About

Clementina Mesaros, MS, PhD, is a Research Associate Professor of Systems Pharmacology and Translational Therapeutics at the University of Pennsylvania's Perelman School of Medicine. She serves as the Director of the Biomolecular Mass Spectrometry Core at the Center of Excellence in Environmental Toxicology and as Associate Director for Shared Resources at the Abramson Cancer Center. Her research interests focus on understanding pathological metabolic changes, particularly in Friedreich’s Ataxia (FRDA), and identifying biomarkers related to exposure and response to major environmental pollutants. Her group investigates how lipid metabolism is disrupted due to mitochondrial dysfunction in FRDA, a disease caused by reduced expression of frataxin, leading to neurodegeneration and cardiomyopathy. Her work includes quantifying lipid accumulation in patient tissues and cells, exploring metabolic alterations, and identifying potential biomarkers for disease progression and therapeutic intervention. Additionally, her research extends to measuring the relationship between environmental toxicants and disease, such as the involvement of toxicants in gestational diabetes, with a focus on mechanisms involving serotonin metabolism and genetic factors. Dr. Mesaros is dedicated to mentoring the next generation of analytical scientists, maintaining advanced mass spectrometry instrumentation, and supervising support staff, students, and postdoctoral fellows.

Research topics

• Internal medicine
• Medicine
• Oncology

Selected publications

• Peripheral frataxin levels govern long-term clinical progression in Friedreich ataxia

  BMJ Neurology Open · 2026-01-01

  articleOpen access

  Background: Novel therapeutics for Friedreich ataxia employ diverse strategies to increase frataxin protein levels, and a better understanding of the relation to clinical outcomes could strengthen their use as pharmacodynamic markers, and potentially as surrogate endpoint in therapeutic development. An elaborate modelling framework was developed to evaluate the suitability of frataxin as a biomarker across assays, tissues and disease stages. Methods: Frataxin levels generated previously through two distinct assay platforms and from two separate clinical cohorts: whole blood frataxin was measured by a lateral-flow immunoassay (LF cohort), and a triple-quadrupole LC-MS/MS method (TQ cohort), which enables separate quantification of mature frataxin (FXN-M) and erythrocyte-specific frataxin (FXN-E). Results were compared descriptively with control and heterozygous carriers, and several distinct modelling strategies were employed to correlate them with clinical function. Results: Both cohorts represented the relevant disease spectrum, with minor differences in both genetic and clinical severity, which correlated with frataxin levels. Heterozygous carriers showed intermediate levels. Modelling confirmed the predictive value of frataxin across multiple clinical assessments, such as age of symptom onset, age at loss of ambulation and long-term progression. GAA1, the shorter repeat expansion, was confirmed as the dominant predictor of frataxin itself, and, in most situations, clinical function. Discussion and conclusion: Although isoform biology and tissue-specific expression remain important considerations, peripheral frataxin quantification provides biologically grounded measure of the pathophysiology and disease progression, with strong potential for application in therapeutic trials. Frataxin is a valid clinical biomarker, and our findings support advancing its candidacy as a surrogate endpoint in Friedreich ataxia.

  PublisherOA PDFDOI

• Ketosis rescues frataxin deficiency and corrects disease phenotypes in an FRDA animal model

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-14

  article

  Abstract Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by deficiency of the mitochondrial protein frataxin. Effective therapeutic options remain limited for FRDA. We previously demonstrated that frataxin regulates ketone body metabolism by modulating 3-Oxoacid CoA-Transferase 1 (OXCT1), the rate-limiting enzyme in ketone body catabolism. However, the mechanisms governing frataxin-dependent control of OXCT1 turnover as well as the contribution of frataxin deficiency-induced OXCT1 reduction to FRDA pathogenesis, have remained unclear. Here, we demonstrate that frataxin regulates OXCT1 protein turnover by inhibiting its ubiquitination and subsequent proteasomal degradation. The N-terminal 40 amino acids of frataxin mediate such events, as overexpression of this region alone blocks ubiquitin-proteasome system (UPS)-dependent OXCT1 degradation. To evaluate the impact of OXCT1 deficiency on FRDA phenotypes, we enhanced OXCT1 reduction by introducing a 50% OXCT1 knockout into frataxin-deficient KIKO mice (KIKO/ OXCT1 ⁺/⁻). While OXCT1 deficiency potentiates cell death in vitro in control and FRDA patient fibroblasts, further OXCT1 reduction in KIKO mice induces ketosis, increases frataxin levels, and improves neurobehavioral performance. The increase in frataxin does not reflect elevated FXN gene transcription but rather enhanced mitochondrial biogenesis, evidenced by increased biogenesis markers, restored mitochondrial morphology and size, and increased mitochondrial gene expression. Fasting-which promotes ketosis-similarly increases frataxin levels and mitochondrial biogenesis markers in older KIKO/ OXCT1 +/− mice. β-hydroxybutyrate administration in FRDA iPSC-derived cardiomyocytes elevates frataxin levels and mitochondrial biogenesis markers, further supporting the beneficial effect of ketosis on frataxin expression and mitochondrial biogenesis. Collectively, our findings demonstrate that ketosis partially restores frataxin levels and ameliorates FRDA-related phenotypes, providing a potential therapeutic strategy for FRDA.

