Biology subjects

Grewal, S. S.

Publications and source records attributed to Grewal, S. S..

9 recordsLinked to original sources

bioRxiv2025

Nutrient/TOR signaling controls Mitochondrial transcription factor A (TFAM) to regulate organismal growth in Drosophila

Animals must adapt their growth to fluctuations in nutrient availability to ensure proper development. While nutrient-sensing tissues coordinate organismal growth through inter-organ signaling, the metabolic changes within these tissues that mediate whole-body growth control remain poorly understood. Using Drosophila larvae, we show that TOR (Target-Of-Rapamycin), a conserved nutrient-sensing kinase, controls developmental growth through regulation of the mitochondrial genome transcription factor TFAM, which controls mitochondrial bioenergetic capacity and metabolic state. We find that nutrient/TOR signaling post-transcriptionally suppresses TFAM protein levels. Furthermore, we find that TOR regulation of TFAM in the larval fat body, a key nutrient-sensing tissue, controls developmental growth. These findings establish a molecular mechanism linking nutrient-sensing pathways to mitochondrial metabolic reprogramming, revealing how environmental nutrient availability coordinates organismal growth through tissue-specific metabolic control.

cell biology↗

bioRxiv2025

Cytokine control of systemic hypoxia tolerance in Drosophila.

Systemic hypoxia--reduction in oxygen supply to all tissues and organs--occurs in both physiological and pathological conditions in animals. Under these conditions, organisms must adapt their physiology to ensure proper functioning and survival. While extensive research has characterized how individual cells sense and adapt to low oxygen conditions, the mechanisms that coordinate whole-body responses to systemic hypoxia remain poorly understood. In this study, we uncover an interorgan signaling response mediated by the cytokine Unpaired-3 (upd3) that is important for systemic hypoxia tolerance in Drosophila. We demonstrate that hypoxia rapidly induces upd3 expression and activates JAK/STAT signaling in both larvae and adults. Interestingly, we discovered a sex-specific requirement for this pathway, with females requiring upd3 for hypoxia survival while males do not. We also identify the intestine as a critical source of hypoxia-induced upd3 and show that gut-derived upd3 signals to the fat body and oenocytes to mediate hypoxia tolerance by promoting nitric oxide synthase expression. Furthermore, we reveal an unexpected role for the canonical hypoxia response transcription factor HIF-1/sima as a molecular brake, preventing lethal upd3 overproduction, revealing that hypoxia survival requires precise cytokine dosage control. Our findings define a gut-to-fat/oenocyte signaling axis that coordinates systemic hypoxia adaptation, highlighting the complex interplay between classic hypoxia response pathways and cytokine signaling in maintaining organismal homeostasis during oxygen limitation. This work provides important insights into how organisms adapt to systemic hypoxia, with potential implications for understanding systemic hypoxia-related human pathologies such as respiratory disorders and sleep apnea.

physiology↗

bioRxiv2023

Hypoxia delays steroid-induced developmental maturation in Drosophila by suppressing EGF signaling.

Animals often grow and develop in unpredictable environments where factors like food availability, temperature, and oxygen levels can fluctuate dramatically. To ensure proper sexual maturation into adulthood, juvenile animals need to adapt their growth and developmental rates to these fluctuating environmental conditions. Failure to do so can result in impaired maturation and incorrect body size. Here we describe a mechanism by which Drosophila larvae adapt their development in low oxygen (hypoxia). During normal development, larvae grow and increase in mass until they reach critical weight (CW), after which point a neuroendocrine circuit triggers the production of the steroid hormone ecdysone from the prothoracic gland (PG), which promotes maturation to the pupal stage. However, when raised in hypoxia (5% oxygen), larvae slow their growth and delay their maturation to the pupal stage. We find that, although hypoxia delays the attainment of CW, the maturation delay occurs mainly because of hypoxia acting late in development to suppress ecdysone production. This suppression operates through a distinct mechanism from nutrient deprivation, occurs independently of HIF-1 alpha and does not involve modulation of PTTH, the main neuropeptide that initiates ecdysone production in the PG. Instead, we find that hypoxia lowers the expression of the EGF ligand, spitz, and that the delay in maturation occurs due to reduced EGFR/ERK signaling in the PG. Our study sheds light on how animals can adjust their development rate in response to changing oxygen levels in their environment. Given that hypoxia is a feature of both normal physiology and many diseases, our findings have important implications for understanding how low oxygen levels may impact animal development in both normal and pathological situations.

