About

Ajit Divakaruni is an Associate Professor in the Department of Molecular and Medical Pharmacology at the University of California Los Angeles (UCLA). His research focuses on cellular metabolism, particularly how it influences immune cell function, cancer, and metabolic diseases. His work involves exploring the regulation of metabolic pathways such as lipid metabolism, mitochondrial function, and amino acid utilization, with a specific interest in macrophage activation, neurodegenerative diseases, and cardiovascular conditions. Dr. Divakaruni's contributions include elucidating mechanisms by which metabolic cofactors and signaling pathways modulate immune responses and disease progression, advancing understanding of the metabolic underpinnings of health and disease.

Research topics

• Biology
• Biochemistry
• Computer Science
• Cell biology
• Immunology
• Chemistry
• Gerontology
• Medical education
• Bioinformatics
• Ecology
• Medicine
• Library science

Selected publications

• Engineering CAR T cells to secrete VEGF-neutralizing scFvs enhances antitumor activity against solid tumors

  Science Translational Medicine · 2026-03-04

  article

  Chimeric antigen receptor (CAR) T cell therapy has shown limited efficacy against solid tumors, which often reside in highly immunosuppressive tumor microenvironments (TMEs). TMEs can be highly abundant in vascular endothelial growth factor A (VEGF), which contributes to immunosuppression and abnormal tumor vasculature. Here, we found that CAR T cells engineered to secrete an anti-VEGF single-chain variable fragment (CAR-αVEGF T cells) achieved superior antitumor efficacy against multiple in vivo models of ovarian cancer and glioma, outperforming conventional CAR T cells with and without combination anti-VEGF antibody therapy. Microscopy, flow cytometry, and transcriptomic analyses revealed that armoring the CAR T cells with anti-VEGF single-chain variable fragments enhanced their activation and mitochondrial fitness and enriched immune-stimulatory signatures among endogenous immune cells in the tumor-bearing brain. Moreover, CAR-αVEGF T cells circumvented multiple detrimental effects associated with on-target CAR T cell therapy, including infiltration of suppressive myeloid cells, exaggerated vasculature abnormalities, and hypoxia. Together, our results provide rationale for the clinical translation of CAR-αVEGF T cells as a safe and potent therapy for solid tumors characterized by elevated VEGF.

  PublisherDOI

• The malate–aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes

  FEBS Journal · 2026-02-18

  articleOpen access

  to sustain glyceraldehyde-3-phosphate dehydrogenase activity. This regeneration is mediated by three main pathways: lactate dehydrogenase, the glycerol-3-phosphate shuttle (GPSh), and the malate-aspartate shuttle (MASh). We previously showed that inhibition of the mitochondrial pyruvate carrier increases energy expenditure in brown adipocytes via MASh activation. However, the specific contribution of MASh to BAT energy metabolism remains poorly defined. Here, we show that MASh is functional and directly regulates lipid metabolism in BAT. Enzymatic activities of cytosolic and mitochondrial malate dehydrogenases and glutamic-oxaloacetic transaminases in BAT were comparable to those in the liver. Using a reconstituted system of isolated BAT mitochondria and cytosolic MASh enzymes, we demonstrated that extra-mitochondrial NADH is efficiently reoxidized in a glutamate-dependent manner via MASh. Genetic silencing of the mitochondrial carriers critical to MASh, namely the oxoglutarate carrier (Ogc) and aspartate-glutamate carrier (Aralar1), had no apparent effects on respiratory rates. However, silencing either Ogc or Aralar1 led to the accumulation of small lipid droplets and impaired norepinephrine-induced lipolysis. Taken together, our data indicate a novel role of MASh in regulating BAT lipid homeostasis with potential implications to body energy expenditure and thermogenesis.

  PublisherOA PDFDOI

• Illuminating spatial dynamics of glutamine metabolism with a sensitive genetically encoded biosensor

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-16

  articleOpen access

  Glutamine is the most abundant amino acid in serum, used as a key nutrient by cells for protein synthesis, energy production, carbon and nitrogen metabolism, and cellular redox balance. The use of glutamine in the cell is highly compartmentalized, but the dynamics of glutamine metabolism across organelles and individual cells are not fully understood. To illuminate subcellular glutamine dynamics, we developed an intracellular glutamine optical reporter, iGlo. We find iGlo is sensitive and specific for glutamine and can be used to measure glutamine uptake, production, and consumption with high spatiotemporal resolution in multiple cell types. Furthermore, multiplexed imaging of iGlo with a lactate biosensor in single cells reveals temporal crosstalk between glucose and glutamine metabolism to maintain energy homeostasis. Thus, iGlo enables the sensitive and precise study of compartmentalized glutamine dynamics and represents a new and enhanced tool for studying the spatiotemporal dynamics and regulation of metabolism.

