bims-mepmim 2022-12-11 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2022–12–11
27 papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Innate antiviral immunity and immunometabolism in hepatocytes.
Nitric oxide regulation of cellular metabolism: Adaptive tuning of cellular energy.
Insights into the Effect of Catalytic Intratumoral Lactate Depletion on Metabolic Reprogramming and Immune Activation for Antitumoral Activity.
Hypoxic activation of PFKFB4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence.
Distinct effects of intracellular vs. extracellular acidic pH on the cardiac metabolome during ischemia and reperfusion.
Vitamin B12 deficiency induces glucose intolerance, delays peak insulin levels and promotes ketogenesis in female rats.
Isolated murine skeletal muscles utilize pyruvate over glucose for oxidation.
Not so neutral lipids: Metabolic regulation of the pre-metastatic niche.
GABA regulates IL-1β production in macrophages.
Glucose metabolism is upregulated in the mononuclear cell proteome during sepsis and supports endotoxin-tolerant cell function.
Ammonia detoxification promotes CD8+ T cell memory development by urea and citrulline cycles.
Metabolic hallmarks of natural killer cells in the tumor microenvironment and implications in cancer immunotherapy.
Decreased propionyl-CoA metabolism facilitates metabolic reprogramming and promotes hepatocellular carcinoma.
The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction.
Blockage of lamin-A/C loss diminishes the pro-inflammatory macrophage response.
Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84.
Extracellular vesicle-derived LINC00511 promotes glycolysis and mitochondrial oxidative phosphorylation of pancreatic cancer through macrophage polarization by microRNA-193a-3p-dependent regulation of plasminogen activator urokinase.
Myeloid-Derived Itaconate Suppresses Antitumor Immunity.
Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis.
Heme-dependent induction of mitophagy program during murine erythroid cell differentiation.
Mitochondrial succinate dehydrogenase function is essential for sperm motility and male fertility.
Inner mitochondrial membrane structure and fusion dynamics are altered in senescent human iPSC-derived and primary rat cardiomyocytes.
Cancer cell-derived type I interferons instruct tumor monocyte polarization.
Glycine inhibits NINJ1 membrane clustering to suppress plasma membrane rupture in cell death.
Dendritic cells direct circadian anti-tumor immune responses.
A plant-derived natural photosynthetic system for improving cell anabolism.
Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction.

Curr Opin Immunol. 2022 Nov 29. pii: S0952-7915(22)00114-5. [Epub ahead of print]80 102267

Innate antiviral immunity and immunometabolism in hepatocytes.

Vasile Mihai Sularea, Jamie A Sugrue, Cliona O'Farrelly.

The human liver mediates whole-body metabolism, systemic inflammation and responses to hepatotropic pathogens. Hepatocytes, the most abundant cell type of the liver, have critical roles in each of these activities. The regulation of metabolic pathways, such as glucose metabolism, lipid biosynthesis and oxidation, influences whole-organism functionality. However, the immune potential of the liver in general and hepatocytes in particular is also determined by metabolic ability. The major shifts in cellular metabolism required to drive activity in immune cells are now well-described. Given the unique functions of hepatocytes in systemic metabolism and inflammation, and their ability to mediate local antiviral innate immunity, the metabolic shifts required to facilitate these activities are likely to be complex and challenging to define. In this review, we explore what is known about the complex metabolic rewiring required for hepatocytes to respond appropriately to viral infection. We also discuss how viruses can manipulate hepatocyte metabolism to facilitate infection.

DOI: https://doi.org/10.1016/j.coi.2022.102267
Nitric Oxide. 2022 Dec 02. pii: S1089-8603(22)00125-2. [Epub ahead of print]

Nitric oxide regulation of cellular metabolism: Adaptive tuning of cellular energy.

Gregory Pappas, Melissa L Wilkinson, Andrew J Gow.