developmental biology↗

bioRxiv2023

Mitochondrial metabolism in Drosophila macrophage-like cells regulates body growth via modulation of cytokine and insulin signaling

Macrophages play key roles in regulating and maintaining tissue and whole-body metabolism in both normal and disease states. While the cell-cell signaling pathway that underlie these functions are becoming clear, less is known about how alterations in macrophage metabolism influence their roles as regulators of systemic physiology. Here we investigate this by examining Drosophila macrophage-like cells called hemocytes. We used knockdown of TFAM, a mitochondrial genome transcription factor, to reduce mitochondrial OxPhos activity specifically in larval hemocytes. We find that this reduction in hemocyte OxPhos leads to a decrease in larval growth and body size. These effects are associated with a suppression of systemic insulin, the main endocrine stimulator of body growth. We also find that TFAM knockdown leads to decreased hemocyte JNK signaling and decreased expression of the TNF alpha homolog, Eiger in hemocytes. Furthermore, we show that genetic knockdown of hemocyte JNK signaling or Eiger expression mimics the effects of TFAM knockdown and leads to a non-autonomous suppression of body size but without altering hemocyte numbers. Our data suggest that modulation of hemocyte mitochondrial metabolism can determine their non-autonomous effects on organismal growth by altering cytokine and systemic insulin signaling. Given that mitochondrial metabolism can be controlled by nutrient availability, our findings may explain how macrophages function as nutrient-responsive regulators of tissue and whole-body physiology and homeostasis.

developmental biology↗

bioRxiv2022

Transcriptome analysis of FOXO-dependent hypoxia gene expression identifies Hipk as a regulator of low oxygen tolerance in Drosophila

When exposed to low oxygen or hypoxia, animals must alter their metabolism and physiology to ensure proper cell-, tissue- and whole-body level adaptations to their hypoxic environment. These alterations often involve changes in gene expression. While extensive work has emphasized the importance of the HIF-1 alpha transcription factor on controlling hypoxia gene expression, less is known about other transcriptional mechanisms. We previously identified the transcription factor FOXO as a regulator of hypoxia tolerance in Drosophila larvae and adults. Here we use an RNA-sequencing approach to identify FOXO-dependent changes in gene expression that are associated with these tolerance effects. We found that hypoxia altered the expression of over 2000 genes and that approximately 40% of these gene expression changes required FOXO. We discovered that hypoxia exposure led to a FOXO-dependent increase in genes involved in cell signaling, such as kinases, GTPase regulators, and regulators of the Hippo/Yorkie pathway. Among these, we identified homeodomain-interacting protein kinase (Hipk) as being required for hypoxia survival. We also found that hypoxia suppresses the expression of genes involved in ribosome synthesis and egg production, and we showed that hypoxia suppresses tRNA synthesis and mRNA translation and reduces female fecundity. Among the downregulated genes, we discovered that FOXO was required for suppression of many ribosomal protein genes and genes involved in oxidative phosphorylation, pointing to a role for FOXO in limiting energetically costly processes such as protein synthesis and mitochondrial activity upon hypoxic stress. This work uncovers a widespread role for FOXO in mediating hypoxia changes in gene expression.

physiology↗

bioRxiv2022

Enteric bacterial infection in Drosophila induces whole-body alterations in metabolic gene expression independently of the Immune Deficiency (Imd) signalling pathway.

