Biology subjects

Mohan, N.

Publications and source records attributed to Mohan, N..

15 recordsLinked to original sources

bioRxiv2026

Novel Streptococcus mitis subsp. mitis Picklauza buccal isolate from individual with idiopathic pulmonary fibrosis containing functional mobile qacG Gene.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by immune dysregulation, fibrosis, and eventual respiratory failure. While the etiology of IPF remains unclear, accumulating evidence implicates the oral and airway microbiome in disease progression, with elevated Streptococcal burden linked to increased mortality. Whether specific taxa actively contribute to IPF pathophysiology or arise secondarily from the damaged lung environment remains unresolved. Here, we characterize "Picklauza," a streptococcal strain isolated from the buccal mucosa of an individual with IPF. Although its average nucleotide identity to a Streptococcus mitis reference genome was 93.855%, analysis with Streptoquod supported classification as Streptococcus mitis subsp. mitis. Genomic analysis identified a 109-amino-acid qacG homolog predicted to encode a small multidrug resistance (SMR)-family efflux transporter. The locus was located near genes associated with mobile genetic elements, raising the possibility of horizontal acquisition. The predicted QacG protein retained residues conserved in the extensively characterized SMR transporter EmrE, and RT-qPCR detected qacG transcripts under standard culture conditions. Nevertheless, Picklauza did not display increased tolerance to benzalkonium chloride, benzethonium chloride, or ethidium bromide compared with S. mitis NCTC 12261. Picklauza also differed from the reference strain in growth kinetics, carbon utilization, and antimicrobial susceptibility. PCR screening detected qacG homologs in three additional oral isolates from patients with IPF. Together, these findings identify a transcriptionally active, putatively mobile qacG homolog in oral streptococci while revealing a disconnect between gene carriage and QAC susceptibility under the conditions tested. This work highlights the need to validate predicted resistance determinants phenotypically and to investigate the mobility and conditional activity of SMR-family genes across genus boundaries in host-associated microbial communities.

microbiology↗

bioRxiv2026

Intratumoural oncolytic HSV-1 reshapes the local and systemic immune landscape through CD8+ T cell reprogramming

Most oncolytic viruses are delivered by intratumoural injection, and local administration can induce regression of both injected and distant tumours in mice and patients. However, the mechanisms by which local viral infection reprograms systemic immunity remain poorly understood. Here we show that intratumoural RP1, an oncolytic HSV-1 encoding GM-CSF and GALV-GP-R-, drives regression of injected and uninjected murine melanoma tumours and prolongs survival. RP1 elicits coordinated CD4 and CD8 T cell infiltration accompanied by local cytokine remodelling, reshaping the immune landscape at both tumour sites. Leveraging the Timer of Cell Kinetics and Activity (Tocky) system and Kaede photoconvertible protein technology, we resolve the temporal dynamics of CD8 T cell responses following local virotherapy and identify two systemically induced, virus-driven CD8 T cell populations distinguished by TCR engagement kinetics: antigen-engaged Timer-positive viral-induced precursors (VIPs) and Timer-negative KLRG1 viral-induced terminal effectors (VITEs). Single-cell transcriptomic and pseudotime analyses reveal divergent differentiation trajectories; VIPs exhibit sustained antigen engagement within the tumour microenvironment (TME), a transcriptional programme associated with self-renewal, and preferential homing to draining lymph nodes. A VIP-associated gene signature correlates with clinical response to RP1 plus PD-1 blockade in the IGNYTE trial of RP1 and nivolumab in PD-1-refractory melanoma and is independently associated with response to immune checkpoint inhibitor (ICI) therapy in melanoma. These findings establish a mechanistic link between local oncolytic virotherapy, systemic CD8 T cell reprogramming, and durable regression of distant lesions in patients.

cancer biology↗

bioRxiv2025

MAP4-MAP7D1 partitioning on tyrosinated-detyrosinated microtubules coordinates lysosome positioning in nutrient signalling

