bioRxiv : the preprint server for biology最新文献

{"title":"Tobacco Carcinogen Induces Persistent DNA Damage and Homologous Recombination Dysregulation in Pancreatic Ductal Carcinogenesis.","authors":"Varunkumar Krishnamoorthy, Vineet K Gupta, Sudhakar Jinka, Supriya Srinivasan, Kumaraswamy H M, Chanjuan Shi, Poorva Poorva, Steven X Chen, Nipun Merchant, Austin R Dosch, Nagaraj Nagathihalli","doi":"10.64898/2026.10.13.758888","DOIUrl":"https://doi.org/10.64898/2026.10.13.758888","url":null,"abstract":"<p><p>Cigarette smoking is a well-established risk factor for the development of pancreatic ductal adenocarcinoma (PDAC), yet the mechanisms by which tobacco carcinogens, such as Nicotine-Derived Nitrosamine Ketone (NNK), drive pancreatic carcinogenesis remain incompletely understood. We investigated the impact of NNK on pancreatic epithelium by treating human pancreatic ductal epithelial cells (HPDE6-E6E7; H6c7) with NNK for 5 or 50 days followed by genome-wide RNA sequencing, qRT-PCR, immunofluorescence, comet assay, and γH2AX ELISA. We assessed γH2AX by immunohistochemistry in human PDAC tissue microarrays and in TCGA-PAAD datasets to identify clinical correlates. Acute NNK exposure (5 days) induced DNA double-strand breaks and activated ATM-γH2AX signaling, accompanied by increased RAD51 and BRCA2 recruitment, consistent with activation of homologous recombination (HR)-mediated DNA repair. In contrast, chronic NNK exposure (50 days) resulted in persistent DNA damage signaling and transcriptional upregulation of HR-associated genes, including RAD51, BRCA1, BRCA2, FANCD2, and PLK1. Despite sustained accumulation of RAD51- and BRCA2-positive repair foci, chronic NNK exposure was associated with altered RAD51 localization, persistent DNA damage, and chromosomal instability, suggesting dysregulation of HR repair fidelity during prolonged genotoxic stress. γH2AX expression was significantly elevated in NNK-treated cells, KRAS-driven premalignant pancreatic lesions, and pancreatic tissues from smokers. Increased γH2AX expression correlated with tumor progression and poor overall survival, while elevated RAD51 expression was associated with adverse outcomes in patients with PDAC. Collectively, these findings reveal a biphasic DNA damage response to NNK characterized by early activation of ATM-γH2AX-dependent DNA repair followed by persistent DNA damage signaling, dysregulated HR repair, and genomic instability during chronic exposure. Tobacco-induced disruption of DNA repair homeostasis may represent a key mechanism driving pancreatic carcinogenesis and supports γH2AX as a clinically relevant prognostic biomarker in tobacco-associated PDAC.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13674594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Convergent and Distinct Transcriptional Signatures in Suicide, Bipolar Disorder, and Major Depressive Disorder.","authors":"Ruchika Mishra, Alexandra M Wamalwa, Giulia Guason, Maura B Dupont","doi":"10.64898/2026.10.14.759202","DOIUrl":"https://doi.org/10.64898/2026.10.14.759202","url":null,"abstract":"<p><p>Globally, a person dies by suicide every 40 seconds, underscoring a major global public health concern. In the United States, suicide is the second leading cause of death among individuals aged 10-34 years. Suicide is a complex, multifactorial phenomenon influenced by genetic and epigenetic factors and is strongly associated with mood disorders, particularly major depressive disorder (MDD) and bipolar disorder (BD). However, the extent to which their molecular signatures converge or diverge across disorders and brain regions remains incompletely understood. To address this gap, we conducted a systematic literature review of suicide, MDD, and BD transcriptomic studies in accordance with PRISMA 2020 guidelines, searching PubMed, Embase, and Web of Science. Eligible studies used human postmortem brain tissue, reported a complete genome-wide transcriptomic list of differentially expressed genes (DEG), and compared suicide decedents with psychiatric non-suicide individuals diagnosed with the same underlying disorder. Regarding BD, studies comparing affected individuals to unaffected controls were included. Single-cell and peripheral-blood studies