Bio


Dr. Arianne Caudal is a postdoctoral fellow at the Stanford Cardiovascular Institute with research interests in cardiac metabolism, disease modeling, and drug discovery. Dr. Caudal received her PhD in Biochemistry from the University of Washington, after conducting thesis work on mitochondrial metabolism and protein-protein interactions in the heart.

Honors & Awards


  • NRSA F32 Postdoctoral Fellowship, NIH (2024)
  • Postdoctoral Fellowship, American Heart Association (2022)
  • Postdoctoral Seed Grant, Cambridge Isotopes (2022)
  • TRAM Pilot Grant, Stanford University (2022)
  • SUMS Training Seed Award, Stanford University (2021)
  • Three Minute Thesis People's Choice Award, University of Washington (2021)
  • Predoctoral Fellowship, American Heart Association (2020-2022)

Stanford Advisors


All Publications


  • Harnessing human genetics and stem cells for precision cardiovascular medicine. Cell genomics Caudal, A., Snyder, M. P., Wu, J. C. 2024; 4 (2): 100445

    Abstract

    Human induced pluripotent stem cell (iPSC) platforms are valuable for biomedical and pharmaceutical research by providing tissue-specific human cells that retain patients' genetic integrity and display disease phenotypes in a dish. Looking forward, combining iPSC phenotyping platforms with genomic and screening technologies will continue to pave new directions for precision medicine, including genetic prediction, visualization, and treatment of heart disease. This review summarizes the recent use of iPSC technology to unpack the influence of genetic variants in cardiovascular pathology. We focus on various state-of-the-art genomic tools for cardiovascular therapies-including the expansion of genetic toolkits for molecular interrogation, in vitro population studies, and function-based drug screening-and their current applications in patient- and genome-edited iPSC platforms that are heralding new avenues for cardiovascular research.

    View details for DOI 10.1016/j.xgen.2023.100445

    View details for PubMedID 38359791

  • Tachycardia-induced metabolic rewiring as a driver of contractile dysfunction. Nature biomedical engineering Tu, C., Caudal, A., Liu, Y., Gorgodze, N., Zhang, H., Lam, C. K., Dai, Y., Zhang, A., Wnorowski, A., Wu, M. A., Yang, H., Abilez, O. J., Lyu, X., Narayan, S. M., Mestroni, L., Taylor, M. R., Recchia, F. A., Wu, J. C. 2023

    Abstract

    Prolonged tachycardia-a risk factor for cardiovascular morbidity and mortality-can induce cardiomyopathy in the absence of structural disease in the heart. Here, by leveraging human patient data, a canine model of tachycardia and engineered heart tissue generated from human induced pluripotent stem cells, we show that metabolic rewiring during tachycardia drives contractile dysfunction by promoting tissue hypoxia, elevated glucose utilization and the suppression of oxidative phosphorylation. Mechanistically, a metabolic shift towards anaerobic glycolysis disrupts the redox balance of nicotinamide adenine dinucleotide (NAD), resulting in increased global protein acetylation (and in particular the acetylation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase), a molecular signature of heart failure. Restoration of NAD redox by NAD+ supplementation reduced sarcoplasmic/endoplasmic reticulum Ca2+-ATPase acetylation and accelerated the functional recovery of the engineered heart tissue after tachycardia. Understanding how metabolic rewiring drives tachycardia-induced cardiomyopathy opens up opportunities for therapeutic intervention.

