The invasive Aedes albopictus in the Doñana World Heritage Site.

BACKGROUND: Aedes albopictus is catalogued as one of the 100 most dangerous species worldwide. Native to Asia, the species has drastically increased its distribution range, reaching all continents except Antarctica. The presence of Ae. albopictus in Spain was first reported in 2004 in Cataluña (NE Spain), and it is spreading in the country. METHODS: We conducted an extensive mosquito monitoring study in the natural protected area of the Doñana National Park (SW Spain) in 2023. After identifying the presence of Ae. albopictus, a mosquito control strategy was developed and implemented to eradicate the species in the area. RESULTS: Overall, 12,652 mosquito females of 14 different species were captured at nine sites within the park. For the first time, the presence of Ae. albopictus was recorded in the area, despite intensive trapping performed at some localities since 2003. The presence of this invasive species in the park is most likely linked to human activities, potentially facilitated by daily car trips of personnel. Although larvae of Culex, Anopheles, and Culiseta mosquitoes were identified in these containers, the presence of Ae. albopictus larvae was not recorded in those locations. In spite of that, the biological larvicide Bacillus thuringiensis israelensis (Bti) was applied to artificial containers potentially used by Ae. albopictus as breeding sites. CONCLUSIONS: This work evidences the high capacity of Ae. albopictus to reach highly conserved natural areas far from urban foci. We discuss the implications of the presence of Ae. albopictus in this endangered ecosystem and the potential control measures necessary to prevent its reintroduction.

Targeted nutritional intervention attenuates experimental lung cancer cachexia.

BACKGROUND: Cachexia, a syndrome with high prevalence in non-small cell lung cancer patients, impairs quality of life and reduces tolerance and responsiveness to cancer therapy resulting in decreased survival. Optimal nutritional care is pivotal in the treatment of cachexia and a recommended cornerstone of multimodal therapy. Here, we investigated the therapeutic effect of an intervention diet consisting of a specific combination of high protein, leucine, fish oil, vitamin D, galacto-oligosaccharides, and fructo-oligosaccharides on the development and progression of cachexia in an orthotopic lung cancer mouse model. METHODS: Eleven-week-old male 129S2/Sv mice were orthotopically implanted with 344P lung epithelial tumour cells or vehicle (control). Seven days post-implantation tumour-bearing (TB) mice were allocated to either intervention- or isocaloric control diet. Cachexia was defined as 5 days of consecutive body weight loss, after which mice were euthanized for tissue analyses. RESULTS: TB mice developed cachexia accompanied by significant loss of skeletal muscle mass and epididymal fat mass compared with sham operated mice. The cachectic endpoint was significantly delayed (46.0 ± 15.2 vs. 34.7 ± 11.4 days), and the amount (-1.57 ± 0.62 vs. -2.13 ± 0.57 g) and progression (-0.26 ± 0.14 vs. -0.39 ± 0.11 g/day) of body weight loss were significantly reduced by the intervention compared with control diet. Moreover, systemic inflammation (pentraxin-2 plasma levels) and alterations in molecular markers for proteolysis and protein synthesis, indicative of muscle atrophy signalling in TB-mice, were suppressed in skeletal muscle by the intervention diet. CONCLUSIONS: Together, these data demonstrate the potential of this multinutrient intervention, targeting multiple components of cachexia, as integral part of lung cancer management.

Three-dimensional culture in a bioengineered matrix and somatic cell complementation to improve growth and survival of bovine preantral follicles.