  PublisherDOI

• Safety and efficacy of individualised exercise and NAD+ precursor supplementation in patients with Friedreich's ataxia in the USA: a single-centre, 2 × 2 factorial, randomised controlled trial

  The Lancet Neurology · 2026-04-17 · 1 citations

  articleOpen access

  BACKGROUND: precursor supplementation with nicotinamide riboside, which have each shown benefits in animal and early clinical studies, on cardiopulmonary fitness in individuals with Friedreich's ataxia. METHODS: . Stage 1 analysis tested the difference between each active treatment versus the control group, and stage 2 analysis (if combination therapy was effective) tested the difference between combination treatment and exercise alone; family-wise type 1 error was maintained <0·05. Analyses were by intention-to-treat. Adverse events were recorded systematically. This trial is registered with ClinicalTrials.gov (NCT04192136) and is complete. FINDINGS: =0·0299) for nicotinamide riboside and exercise in combination. Combination therapy was not statistically different from exercise alone (difference -0·05 ([95% CI -0·10 to 0·21]; p=0·49). Adverse events were all mild or moderate, and included gastrointestinal symptoms, falls, upper respiratory infections, and skin rashes. At least one moderate adverse event of interest in these categories was reported by seven (41%) participants in the control group; six (35%) in the nicotinamide riboside and no exercise group; three (19%) in the placebo and exercise group; and four (25%) in the nicotinamide plus exercise group. INTERPRETATION: The combination of nicotinamide riboside plus exercise for 12 weeks was safe and increased cardiopulmonary fitness in children and adults with Friedreich's ataxia. Longer studies are needed to establish whether adding nicotinamide riboside to exercise could be considered as part of a long-term, comprehensive treatment approach. FUNDING: US National Institutes of Health and Friedreich's Ataxia Research Alliance.

  PublisherDOI

• Environmental Amino Acid Sensing Regulates the Rate of ASC Translation and NLRP3 Inflammasome Assembly

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-20 · 1 citations

  articleOpen access

  ABSTRACT The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein signaling complex that triggers pyroptotic cell death and interleukin (IL)-1 family cytokine release during infection and cell injury. Its assembly is driven by the adaptor protein, apoptosis-associated speck-like protein containing a CARD (ASC), whose filamentation forms a supramolecular speck upon NLRP3 activation to amplify inflammasome signaling. While the NLRP3 inflammasome is well appreciated as a sensor of environmental danger and damage, little is known about how homeostatic environmental factors like dietary metabolites regulate its activity. Here, we find that environmental availability of the branched-chain amino acids (BCAAs), leucine, isoleucine, and valine, controls NLRP3 inflammasome assembly. While ASC is typically viewed as a constitutively expressed, unregulated inflammasome component, we find that Toll-like receptor 4 (TLR4) activation triggers localization of ASC mRNA to the perinuclear space. Moreover, our data demonstrate that ASC undergoes TLR4-driven translational bursting from polyribosomes during inflammasome priming. This translational engagement is dependent on BCAA availability and mechanistic target of rapamycin (mTOR) activity, which regulate the kinetics of inflammasome assembly. In contrast, the translation of NLRP3 and caspase-1 is largely insensitive to these inputs. Furthermore, we find that BCAAs regulate NLRP3 inflammasome activation in both mouse and human macrophages, in the context of bacterial infection, and during lipopolysaccharide (LPS)-induced sepsis in vivo . Altogether, this work unveils a novel inflammasome priming event governed by the amino acid environment. These findings further highlight how the activity of proteins maintained in equilibrium like ASC can be dynamically regulated through rapid changes in mRNA translation.