    View details for DOI 10.1038/s41551-023-01134-x

    View details for PubMedID 38012305

    View details for PubMedCentralID 5336809

  • Mitochondrial interactome quantitation reveals structural changes in metabolic machinery in the failing murine heart. Nature cardiovascular research Caudal, A., Tang, X., Chavez, J. D., Keller, A., Mohr, J. P., Bakhtina, A. A., Villet, O., Chen, H., Zhou, B., Walker, M. A., Tian, R., Bruce, J. E. 2022; 1 (9): 855-866

    Abstract

    Advancements in cross-linking mass spectrometry (XL-MS) bridge the gap between purified systems and native tissue environments, allowing the detection of protein structural interactions in their native state. Here we use isobaric quantitative protein interaction reporter technology (iqPIR) to compare the mitochondria protein interactomes in healthy and hypertrophic murine hearts, 4 weeks post-transaortic constriction. The failing heart interactome includes 588 statistically significant cross-linked peptide pairs altered in the disease condition. We observed an increase in the assembly of ketone oxidation oligomers corresponding to an increase in ketone metabolic utilization; remodeling of NDUA4 interaction in Complex IV, likely contributing to impaired mitochondria respiration; and conformational enrichment of ADP/ATP carrier ADT1, which is non-functional for ADP/ATP translocation but likely possesses non-selective conductivity. Our application of quantitative cross-linking technology in cardiac tissue provides molecular-level insights into the complex mitochondria remodeling in heart failure while bringing forth new hypotheses for pathological mechanisms.

    View details for DOI 10.1038/s44161-022-00127-4

    View details for PubMedID 36405497

  • Generation of human induced pluripotent stem cell lines carrying heterozygous PLN mutation from dilated cardiomyopathy patients. Stem cell research Caudal, A., Mondejar-Parreno, G., Vera, C. D., Williams, D. R., Shenoy, S. P., Liang, D., Wu, J. C. 2022; 63: 102855

    Abstract

    Familial dilated cardiomyopathy (DCM) is among the most prevalent forms of inherited heart disease. Here, two human-induced pluripotent stem cell (iPSC) lines were generated from peripheral blood mononuclear cells (PBMCs) from DCM patients carrying different mutations in the phospholamban encoding-gene (PLN). Both iPSC lines exhibited normal morphology, karyotype, pluripotency marker expression, and differentiation into the three germ layers. These patient-specific iPSC lines serve as valuable in vitro models for DCM pathology caused by PLN mutations.

    View details for DOI 10.1016/j.scr.2022.102855

    View details for PubMedID 35853412

  • Human Induced Pluripotent Stem Cells for Studying Mitochondrial Diseases in the Heart. FEBS letters Caudal, A., Ren, L., Tu, C., Wu, J. C. 2022

    Abstract

    Mitochondrial dysfunction is known to contribute to a range of diseases, and primary mitochondrial defects strongly impact high-energy organs such as the heart. Platforms for high-throughput and human-relevant assessment of mitochondrial diseases are currently lacking, hindering the development of targeted therapies. In the past decade, human induced pluripotent stem cells (iPSCs) have become a promising technology for drug discovery in basic and clinical research. In particular, human iPSC-derived cardiomyocytes (iPSC-CMs) offer a unique tool to study a wide range of mitochondrial functions and possess the potential to become a key translational asset for mitochondrial drug development. This review summarizes mitochondrial functions and recent therapeutic discoveries, advancements, and limitations of using iPSC-CMs to study mitochondrial diseases of the heart with an emphasis on cardiac applications.

    View details for DOI 10.1002/1873-3468.14444

    View details for PubMedID 35788991

  • Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts. The Journal of clinical investigation Zhou, B., Caudal, A., Tang, X., Chavez, J. D., McMillen, T. S., Keller, A., Villet, O., Zhao, M., Liu, Y., Ritterhoff, J., Wang, P., Kolwicz, S. C., Wang, W., Bruce, J. E., Tian, R. 2022; 132 (10)