Purpose: Novel assisted reproductive technologies that capitalize on the preantral follicle population and utilize stem cell biology are greatly warranted. In this study, we explored the use of poly(ethylene glycol) (PEG) bioengineered hydrogels for bovine preantral follicle culture with or without ovarian cell co-culture, and examined the propensity of bovine embryonic stem cells (bESCs) to differentiate towards gonadal somatic cells. Together, these technological advances can be complemented to develop a sustainable and dynamic follicle culture system similar to the ovarian microenvironment. Methods: Bovine preantral follicles at the primary and early secondary stages were cultured in two-dimensional (2D) control or encapsulated in PEG hydrogels (3D) to assess growth and then co-cultured in PEG hydrogels with bovine ovarian cells (BOCs) to determine cell and follicle viability. In a separate experiment, we tested protocols to modulate WNT, FGF and BMP4 signaling to drive differentiation of bESCs towards the intermediate mesoderm and bipotential gonad-like fate and measured gene and protein expression of key lineage markers. Results: Primary follicles (40-60 µm), but not early secondary follicles (61-70 µm), grew over the 10-day culture period in PEG hydrogels compared to 2D control. However, follicles co-encapsulated with BOCs in hydrogels did not maintain viability and BOCs lost stromal cell signature over the culture period. When bESCs were induced towards gonadal somatic cells under WNT signaling activation, bFGF and BMP4 were dispensable to upregulate intermediate mesoderm ( LHX1 ) and early coelomic epithelium/bipotential gonad markers ( OSR1 , GATA4 , WT1 ). Higher BMP4 concentrations upregulated the lateral plate mesoderm marker FOXF1 . Expression of PAX3 did not change over the course of the culture, indicating that the paraxial mesoderm lineage was not induced. Conclusions: Culture of preantral follicles at the primary stage in PEG hydrogels resulted in follicle growth compared to 2D system, although the benefit of the 3D system was inconsistent. BOCs did not maintain their identity in the PEG hydrogels; collectively, these results demonstrate that the PEG hydrogels can be a potential culture system for early stage follicles after refinements are implemented. These refinements could include the addition of ESC-derived ovarian somatic cells using protocols such as the one described here. CAPSULE SUMMARY: We demonstrate that three-dimensional bioengineered hydrogels could aid in the survival and growth of small bovine preantral follicles. Moreover, bovine embryonic stem cells have the potential to differentiate towards precursors of somatic gonadal cell types, presenting an alternative cell source for preantral follicle co-culture.

Home range in genus Capra: from polygons to Brownian bridges of scabietic and healthy Iberian ibexes (Capra pyrenaica).

Home range and home range overlap can be used to describe use of space and movement of wildlife. During the last years, advancements in technology have greatly improved our understanding of animal movement, especially among large herbivores. Wild ungulate abundance and distribution have increased in temperate areas. Moreover, their diseases-including sarcoptic mange in the Iberian Ibex (Capra pyrenaica)-have become a cause of concern for livestock, public health, and wildlife conservation. In this study, we first reviewed existing literature on the home range of species in the genus Capra. We then analyzed data from 52 GPS-GSM-collared Iberian ibexes, of which 33 were healthy and 19 were affected by sarcoptic mange from 3 different populations in the southeastern Iberian Peninsula to analyze: (1) differences in size and characteristics of home ranges obtained by the 3 most commonly used methodologies-minimum convex polygon, kernel density estimation, and Brownian bridges movement models (BBMMs); and (2) the impact of endemic sarcoptic mange on Iberian Ibex home range. The literature review revealed that available information on spatial behavior of Capra spp. was based only on 3 species, including the Iberian Ibex, estimated through a diversity of methods which made it difficult to compare results. We found positive correlations among the different home range estimation methods in the Iberian Ibex, with BBMMs proving to be the most accurate. This study is the first to use BBMMs for estimating home range in this species, and it revealed a marked seasonal behavior in spatial use, although sarcoptic mange smoothed such seasonal pattern. The seasonal overlaps obtained suggest that core areas of the Iberian Ibex change within wider home range areas, which are ecological parameters relevant to identifying key areas for species management and conservation.

Sex and APOE genotype influence respiratory function under hypoxic and hypoxic-hypercapnic conditions.

The apolipoprotein E (APOE) gene has been studied due to its influence on Alzheimer's disease (AD) development and work in an APOE mouse model recently demonstrated impaired respiratory motor plasticity following spinal cord injury (SCI). Individuals with AD often copresent with obstructive sleep apnea (OSA) characterized by cessations in breathing during sleep. Despite the prominence of APOE genotype and sex as factors in AD progression, little is known about the impact of these variables on respiratory control. Ventilation is tightly regulated across many systems, with respiratory rhythm formation occurring in the brainstem but modulated in response to chemoreception. Alterations within these modulatory systems may result in disruptions of appropriate respiratory control and ultimately, disease. Using mice expressing two different humanized APOE alleles, we characterized how sex and the presence of APOE3 or APOE4 influences ventilation during baseline breathing (normoxia) and during respiratory challenges. We show that sex and APOE genotype influence breathing during hypoxic challenge, which may have clinical implications in the context of AD and OSA. In addition, female mice, while responding robustly to hypoxia, were unable to recover to baseline respiratory levels, emphasizing sex differences in disordered breathing.NEW & NOTEWORTHY This study is the first to use whole body plethysmography (WBP) to measure the impact of APOE alleles on breathing under normoxia and during adverse respiratory challenges in a targeted replacement Alzheimer's model. Both sex and genotype were shown to affect breathing under normoxia, hypoxic challenge, and hypoxic-hypercapnic challenge. This work has important implications regarding the impact of genetics on respiratory control as well as applications pertaining to conditions of disordered breathing including sleep apnea and neurotrauma.