were excluded because unavailable for suicide. Curated suicide and BD DEG datasets were integrated with a published bulk transcriptomic dataset of MDD. We identified both shared and disease-specific molecular signatures across suicide, BD, and MDD, and identified DEGs shared across brain regions and those that were region-specific. A total of 276 genes were shared across all three conditions, implicating cellular stress, hypoxia (VEGFA, ADM, NDRG1, DDIT4), immune and inflammatory signaling through TNFα/NF-κB (IL1B, ICAM1, NFE2L2) and IL6-JAK-STAT3 pathways (STAT3, SOCS3, IL1R1m OSMR), complement activation (CIR, SERPiNA1, LGALS3), extracellular matrix remodeling (COL4A1, SERPINH1, PLOD2), and unfolded protein response (BAG3, WFS1, MTHFD2). Suicide-associated DEGs were prominently downregulated, and involved metal-ion homeostasis, stress responses, synaptic regulation, and circadian pathways, whereas BD showed downregulation in synaptic and vesicle-related processes alongside region-specific metabolic dysregulation. MDD exhibited changes in RNA processing, ribosomal function, and protein synthesis. Genetic integration revealed that 133 genes shared between BD and MDD had gene variants associated with the corresponding condition per GWAS. Transcription factor analysis identified 20 regulatory factors with altered activity across all three conditions despite differences in their predicted downstream targets. Overall, these findings suggest that suicide, MDD, and BD share aspects of their molecular and regulatory pathophysiology while exhibiting distinct patterns, including in a region-specific manner.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13674596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149217976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibrosis burden and spatial pattern affect left atrial appendage stasis in multi-beat multi-physics simulations.","authors":"Yvonne Stöcker, Christoph M Augustin, Manuel Guerrero-Hurtado, Oscar Flores, Alejandro Gonzalo, Åshild Telle, Patrick Boyle, Nazem Akoum, Juan C Del Alamo, Manuel García-Villalba","doi":"10.64898/2026.09.26.754330","DOIUrl":"10.64898/2026.09.26.754330","url":null,"abstract":"<p><p><b>Purpose:</b> Atrial fibrosis is associated with thromboembolic risk in atrial fibrillation, but it remains unclear how fibrosis-related contractile impairment alters blood transport in the left atrium (LA) and left atrial appendage (LAA). Prior multi-physics simulations coupling electromechanical (EM) and computational fluid dynamics (CFD) models showed that fibrosis impairs LA function and flow, but were limited to booster-only contraction and could not separate the effects of fibrosis burden from its spatial distribution. Here, we examined how fibrosis burden and spatial pattern independently relate to long-term LA and LAA hemodynamics in full-cycle, multi-beat simulations on a common LA anatomy. <b>Methods:</b> Three fibrosis patterns derived from late gadolinium enhancement MRI were applied globally to a common LA anatomy at matched burdens of 15.6% and 31.2%, yielding six global-fibrosis cases and a non-fibrotic reference. Two patterns were also confined to the LAA at local burdens of 10%, 25%, and 50%, yielding six LAA-fibrosis cases. A 3D EM model of the LA anatomy coupled to a 0D circulatory model resolved the reservoir, conduit, and booster phases, and the EM-derived wall motion drove subsequent multi-beat CFD simulations. Region-specific emptying fraction (EF), non-dimensional kinetic energy (KE), and the 90th percentile of blood residence time (T _R ) were evaluated in the LA and LAA. <b>Results:</b> Left ventricular stroke volume remained nearly constant across cases, whereas increasing global fibrosis burden progressively reduced LA and LAA EF (LA: 36% to 30-31%; LAA: 44% to 28-38%), lowered both active and passive LA EF, and monotonically increased LA T _R across all patterns. Non-dimensional LA KE showed an approximately quadratic association with LA EF across patterns, whereas LAA KE was more scattered but still increased with LAA EF. In contrast, the 90th percentile of LAA T _R did not increase monotonically with decreasing LAA EF for one pattern. When fibrosis was confined to the LAA, non-dimensional LAA