on Health Status

Understanding dynamics and co-regulatory patterns in the human proteome is a promising path for unraveling the molecular basis of health and disease. Nevertheless, there remains an open challenge in extracting concise information from high-throughput proteomic data that can effectively characterize and predict health. We develop novel statistical and computational pipelines to tackle this problem in a longitudinal saliva proteomics data set collected throughout the awakening response in six healthy controls and six subjects with severe mitochondrial disease (MitoD), a clinical condition caused by genetic mitochondrial defects that affects cellular energy transformation and alters multiple dimensions of health. We undertook three independent unsupervised approaches to characterize proteome dynamics and assessed their ability to separate MitoD individuals from controls. First, we designed a permutation test to detect the global difference in the proteomic co-regulation structure between healthy and unhealthy subjects. Second, we performed non-linear embedding and cluster analysis on elasticity to capture a more complicated relationship between health and the proteome. Third, we developed a machine learning algorithm to extract low-dimensional representations of the proteome dynamic and use them to cluster subjects into healthy and unhealthy groups without any knowledge of their true status. All three methods showed clear differences between MitoD individuals and controls. Our results revealed a significant and consistent association between MitoD status and the saliva proteome at multiple levels during the awakening response, including its dynamic change, co-regulation structure, and elasticity. This connection is not restricted to a few MitoD-specific proteins but spreads over a wide range of proteins from many body functions and pathways. Pipelines such as those shown here are the first step toward establishing interpretable and accurate prediction rules for health based on proteome dynamics.

bioinformatics↗

bioRxiv2025

A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity

Mitochondria are a diverse family of organelles with highly specialized functions. While they share common features, their molecular and functional diversity remains underexplored. Here, we introduce a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes, or mitotypes. By distilling hundreds of validated mitochondrial genes into 149 biologically interpretable MitoPathway scores, this streamlined mitotyping framework enables investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomic data across a variety of natural and experimental contexts. Using this approach, we show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, characterize robust longitudinal and perturbation-induced metabolic plasticity in cultured human fibroblasts, and resolve cell-type and single-cell mitochondrial recalibrations across the human brain and sperm developmental trajectory. Together, this framework provides a practical and extensible approach for analyzing mitochondrial specialization in complex biological systems.

cell biology↗

bioRxiv2025

Mapping the GDF15 Arm of the Integrated Stress Response in Human Cells and Tissues

Mitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through the secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined, particularly across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to eleven metabolic perturbations, including genetic and pharmacological mitochondrial OxPhos defects, we showed that the ISR has multiple arms and developed an ISRGDF15 index quantifying the GDF15 arm of ISR activation in human cells. The ISRGDF15 index was validated using optogenetic activation of the ISR protein kinase R (PKR) in a stable cell line, demonstrating its rapid kinetics preceding to GDF15 gene expression. We then deployed the ISRGDF15 index across 44 postmortem human tissues, reporting that the ISRGDF15 was upregulated in the heart of individuals who died of an acute cause in the emergency room, whereas it was preferentially upregulated in the brain of individuals who died as inpatients after protracted hospital stays. ISRGDF15 was also moderately, positively correlated with age across all tissues. These data highlight multiple distinct ISR pathways and clarify which genes are related to the GDF15 arm of the ISR, yielding an ISRGDF15 index that can be used to investigate tissue-specific and age-related ISR activation in both in vitro cultures and human tissues. Ultimately, we expand our knowledge of the GDF15 arm of the ISR in humans, show its inducibility by the ISR kinase PKR, and demonstrate its applicability to detect ISR activation in specific human tissues.

cell biology↗

bioRxiv2025

Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging

Altered mitochondria biology can accelerate biological aging, but scalable biomarkers of mitochondrial health for population studies are lacking. We examined two potential candidates: 1) cell-free mitochondrial DNA (cf-mtDNA), a marker of mitochondrial signaling elevated with disease states accessible as distinct biological entities from plasma or serum; and 2) growth differentiation factor 15 (GDF15), an established biomarker of biological aging downstream of mitochondrial energy transformation defects and stress signaling. In a cohort of 430 participants aged 24-84 (54.2% women), we measured plasma and serum cf-mtDNA, and plasma GDF15 levels at two timepoints 5 years apart, then assessed their associations with age, BMI, diabetes, sex, health-related behaviors, and psychosocial factors. As expected, GDF15 showed a positive, exponential association with age (r=0.66, p<0.0001) and increased by 33% over five years. cf-mtDNA was not correlated with GDF15 or age. BMI and sex were also not related to cf-mtDNA nor GDF15. Type 2 diabetes was only positively associated with GDF15. Exploring potential drivers of systemic mitochondrial stress signaling, we report a novel association linking higher education to lower age-adjusted GDF15 (r=-0.14, p<0.0034), both at baseline and the 5-year follow up, highlighting a potential influence of psychosocial factors on mitochondrial health. Overall, our findings among adults spanning six decades of lifespan establish associations between age, diabetes and GDF15, an emerging marker of mitochondrial stress signaling. Further studies are needed to determine if the associations of blood GDF15 with age and metabolic stress can be moderated by psychosocial factors or health-related behaviors.

physiology↗

bioRxiv2025

Immune cell mitochondrial phenotypes are largely preserved in mitochondrial diseases and do not reflect disease severity