  PublisherOA PDFDOI

• Small-molecule binding-site discovery using silyl ether-enabled chemoproteomics

  Nature Chemistry · 2026-04-27

  articleOpen access

  For chemical probe and drug discovery campaigns, the pairing of mass spectrometry-based chemoproteomics with photoaffinity labelling has emerged as a favoured approach for target discovery and mode of action assignment. However, photocrosslinked peptide-compound adducts raise analytic challenges for quantitative binding site discovery. Here, to address these challenges, we establish the Silyl Ether Enables Chemoproteomic Interaction and Target Engagement (SEE-CITE) method. SEE-CITE incorporates a fully functionalized chemically cleavable photocrosslinking handle that enables precise site-of-labelling identification and head-to-head comparisons of relative binding site engagement by chemically diverse compounds. To ensure high-confidence localization of labelled residues, we extended the MSFragger algorithm of the FragPipe computational platform to report localization scores customized for photoaffinity labelling and SEE-CITE data. When applied to scout fragments and analogues of select FDA-approved kinase inhibitors, SEE-CITE delineates known drug binding sites and uncovers small-molecule binding sites that affect the protein activity of RTN4 and COX5A.

  PublisherDOI

• Chronic cold exposure induces plasticity of mitochondrial calcium uptake in beige and brown fat of UCP1-deficient mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-18

  articleOpen access

  ABSTRACT Brown adipose tissue (BAT) is a unique tissue with mitochondria specialized for thermogenesis via the BAT-specific uncoupling protein 1 (UCP1). Ucp1 -/- mice cannot tolerate acute exposure to cold, illustrating the necessity of UCP1 for efficient mitochondrial thermogenesis. However, these mice adapt to low temperatures through a gradual acclimation process, suggesting a high degree of mitochondrial plasticity in brown and beige fat cells. This phenomenon, which remains to be fully elucidated, indicates the potential for these mitochondria to implement effective thermogenic mechanisms in the absence of uncoupling protein 1 (UCP1). Here, we investigated mitochondrial remodeling in beige and brown fat of Ucp1 -/- mice to determine how they fulfill their thermogenic role. Upon gradual acclimation to a cold environment, Ucp 1 -/- mice exhibited body metabolic parameters and temperatures in the interscapular region similar to those of wild-type mice of BAT, highlighting effective thermogenesis. Interestingly, mitochondrial patch-clamp analysis and a mitochondrial Ca 2+ swelling assay revealed a dramatic increase in Ca 2+ uptake depending on the mitochondrial calcium uniporter (MCU) in BAT mitochondria from Ucp1 -/- mice when robust thermogenesis was required. Mitochondrial remodeling was accompanied by markedly increased tethering between mitochondria and the endoplasmic reticulum (ER) in Ucp1 -/- mice, confirming a significant restructuring of the contact sites between the ER and mitochondria, likely to adapt to a new Ca 2+ homeostasis. Respiratory complexes also underwent significant reorganization, which partly led to a reduction in their assembly. Levels of ATP synthase and its F1 subcomplex increased, suggesting a major source of ATP consumption and energy expenditure. We propose a new role for MCU as a key regulator of mitochondrial plasticity, enabling efficient thermogenesis in beige and brown adipose tissues in the absence of UCP1.

  PublisherOA PDFDOI

• Pro-inflammatory macrophage activation does not require inhibition of oxidative phosphorylation

  EMBO Reports · 2025-01-03 · 10 citations

  articleOpen accessSenior author

  Pro-inflammatory macrophage activation is a hallmark example of how mitochondria serve as signaling organelles. Oxidative phosphorylation sharply decreases upon classical macrophage activation, as mitochondria are thought to shift from ATP production towards accumulating signals that amplify effector function. However, evidence is conflicting regarding whether this collapse in respiration is essential or dispensable. Here we systematically examine this question and show that reduced oxidative phosphorylation is not required for pro-inflammatory macrophage activation. Different pro-inflammatory stimuli elicit varying effects on bioenergetic parameters, and pharmacologic and genetic models of electron transport chain inhibition show no causative link between respiration and macrophage activation. Furthermore, the signaling metabolites succinate and itaconate can accumulate independently of characteristic breaks in the TCA cycle in mouse and human macrophages, and peritoneal macrophages can be activated in vivo without inhibition of oxidative phosphorylation. The results indicate there is plasticity in the metabolic phenotypes that can support pro-inflammatory macrophage activation.