Microtubule-associated proteins (MAPs) and tubulin post-translational modifications (PTMs) together shape a dynamic intracellular landscape for motor-driven transport, yet how the "MAP-PTM crosstalk" regulates organelle positioning remains unclear. Here, we show that MAP4 and MAP7D1 selectively partition onto distinct microtubule subsets demarcated by tyrosination and detyrosination, respectively, creating specialized tracks for kinesin motors. MAP4s preferential binding depends on its projection domain, while expanded microtubule lattice states mediate MAP7D1s enrichment on detyrosinated microtubules. Remarkably, rigor kinesin-1 (KIF5B-R) predominantly localizes to detyrosinated, MAP7D1-coated tracks, whereas rigor kinesin-3 (KIF1A) prefers tyrosinated, MAP4-decorated microtubules. We further find that the local density of MAP4 and MAP7D1 on microtubules fine-tunes lysosomal movement and directional transport. Moreover, MAP density is modulated to coordinate lysosomal reorganization in response to nutrient availability. During starvation MAP7D1 density on microtubules increases while MAP4 density decreases, localizing lysosomes to the perinuclear region. Conversely, with nutrient stimulation, MAPD1 density declines, allowing lysosomes to migrate towards the cell periphery. Altering the cellular levels of MAP4 and MAP7D1, either up or down, hinders lysosomal motility, trapping them near the nucleus and impairing their responsiveness to nutrient stimulation. Together, our findings reveal two distinct MAP-PTM circuits, a MAP4-tyrosination-kinesin-3 axis and a MAP7D1- detyrosination-kinesin-1 axis, that govern lysosome positioning for nutrient signaling, highlighting the combinatorial logic of MAP and tubulin codes in shaping microtubule function.

cell biology↗

bioRxiv2025

mTORC1 signaling modulate microtubule tyrosination/detyrosination status to regulate lysosome dynamics

Lysosomes integrate nutrient sensing and metabolic signaling by dynamically repositioning within the cytoplasm. While motors and lysosomal surface adaptors driving this movement are well studied, how the microtubule cytoskeleton specifies lysosomal transport and its coupling to mechanistic target of rapamycin complex 1 (mTORC1) signaling remains unclear. Here, we show that tubulin post-translational modifications (PTMs) define the tracks that guide nutrient-responsive lysosome positioning. Using super-resolution imaging and biochemical assays, we demonstrate that lysosomes carrying active mTORC1 preferentially traffic along tyrosinated microtubules to reach the cell periphery, whereas detyrosinated microtubules restrict their motility. Nutrient stimulation enhances this outward transport, while concurrently suppressing microtubule detyrosination through mTORC1-S6K1 signaling, likely via inhibition of vasohibin activity. This ensures selective expansion of tyrosinated microtubule tracks to sustain mTORC1 signaling. Strikingly, in cancer cells where aberrant mTORC1 activity correlates with altered microtubule tyrosination, restoring microtubule detyrosination rescues mTORC1 hyperactivation and suppresses cell migration and epithelial-to-mesenchymal transition. Thus, demonstrating that tubulin post-translational modifications (PTMs) define the tracks that guide the positioning of nutrient-responsive lysosomes. These findings uncover a crosstalk between mTORC1 and tubulin tyrosination/detyrosination status that couples nutrient availability to lysosomal dynamics and identify microtubule tyrosination as a regulatory node with therapeutic potential in cancer.

cell biology↗

bioRxiv2025

Suppressing microtubule detyrosination augments AAV2 endosomal escape and gene delivery.

Adeno-associated virus (AAV) is a widely used vector for gene delivery, yet the host intracellular trafficking barriers often limit its efficacy. Here, we identify microtubule detyrosination--a tubulin post-translational modification--as a key regulator of AAV2 endo-lysosomal processing. Using super-resolution microscopy (SIM/STORM), we show that upon AAV2 endocytosis, the host upregulates microtubule detyrosination via GSK3{beta}-CLASP2 signaling axis. Single particle tracking of the virus reveals that detyrosinated microtubules form a physical and functional barrier, restricting AAV2 motility and promoting lysosomal trapping. Restoring microtubule tyrosination--via tubulin-tyrosine ligase overexpression or pharmacological inhibition of detyrosination with parthenolide--boosted AAV2 endosomal escape, perinuclear accumulation, and gene delivery in cells. Notably, a clinically relevant prodrug of parthenolide, DMAPT, also displayed a similar trend of enhanced AAV2-driven factor IX expression in hemophilia B mouse models. Our findings uncover a host mechanism that reshapes the microtubule landscape to restrict AAV2 trafficking and identify microtubule detyrosination as a novel druggable target to improve AAV2-based gene therapies.