Imbalance in Glucose Metabolism Regulates the Transition of Microglia from Homeostasis to Disease-Associated Microglia Stage 1.

Microglia undergo two-stage activation in neurodegenerative diseases, known as disease-associated microglia (DAM). TREM2 mediates the DAM2 stage transition, but what regulates the first DAM1 stage transition is unknown. We report that glucose dyshomeostasis inhibits DAM1 activation and PKM2 plays a role. As in tumors, PKM2 was aberrantly elevated in both male and female human AD brains, but unlike in tumors, it is expressed as active tetramers, as well as among TREM2+ microglia surrounding plaques in 5XFAD male and female mice. snRNAseq analyses of microglia without Pkm2 in 5XFAD mice revealed significant increases in DAM1 markers in a distinct metabolic cluster, which is enriched in genes for glucose metabolism, DAM1, and AD risk. 5XFAD mice incidentally exhibited a significant reduction in amyloid pathology without microglial Pkm2 Surprisingly, microglia in 5XFAD without Pkm2 exhibited increases in glycolysis and spare respiratory capacity, which correlated with restoration of mitochondrial cristae alterations. In addition, in situ spatial metabolomics of plaque-bearing microglia revealed an increase in respiratory activity. These results together suggest that it is not only glycolytic but also respiratory inputs that are critical to the development of DAM signatures in 5XFAD mice.

The prohibition of recreational hunting of wild ungulates in Spanish National Parks: Challenges and opportunities.

A new regulation has led to the prohibition of recreational hunting on estates located within Spanish National Parks (NPs). Before the ban, eleven NPs in Spain had already reported negative ecological consequences associated with high densities of wild ungulates. The new situation that has occurred after the ban signifies that policies with which to control populations of wild ungulates in NPs, most of which do not have a sufficient natural capacity to regulate populations, depend exclusively on the parks' authorities. The banning of recreational hunting implies a series of social, ecological, economic and logistic challenges. The control of wild ungulate populations in NPs requires: i) the legal basis for culling; ii) social acceptance as regards removing animals and the extractive procedures employed in NPs; iii) the long-term monitoring of wild ungulates and the damages that they cause, and iv) sufficient financial and human resources. A more integrated management and policy plan is, therefore, required, which should be supported by two pillars: i) the sustainability of natural resources and the conservation of functional environments, and ii) providing society with explanations regarding the need to manage wild ungulates. In order to bridge the potential gap between these key pillars, it is important to involve stakeholders in the decision-making processes concerning wild ungulate management. The forthcoming changes in Spanish NPs provide a promising opportunity to make a substantial improvement to wild ungulate management in these protected areas. This management approach could, moreover, serve as an example and be transferred to other protected spaces.

Risk of heart failure in ambulatory resistant hypertension: a meta-analysis of observational studies.

The impact of ambulatory resistant hypertension (ARH) on the occurrence of heart failure (HF) is not yet completely known. We performed for the first time a meta-analysis, by using published data or available data from published databases, on the risk of HF in ARH. Patients with ARH (24-h BP ≥ 130/80 mmHg during treatment with ≥3 drugs) were compared with those with controlled hypertension (CH, clinic BP < 140/90 mmHg and 24-h BP < 130/80 mmHg regardless of the number of drugs used), white coat uncontrolled resistant hypertension (WCURH, clinic BP ≥ 140/90 mmHg and 24-h BP < 130/80 mmHg in treated patients) and ambulatory nonresistant hypertension (ANRH, 24-h BP ≥ 130/80 mmHg during therapy with ≤2 drugs). We identified six studies/databases including 21,365 patients who experienced 692 HF events. When ARH was compared with CH, WCURH, or ANRH, the overall adjusted hazard ratio for HF was 2.32 (95% confidence interval (CI) 1.45-3.72), 1.72 (95% CI 1.36-2.17), and 2.11 (95% CI 1.40-3.17), respectively, (all P < 0.001). For some comparisons a moderate heterogeneity was found. Though we did not find variables that could explain the heterogeneity, sensitivity analyses demonstrated that none of the studies had a significant influential effect on the overall estimate. When we evaluated the potential presence of publication bias and small-study effect and adjusted for missing studies identified by Duval and Tweedie's method the estimates were slightly lower but remained significant. This meta-analysis shows that treated hypertensive patients with ARH are at approximately twice the risk of developing HF than other ambulatory BP phenotypes.