  PublisherOA PDFDOI

• Metabolic and transcriptional plasticity supports CD8+ T cell resilience and anti-tumor immunity under nutrient stress

  Immunity · 2026-04-30

  article
  PublisherDOI

• Membrane Molecular Species Remodeling as a Signature of ω-3 Fatty Acid Action in Cultured Neural Cells

  ASN NEURO · 2026-03-22

  articleOpen access

  Omega-3 polyunsaturated fatty acids (ω3 PUFAs) are critical structural components of neuronal membranes, yet the molecular specificity of their incorporation within neural cells remains incompletely defined. We integrated untargeted and targeted lipidomics with lipid ontology analysis and coarse-grained membrane simulations to characterize remodeling in primary rat cortical neurons and neuron-astrocyte co-cultures following supplementation with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), or docosapentaenoic acid (DPA). Each ω3 PUFA produced a distinct lipidomic signature. DHA showed the most consistent incorporation, selectively enriching phosphatidylethanolamine (PE) species-particularly PE(18:0/22:6) and PE(18:1/22:6)-associated with membrane curvature and organelle organization. Ontology analysis linked DHA supplementation to intrinsic curvature-related membrane features, and membrane simulations demonstrated enhanced collective bilayer bending without substantial changes in overall membrane thickness. EPA preferentially increased EPA-containing PE species without elevating DHA levels, whereas DPA effects were variable and culture-dependent, indicating selective metabolic handling of individual ω3 species. Differences between neurons and neuron-astrocyte co-cultures underscore the importance of cellular context in ω3-driven remodeling. By resolving ω3 incorporation at molecular species resolution and linking compositional changes to predicted membrane behavior, this study provides a structural framework for understanding how dietary ω3 fatty acids may influence neuronal membrane organization and cellular resilience.

  PublisherDOI

• Individualized exercise and NAD+ precursor supplementation in Friedreich’s Ataxia: a randomized controlled trial

  SSRN Electronic Journal · 2025-01-01

  preprintOpen access
  PublisherDOI

• Abstract A078: Choline metabolism promotes the immunosuppressive function of pancreatic tumor macrophages

  Cancer Research · 2025-09-28

  article

  Abstract Macrophages contribute to immunosuppression and tumor progression in the pancreatic tumor microenvironment. Recent studies highlight the role of metabolic reprogramming in regulating macrophage function. Targeting altered metabolism in PDAC macrophages is a potential strategy to modulate their function and inhibit tumor progression. We characterized the metabolic state of tumor macrophages in a subcutaneous PDAC mouse model using liquid chromatography-mass spectrometry (LCMS) based untargeted metabolomics. We identified glycerophosphocholine (GPC), an intermediate in choline metabolism, as significantly elevated in PDAC macrophages. To further investigate the role of choline metabolism in regulating PDAC macrophage function, we used an in vitro macrophage model supplemented with PDAC tumor conditioned media (CM). Metabolomics analysis revealed elevated choline metabolites in the tumor CM supplemented macrophages. Using stable isotope labelled choline tracing, we show an increased fractional contribution of media choline to downstream choline metabolites including GPC. Using qPCR and flow cytometry, we show that Inhibiting choline metabolism using choline kinase inhibitors increased the expression of pro-inflammatory M1 macrophage markers and decreased anti-inflammatory M2 markers. This suggests a novel role for choline metabolism in promoting the anti-inflammatory state in PDAC macrophages. In vivo injection of a choline kinase inhibitor reduced tumor growth in mice bearing subcutaneous PDAC tumors. Our findings suggest that targeting choline metabolism in PDAC macrophages may offer a promising strategy to regulate their immunosuppressive function and inhibit pancreatic tumor progression. Citation Format: Vineeth Vengayil, Joseph A. Tandurella, Kelsey M. Nemec, Mariko L. Bennett, F. Chris . Bennett, Clementina Mesaros, Caroline R. Bartman. Choline metabolism promotes the immunosuppressive function of pancreatic tumor macrophages [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A078.