cell biology↗

bioRxiv2025

Genotype-Phenotype Distinctions in Spastic Paraplegia 4 Reveal HDAC6 as a Therapeutic Target

Spastic Paraplegia 4 (SPG4) is the most prevalent form of Hereditary Spastic Paraplegia (HSP), a neurodegenerative disorder characterized by progressive lower limb spasticity and debilitating gait impairment, primarily driven by axonal degeneration of corticospinal motor neurons (CSMNs). Caused by mutations in the SPAST gene encoding spastin, an AAA-ATPase involved in microtubule severing and intracellular organelle function, SPG4 accounts for 40-50% of autosomal dominant HSP cases, yet without effective treatments. Although reduced microtubule acetylation has emerged as a key pathological mechanism, whether and how distinct mutations lead to microtubule deacetylation and subsequent neurodegeneration remains unclear. To address this, we generated isogenic human induced pluripotent stem cell (hiPSC) lines with two distinct heterozygous SPAST mutations - SPASTWT/C448Y (missense) and SPASTWT/S245X (truncation). Employing an innovative differentiation protocol, we created human motor cortical organoids enriched in CSMNs, providing a robust platform to study SPG4 pathophysiology. These organoids revealed striking genotype-phenotype distinctions, with mutation-specific variations in CSMN loss, axonal degeneration and neuronal activities, mirroring clinical heterogeneity. Mechanistic studies identified aberrant activation of histone deacetylase 6 (HDAC6), a major neuronal microtubule deacetylase, as a key driver of SPG4 pathology. This dysregulation was specifically attributed to mutant M1-spastin, the longer isoform of spastin. Remarkably, pharmacological inhibition of HDAC6 with Tubastatin A restored microtubule acetylation status and mitigated axonal degeneration in both SPAST-mutant organoids, with corresponding improvements in corticospinal tract integrity and gait deficits validated in SPG4-transgenic mice. Collectively, our study establishes isogenic hiPSC-derived motor cortical organoids as a robust human model for corticospinal motor neuron degeneration and identifies HDAC6 hyperactivation as a central pathogenic mechanism and viable therapeutic target in SPG4.

neuroscience↗

bioRxiv2025

Stress-Induced Alteration of Small Extracellular Vesicles Drives Amyloid-Beta Sequestration and Exacerbates Alzheimer's Disease Pathogenesis

While small extracellular vesicles (sEVs) are implicated in amyloid-beta (A{beta}) trafficking, the mechanisms governing their interaction with A{beta} aggregates and plaque formation remain unresolved. Here, we report a paradigm-shifting discovery: sEVs undergo dynamic structural remodelling in response to stress, enabling selective binding to A{beta} aggregates-a phenomenon absent under normal physiological conditions. Using multimodal stressors, including mechanical (ultrasonication/agitation), physical (hyperthermia), and biological (oxidative damage), we demonstrate that stress-modified sEVs exhibit high-affinity binding to small A{beta} aggregates (SA) through scaffold reorganization, as validated by super-resolution microscopy and quantitative colocalization assays. Crucially, these remodelled sEVs act as potent carriers, enhancing SA internalization by neuronal cells in vitro. Strikingly, in post-mortem Alzheimers disease (AD) brains and APP-PS1 transgenic mice, sEVs were spatially enriched at amyloid plaque margins, suggesting a direct role in A{beta} sequestration and plaque expansion. Consistent with clinical relevance, sEVs isolated from AD patients exhibited an intrinsic SA-binding capacity, recapitulating stress-induced interactions observed experimentally. Our findings reveal that stress-primed sEVs function as pathological chaperones, binding to and internalizing A{beta} aggregates, thereby accelerating plaque nucleation and disease progression. This study provides the first evidence of stress-mediated sEV plasticity as a critical driver of A{beta} pathology, redefining therapeutic strategies targeting extracellular vesicle biology in neurodegenerative disorders. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/655679v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@107c76borg.highwire.dtl.DTLVardef@1b56848org.highwire.dtl.DTLVardef@d18636org.highwire.dtl.DTLVardef@1c26db4_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