  Nitric oxide can interact with a wide range of proteins including many that are involved in metabolism. In this review we have summarized the effects of NO on glycolysis, fatty acid metabolism, the TCA cycle, and oxidative phosphorylation with reference to skeletal muscle. Low to moderate NO concentrations upregulate glucose and fatty acid oxidation, while higher NO concentrations shift cellular reliance toward a fully glycolytic phenotype. Moderate NO production directly inhibits pyruvate dehydrogenase activity, reducing glucose-derived carbon entry into the TCA cycle and subsequently increasing anaploretic reactions. NO directly inhibits aconitase activity, increasing reliance on glutamine for continued energy production. At higher or prolonged NO exposure, citrate accumulation can inhibit multiple ATP-producing pathways. Reduced TCA flux slows NADH/FADH entry into the ETC. NO can also inhibit the ETC directly, further limiting oxidative phosphorylation. Moderate NO production improves mitochondrial efficiency while improving O2 utilization increasing whole-body energy production. Long-term bioenergetic capacity may be increased because of NO-derived ROS, which participate in adaptive cellular redox signaling through AMPK, PCG1-α, HIF-1, and NF-κB. However, prolonged exposure or high concentrations of NO can result in membrane depolarization and opening of the MPT. In this way NO may serve as a biochemical rheostat matching energy supply with demand for optimal respiratory function.

Keywords:  Cellular respiration; Exercise; Glycolysis; Metabolism; Mitochondria; Nitric oxide

DOI:  https://doi.org/10.1016/j.niox.2022.11.006
Adv Sci (Weinh). 2022 Dec 07. e2204808

Insights into the Effect of Catalytic Intratumoral Lactate Depletion on Metabolic Reprogramming and Immune Activation for Antitumoral Activity.

Junlong Zhao, Zhimin Tian, Shoujie Zhao, Dayun Feng, Zhixiong Guo, Liangzhi Wen, Yejing Zhu, Fenghua Xu, Jun Zhu, Shouzheng Ma, Jie Hu, Tao Jiang, Yongquan Qu, Dongfeng Chen, Lei Liu.

  Lactate, a characteristic metabolite of the tumor microenvironment (TME), drives immunosuppression and promotes tumor progression. Material-engineered strategies for intratumoral lactate modulations demonstrate their promise for tumor immunotherapy. However, understanding of the inherent interconnections of material-enabled lactate regulation, metabolism, and immunity in the TME is scarce. To address this issue, urchin-like catalysts of the encapsulated Gd-doped CeO2 , syrosingopine, and lactate oxidase are used in ZIF-8 (USL, where U, S, and L represent the urchin-like Gd-doped CeO2 @ZIF-8, syrosingopine, and lactate oxidase, respectively) and orthotopic tumor models. The instructive relationships of intratumoral lactate depletion, metabolic reprogramming, and immune activation for catalytic immunotherapy of tumors is illustrated. The catalysts efficiently oxidize intratumoral lactate and significantly promote tumor cell apoptosis by in situ-generated ·OH, thereby reducing glucose supply and inducing mitochondrial damage via lactate depletion, thus reprogramming glycometabolism. Subsequently, such catalytic metabolic reprogramming evokes both local and systemic antitumor immunity by activating M1-polarizaed macrophages and CD8+ T cells, leading to potent antitumor immunity. This study provides valuable mechanistic insights into material-interfered tumor therapy through intratumoral lactate depletion and consequential connection with metabolic reprogramming and immunity remodeling, which is thought to enhance the efficacy of immunotherapy.

Keywords:  catalysis; immunotherapy; lactate; metabolism; tumor

DOI:  https://doi.org/10.1002/advs.202204808
Cell Rep. 2022 Dec 06. pii: S2211-1247(22)01639-4. [Epub ahead of print]41(10): 111756

Hypoxic activation of PFKFB4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence.

Tao Dai, Spencer R Rosario, Eriko Katsuta, Abhisha Sawant Dessai, Emily J Paterson, Aaron T Novickis, Eduardo Cortes Gomez, Bokai Zhu, Song Liu, Hai Wang, Scott I Abrams, Mukund Seshadri, Wiam Bshara, Subhamoy Dasgupta.