KE collapsed onto a single relationship with LAA EF for both patterns, whereas LAA T _R followed distinct, non-monotonic trends. <b>Conclusions</b> : Fibrosis burden, through its association with functional impairment, predominantly governed whole-LA hemodynamics, whereas LAA stasis additionally depended on the spatial distribution of fibrosis. In the LAA-fibrosis cases, LAA EF was a robust descriptor of chamber-averaged KE regardless of fibrosis pattern, but did not fully explain LAA residence time. These findings support evaluating imaging-derived fibrosis pattern, in addition to fibrosis burden and functional metrics, as a potential determinant of LAA transport and stasis. Its incremental value for thrombogenic-risk assessment requires prospective clinical validation.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relatedness of Gardnerella prophages and their endolysins.","authors":"Brandon S Maust, Kira A Griswold, Monique Khim, Sandhya Subramanian, Bart Staker, Peter J Myler, Brian R Kullin, Anna-Ursula Happel, Arvind Varsani, Heather B Jaspan","doi":"10.64898/2026.09.28.754664","DOIUrl":"10.64898/2026.09.28.754664","url":null,"abstract":"<p><p>The Gardnerella genus includes a complex sub-taxonomy of bacterial species and subgroups which have been implicated in bacterial vaginosis. We analyzed G. leopoldii, G. swidsinski, G. piotii, and G. vaginalis genomes available in public databases and predicted proviral sequences using Cenote-Taker3. We clustered 266 prophage sequences into 140 viral genera level groupings that encode four distinct gene clusters and 19 different lysin proteins. Analysis of the bacterial and prophage sequence phylogenies reveals that while there were no specific prophage sequence lineages that infected each bacterial host, there is clustering of the prophage sequences by bacterial species within the Gardnerella genus.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The CAHRA Challenge: A Community-Wide Assessment of Cryo-EM Heterogeneous Reconstruction Algorithms.","authors":"J Ryan Feathers, Robert C Heeter, Geoffrey Woollard, Sonya M Hanson, Pilar Cossio, Joel Greer, Tom Burnley, Ellen D Zhong","doi":"10.64898/2026.09.15.751515","DOIUrl":"10.64898/2026.09.15.751515","url":null,"abstract":"<p><p>The ability of cryo-electron microscopy (cryo-EM) to interrogate the atomic structure and motion of biomolecules has motivated the development of a wide range of algorithms for heterogeneity analysis. However, evaluating and comparing these methods remains challenging because ground-truth structures are generally unknown for experimental samples. Here, we introduce the 2026 Community-Wide Assessment of Heterogeneous Reconstruction Algorithms (CAHRA), a community-wide challenge centered on three benchmark datasets that probe distinct tasks in heterogeneity analysis. These include (1) compositional heterogeneity arising from mixtures of distinct protein complexes, (2) continuous conformational variability and atomic modeling, and (3) entanglement between molecular conformation and image pose. We describe the design, construction, and validation of these datasets, as well as their use in the recently completed CAHRA Challenge.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149032856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omic spatial mapping of the human habenula defines the molecular and anatomical organization of medial and lateral subregions.","authors":"Kelsey D Montgomery, Jonathan M Werner, Nicholas J Eagles, Chunyu Liu, Cynthia S Cardinault, Svitlana V Bach, Atharv Chandra, Ruth Zhang, Sarah E Maguire, Heena R Divecha, Amy Deep-Soboslay, Ryan A Miller, Louise A Huuki-Myers, Rahul A Bharadwaj, Joel E Kleinman, Thomas M Hyde, Brion Maher, Leonardo Collado-Torres, Kristen R Maynard","doi":"10.64898/2026.09.30.755667","DOIUrl":"10.64898/2026.09.30.755667","url":null,"abstract":"<p><p>The habenula (Hb) is a small epithalamic midline structure critical for reward processing and mood regulation that is implicated in many complex brain disorders, including depression and addiction. The molecular anatomy of the Hb has been well-characterized in model organisms, but little is known about its organization in the human brain, including the