LC3 forms functional nanocluster on autophagosome

Autophagosome biogenesis relies on the intricate coordination of proteins and lipids, with LC3B proteins persistently anchored to the double-membraned autophagosomes through a lipid anchor. However, little is known about how LC3B is organized in high concentration, its spatial distribution, and the mechanisms underlying its protein-mediated tethering on membranes. Using molecular dynamics simulations and super-resolution microscopy, we demonstrate that LC3B self-assembles to form higher-order clusters, averaging 150 nm in size. Interestingly, simulations provided cue for LC3B and phosphatidylinositol lipid specificity, and STORM imaging confirmed a clear overlap of LC3B-enriched regions with phosphatidylinositol-3-phosphate lipids. Together, LC3B nanoclusters on these lipids form spatially distinct "islands" on the autophagosome. Additionally, molecular analysis of 296 clusters revealed that clustering is driven by a unique rear binding pocket in Loop6 defined by alternating hydrophobic and polar residues. We generated four mutants to disrupt the characteristic self-assembly motif, with all four mutants resulting in aberrant cluster formation and impaired autophagosome motility. These findings highlight that LC3B self-assembly is crucial for autophagy and suggest a spatiotemporal mechanism regulating LC3B function.

biophysics↗

bioRxiv2024

Functional screen for mediators of onco-mRNA translation specificity

Oncogenic protein dosage is tightly regulated to enable cancer cells to adapt and survive. Whether this is regulated at the level of translational control and the key factors in cis and trans remain unknown. The Myc oncogene is a central paradigm of an exquisitely regulated oncogene and a major driver of pancreatic ductal adenocarcinoma (PDAC). Using a functional genome-wide CRISPRi screen in PDAC cells, we identified activators of selective MYC translation through its 5 untranslated region (5UTR) and validated four RNA binding proteins (RBPs), including epitranscriptome modifiers. Among these RBPs, our top hit was RBM42, which is highly expressed in PDAC and predicts poor survival. Combining polysome sequencing and CLIP-seq analyses, we find that RBM42 binds and selectively regulates the translation of MYC and a precise, yet vital suite of pro-oncogenic transcripts, including JUN and EGFR. Mechanistically, employing IP-mass spectrometry analysis, we find that RMB42 is a novel ribosome-associated protein (RAP). Using DMS-Seq and mutagenesis analysis, we show that RBM42 directly binds and remodels the MYC 5UTR RNA structure, facilitating the formation of the translation pre-initiation complex. Importantly, RBM42 is necessary for human PDAC cell growth and fitness and PDAC tumorigenesis in xenograft mouse models in a Myc-dependent manner in vivo. In PDAC patient samples, RBM42 expression is correlated with Myc protein levels and transcriptional activity. This work transforms our understanding of the translational code in cancer and offers a new therapeutic opening to target the expression of oncogenes.

cancer biology↗

bioRxiv2024

Hippo-TOR Signaling Crosstalks Underpin Microtubule Acetylation-linked Carcinogenesis in Drosophila Squamous Epithelia

Protooncogenes, which can also function as tumor suppressors, are termed double agents. The Hippo pathway transcriptional coactivators YAP/TAZ and their Drosophila homolog Yorkie (Yki) are known oncogenes. Paradoxically, in squamous epithelia, they are constitutively active yet non-oncogenic and can even function as tumor suppressors. We previously found that loss of Yki in the Drosophila male accessory gland (MAG) squamous epithelium promotes squamous cell carcinoma (SCC) by upregulating TOR signaling, but the mechanism was unknown. Here, we show that this tumorigenesis stems from TOR-mediated hyperacetylation of -tubulin. This pathway is tissue-specific, as the ovarian follicular epithelium is resistant to Yki loss. A comparison of MAG and follicular epithelia single-cell transcriptomic data revealed their distinct Yki-TOR signaling states, suggesting lineage-specific mechanoconstraints in these two lineages. Our results identify suppression of TOR-driven -tubulin acetylation as the mechanistic basis for Ykis role as a double-agent in select squamous epithelia.

developmental biology↗

bioRxiv2024

Combination of oncolytic Maraba virus with immune checkpoint blockade overcomes therapy resistance in an immunologically cold model of advanced melanoma with dysfunctional T cell receptor signalling.