  Cancer cells encounter a hostile tumor microenvironment (TME), and their adaptations to metabolic stresses determine metastatic competence. Here, we show that the metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) is induced in hypoxic tumors acquiring metabolic plasticity and invasive phenotype. In mouse models of breast cancer, genetic ablation of PFKFB4 significantly delays distant organ metastasis, reducing local lymph node invasion by suppressing expression of invasive gene signature including integrin β3. Photoacoustic imaging followed by metabolomics analyses of hypoxic tumors show that PFKFB4 drives metabolic flexibility, enabling rapid detoxification of reactive oxygen species favoring survival under selective pressure. Mechanistically, hypoxic induction triggers nuclear translocation of PFKFB4 accentuating non-canonical transcriptional activation of HIF-1α, and breast cancer patients with increased nuclear PFKFB4 in their tumors are found to be significantly associated with poor prognosis. Our findings imply that PFKFB4 induction is crucial for tumor cell adaptation in the hypoxic TME that determines metastatic competence.

Keywords:  CP: Cancer; CP: Metabolism; breast cancer; hypoxia; metabolism; metastasis; redox; stress; transcription; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2022.111756
J Mol Cell Cardiol. 2022 Dec 05. pii: S0022-2828(22)00568-5. [Epub ahead of print]174 101-114

Distinct effects of intracellular vs. extracellular acidic pH on the cardiac metabolome during ischemia and reperfusion.

Alexander S Milliken, Jessica H Ciesla, Sergiy M Nadtochiy, Paul S Brookes.

  Tissue ischemia results in intracellular pH (pHIN) acidification, and while metabolism is a known driver of acidic pHIN, less is known about how acidic pHIN regulates metabolism. Furthermore, acidic extracellular (pHEX) during early reperfusion confers cardioprotection, but how this impacts metabolism is unclear. Herein we employed LCMS based targeted metabolomics to analyze perfused mouse hearts exposed to: (i) control perfusion, (ii) hypoxia, (iii) ischemia, (iv) enforced acidic pHIN, (v) control reperfusion, and (vi) acidic pHEX (6.8) reperfusion. Surprisingly little overlap was seen between metabolic changes induced by hypoxia, ischemia, and acidic pHIN. Acidic pHIN elevated metabolites in the top half of glycolysis, and enhanced glutathione redox state. Meanwhile, acidic pHEX reperfusion induced substantial metabolic changes in addition to those seen in control reperfusion. This included elevated metabolites in the top half of glycolysis, prevention of purine nucleotide loss, and an enhancement in glutathione redox state. These data led to hypotheses regarding potential roles for methylglyoxal inhibiting the mitochondrial permeability transition pore, and for acidic inhibition of ecto-5'-nucleotidase, as potential mediators of cardioprotection by acidic pHEX reperfusion. However, neither hypothesis was supported by subsequent experiments. In contrast, analysis of cardiac effluents revealed complex effects of pHEX on metabolite transport, suggesting that mildly acidic pHEX may enhance succinate release during reperfusion. Overall, each intervention had distinct and overlapping metabolic effects, suggesting acidic pH is an independent metabolic regulator regardless which side of the cell membrane it is imposed.

Keywords:  Acidosis; Hypoxia; Ischemia; Metabolism; Purines; pH

DOI:  https://doi.org/10.1016/j.yjmcc.2022.11.008
J Endocrinol. 2022 Dec 01. pii: JOE-22-0158. [Epub ahead of print]

Vitamin B12 deficiency induces glucose intolerance, delays peak insulin levels and promotes ketogenesis in female rats.

Elliott Neal, Vinod Kumar, Karin Borges, James Sm Cuffe.

Vitamin B12 (B12) deficiency is common among individuals with diabetes mellitus but it is unknown if B12 deficiency contributes to impaired glucose homeostasis in this disorder. Female Sprague-Dawley rats were assigned to a control or B12 deficient diet for 4 weeks. Intraperitoneal glucose tolerance tests were performed after 25 days and blood and liver samples were collected for metabolic profiling. B12 deficiency resulted in a prediabetic-like phenotype characterised by glucose intolerance, a delayed peak in plasma insulin levels following a glucose challenge and increased ketogenesis. We attributed increased ketogenesis to reduced liver anaplerosis, which limited availability of the TCA cycle intermediates citrate and succinate. This was associated with increased Mut mRNA levels and citrate synthase activity and lower succinyl-CoA availability. One carbon metabolite levels were altered in plasma and the liver, which was linked to reduced methylation capacity, altered amino acid levels and elevated Slc7a5 mRNA expression. Plasma folate and biotin levels were reduced, as were the majority of B vitamins in the liver. Changes in these B12-dependent processes and reduced B vitamin amounts likely contributed to deficits in glucose handling. Our findings highlight that B12 deficiency may promote the development of metabolic disorders like diabetes mellitus and emphasise the importance of adequate B12 intake for metabolic health.

