Biology subjects

Kumar, A.

Publications and source records attributed to Kumar, A..

At least 397 records · Page 22Linked to original sources

bioRxiv2022

Investigating the folding dynamics of NS2B protein of Zika virus

NS2B protein of the Zika virus acts as a co-factor for NS3 protease where only the cytosolic domain of NS2B is sufficient for the protease activity. At the same time, NS2B also involves in remodeling the NS3 protease structure. In isolation, we previously proved the NS2B cytosolic domain (residues 49-95) as a disordered type peptide conformation. Further, this study investigated the overall dynamics of NS2B full-length protein. Our Alphafold2 structure modeling system revealed surprising similarities between selected flavivirus NS2B proteins. This similarity reflects that the NS2B protein across flavivirus is conserved fold-wise. The MD simulation of Zika virus NS2B full-length protein shows that the cytosolic domain as a part of full-length protein is a disorder region supporting our previous experimental finding, which suggests the disordered nature of the cytosolic domain in isolation. Since the cytosolic domain of NS2B is essential for protease activity, we have also investigated the folding and dynamics of the NS2B cytosolic domain (residues 49-95) that shows the disorder to alpha helix transition in TFE. On the other hand, in the presence of SDS, macromolecular crowder like ficoll and PEG do not induce secondary structural change. This dynamics study could have implications for some unknown folds of the NS2B protein.

biophysics↗

bioRxiv2022

Evaluation of the safety, immunogenicity and efficacy of a new live-attenuated lumpy skin disease vaccine in India

Lumpy skin disease (LSD) was reported for the first time in India in 2019 and since then, it has become endemic. Since a homologous (LSD-virus based) vaccine was not available in the country, goatpox virus (GPV)-based heterologous vaccine was authorized for mass immunization against LSD in cattle. This study describes the evaluation of safety, immunogenicity and efficacy of a new live-attenuated LSD vaccine developed using an Indian field strain (LSDV/India/2019/Ranchi). The virus was attenuated by continuous passage (P=50) in Vero cells. The vaccine (50th LSDV passage in Vero cells, named as Lumpi-ProVacInd) did not induce any local or systemic reaction upon its experimental inoculation in calves (n=10). At day 30 post-vaccination (pv), the vaccinated animals were shown to develop antibody- and cell-mediated immune response and exhibited complete protection upon virulent LSDV challenge. We observed a minimum Neethling response (0.018% animals; 5 out of 26940 animals) of the vaccine in field trials among 26940 animals. There was no significant reduction in the milk yield in lactating animals (n=10108), besides there was no abortion or any other reproductive disorder in the pregnant animals (n=2889). Sero-conversion was observed in 85.18% animals in the field by day 30 pv.

microbiology↗

bioRxiv2022

Role of interneuron subtypes in controlling trial-by-trial output variability in theneocortex

Trial-by-trial variability is a ubiquitous property of neuronal activity in vivo and affects the stimulus response. Computational models have revealed how local network structure and feedforward inputs control the trial-by-trial variability. However, the role of input statistics and different interneuron subtypes in shaping the trial-by-trial variability was less understood. Here we investigated the dynamics of stimulus response in a model of cortical microcircuit with one excitatory and three inhibitory interneuron populations (PV, SST, VIP). We show that the variance ratio of inputs to different neuron populations and input covariances are the main determinants of output trial-by-trial variability. The effect of input covariances is contingent on the input variance ratios. In general, the network shows smaller output trial-by-trial variability in a PV-dominated regime than in an SST-dominated regime. Our work reveals mechanisms by which output trial-by-trial variability can be controlled in a context, state, and task-dependent manner.