BackgroundOver the past decade, cancer immunotherapies have revolutionised the treatment of melanoma; however, responses vary across patient populations. Recently, baseline tumour size has been identified as an independent prognostic factor for overall survival in melanoma patients receiving immune checkpoint inhibitors (ICIs). MG1 is a novel oncolytic agent with broad tumour tropism that has recently entered early phase clinical trials. The aim of this study was to characterise T cell responses in human and mouse melanoma models following MG1 treatment and to establish if features of the tumour immune microenvironment (TIME) at two distinct tumour burdens would impact the efficacy of oncolytic virotherapy. MethodsHuman 3D in vitro priming assays were performed to measure anti-tumour and anti-viral T cell responses following MG1 infection. TCR sequencing, T2 killing assay, and peptide recall assays were used to assess the evolution of the TCR repertoire, and measure specific T cell responses, respectively. In vivo, subcutaneous 4434 melanomas were characterised using RNAseq, immunohistochemistry (IHC), and flow cytometry. The effectiveness of intra-tumoural MG1 was assessed in advancing 4434 tumours and the generation of anti-tumour and anti-viral T cells measured by splenocyte recall assays. Finally, combination MG1 and -PD-1 therapy was investigated in advanced 4434 tumours. ResultsMG1 effectively primed functional cytotoxic T cells (CTLs) against tumour associated antigens (TAA) as well as virus-derived peptides, as assessed using peptide recall and T2 killing assays, respectively. TCR sequencing revealed that MG1-primed CTL comprised larger clusters of similar CDR3 amino acid sequences compared to controls. In vivo testing of MG1 demonstrated that MG1 monotherapy was highly effective at treating early disease, resulting in 90% cures; however, the efficacy of MG1 reduced as the disease burden (local tumour size) increased, and the addition of -PD-1 was required to overcome resistance in more advanced disease. Differential gene expression profiles revealed that increased tumour burden was associated with an immunologically colder TIME. Furthermore, analysis of TCR signalling in advancing tumours demonstrated a different dynamic of TCR engagement compared to smaller tumours, in particular a shift in antigen recognition by CD4+ cells, from conventional to regulatory subset. ConclusionCombination of MG1 with PD-1 overcomes therapy resistance in an immunologically cold model of advanced melanoma.

cancer biology↗

bioRxiv2023

Hippo effector, Yorkie, is a Tumor Suppressor in Select Drosophila Squamous Epithelia

Out-of-context gain of nuclear signaling of mammalian YAP/TAZ or Drosophila Yki--the transcription cofactors of the highly conserved Hippo tumor suppressor pathway--is oncogenic. By contrast, in mechanically strained squamous epithelia (SE), YAP/TAZ/Yki displays developmentally programmed nuclear translocation, leading to its constitutive signaling. How organ homeostasis is maintained in constitutively YAP/TAZ/Yki signaling SE is unclear. Here, we show that Yki signaling negatively regulates the cell growth-promoting PI3K/Akt/TOR signaling in the SEs in the tubular organs of Drosophila. Thus, in the adult male accessory gland (MAG), knockdown of Yki signaling upregulates PI3K/Akt/TOR signaling in its SE-lined lumen, inducing cell hypertrophy, culminating in squamous cell carcinoma (SCC). MAG SCC-bearing adults display early mortality due to cancer cachexia, which is reversed by simultaneous knockdown of a secreted factor, ImpL2--a Drosophila homolog of mammalian IGFBP7--without arresting tumor progression per se. By contrast, a knockdown of PI3K/Akt/TOR signaling suppresses MAG SCC, reversing adult mortality. In the SE-lined lumens in other tubular organs, like the dorsal trunk of larval tracheal airways or adult Malpighian tubules, too, knockdown of Yki signaling triggers PI3K/Akt/TOR-induced cell hypertrophy and loss of epithelial homeostasis, culminating in their tumor-like transformation. Thus, Yki signaling turns tumor suppressive in the SEs of tubular organs in Drosophila by arresting runaway PI3K/Akt/TOR signaling.

cancer biology↗

bioRxiv2023

Hormonal Interventions for optimizing reproductive efficiency in pigs at Farmers field