DOI: https://doi.org/10.1530/JOE-22-0158
Metabolomics. 2022 Dec 08. 18(12): 105

Isolated murine skeletal muscles utilize pyruvate over glucose for oxidation.

Ram B Khattri, Jason Puglise, Terence E Ryan, Glenn A Walter, Matthew E Merritt, Elisabeth R Barton.

   INTRODUCTION: Fuel sources for skeletal muscle tissue include carbohydrates and fatty acids, and utilization depends upon fiber type, workload, and substrate availability. The use of isotopically labeled substrate tracers combined with nuclear magnetic resonance (NMR) enables a deeper examination of not only utilization of substrates by a given tissue, but also their contribution to tricarboxylic acid (TCA) cycle intermediates.
OBJECTIVES: The goal of this study was to determine the differential utilization of substrates in isolated murine skeletal muscle, and to evaluate how isopotomer anlaysis provided insight into skeletal muscle metabolism.
METHODS: Isolated C57BL/6 mouse hind limb muscles were incubated in oxygenated solution containing uniformly labeled 13C6 glucose, 13C3 pyruvate, or 13C2 acetate at room temperature. Isotopomer analysis of 13C labeled glutamate was performed on pooled extracts of isolated soleus and extensor digitorum longus (EDL) muscles.
RESULTS: Pyruvate and acetate were more avidly consumed than glucose with resultant increases in glutamate labeling in both muscle groups. Glucose incubation resulted in glutamate labeling, but with high anaplerotic flux in contrast to the labeling by pyruvate. Muscle fiber type distinctions were evident by differences in lactate enrichment and extent of substrate oxidation.
CONCLUSION: Isotope tracing experiments in isolated muscles reveal that pyruvate and acetate are avidly oxidized by isolated soleus and EDL muscles, whereas glucose labeling of glutamate is accompanied by high anaplerotic flux. We believe our results may set the stage for future examination of metabolic signatures of skeletal muscles from pre-clinical models of aging, type-2 diabetes and neuromuscular disease.

Keywords:  Glucose metabolism; Metabolic tracer; Nuclear magnetic resonance (NMR); Skeletal muscle metabolism; Substrate specificity

DOI:  https://doi.org/10.1007/s11306-022-01948-x
Cell Metab. 2022 Dec 06. pii: S1550-4131(22)00498-3. [Epub ahead of print]34(12): 1899-1900

Not so neutral lipids: Metabolic regulation of the pre-metastatic niche.

Joshua D Schoenfeld, Santosha A Vardhana.

How primary tumors alter distant tissue sites to facilitate seeding and metastasis remains unclear. In this issue, Gong et al. demonstrate that IL-1β-dependent lipid accumulation in lung mesenchymal cells supports both tumor growth and NK cell dysfunction, facilitating lung metastasis of primary breast tumors.

DOI: https://doi.org/10.1016/j.cmet.2022.11.007
Cell Rep. 2022 Dec 06. pii: S2211-1247(22)01653-9. [Epub ahead of print]41(10): 111770

GABA regulates IL-1β production in macrophages.

Jian Fu, Ziyi Han, Zebiao Wu, Yaoyao Xia, Guan Yang, Yulong Yin, Wenkai Ren.

  Neurotransmitters have been well documented to determine immune cell fates; however, whether and how γ-amino butyric acid (GABA) shapes the function of innate immune cells is still obscure. Here, we demonstrate that GABA orchestrates macrophage maturation and inflammation. GABA treatment during macrophage maturation inhibits interleukin (IL)-1β production from inflammatory macrophages. Mechanistically, GABA enhances succinate-flavin adenine dinucleotide (FAD)-lysine specific demethylase1 (LSD1) signaling to regulate histone demethylation of Bcl2l11 and Dusp2, reducing formation of the NLRP3-ASC-Caspase-1 complex. The GABA-succinate axis reduces succinylation of mitochondrial proteins to promote oxidative phosphorylation (OXPHOS). We also find that GABA alleviates lipopolysaccharides (LPS)-induced sepsis as well as high-fat-diet-induced obesity in mice. Our study shows that GABA regulates pro-inflammatory macrophage responses associated with metabolic reprogramming and protein succinylation, suggesting a strategy for treating macrophage-related inflammatory diseases.