neuroscience↗

bioRxiv2022

Vector-valued dopamine improves learning of continuous outputs in the striatum

It is well established that midbrain dopaminergic neurons support reinforcement learning (RL) in the basal ganglia by transmitting a reward prediction error (RPE) to the striatum. In particular, different computational models and experiments have shown that a striatumwide RPE signal can support RL over a small discrete set of actions (e.g. no/no-go, choose left/right). However, there is accumulating evidence that the basal ganglia functions not as a selector between predefined actions, but rather as a dynamical system with graded, continuous outputs. To reconcile this view with RL, there is a need to explain how dopamine could support learning of dynamic outputs, rather than discrete action values. Inspired by the recent observations that besides RPE, the firing rates of midbrain dopaminergic neurons correlate with motor and cognitive variables, we propose a model in which dopamine signal in the striatum carries a vector-valued error feedback signal (a loss gradient) instead of a homogeneous scalar error (a loss). Using a recurrent network model of the basal ganglia, we show that such a vector-valued feedback signal results in an increased capacity to learn a multidimensional series of real-valued outputs. The corticostriatal plasticity rule we employed is based on Random Feedback Learning Online learning and is a fully local, "three-factor" product of the presynaptic firing rate, a post-synaptic factor and the unique dopamine concentration perceived by each striatal neuron. Crucially, we demonstrate that under this plasticity rule, the improvement in learning does not require precise nigrostriatal synapses, but is compatible with random placement of varicosities and diffuse volume transmission of dopamine.

neuroscience↗

bioRxiv2022

CRISPR correction of GBA mutation in hiPSCs restores normal function to Gaucher macrophages and increases their susceptibility to Mycobacterium tuberculosis

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the {beta}-glucocerebrosidase (GCase) GBA gene, which result in macrophage dysfunction. To investigate whether correction of GBA mutations restores normal function to Gaucher macrophages, we performed CRISPR editing of homozygous L444P (1448T[->]C) GBA mutation in Type 2 GD (GBA-/-) hiPSCs, which yielded both heterozygous (GBA+/-) and homozygous (GBA+/+) isogenic lines. Macrophages derived from GBA-/-, GBA+/- and GBA+/+ hiPSCs, were compared for GCase enzymatic activity, motility, and phagocytosis, all of which showed that GBA mutation correction restores normal macrophage functions. Furthermore, we investigated whether lysosomal disorders drive susceptibility to Mycobacterium tuberculosis, by infecting GBA-/-, GBA+/- and GBA+/+ macrophages with the virulent H37Rv lab strain. The results showed that impaired mobility and phagocytic activity of Gaucher macrophages, correlated with reduced levels of TB engulfment and TB multiplication, supporting the hypothesis that GD may be protective against tuberculosis.

genomics↗

bioRxiv2022

Comparative pharmacology of direct oral anticoagulants and vitamin K antagonist.

BackgroundThe prevalence of thrombus and use of anticoagulants is routine in clinical cardiology practice. Vitamin K antagonists (VKA) and/or Direct oral anticoagulants (DOAC) are used for resolution of the thrombus. Despite similar anticoagulation efficacy, use of DOAC is preferred due to their superior safety margin and reduced risk of bleeding. Currently the following DOAC are available for the prevention of thrombosis, i.e., dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban. This study evaluates the comparative pharmacology of these DOAC and VKA to assess clinical preference. Materials and MethodsThe human specific targets of DOAC and VKA (Warfarin) were identified from the SwissTargetPrediction server and analysed for their affinity. The targets were subclassified into functional categories and the relative proportion of each of the functional categories among the total number of targets was estimated. A novel concentration affinity (CA) ratio system was developed for the drugs to assess their safety margin and compared. ResultsThe following targets were identified has high affinity targets of DOAC or VKA i.e., coagulation factor X, hERG, matriptase, multidrug and toxin extrusion protein 1, plasminogen, quinone reductase 1 & 2, serine protease hepsin, solute carrier family 22 member 2 and thrombin. Apixaban and rivaroxaban were observed to have superior anticoagulation pharmacology compared to the other DOAC or VKA. Edoxaban and betrixaban were observed to have affinity against hERG, which carries the risk of prolonging QT interval and triggering ventricular tachyarrhythmia. ConclusionThis study shows the comparative pharmacology of DOAC and VKA and suggests preferential use of apixaban or rivaroxaban due to their superior pharmacodynamic effects and wider safety margin.

pharmacology and toxicology↗

bioRxiv2022

Genome-scale CRISPR screening reveals host factors required for ribosome formation and viral replication