    Abstract

    In hypertrophied and failing hearts, fuel metabolism is reprogrammed to increase glucose metabolism, especially glycolysis. This metabolic shift favors biosynthetic function at the expense of ATP production. Mechanisms responsible for the switch are poorly understood. We found that inhibitory factor 1 of the mitochondrial FoF1-ATP synthase (ATPIF1), a protein known to inhibit ATP hydrolysis by the reverse function of ATP synthase during ischemia, was significantly upregulated in pathological cardiac hypertrophy induced by pressure overload, myocardial infarction, or α-adrenergic stimulation. Chemical cross-linking mass spectrometry analysis of hearts hypertrophied by pressure overload suggested that increased expression of ATPIF1 promoted the formation of FoF1-ATP synthase nonproductive tetramer. Using ATPIF1 gain- and loss-of-function cell models, we demonstrated that stalled electron flow due to impaired ATP synthase activity triggered mitochondrial ROS generation, which stabilized HIF1α, leading to transcriptional activation of glycolysis. Cardiac-specific deletion of ATPIF1 in mice prevented the metabolic switch and protected against the pathological remodeling during chronic stress. These results uncover a function of ATPIF1 in nonischemic hearts, which gives FoF1-ATP synthase a critical role in metabolic rewiring during the pathological remodeling of the heart.

    View details for DOI 10.1172/JCI155333

    View details for PubMedID 35575090

    View details for PubMedCentralID PMC9106352

  • Increasing fatty acid oxidation elicits a sex-dependent response in failing mouse hearts. Journal of molecular and cellular cardiology Ritterhoff, J., McMillen, T. S., Villet, O., Young, S., Kolwicz, S. C., Senn, T., Caudal, A., Tian, R. 2021; 158: 1-10

    Abstract

    Reduced fatty acid oxidation (FAO) is a hallmark of metabolic remodeling in heart failure. Enhancing mitochondrial long-chain fatty acid uptake by Acetyl-CoA carboxylase 2 (ACC2) deletion increases FAO and prevents cardiac dysfunction during chronic stresses, but therapeutic efficacy of this approach has not been determined.Male and female ACC2 f/f-MCM (ACC2KO) and their respective littermate controls were subjected to chronic pressure overload by TAC surgery. Tamoxifen injection 3 weeks after TAC induced ACC2 deletion and increased FAO in ACC2KO mice with pathological hypertrophy.ACC2 deletion in mice with pre-existing cardiac pathology promoted FAO in female and male hearts, but improved cardiac function only in female mice. In males, pressure overload caused a downregulation in the mitochondrial oxidative function. Stimulating FAO by ACC2 deletion caused unproductive acyl-carnitine accumulation, which failed to improve cardiac energetics. In contrast, mitochondrial oxidative capacity was sustained in female pressure overloaded hearts and ACC2 deletion improved myocardial energetics. Mechanistically, we revealed a sex-dependent regulation of PPARα signaling pathway in heart failure, which accounted for the differential response to ACC2 deletion.Metabolic remodeling in the failing heart is sex-dependent which could determine the response to metabolic intervention. The findings suggest that both mitochondrial oxidative capacity and substrate preference should be considered for metabolic therapy of heart failure.

    View details for DOI 10.1016/j.yjmcc.2021.05.004

    View details for PubMedID 33989657

    View details for PubMedCentralID PMC8405556

  • Increasing Fatty Acid Oxidation Prevents High-Fat Diet-Induced Cardiomyopathy Through Regulating Parkin-Mediated Mitophagy. Circulation Shao, D., Kolwicz, S. C., Wang, P., Roe, N. D., Villet, O., Nishi, K., Hsu, Y. A., Flint, G. V., Caudal, A., Wang, W., Regnier, M., Tian, R. 2020; 142 (10): 983-997