Keywords:  CP: Immunology; FAD; GABA; macrophage; succinate; succinylation

DOI:  https://doi.org/10.1016/j.celrep.2022.111770
Front Immunol. 2022 ;13 1051514

Glucose metabolism is upregulated in the mononuclear cell proteome during sepsis and supports endotoxin-tolerant cell function.

Bianca Lima Ferreira, Mônica Bragança Sousa, Giuseppe Gianini Figueirêdo Leite, Milena Karina Colo Brunialti, Erika Sayuri Nishiduka, Alexandre Keiji Tashima, Tom van der Poll, Reinaldo Salomão.

  Metabolic adaptations shape immune cell function. In the acute response, a metabolic switch towards glycolysis is necessary for mounting a proinflammatory response. During the clinical course of sepsis, both suppression and activation of immune responses take place simultaneously. Leukocytes from septic patients present inhibition of cytokine production while other functions such as phagocytosis and production of reactive oxygen species (ROS) are preserved, similarly to the in vitro endotoxin tolerance model, where a first stimulation with lipopolysaccharide (LPS) affects the response to a second stimulus. Here, we sought to investigate how cellular metabolism is related to the modulation of immune responses in sepsis and endotoxin tolerance. Proteomic analysis in peripheral blood mononuclear cells (PBMCs) from septic patients obtained at intensive care unit admission showed an upregulation of proteins related to glycolysis, the pentose phosphate pathway (PPP), production of ROS and nitric oxide, and downregulation of proteins in the tricarboxylic acid cycle and oxidative phosphorylation compared to healthy volunteers. Using the endotoxin-tolerance model in PBMCs from healthy subjects, we observed increased lactate production in control cells upon LPS stimulation, while endotoxin-tolerant cells presented inhibited tumor necrosis factor-α and lactate production along with preserved phagocytic capacity. Inhibition of glycolysis and PPP led to impairment of phagocytosis and cytokine production both in control and in endotoxin-tolerant cells. These data indicate that glucose metabolism supports leukocyte functions even in a condition of endotoxin tolerance.

Keywords:  LPS; PBMCs; endotoxin-tolerance; glycolysis; immunometabolism; pentose phosphate pathway; sepsis

DOI:  https://doi.org/10.3389/fimmu.2022.1051514
Nat Immunol. 2022 Dec 05.

Ammonia detoxification promotes CD8+ T cell memory development by urea and citrulline cycles.

Ke Tang, Huafeng Zhang, Jinghui Deng, Dianheng Wang, Shichuan Liu, Shuya Lu, Qingfa Cui, Chen Chen, Jincheng Liu, Zhuoshun Yang, Yonggang Li, Jie Chen, Jiadi Lv, Jingwei Ma, Bo Huang.

Amino acid metabolism is essential for cell survival, while the byproduct ammonia is toxic and can injure cellular longevity. Here we show that CD8+ memory T (TM) cells mobilize the carbamoyl phosphate (CP) metabolic pathway to clear ammonia, thus promoting memory development. CD8+ TM cells use β-hydroxybutyrylation to upregulate CP synthetase 1 and trigger the CP metabolic cascade to form arginine in the cytosol. This cytosolic arginine is then translocated into the mitochondria where it is split by arginase 2 to urea and ornithine. Cytosolic arginine is also converted to nitric oxide and citrulline by nitric oxide synthases. Thus, both the urea and citrulline cycles are employed by CD8+ T cells to clear ammonia and enable memory development. This ammonia clearance machinery might be targeted to improve T cell-based cancer immunotherapies.

DOI: https://doi.org/10.1038/s41590-022-01365-1
Oncogene. 2022 Dec 06.

Metabolic hallmarks of natural killer cells in the tumor microenvironment and implications in cancer immunotherapy.