Viruses are known to co-opt host machinery for translation initiation, but less is known about which host factors are required for the formation of ribosomes used to synthesize viral proteins. Using a loss of function CRISPR screen, we show that synthesis of a flavivirus encoded reporter depends on multiple host factors, including several 60S ribosome biogenesis proteins. Viral phenotyping revealed that two of these factors, SBDS, a known ribosome biogenesis factor, and the relatively uncharacterized protein SPATA5, were broadly required for replication of flaviviruses, coronaviruses, alphaviruses, paramyxoviruses, an enterovirus, and a poxvirus. Mechanistic studies revealed that loss of SPATA5 caused defects in ribosomal RNA processing and ribosome assembly, suggesting that this human protein may be a functional ortholog of yeast Drg1. These studies implicate specific ribosome biogenesis proteins as viral host dependency factors that are required for synthesis of virally encoded protein and accordingly, optimal viral replication.

microbiology↗

bioRxiv2022

Cryo-EM structures of amyloid-beta filaments with the Arctic mutation (E22G) from human and mouse brains

The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-{beta} (A{beta})], causes dominantly inherited Alzheimers disease. Here we report the high-resolution cryo-EM structures of A{beta} filaments from the frontal cortex of a previously described case (A{beta}PParc1) with the Arctic mutation. Most filaments consist of two pairs of non-identical protofilaments that comprise residues V12-V40 (human Arctic fold A) and E11-G37 (human Arctic fold B). They have a substructure (residues F20-G37) in common with the folds of type I and type II A{beta}42. When compared to the structures of wild-type A{beta}42 filaments, there are subtle conformational changes in the human Arctic folds, because of the lack of a side chain at G22, which may strengthen hydrogen bonding between mutant A{beta} molecules and promote filament formation. A minority of A{beta}42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of A{beta} filaments with the Arctic mutation from mouse knock-in line AppNL-G-F. Most filaments are made of two identical mutant protofilaments that extend from D1-G37 (murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The murine Arctic fold differs from the human Arctic folds, but shares some substructure.

neuroscience↗

bioRxiv2022

Identification of Potential DNA Gyrase Inhibitors: Virtual Screening, Extra-Precision Docking and Molecular Dynamics Simulation Study

DNA gyrase brings negative supercoils into DNA and loosens up certain positive supercoils that collect during replication and transcription and is a notable antibacterial target. To fight against the menace of antibiotic-resistant bacterial infections, we have employed various computational tools like high throughput virtual screening (HTVS), standard precision (SP), extra precision (XP), and molecular dynamics (MD) simulation studies to identify some potential DNA gyrase inhibitors. A focused library of 5968 anti-bacterial compounds was screened using the HTVS docking protocol of the glide module of Maestro. The top 200 docked compounds were further filtered using SP and XP docking protocols and their free binding energies were calculated using MM-GBSA studies. Binding and stability of the top two compounds which showed better docking score than the co-crystallized ligand (clorobiocin) of DNA gyrase (PDB ID: 1KZN) was further probed by MD simulation of 100 ns using GROMACS. MD simulation study suggested that the compounds AM1 and AM5 form a stable complex with DNA gyrase with a good number of hydrogen bonds. XP docking study showed that interaction with the crucial amino acids for compounds AM1 and AM5 was like the co-crystallized ligand. These compounds were also predicted to be drug-like molecules with good water solubility and excellent absorption profiles. Based on the above studies, herein we report compounds AM1 (1R,3S)-1-(2-((3-(ammoniomethyl)phenyl)amino)-2-oxoethyl)-3-carbamoylpiperidin-1-ium and AM5 (1S,2s,4R)-4-ammonio-6-ethyl-1-methylspiro[chromane-2,4-piperidin]-1-ium as potential DNA gyrase inhibitors which can be further developed as a potential drug against the menace of antibiotic resistance.

bioinformatics↗

bioRxiv2022

Transcription factor HSFA7b controls ethylene signaling and meristem maintenance at the shoot apical meristem during thermomemory

The shoot apical meristem (SAM) is responsible for overall shoot growth by generating all above-ground structures. Recent research identified that the SAM displays an autonomous heat stress (HS) memory of a previous non-lethal HS event. Considering the importance of the SAM for plant growth it is essential to unlock how its thermomemory is mechanistically controlled. Here, we report that HEAT SHOCK TRANSCRIPTION FACTOR A7b (HSFA7b) plays a crucial role in this process in Arabidopsis. We found that HSFA7b directly regulates ethylene response at the SAM by binding to promoters of key regulators of ethylene signaling including ETHYLENE-INSENSITIVE 3 to establish thermotolerance. Moreover, HSFA7b controls maintenance of the SAM stem cell pool during thermomemory by regulating the expression of the master regulator WUSCHEL through direct transcriptional activation of the SPLAYED chromatin remodelling factor.