transcriptomic and epigenetic signatures of spatially-organized lateral (LHb) and medial (MHb) cell types. Here, we generated a high resolution spatiomolecular map of the human Hb using both multiomic single nucleus sequencing (snMultiome) and spatially-resolved transcriptomics. We measured gene expression and chromatin accessibility across 4 MHb and 5 LHb neuronal cell types as defined by transcriptomic conservation with rodents and zebrafish. We identified cell type-specific molecular specializations related to GABAergic and glutamatergic signaling as well as regulatory relationships between open chromatin regions, transcription factors, and target genes associated with depression and addiction. High resolution spatial transcriptomics identified the anatomical location of heterogeneous LHb subpopulations, including two putative inhibitory populations in the LHb. We further characterized cell-type relationships between Hb neurons and glial subtypes and predicted ligand-receptor interactions between LHb and MHb neurons. Finally, we delineated Hb cell types and spatial domains enriched in genes associated with genetic risk for psychiatric disorders, identifying the strongest enrichment in the MHb. Collectively, the generated data and analyses resolve the spatiomolecular organization of the human Hb and identify molecular-genetic associations with neuropsychiatric disease.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Individual variation in the accuracy of saccades to sounds is correlated with the properties of eye movement-related eardrum oscillations (EMREOs).","authors":"Jesse L Herche, Cynthia D King, Jennifer M Groh","doi":"10.64898/2026.05.13.724941","DOIUrl":"10.64898/2026.05.13.724941","url":null,"abstract":"<p><p>Calibration of sound localization behavior in species with mobile eyes requires not only accurate visual input but also accurate oculomotor signals across the lifespan. The recent discovery of eye movement-related eardrum oscillations suggest that oculomotor signals may be incorporated into auditory processing at the level of the ear. One inference of this discovery is that individual variation in such signals might be correlated with individual variation in sound localization accuracy. Here, we tested this hypothesis in humans with normal hearing. We discovered that there is considerable variation in the accuracy of saccades to sounds even in normal individuals: median horizontal errors ranged from 2-6 deg., and median vertical errors could be as large as 36 deg. We separated the subject pool into groups with 'good' performance (median vectorial error < 8 deg) vs 'poor' performance (median vectorial error > 10 deg) and evaluated their respective EMREOs. The EMREOs differed across the two groups in how horizontal saccade amplitude and vertical initial eye position were encoded, with considerable individual variation in the 'poor' group. These results are consistent with the interpretation that EMREOs are associated with underlying processes that ensure the accuracy of sound localization.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13192641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148019986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unbiased, systematic surfaceome profiling of Acute Leukemia to identify novel immunotherapy targets.","authors":"Benson M George, Anna Rodriguez-Pöhnlein, Donavelle J DeCastro, Jennifer Porat, Benyu Zhou, Dinah M Abeja, Ryan J Lumpkin, Rebecca J Metivier, Anna Schmoker, Wencke Walter, Torsten Haferlach, Yana Pikman, Katherine A Donovan, Kimberly Stegmaier, Eric S Fischer, Franziska Wachter, Ryan A Flynn","doi":"10.64898/2026.09.16.752145","DOIUrl":"10.64898/2026.09.16.752145","url":null,"abstract":"<p><p>Cell surface proteomics provides a direct topological assessment of the outer membrane of cells and enables the capture of low abundance proteins that may be missed by whole cell proteomics. Here we present an unbiased atlas of the whole cell and surface proteomes of 25 commonly used leukemic cell lines, encompassing both lymphoid and myeloid lineages, and a variety of driver mutations. Paired-wise analysis highlights recurrent surface proteins that are not detected by whole cell proteomics. Coupling this dataset to RNA-sequencing, we also discovered genes where protein and RNA abundances are discordant. In KMT2A-rearranged AML, CD70 expression was increased across cell lines and validated in primary patient samples, supporting CD70 as a candidate therapeutic target in this disease. Several proteins are enriched in the surface proteomes but lack surface annotation, adding to the list of non-canonical cell surface proteins, including RNA-binding proteins, an emerging class of candidate immunotherapeutic targets.