    Abstract

    Increased fatty acid oxidation (FAO) has long been considered a culprit in the development of obesity/diabetes mellitus-induced cardiomyopathy. However, enhancing cardiac FAO by removing the inhibitory mechanism of long-chain fatty acid transport into mitochondria via deletion of acetyl coenzyme A carboxylase 2 (ACC2) does not cause cardiomyopathy in nonobese mice, suggesting that high FAO is distinct from cardiac lipotoxicity. We hypothesize that cardiac pathology-associated obesity is attributable to the imbalance of fatty acid supply and oxidation. Thus, we here seek to determine whether further increasing FAO by inducing ACC2 deletion prevents obesity-induced cardiomyopathy, and if so, to elucidate the underlying mechanisms.We induced high FAO in adult mouse hearts by cardiac-specific deletion of ACC2 using a tamoxifen-inducible model (ACC2 iKO). Control and ACC2 iKO mice were subjected to high-fat diet (HFD) feeding for 24 weeks to induce obesity. Cardiac function, mitochondria function, and mitophagy activity were examined.Despite both control and ACC2 iKO mice exhibiting a similar obese phenotype, increasing FAO oxidation by deletion of ACC2 prevented HFD-induced cardiac dysfunction, pathological remodeling, and mitochondria dysfunction, as well. Similarly, increasing FAO by knockdown of ACC2 prevented palmitate-induced mitochondria dysfunction and cardiomyocyte death in vitro. Furthermore, HFD suppressed mitophagy activity and caused damaged mitochondria to accumulate in the heart, which was attenuated, in part, in the ACC2 iKO heart. Mechanistically, ACC2 iKO prevented HFD-induced downregulation of parkin. During stimulation for mitophagy, mitochondria-localized parkin was severely reduced in control HFD-fed mouse heart, which was restored, in part, in ACC2 iKO HFD-fed mice.These data show that increasing cardiac FAO alone does not cause cardiac dysfunction, but protects against cardiomyopathy in chronically obese mice. The beneficial effect of enhancing cardiac FAO in HFD-induced obesity is mediated, in part, by the maintenance of mitochondria function through regulating parkin-mediated mitophagy. Our findings also suggest that targeting the parkin-dependent mitophagy pathway could be an effective strategy against the development of obesity-induced cardiomyopathy.

    View details for DOI 10.1161/CIRCULATIONAHA.119.043319

    View details for PubMedID 32597196

    View details for PubMedCentralID PMC7484440

  • A novel approach to measure mitochondrial respiration in frozen biological samples. The EMBO journal Acin-Perez, R., Benador, I. Y., Petcherski, A., Veliova, M., Benavides, G. A., Lagarrigue, S., Caudal, A., Vergnes, L., Murphy, A. N., Karamanlidis, G., Tian, R., Reue, K., Wanagat, J., Sacks, H., Amati, F., Darley-Usmar, V. M., Liesa, M., Divakaruni, A. S., Stiles, L., Shirihai, O. S. 2020; 39 (13): e104073

    Abstract

    Respirometry is the gold standard measurement of mitochondrial oxidative function, as it reflects the activity of the electron transport chain complexes working together. However, the requirement for freshly isolated mitochondria hinders the feasibility of respirometry in multi-site clinical studies and retrospective studies. Here, we describe a novel respirometry approach suited for frozen samples by restoring electron transfer components lost during freeze/thaw and correcting for variable permeabilization of mitochondrial membranes. This approach preserves 90-95% of the maximal respiratory capacity in frozen samples and can be applied to isolated mitochondria, permeabilized cells, and tissue homogenates with high sensitivity. We find that primary changes in mitochondrial function, detected in fresh tissue, are preserved in frozen samples years after collection. This approach will enable analysis of the integrated function of mitochondrial Complexes I to IV in one measurement, collected at remote sites or retrospectively in samples residing in tissue biobanks.