Landscape and mosquito community impact the avian Plasmodium infection in Culex pipiens.

Avian malaria parasites provide an important model for studying host-pathogen interactions, yet understanding their dynamics in vectors under natural conditions is limited. We investigated the effect of vector abundance, species richness and diversity, and habitat characteristics on avian Plasmodium prevalence and lineage richness in Culex pipiens across 45 urban, natural, and rural localities in southern Spain. Analyzing 16,574 mosquitoes grouped in 768 mosquito pools, 32.7% exhibited parasite presence. 13 different Plasmodium lineages were identified, with the lineage SYAT05 being the most commonly found. Parasite prevalence positively correlated with the distance to saltmarshes and rivers, but negatively with the distance to total water source. Parasite lineage diversity was higher in natural than in rural areas and positively correlated with mosquito species richness. These results emphasize the complex dynamics of avian Plasmodium in the wild, with habitat characteristics and vector community driving the parasite transmission by mosquito vectors.

Clinical trial design for assessing hypertension medications: are critical circadian chronopharmacological principles being taking into account?

INTRODUCTION: Clinical hypertension trials typically rely on homeostatic principles, including single time-of-day office blood pressure (BP) measurements (OBPM), rather than circadian chronopharmacological principles, including ambulatory monitoring (ABPM) done around-the-clock to derive the asleep systolic BP (SBP) mean and sleep-time relative SBP decline - jointly the strongest prognosticators of cardiovascular disease (CVD) risk and true definition of hypertension - to qualify participants and assess outcomes. AREAS COVERED: Eight chronopharmacological elements are indispensable for design and conduct of hypertension medication trials, mainly those on ingestion-time differences in effects, and also a means of rating quality of investigations. Accordingly, we highlight the findings and shortcomings of: (i) 155 such ingestion-time trials, 83.9% finding at-bedtime/evening treatment more beneficial than conventional upon-awakening/morning treatment; (ii) HOPE and ONTARGET CVD outcomes investigations assessing in the former add-on ramipril at-bedtime and in the latter telmisartan, ramipril, or both in combination in the morning; and (iii) pragmatic TIME CVD outcomes trial. EXPERT OPINION: Failure to incorporate chronopharmacological principals - including ABPM to derive asleep SBP and SBP dipping to qualify subjects as hypertensive and assess CVD risk - results in deficient study design, dubious findings, and unnecessary medical controversy at the expense of advances in patient care.

Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders.

Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors of this enzyme. Here, we report the preclinical characterization of MZ-101, a small molecule that potently inhibits GYS1 in vitro and in vivo without inhibiting GYS2, a related isoform essential for synthesizing liver glycogen. Chronic treatment with MZ-101 depleted muscle glycogen and was well tolerated in mice. Pompe disease, a glycogen storage disease caused by mutations in acid α glucosidase (GAA), results in pathological accumulation of glycogen and consequent autophagolysosomal abnormalities, metabolic dysregulation, and muscle atrophy. Enzyme replacement therapy (ERT) with recombinant GAA is the only approved treatment for Pompe disease, but it requires frequent infusions, and efficacy is limited by suboptimal skeletal muscle distribution. In a mouse model of Pompe disease, chronic oral administration of MZ-101 alone reduced glycogen buildup in skeletal muscle with comparable efficacy to ERT. In addition, treatment with MZ-101 in combination with ERT had an additive effect and could normalize muscle glycogen concentrations. Biochemical, metabolomic, and transcriptomic analyses of muscle tissue demonstrated that lowering of glycogen concentrations with MZ-101, alone or in combination with ERT, corrected the cellular pathology in this mouse model. These data suggest that substrate reduction therapy with GYS1 inhibition may be a promising therapeutic approach for Pompe disease and other glycogen storage diseases.