When infected by intestinal pathogenic bacteria, animals initiate both local and systemic defence responses. These responses are required to reduce pathogen burden and also to alter host physiology and behaviour to promote infection tolerance, and they are often mediated through alterations in host gene expression. Here, we have used transcriptome profiling to examine gene expression changes induced by enteric infection with the gram-negative bacteria Pseudomonas entomophila (P.e) in adult female Drosophila. We find that infection induces a strong upregulation of metabolic gene expression, including gut and fat body-enriched genes involved in lipid transport, lipolysis, and beta-oxidation, as well as glucose and amino acid metabolism genes. Furthermore, we find that the classic innate immune deficiency (Imd)/Relish/NF-KappaB pathway is not required for, and in some cases limits, these infection-mediated increases in metabolic gene expression. We also see that enteric infection with P.e. down regulates the expression of many transcription factors and cell-cell signaling molecules, particularly those previously shown to be involved in gut-to-brain and neuronal signaling. Moreover, as with the metabolic genes, these changes occurred largely independent of the Imd pathway. Together, our study identifies many metabolic, signaling and transcription factor gene expression changes that may contribute to organismal physiological and behavioural responses to enteric pathogen infection.

physiology↗

bioRxiv2021

TOR signalling is required for host lipid metabolic remodelling and survival following enteric infection in Drosophila

When infected by enteric pathogenic bacteria, animals need to initiate local and whole-body defence strategies. While most attention has focused on the role of innate immune anti-bacterial responses, less is known about how changes in host metabolism contribute to host defence. Using Drosophila as a model system, we identify induction of intestinal target-of-rapamycin (TOR) kinase signalling as a key adaptive metabolic response to enteric infection. We find TOR is induced independently of the IMD innate immune pathway, and functions together with IMD signalling to promote infection survival. These protective effects of TOR signalling are associated with re-modelling of host lipid metabolism. Thus, we see that TOR switches intestinal metabolism to lipolysis and fatty acid oxidation. In addition, TOR is required to limit excessive infection mediated wasting of adipose lipid stores by promoting an increase in the levels of fat body-expressed de novo lipid synthesis genes. Our data support a model in which induction of TOR represents a host tolerance response to counteract infection-mediated lipid wasting in order to promote survival.

physiology↗

bioRxiv2021

Serotonergic neuron ribosomes regulate the neuroendocrine control of Drosophila development.

The regulation of ribosome function is a conserved mechanism of growth control. While studies in single cell systems have defined how ribosomes contribute to cell growth, the mechanisms that link ribosome function to organismal growth are less clear. Here we explore this issue using Drosophila Minutes, a class of heterozygous mutants for ribosomal proteins (Rps). These animals exhibit a delay in larval development caused by decreased production of the steroid hormone ecdysone, the main regulator of larval maturation. We found that this developmental delay is not caused by decreases in either global ribosome numbers or translation rates. Instead, we show that they are due in part to loss of Rp function specifically in a subset of serotonin (5-HT) neurons that innervate the prothoracic gland to control ecdysone production. We found that these 5-HT neurons have defective secretion in Minute animals, and that overexpression of synaptic vesicle proteins in 5-HTergic cells can partially reverse the Minute developmental delay. These results identify a cell-specific role for ribosomal function in the neuroendocrine control of animal growth and development.

developmental biology↗

bioRxiv2019

FOXO mediates organismal hypoxia tolerance by regulating NF-κB in Drosophila

Exposure of tissues and organs to low oxygen (hypoxia) occurs in both physiological and pathological conditions in animals. Under these conditions, organisms have to adapt their physiology to ensure proper functioning and survival. Here we define a role for the transcription factor FOXO as a mediator of hypoxia tolerance in Drosophila. We find that upon hypoxia exposure, FOXO transcriptional activity is rapidly induced in both larvae and adults. Moreover, we see that foxo mutant animals show misregulated glucose metabolism in low oxygen and subsequently exhibit reduced hypoxia survival. We identify the innate immune transcription factor, NF-KappaB/Relish, as a key FOXO target in the control of hypoxia tolerance. We find that expression of Relish and its target genes are increase in a FOXO-dependent manner in hypoxia, and that relish mutant animals show reduced survival in hypoxia. Together, these data indicate that FOXO is a hypoxia inducible factor that mediates tolerance to low oxygen by inducing immune-like responses.

cell biology↗