plant biology↗

bioRxiv2022

A Model For Hierarchical Memory Storage in Piriform Cortex

How the brain stores and retrieves memories is an important unsolved problem in neuroscience. It is commonly believed that memories are represented in the brain by distinct patterns of neural activity. Attractor dynamics has been proposed as one of the theoretical frameworks for learning and memory in neural networks. However, most of the prior theoretical work typically assumes that the neural network consists of fully-connected, binary neurons and that neuronal representations of memories are uncorrelated. In this paper, we propose a model consisting of continuously varying, rate-based, sparse neural network with a local learning rule which stores correlated patterns organized into multiple uncorrelated classes. We perform analytical calculations to compute maximum storage capacity and basin of attraction. It is found that increasing pattern correlation decreases storage capacity, and increasing the memory load decreases basin of attraction. We also study rate-based and spiking based neural network with separate excitatory and inhibitory populations and tight EI balance. Recent experimental work indicates that piriform cortex exhibits attractor dynamics and possibly stores hierarchically correlated patterns. So, we consider this work as a model for olfactory memory storage.

neuroscience↗

bioRxiv2022

PIC50: An open source tool for interconversion of PIC50 values and IC50 for efficient data representation and analysis

Half-maximal inhibitory concentration (IC50) is used to determine the potency of a drug against a variety of enzymes/ biological targets associated with the pathogenesis of multiple disorders. The IC50 values can be depicted in multiple ways, which makes it difficult to analyze the results presented in different concentrations. Representing data in the form of PIC50 values depicting the IC50 values as the negative logarithm of IC50 in molar concentration is considered to be a better approach as it not only makes data easily understandable but also eliminates the possibility of errors in data representation and reproducibility. Considering the importance of data representation for a better understanding of data and comparing efficacy and potency of the drugs, besides, the significance of PIC50 value in the field of CADD, we found that at present there is no single open-source software available to convert the IC50 values to PIC50 values and vice versa from millimolar to picomolar range. Therefore, in the present study, we develop a tool that could help researchers to interconvert IC50 values and PIC50 values in a reliable way to eliminate the possibility of errors. We validated our tool through three case studies where the data generated by our tool was found to be 100% accurate. Moreover, we present a case where data was published in literature with errors in calculated PIC50 values and demonstrated the importance and reliability of our tool.

bioinformatics↗

bioRxiv2022

A fast-killing tyrosine amide ((S)-SW228703) with blood and liver-stage antimalarial activity associated with the Cyclic Amine Resistance Locus (PfCARL)

Current malaria treatments are threatened by drug resistance and new drugs are urgently needed. In a phenotypic screen for new antimalarials, we identified (S)-SW228703 ((S)-SW703), a tyrosine amide with asexual blood and liver stage activity and a fast-killing profile. Resistance to (S)-SW703 is associated with mutations in Plasmodium falciparum cyclic amine resistance locus (PfCARL) and P. falciparum acetyl CoA transporter (PfACT), similarly to several other compounds that share features such as fast activity and liver-stage activity. Compounds with these resistance mechanisms are thought to act in the ER, though their target(s) are unknown. The tyramine of (S)-SW703 is shared with some reported PfCARL-associated compounds; however, we observed that strict S-stereochemistry was required for activity of (S)-SW703, suggesting differences in mechanism of action or binding mode. (S)-SW703 provides a new chemical series with broad activity on multiple life-cycle stages and a fast-killing mechanism of action, available for lead optimization to generate new treatments for malaria.