Voltage-gated potassium channels control extended access cocaine seeking: a role for nucleus accumbens astrocytes.

Dopaminergic signaling in the nucleus accumbens shell (NAc) regulates neuronal activity relevant to reward-related learning, including cocaine-associated behaviors. Although astrocytes respond to dopamine and cocaine with structural changes, the impact of dopamine and cocaine on astrocyte functional plasticity has not been widely studied. Specifically, behavioral implications of voltage-gated channel activity in the canonically non-excitable astrocytes are not known. We characterized potassium channel function in NAc astrocytes following exposure to exogenous dopamine or cocaine self-administration training under short (2 h/day) and extended (6 h/day) access schedules. Electrophysiological, Ca2+ imaging, mRNA, and mass spectrometry tools were used for molecular characterization. Behavioral effects were examined after NAc-targeted microinjections of channel antagonists and astroglial toxins. Exogenous dopamine increased activity of currents mediated by voltage-gated (Kv7) channels in NAc astrocytes. This was associated with a ~5-fold increase in expression of Kcnq2 transcript level in homogenized NAc micropunches. Matrix-assisted laser desorption/ionization mass spectrometry revealed increased NAc dopamine levels in extended access, relative to short access, rats. Kv7 inhibition selectively increased frequency and amplitude of astrocyte intracellular Ca2+ transients in NAc of extended access rats. Inhibition of Kv7 channels in the NAc attenuated cocaine-seeking in extended access rats only, an effect that was occluded by microinjection of the astrocyte metabolic poison, fluorocitrate. These results suggest that voltage-gated K+ channel signaling in NAc astrocytes is behaviorally relevant, support Kv7-mediated regulation of astrocyte Ca2+ signals, and propose novel mechanisms of neuroglial interactions relevant to drug use.

MetaVision3D: Automated Framework for the Generation of Spatial Metabolome Atlas in 3D.

High-resolution spatial imaging is transforming our understanding of foundational biology. Spatial metabolomics is an emerging field that enables the dissection of the complex metabolic landscape and heterogeneity from a thin tissue section. Currently, spatial metabolism highlights the remarkable complexity in two-dimensional space and is poised to be extended into the three-dimensional world of biology. Here, we introduce MetaVision3D, a novel pipeline driven by computer vision techniques for the transformation of serial 2D MALDI mass spectrometry imaging sections into a high-resolution 3D spatial metabolome. Our framework employs advanced algorithms for image registration, normalization, and interpolation to enable the integration of serial 2D tissue sections, thereby generating a comprehensive 3D model of unique diverse metabolites across host tissues at mesoscale. As a proof of principle, MetaVision3D was utilized to generate the mouse brain 3D metabolome atlas (available at https://metavision3d.rc.ufl.edu/ ) as an interactive online database and web server to further advance brain metabolism and related research.

TgLaforin, a glucan phosphatase, reveals the dynamic role of storage polysaccharides in Toxoplasma gondii tachyzoites and bradyzoites.

The asexual stages of Toxoplasma gondii are defined by the rapidly growing tachyzoite during the acute infection and by the slow growing bradyzoite housed within tissue cysts during the chronic infection. These stages represent unique physiological states, each with distinct glucans reflecting differing metabolic needs. A defining feature of T. gondii bradyzoites is the presence of insoluble storage glucans known as amylopectin granules (AGs) that are believed to play a role in reactivation, but their functions during the chronic infection remain largely unexplored. More recently, the presence of storage glucans has been recognized in tachyzoites where their precise function and architecture have yet to be fully defined. Importantly, the T. gondii genome encodes activities needed for glucan turnover: a glucan phosphatase (TgLaforin; TGME49_205290) and a glucan kinase (TgGWD; TGME49_214260) that catalyze a cycle of reversible glucan phosphorylation required for glucan degradation by amylases. The expression of these enzymes in tachyzoites supports the existence of a storage glucan, evidence that is corroborated by specific labeling with the anti-glycogen antibody IV58B6. Disruption of reversible glucan phosphorylation via a CRISPR/Cas9 knockout (KO) of TgLaforin revealed no growth defects under nutrient-replete conditions in tachyzoites. However, the growth of TgLaforin-KO tachyzoites was severely stunted when starved of glutamine, even under glucose replete conditions. The loss of TgLaforin also resulted in the attenuation of acute virulence in mice accompanied by a lower cyst burden. Defective cyst formation due to profound changes in AG morphology was also observed in TgLaforin-KO parasites, both in vitro and in vivo. Together, these data demonstrate the importance of glucan turnover across the T. gondii asexual cycle. These findings, alongside our previously identified class of small molecules that inhibit TgLaforin, implicate reversible glucan phosphorylation as a legitimate target for the development of new drugs against chronic T. gondii infections.