    View details for DOI 10.15252/embj.2019104073

    View details for PubMedID 32432379

    View details for PubMedCentralID PMC7327496

  • Targeting NAD+ Metabolism as Interventions for Mitochondrial Disease. Scientific reports Lee, C. F., Caudal, A., Abell, L., Nagana Gowda, G. A., Tian, R. 2019; 9 (1): 3073

    Abstract

    Leigh syndrome is a mitochondrial disease characterized by neurological disorders, metabolic abnormality and premature death. There is no cure for Leigh syndrome; therefore, new therapeutic targets are urgently needed. In Ndufs4-KO mice, a mouse model of Leigh syndrome, we found that Complex I deficiency led to declines in NAD+ levels and NAD+ redox imbalance. We tested the hypothesis that elevation of NAD+ levels would benefit Ndufs4-KO mice. Administration of NAD+ precursor, nicotinamide mononucleotide (NMN) extended lifespan of Ndufs4-KO mice and attenuated lactic acidosis. NMN increased lifespan by normalizing NAD+ redox imbalance and lowering HIF1a accumulation in Ndufs4-KO skeletal muscle without affecting the brain. NMN up-regulated alpha-ketoglutarate (KG) levels in Ndufs4-KO muscle, a metabolite essential for HIF1a degradation. To test whether supplementation of KG can treat Ndufs4-KO mice, a cell-permeable KG, dimethyl ketoglutarate (DMKG) was administered. DMKG extended lifespan of Ndufs4-KO mice and delayed onset of neurological phenotype. This study identified therapeutic mechanisms that can be targeted pharmacologically to treat Leigh syndrome.

    View details for DOI 10.1038/s41598-019-39419-4

    View details for PubMedID 30816177

    View details for PubMedCentralID PMC6395802

  • Chemical Crosslinking Mass Spectrometry Analysis of Protein Conformations and Supercomplexes in Heart Tissue. Cell systems Chavez, J. D., Lee, C. F., Caudal, A., Keller, A., Tian, R., Bruce, J. E. 2018; 6 (1): 136-141.e5

    Abstract

    While modern structural biology technologies have greatly expanded the size and type of protein complexes that can now be studied, the ability to derive large-scale structural information on proteins and complexes as they exist within tissues is practically nonexistent. Here, we demonstrate the application of crosslinking mass spectrometry to identify protein structural features and interactions in tissue samples, providing systems structural biology insight into protein complexes as they exist in the mouse heart. This includes insights into multiple conformational states of sarcomere proteins, as well as interactions among OXPHOS complexes indicative of supercomplex assembly. The extension of crosslinking mass spectrometry analysis into the realm of tissues opens the door to increasing our understanding of protein structures and interactions within the context of the greater biological system.

    View details for DOI 10.1016/j.cels.2017.10.017

    View details for PubMedID 29199018

    View details for PubMedCentralID PMC5799023

  • Mitochondrial protein interactome elucidated by chemical cross-linking mass spectrometry. Proceedings of the National Academy of Sciences of the United States of America Schweppe, D. K., Chavez, J. D., Lee, C. F., Caudal, A., Kruse, S. E., Stuppard, R., Marcinek, D. J., Shadel, G. S., Tian, R., Bruce, J. E. 2017; 114 (7): 1732-1737

    Abstract

    Mitochondrial protein interactions and complexes facilitate mitochondrial function. These complexes range from simple dimers to the respirasome supercomplex consisting of oxidative phosphorylation complexes I, III, and IV. To improve understanding of mitochondrial function, we used chemical cross-linking mass spectrometry to identify 2,427 cross-linked peptide pairs from 327 mitochondrial proteins in whole, respiring murine mitochondria. In situ interactions were observed in proteins throughout the electron transport chain membrane complexes, ATP synthase, and the mitochondrial contact site and cristae organizing system (MICOS) complex. Cross-linked sites showed excellent agreement with empirical protein structures and delivered complementary constraints for in silico protein docking. These data established direct physical evidence of the assembly of the complex I-III respirasome and enabled prediction of in situ interfacial regions of the complexes. Finally, we established a database and tools to harness the cross-linked interactions we observed as molecular probes, allowing quantification of conformation-dependent protein interfaces and dynamic protein complex assembly.

    View details for DOI 10.1073/pnas.1617220114

    View details for PubMedID 28130547

    View details for PubMedCentralID PMC5321032