microbiology↗

bioRxiv2022

Deubiquitinase USP1 influences the dedifferentiation of mouse pancreatic β-cells

Diabetes is a metabolic disease caused majorly due to loss of insulin secreting {beta}-cells. Along with apoptosis, recent reports revealed dedifferentiation to be the added reason for the reduced {beta}-cell mass. The Ubiquitin Proteasome system comprising of E3 ligase and deubiquitinases (DUBs) control several key aspects of pancreatic {beta}-cell functions. The role of deubiquitinases in orchestrating the dedifferentiation process in several cancers have been well deciphered, but its role in dedifferentiation of pancreatic {beta}-cells remains elusive. In this study, screening for key DUBs that regulate dedifferentiation, identified USP1 to be specifically involved in the process. Inhibition of USP1 either by genetic intervention or small molecule inhibitor ML323 restored epithelial phenotype of {beta}-cells, but not with inhibition of other DUBs. Conversely overexpression of USP1 was sufficient to dedifferentiate {beta}-cells, even in absence of dedifferentiation inducing cues. Mechanistic insight showed USP1 to probably mediate its effect via modulating the expression of Inhibitor of Differentiation (ID) 2. Further, in an in vivo streptozotocin (STZ) induced dedifferentiation mouse model system, treatment with ML323 rescued the hyperglycaemic state. Overall, this study assigns a novel role to USP1 in dedifferentiation of {beta}-cells and its inhibition may have a therapeutic application of reducing the {beta}-cell loss during diabetes.

cell biology↗

bioRxiv2022

2D-QSAR and Molecular Docking based virtual screening of the herbal molecules against Alzheimers Disorder: An approach to predict CNS activity

Acetylcholinesterase (AChE) is one of the key enzyme targets that have been used clinically for the management of Alzheimers Disorder (AD). Numerous reports in the literature predict and demonstrate in-vitro, and in-silico anticholinergic activity of synthetic and herbal molecules, however, the majority of them failed to reproduce the results in preclinical or clinical settings. To address these issues, we developed a 2D-QSAR model that could not only efficiently predict the AChE inhibitory activity of herbal molecules but also predicted their potential to cross BBB to exert their beneficial effects during AD. Applying this model, virtual screening of the herbal molecules was performed and amentoflavone, asiaticoside, astaxanthin, bahouside, biapigenin, glycyrrhizin, hyperforin, hypericin, and tocopherol were predicted as the most promising herbal molecules for inhibiting AChE. Results were validated through molecular docking studies against human AChE (PDB ID: 4EY7). To determine whether or not these molecules can cross BBB to inhibit AChE within the CNS for being beneficial for the management of AD, we determined a CNS PPO score, which was found in the range of 1 to 3.76. Overall, the best results were observed for amentoflavone and our results demonstrated a PIC50 value of 7.377 nM, molecular docking score of -11.5 kcal/mol, and CNS MPO score of 3.76. In conclusion, we successfully developed a reliable and efficient 2D-QSAR model and predicted amentoflavone to be the most promising molecule that could inhibit human AChE enzyme within the CNS and could prove beneficial for the management of AD.

bioinformatics↗

bioRxiv2022

Pharmacologic Inhibition of DYRK1A Results in MYC Hyperactivation and ERK Hyperphosphorylation rendering KMT2A-R ALL Cells Sensitive to BCL2 Inhibition

KMT2A-rearranged (KMT2A-R) B cell acute lymphoblastic leukemia (ALL) is a high-risk disease in children and adults that is often chemotherapy resistant. To identify non-cytotoxic approaches to therapy, we performed a domain-specific kinome-wide CRISPR screen in KMT2A-R cell lines and patient derived xenograft samples (PDX) and identified dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as a potential target. Pharmacologic inhibition of the KMT2A-fusion transcriptional co-regulator Menin released the KMT2A-fusion complex from the DYRK1A promoter thereby lowering DYRK1A expression levels confirming DYRK1A as a direct target of the KMT2A fusion oncogene. Direct pharmacologic inhibition of DYRK1A decreased cell proliferation of KMT2A-R ALL, thereby confirming the requirement of DYRK1A in this ALL subtype. To further understand the biologic function of DYRK1A in KMT2A-R ALL, we leveraged pharmacologic DYRK1A inhibitors in KMT2A-R PDX and cell line models. DYRK1A inhibition consistently led to upregulation of MYC protein levels, and hyperphosphorylation of ERK, which we confirmed via in vivo treatment experiments. Furthermore, DYRK1A inhibition decreased ALL burden in mice. Our results further demonstrate that DYRK1A inhibition induces the proapoptotic factor BIM, but ERK hyperphosphorylation is the driving event that induces cell cycle arrest. In contrast, combined treatment of KMT2A-R ALL cells in vitro and in vivo with DYRK1A inhibitors and the BCL2 inhibitor, venetoclax, synergistically decreases cell survival and reduced the leukemic burden in mice. Taken together these results demonstrate a unique function of DYRK1A specially in KMT2A-R ALL. Synergistic inhibition of DRYK1A and BCL2 may provide a low-toxic approach to treat this high risk ALL subtype.