  PublisherDOI

• Radioactive Tracing of Testosterone Reveals Minimal Formation of 5α-DHT in SGBS Cells and Human Primary Adipocytes

  Journal of the Endocrine Society · 2025-05-16 · 1 citations

  articleOpen access

  Abstract Hyperandrogenism is associated with polycystic ovary syndrome (PCOS), acne, and alopecia. In PCOS, subcutaneous fat has been shown to contribute to hyperandrogenism through increased testosterone (T) production which is accompanied by an increase in the intra-adipose 5α-dihydrotestosterone (5α-DHT):T ratio. However, whether 5α-DHT is produced in isolated adipocytes is uncertain. Here we investigated the ability of subcutaneous human adipocytes to synthesize and inactivate 5α-DHT in a model of subcutaneous white adipocytes, Simpson-Golabi-Behmel syndrome (SGBS) cells, and primary adipocytes. We quantified the transcripts of genes involved in the biosynthesis of 5α-DHT (AKR1C3, SRD5A1, SRD5A2, and HSD17B6) and the inactivation of 5α-DHT (AKR1C1 and AKR1C2). We found that genes that inactivate 5α-DHT were more abundantly transcribed than genes that biosynthesize 5α-DHT. This trend was reflected by radioisotope tracing. We developed a radiochromatographic method involving high-performance liquid chromatography and in-line detection of radioactive analytes with precision and accuracy within the 15% tolerance allowable by the US Food and Drug Administration criteria for analytical assays. The lower limit of detection and quantification for 5α-DHT was 3.4 pg and 15 pg, respectively. The formation of 5α-DHT was barely detectable when starting with either 10 nM T or 3α-androstanediol (3α-diol). Conversely, 5α-DHT was rapidly metabolized to 3α-diol but not 3β-diol. 3α-Diol was the major metabolite despite comparable levels of AKR1C1 and AKR1C2 transcripts. The same result was observed in both cell lines. Our data reveal that adipocytes do not biosynthesize 5α-DHT from testosterone. By contrast, 5α-DHT is rapidly metabolized by AKR1C2 in subcutaneous adipocytes.

  PublisherOA PDFDOI

• Chemoresistance of TP53 mutant acute myeloid leukemia requires the mevalonate byproduct, geranylgeranyl pyrophosphate, for induction of an adaptive stress response

  Leukemia · 2025-07-09 · 9 citations

  articleOpen access

  Abstract Acute myeloid leukemia with mutations in TP53 ( TP53 mut AML) is fatal with a median survival of 6 months. RNA sequencing on purified AML patient samples showed that TP53 mut AML had higher expression of mevalonate pathway genes. Using novel, isogenic TP53 mut AML cell lines and primary samples, we determined that TP53 mut AML resistance to AML chemotherapy cytarabine (AraC) correlated with increased mevalonate pathway activity, a lower induction of reactive oxygen species (ROS), and a mitochondrial response with increased mitochondrial mass and oxidative phosphorylation. Pretreatment with the statin class of mevalonate pathway inhibitors reversed these effects and chemosensitized TP53 mut AML. The geranylgeranyl pyrophosphate (GGPP) branch of the mevalonate pathway was required for TP53 mut AML chemoresistance. In addition to its role in mitochondria biogenesis, we identified a novel function of GGPP in regulating glutathione for management of AraC-induced ROS. However, statins alone were inadequate to fully reverse chemoresistance in vivo and in a retrospective study of 364 TP53 mut AML patients who received chemotherapy concurrently with a statin. Finally, we identified clinical settings and strategies to successfully target the mevalonate pathway, particularly to address the unmet need of TP53 mut AML.

  PublisherOA PDFDOI

Frequent coauthors

• Ian A. Blair

  University of Pennsylvania

  431 shared

• Nathaniel W. Snyder

  94 shared

• T.M. Penning

  University of Pennsylvania

  87 shared

• Jimmy P. Xu

  85 shared

• Brian Keith

  59 shared

• Ranjana Mitra

  58 shared

• David R. Lynch

  Children's Hospital of Philadelphia

  58 shared

• David A. Potter

  58 shared

Labs

• Mesaros GroupPI

Education

• Post-doctoral Fellow, Pharmacology

  University of Pennsylvania

  2007

• PhD, Chemistry

  Case Western Reserve University

  2005

Awards & honors

• NIH S10 grant for acquisition of a new state-of-the-art LC-H…
• Best Poster Presentation Award by an undergraduate student a…