  PublisherOA PDFDOI

• IGF2BP3 redirects glycolytic flux to promote one-carbon metabolism and RNA methylation

  Cell Reports · 2025-09-27 · 2 citations

  articleOpen access

  A modifications on mRNA. Taken together, these data suggest the intriguing hypothesis that IGF2BP3 rewrites the epitranscriptome in leukemia cells. Furthermore, this work highlights an interconnection between oncogenic metabolism and RNA modifications, suggesting that pervasive gene expression changes necessary for oncogenesis may be perpetuated by post-transcriptional gene regulation.

  PublisherDOI

• Identification of serine as an essential amino acid for human NK cell effector functions 3897

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description Natural killer (NK) cells are innate lymphoid cells with potent antitumor function. Upon cytokine stimulation, NK cells undergo dramatic metabolic reprogramming to provide energy and biomolecules for increased proliferation, production of inflammatory cytokines, and cytotoxicity. However, the global metabolic adaptations induced in cytokine-activated human NK cells are poorly understood. To address this, we performed unbiased metabolomics on naïve and IL-2/15-stimulated primary human NK cells and identified an enrichment in serine/glycine metabolic processes upon activation. Ex vivo serine restriction of human NK cells prevented cytokine-induced upregulation of glucose metabolism, mitochondrial respiration, and mTOR signaling, leading to impaired effector function. Comprehensive isotope-labeled serine tracing indicated that serine contributes to sphingolipid and one carbon metabolism, and tuning glutathione synthesis with CRISPR was sufficient to skew NK cells toward inflammatory or cytotoxic profiles. Glucose tracing revealed that human NK cells fail to synthesize serine de novo due to absent expression of the serine synthesis enzyme PHGDH. CRISPR activation-mediated overexpression of PHGDH in human NK cells restored function and synergized with dietary serine restriction in vivo to control solid tumor growth. These findings identify serine as a key mediator of human NK cell metabolic reprogramming and show that engineering serine metabolism can enhance NK cell therapy. Funding Sources Supported by NIH R01AI145997, R01AI174519, T32GM008042, T32GM152342, T32AI007323, and 1F30AI181449-01. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

  PublisherOA PDFDOI

• ¹³ C tracing in synaptosomes reveals that SGLT2 inhibition with dapagliflozin prevents metabolic deficits in the 5X-FAD model of Alzheimer’s Disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-03 · 1 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Metabolic dysfunction is linked to several forms of age-related neurodegeneration including Alzheimer’s Disease (AD), and targeting brain energy metabolism is an increasingly attractive mode of therapeutic intervention. However, commonly used in vitro methods to identify specific metabolic pathways of interest in preclinical models of neurodegenerative disease have considerable limitations. They are prone to subselection of sample material, unable to identify cell type-specific effects, or cannot identify metabolic defects upstream of mitochondria. Here we address these challenges by validating a method for stable isotope tracing with isolated synaptic nerve terminals, or ‘synaptosomes’. We further applied this approach to study glucose metabolism in synaptosomes isolated from the 5X-FAD mouse model of AD treated with the antidiabetic sodium-glucose linked transporter-2 (SGLT-2) inhibitor Dapagliflozin. Treatment with Dapagliflozin preserved steady-state levels of synaptosomal metabolites and enrichment from labeled glucose into citrate that was reduced in the 5X-FAD model. These changes correlated with trends towards improved spatial working memory but not amyloid burden. The results highlight the utility of stable isotope tracing in synaptosomes to identify precise sites of metabolic dysfunction and mechanisms of action for metabolic drug candidates in preclinical models of neurodegeneration.

  PublisherOA PDFDOI

• Species-specific serine metabolism differentially controls natural killer cell functions

  Nature Metabolism · 2025-08-14 · 2 citations

  articleOpen access
  PublisherOA PDFDOI

Recent grants

• Understanding How Metabolic Cofactors Control Cell Function and Fate

  NIH · $2.4M · 2020–2030

Frequent coauthors

• Anne N. Murphy

  Metropolitan State University of Denver

  71 shared

• Martin D. Brand

  35 shared

• Christian M. Metallo

  34 shared

• Anthony E. Jones

  University of California, Los Angeles

  25 shared

• Linsey Stiles

  University of California, Los Angeles

  18 shared

• Orian S. Shirihai

  18 shared

• George W. Rogers

  Agilent Technologies (United States)

  14 shared

• Heather R. Christofk

  14 shared

Labs

• Ajit Divakaruni LabPI

Awards & honors

• Suzanne Eaton, Ph.D. Memorial Prize
• Taylor M. Brown Memorial Award
• Asrican Sophie & Jack Award