cancer biology↗

bioRxiv2022

Alendronate Conjugate for Targeted Delivery to Bone-Forming Prostate Cancer

Bone is the primary metastasis site for lethal prostate cancer, often resulting in poor prognosis, crippling pain, and diminished functioning that drastically reduce both quality of life and survivability. Uniquely, prostate cancer bone metastasis induces aberrant bone overgrowth, due to an increase of osteoblasts induced by tumor-secreted bone morphogenetic protein 4 (BMP4). Conjugating drugs to substances that target the tumor-induced bone area within the metastatic tumor foci would be a promising strategy for drug delivery. To develop such a strategy, we conjugated a near infrared (NIR) fluorescent probe, the dye Cy5.5, to serve as a surrogate for drugs, with alendronate, which targets bone. Characterization, such as infrared spectroscopy, confirmed the synthesis of the Cy5.5-ALN conjugate. The maximum absorbance of free Cy5.5, which was at 675 nm, did not change upon conjugation. Alendronate targeted the bone component hydroxyapatite in a dose-dependent manner up to 2.5 M, with a maximum of 85% of Cy5.5-ALN bound to hydroxyapatite, while free Cy5.5 alone had 6% binding. In in vitro cell binding studies, Cy5.5-ALN bound specifically with mineralized bone matrix of differentiated MC3T3-E1 cells or 2H11 endothelial cells that were induced to become osteoblasts through endothelial-to-osteoblast transition, the underlying mechanism of prostate-cancer-induced bone formation. Neither Cy5.5-ALN nor free Cy5.5 bound to undifferentiated MC3T3-E1 or 2H11 cells. Bone-targeting efficiency studies in non-tumor-bearing mice revealed accumulation over time in the spine, jaw, knees, and paws injected with Cy5.5-ALN, and quantification showed higher accumulation in femurs than in muscle at up to 28 days, while the free Cy5.5 dye was observed circulating without preferential accumulation and decreased over time. There was a linear relationship with fluorescence when the injected concentration of Cy5.5-ALN was between 0.313 and 1.25 nmol/27 g of mouse, as quantified in mouse femurs both in vivo and ex vivo. Ex vivo evaluation of bone-targeting efficiency in nude mice was 3 times higher for bone-forming C4-2b-BMP4 tumors compared to non-bone-forming C4-2b tumors (p-value < 0.001). Fluorescence microscopy imaging of the tumors showed that Cy5.5-ALN co-localized with the bone matrix surrounding tumor-induced bone, but not with the viable tumor cells. Together, these results suggest that a drug-ALN conjugate is a promising approach for targeted delivery of drug to the tumor-induced bone area in the metastatic foci of prostate cancer.

biochemistry↗

bioRxiv2022

Inter-organelle crosstalk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress

Proliferating cells rely on acetyl-CoA to support membrane biogenesis and acetylation. Several organelle-specific pathways are available for provision of acetyl-CoA as nutrient availability fluctuates, so understanding how cells maintain acetyl-CoA flux under such stresses is critically important. To this end we applied 13C isotope tracing cell lines deficient in these mitochondrial (ATP-citrate lyase; ACLY-), cytosolic, (acetyl-CoA synthetase (ACSS2-), and peroxisomal (peroxisomal biogenesis factor 5; PEX5-) dependent pathways. ACLY knockout in multiple cell lines reduced fatty acid synthesis and increased reliance on extracellular lipids or acetate. Knockout of both ACLY and ACSS2 (DKO) severely stunted but did not entirely block proliferation, suggesting alternate pathways can support acetyl-CoA homeostasis. Metabolic tracing and PEX5 knockout studies link peroxisomal oxidation of exogenous lipids as a major source of acetyl-CoA for lipogenesis and histone acetylation, highlighting a role for inter-organelle crosstalk in supporting cell survival in response to nutrient fluctuations. TeaserWe quantify how acetyl-CoA metabolism is supported by distinct pathways spanning mitochondria, cytosol, and peroxisomes using comprehensive tracing applied to knockout cells.

bioengineering↗