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149032760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Male and female mice achieve equivalent protection against heterologous SARS-CoV-2 infection through divergent immune mechanisms.","authors":"Devin Kenney, Mao Matsuo, Andrea Pantelias, Joseph Leger, Ava Kaplan, Faith Cerbo, Da-Yuan Chen, Scott Adams, Giulia Unali, Douglas Wallace, Mohsan Saeed, Anna Belkina, Christelle Harly, Florian Douam","doi":"10.64898/2026.09.28.755090","DOIUrl":"10.64898/2026.09.28.755090","url":null,"abstract":"<p><p>Biological sex is a major determinant of antiviral immunity, yet how it shapes lung-resident antiviral immunity remains poorly understood. We report that prior mild SARS-CoV-2 BA.1 infection protects mice from lethal heterologous Delta challenge through distinct sex-biased immune mechanisms. Although heterologous protection is clinically equivalent between sexes, T- and B-cell depletions before BA.1 exposure abrogate protection only in males. Depletion with anti-CD4, but not anti-CD8, abolishes protection in both sexes, but co-depletion with anti-CD4/anti-CD8 partially restores protection in females only. Further, females exhibit enhanced IFN-gamma-associated myeloid inflammation upon secondary Delta infection. Using lymphoid-deficient mice that display female-biased resistance to Delta infection, IFN-gamma treatment provides partial protection to naive males against Delta. Female resistance is lost after previous BA.1 exposure, highlighting the importance of lymphoid-mediated inflammatory regulation. Together, equivalent antiviral protection against heterologous respiratory viral infection is governed by sexually dimorphic mechanisms, with significant implications for designing mucosal vaccines and immunotherapies.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ringer Loss in <i>Drosophila</i> Uncovers Mitochondrial Complex I Deficits Relevant to Human Parkinson's Disease.","authors":"Haven G Tillmon, Savannah K Boyen, Raquel Velazquez, Michelle E Urbina-Berlanga, Marco Sciortino, Swati Banerjee","doi":"10.64898/2026.07.27.741040","DOIUrl":"10.64898/2026.07.27.741040","url":null,"abstract":"<p><p>Tubulin polymerization promoting proteins (TPPPs) are known for their cytoskeletal regulation across species; however, emerging evidence suggests broader cellular functions, including potential roles in mitochondrial biology. Here, we identify the <i>Drosophila</i> homolog of human TPPP, Ringer, as a previously unrecognized regulator of mitochondrial bioenergetics and electron transport chain Complex I (CI) function. Ringer is enriched in the mitochondrial matrix, and its loss results in reduced levels of multiple CI subunits and assembly factors and a significant decrease in CI enzymatic activity. Notably, in addition to TPPP dysfunction, similar deficits are observed in postmortem human Parkinson's disease (PD) brain tissues, underscoring the translational relevance of our <i>Drosophila</i> model. Pharmacological administration of resveratrol, a reactive oxygen species (ROS) scavenger, reduces mitochondrial superoxide levels and improves CI enzymatic activity and ATP production in <i>ringer</i> mutants, demonstrating that targeted antioxidant therapeutics can improve bioenergetic functions in <i>ringer</i> mutants. Together, these findings establish Ringer as a key regulator of mitochondrial bioenergetics and reveal Ringer-induced CI dysfunction as a phenotype relevant to mitochondrial abnormalities observed in PD, and provide a robust and translationally meaningful framework for investigating mitochondrial dysfunction in PD.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148804627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}