ObjectiveOptimizing reproductive efficiency in terms of estrus induction and production performance using simplified hormonal intervention using GnRH, gonadotropins and progesterone at farmers field conditions to bred animals with superior quality semen and also to reduce the maintenance cost. MethodThe present study was planned for optimizing reproductive efficiency using four different easily available hormonal agents with simplified protocols at farmers field. A total of 126 females were used in the study. Hormonal protocols I, II, III and IV using GnRH + (PMSG+ hCG), (PMSG+ hCG), PMSG alone and prepared progesterone gel respectively were used for estrus induction in gilts and sows. ResultsThe estrus induction/rate was (77.77%, 81.36%, 78.57% and 50% respectively. The corresponding figures for interval (hrs) of heat exhibition from hormonal administration (121.33{+/-}4.93, 121.54{+/-}3.60, 78.52{+/-}4.52 and 192{+/-}24), conception rate (%) (72.22%, 81.25%, 68.18% and 33.33%) farrowing rate (55.55%, 68.29%, 68.18% and 33.33 %), total litter size at birth (7.2{+/-}0.64, 7.90{+/-}0.47, 8.90{+/-}0.47 and 7.00{+/-}0) and hormonal cost (Rs.) per animal (570, 335, 280 and 250 Rs.) were respectively. The easier to use protocol was III followed by II, I and IV. ConclusionIt was found that protocol II and III are effective and easier so can be used for optimizing reproductive efficiency in pigs at farmers field.

physiology↗

bioRxiv2020

Shear flow-driven actin re-organization induces ICAM-1 nanoclustering on endothelial cells that impact T-cell migration

The leukocyte specific {beta}2-integrin LFA-1, and its ligand ICAM-1 expressed on endothelial cells (ECs), are involved in the arrest, adhesion and transendothelial migration of leukocytes. Although the role of mechanical forces on LFA-1 activation is well established, the impact of forces on its major ligand ICAM-1, has received less attention. Using a parallel-plate flow chamber combined with confocal and super-resolution microscopy, we show that prolonged shear-flow induces a global translocation of ICAM-1 on ECs upstream of flow direction. Interestingly, shear-forces promoted ICAM-1 nanoclustering prior to LFA-1 engagement. This spatial nanoscale organization was driven by actin cytoskeleton re-arrangements induced by shear-force. We further assessed the impact of prolonged shear-stress EC stimulation on T cell migration. T cells adhered to mechanically pre-stimulated ECs developed a more pro-migratory phenotype, migrated faster and exhibited shorter EC interactions than when adhered to non-mechanically stimulated ECs. Together, our results indicate that shear-forces increase the number of ICAM-1/LFA-1 bonds due to ICAM-1 nanoclustering, strengthening adhesion and thereby reducing actin retrograde flow of T-cells, leading to their increased migration speed. Our data also underscores the importance of mechanical forces regulating the spatial organization of cell membrane receptors and their contribution to adhesion regulation, regardless of integrin activation. Summary statementWe show that shear forces promote ICAM-1 spatial re-arrangement and actin-dependent nanoclustering on ECs prior to integrin engagement. This mechanism might be important for firm leukocyte adhesion and migration during the immune response.

cell biology↗

bioRxiv2019

Anabolic SIRT4 exerts retrograde control over TORC1 signalling by glutamine sparing in the mitochondria

Anabolic and catabolic signalling mediated via mTOR and AMPK have to be intrinsically coupled to mitochondrial functions for maintaining homeostasis and mitigate cellular/organismal stress. Although, glutamine is known to activate mTOR, if/how differential mitochondrial utilization of glutamine impinges on mTOR signalling is less explored. Mitochondrial SIRT4, which unlike other sirtuins is induced in a fed state, is known to inhibit catabolic signalling/pathways through AMPK-PGC1a/SIRT1-PPARa axis and negatively regulate glutamine metabolism via TCA cycle. However, physiological significance of SIRT4 functions during a fed state is still unknown. Here, we establish SIRT4 as key anabolic factor that activates TORC1 signalling and regulates lipogenesis, autophagy and cell proliferation. Mechanistically, we demonstrate that the ability of SIRT4 to inhibit anaplerotic conversion of glutamine to -ketoglutarate potentiates TORC1. Interestingly, we also show that mitochondrial glutamine sparing or utilization is critical for differentially regulating TORC1 under fed and fasted conditions. Moreover, we conclusively show that differential expression of SIRT4 during fed and fasted states is vital for coupling mitochondrial energetics and glutamine utilization with anabolic pathways. These significant findings also illustrate that SIRT4 integrates nutrient inputs with mitochondrial retrograde signals to maintain a balance between anabolic and catabolic pathways.

physiology↗