RIT1 regulation of CNS lipids RIT1 deficiency Alters cerebral lipid metabolism and reduces white matter tract oligodendrocytes and conduction velocities.

Oligodendrocytes (OLs) generate lipid-rich myelin membranes that wrap axons to enable efficient transmission of electrical impulses. Using a RIT1 knockout mouse model and in situ high-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) coupled with MS-based lipidomic analysis to determine the contribution of RIT1 to lipid homeostasis. Here, we report that RIT1 loss is associated with altered lipid levels in the central nervous system (CNS), including myelin-associated lipids within the corpus callosum (CC). Perturbed lipid metabolism was correlated with reduced numbers of OLs, but increased numbers of GFAP+ glia, in the CC, but not in grey matter. This was accompanied by reduced myelin protein expression and axonal conduction deficits. Behavioral analyses revealed significant changes in voluntary locomotor activity and anxiety-like behavior in RIT1KO mice. Together, these data reveal an unexpected role for RIT1 in the regulation of cerebral lipid metabolism, which coincide with altered white matter tract oligodendrocyte levels, reduced axonal conduction velocity, and behavioral abnormalities in the CNS.

Loss of carnitine palmitoyltransferase 1a reduces docosahexaenoic acid-containing phospholipids and drives sexually dimorphic liver disease in mice.

BACKGROUND AND AIMS: Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the role of liver-specific CPT1a on hepatic lipid metabolism. APPROACH AND RESULTS: Male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (60% kcal fat) for 15 weeks. Mice were necropsied after a 16 h fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging, kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis (Plin2, Cidec, G0S2) and in polyunsaturated fatty acid metabolism (Elovl5, Fads1, Elovl2), while only female LKO mice increased genes involved in inflammation (Ly6d, Mmp12, Cxcl2). Kinase profiling showed decreased protein kinase A activity, which coincided with increased PLIN2, PLIN5, and G0S2 protein levels and decreased triglyceride hydrolysis in LKO mice. CONCLUSIONS: Liver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury.

Inhibition of mitochondrial fission activates glycogen synthesis to support cell survival in colon cancer.

Metabolic reprogramming has been recognized as one of the major mechanisms that fuel tumor initiation and progression. Our previous studies demonstrate that activation of Drp1 promotes fatty acid oxidation and downstream Wnt signaling. Here we investigate the role of Drp1 in regulating glycogen metabolism in colon cancer. Knockdown of Drp1 decreases mitochondrial respiration without increasing glycolysis. Analysis of cellular metabolites reveals that the levels of glucose-6-phosphate, a precursor for glycogenesis, are significantly elevated whereas pyruvate and other TCA cycle metabolites remain unchanged in Drp1 knockdown cells. Additionally, silencing Drp1 activates AMPK to stimulate the expression glycogen synthase 1 (GYS1) mRNA and promote glycogen storage. Using 3D organoids from Apcf/f/Villin-CreERT2 models, we show that glycogen levels are elevated in tumor organoids upon genetic deletion of Drp1. Similarly, increased GYS1 expression and glycogen accumulation are detected in xenograft tumors derived from Drp1 knockdown colon cancer cells. Functionally, increased glycogen storage provides survival advantage to Drp1 knockdown cells. Co-targeting glycogen phosphorylase-mediated glycogenolysis sensitizes Drp1 knockdown cells to chemotherapy drug treatment. Taken together, our results suggest that Drp1-loss activates glucose uptake and glycogenesis as compensative metabolic pathways to promote cell survival. Combined inhibition of glycogen metabolism may enhance the efficacy of chemotherapeutic agents for colon cancer treatment.