ObjectiveTo profile immune cell mitochondrial phenotypes in mitochondrial diseases (MitoD) and evaluate how those phenotypes relate to disease manifestations or biomarkers. MethodsWe profiled mitochondrial content and OxPhos enzymatic activities in isolated monocytes, lymphocytes, neutrophils, platelets, and mixed peripheral blood mononuclear cells (PBMCs) from 37 individuals with MitoD (m.3243A>G, n=23; single, large-scale mitochondrial DNA (mtDNA) deletions, n=14) and 68 healthy women and men from the MiSBIE study. ResultsWe first confirm and quantify robust cell type differences in mitochondrial content, activities of OxPhos complexes I, II, and IV, and the mitochondrial respiratory capacity (MRC) index. In relation to MitoD, neither mitochondrial content nor OxPhos capacity were consistently affected, other than a mild monocyte-specific reduction in complex I (partially mtDNA encoded) relative to complex II (entirely nDNA encoded), consistent with the mtDNA defects examined. Relative to the large differences in cell type-specific mitochondrial phenotypes, differences in MitoD relative to controls were generally small (<25%) across mitochondrial measures. The MitoD biomarkers GDF15 and FGF21, as well as clinical disease severity measures, were most strongly related to mitochondrial abnormalities in platelets, and most weakly related to mitochondrial OxPhos capacity in lymphocytes, which are known to eliminate mtDNA defects. Finally, comparing PBMCs collected in the morning/fasted state to the afternoon/fed state following a stressful experience, we report significant time-dependent changes in mitochondrial biology over the time scale of hours. ConclusionsOverall, these results demonstrate that the dynamic and cell-type specific mitochondrial phenotypes are preserved in mitochondrial diseases and are generally unrelated to the severity of MitoD symptoms.

pathology↗

bioRxiv2024

The gut microbiome promotes mitochondrial respiration in the brain of a Parkinson's disease mouse model

The pathophysiology of Parkinsons disease (PD) involves gene-environment interactions that impair various cellular processes such as autophagy, lysosomal function, or mitochondrial dysfunction. Specifically, mitochondria-associated gene mutations increase PD risk, mitochondrial respiration is altered in the PD brain, and mitochondrial-damaging toxins cause PD-like motor and gastrointestinal symptoms in animal models. The gut microbiome is altered in PD patients and represents an environmental risk, however a relationship between mitochondrial function and the microbiome in PD has not been previously established. Herein, we report that striatal mitochondria are functionally overactive in -synuclein-overexpressing (ASO) mice, a model of PD, and that microbiome depletion restores respiration and mitochondria-associated gene expression patterns to wild-type levels. ASO mice harboring a complex microbiome produce increased reactive oxygen species in the striatum whereas germ-free counterparts express elevated levels of antioxidant proteins that may buffer against oxidative damage. Indeed, antioxidant treatment improves motor performance in ASO mice and, remarkably, blocking oxidant scavenging in germ-free mice induces -synuclein-dependent motor deficits. Thus, the gut microbiome increases mitochondrial respiration and oxidative stress in the brain, which enhances motor symptoms in a mouse model of PD.

physiology↗

bioRxiv2024

Transcriptomic plasticity in hybrid schistosomes can contribute to their zoonotic potential

Hybrids between Schistosoma haematobium and S. bovis are linked to both human and animal infections, highlighting the complex interspecies interactions that contribute to the spread of schistosomiasis. Additionally, S. bovis can infect multiple ruminant hosts, facilitating cross- species transmission and increasing the risk of zoonotic outbreaks. In this study, we investigated transcriptomic plasticity as a potential mechanism enabling hybrid schistosomes to adapt to alternative definitive hosts. We focused on two contexts: 1) introgressed S. haematobium x S. bovis hybrids, which demonstrated higher virulence in sheep compared to parental S. bovis, and 2) S. bovis infecting different host species. Our analysis uncovered 366 differentially expressed genes (DEGs), representing 4% of the total protein-coding genes, between introgressed hybrids and parental S. bovis in sheep. We also identified transcriptomic changes in S. bovis across different mammalian hosts (hamster and sheep), with around 30% of the total genes differentially expressed, demonstrating that S. bovis parasites display a high transcriptomic plasticity, allowing them to infect different definitive hosts. Shared enriched biological processes during introgression and host change include nuclear-transcribed mRNA catabolic processes, inner mitochondrial membrane organization, microtubule-based movement, response to endoplasmic reticulum stress, and sensory perception. These findings suggest that transcriptomic plasticity in S. bovis and hybrid worms enhance their ability to adapt and infect diverse host species, potentially increasing their zoonotic potential. This raises concerns for schistosomiasis epidemiology, as this plasticity could expand the parasites transmission capacity and complicate control efforts.

evolutionary biology↗

bioRxiv2024

Associations between prenatal distress, mitochondrial health, and gestational age: findings from two pregnancy studies in the USA and Turkey

ObjectiveThis study examined associations between mitochondrial markers--circulating cell-free mitochondrial DNA (cf-mtDNA) and Growth Differentiation Factor-15 (GDF15)--with maternal distress and pregnancy outcomes. MethodParticipants were drawn from two pregnancy studies, EPI (N=187, USA) and BABIP (N=198, Turkey). Plasma cf-mtDNA and GDF15 levels were quantified using qPCR and ELISA assays. ResultsPlasma cf-mtDNA levels did not significantly vary across pregnancy, while plasma GDF15 levels increased from early to late pregnancy and decreased postpartum. Late 2nd trimester plasma GDF15 was negatively correlated with pre-pregnancy BMI (p=0.035) and gestational age (p=0.0048) at birth. Early 2nd trimester maternal distress was associated with lower cf-mtDNA (p<0.05) and a trend for lower GDF15. Higher pre-pregnancy BMI and late-pregnancy maternal distress were linked to smaller postpartum GDF15 declines in EPI (p<0.05). ConclusionThis study reveals distinct plasma cf-mtDNA and GDF15 patterns during the perinatal period, linking mitochondrial markers to maternal distress and pregnancy outcomes.

physiology↗