Yuqing Yang, Lin Chen, Bohao Zheng, Shengtao Zhou.

Natural killer (NK) cells belong to the early responder group against cancerous cells and viral infection. Emerging evidence reveals that distinct metabolic reprogramming occurs concurrently with activation and memory formation of NK cells. However, metabolism of NK cells is disturbed in the tumor immune microenvironment, which may promote tumor progression while limiting immunotherapy responses. In this review, we highlight how cell metabolism influences NK cell activity, the key molecular regulators of NK cell metabolism, and emerging strategies to alter metabolism to improve cytotoxicity of NK cells to kill tumor cells for cancer patients.

DOI: https://doi.org/10.1038/s41388-022-02562-w
J Hepatol. 2022 Nov 30. pii: S0168-8278(22)03311-6. [Epub ahead of print]

Decreased propionyl-CoA metabolism facilitates metabolic reprogramming and promotes hepatocellular carcinoma.

Jiaqi Sun, Jun Ding, Qingsong Shen, Xiyang Wang, Min Wang, Yongping Huang, Xuechun Zhang, Huan Zhu, Feng Zhang, Dongde Wu, Min Peng, Zhonglin Zhang, Yufeng Yuan, Wenhua Li, Zhi-Gang She, Xiaojing Zhang, Hongliang Li, Peng Zhang, Zan Huang.

   BACKGROUND & AIMS: Alterations of multiple metabolites characterize distinct features of metabolic reprograming in hepatocellular carcinoma (HCC). However, most metabolites including propionyl-CoA (Pro-CoA) are illusive for their functions in metabolic reprograming and hepatocarcinogenesis. This study aims to dissect how Pro-CoA metabolism affects these processes.
METHODS: TCGA data and HCC samples were used to analyze the ALDH6A1-mediated Pro-CoA metabolism and its correlation with HCC. Multiple metabolites were assayed by targeted mass spectrometry. The function of ALDH6A1-generated Pro-CoA was evaluated by HCC proliferation, migration, xenograft nude mouse model and primary liver cancer mouse models. Nontargeted metabolomic and targeted energy metabolomic analyses followed by multiple biochemical assays were performed to dissect the underlying mechanisms.
RESULTS: Decreases in Pro-CoA and its derivative propionyl-L-carnitine (PLC) due to ALDH6A1 downregulation were tightly associated with HCC. Functionally, ALDH6A1-mediated Pro-CoA metabolism suppressed HCC proliferation and impaired hepatocarcinogenesis in mice. The aldehyde dehydrogenase activity was indispensable for the ALDH6A1 function while Pro-CoA carboxylases antagonized ALDH6A1 function by eliminating Pro-CoA. Mechanistically, ALDH6A1 caused a signature enrichment of central carbon metabolism in cancer and impaired energy metabolism: ALDH6A1-generated Pro-CoA suppressed citrate synthase (CS) activity that subsequently reduced TCA cycle flux, impaired mitochondrial respiration and membrane potential, and decreased ATP production. Moreover, Pro-CoA metabolism generated 2-methylcitric acid (MCA), which mimicked the inhibitory effect of Pro-CoA on CS and dampened mitochondrial respiration and HCC proliferation.
CONCLUSIONS: Our study unveils novel features that the decline of ALDH6A1-mediated Pro-CoA metabolism contributes to metabolic remodeling and facilitates hepatocarcinogenesis. Pro-CoA, PLC and MCA may serve as novel metabolic biomarkers for diagnosis and therapy of HCC. Pro-CoA metabolism may provide potential targets for development of novel strategies against HCC.
IMPACT AND IMPLICATIONS: Our study presents new insights on metabolic reprogramming and hepatocarcinogenesis attribute to the decline of ALDH6A1-mediated propionyl-CoA. These findings may enrich molecular and metabolic indicators for physicians to improve clinical practice. These biomarkers may potentially be used for diagnosis and serve as targets for the development of therapeutic strategies against HCC.

Keywords:  2-Methylcitric acid; ALDH6A1; Metabolic reprogramming; Propionyl-CoA; Propionyl-L-carnitine

DOI:  https://doi.org/10.1016/j.jhep.2022.11.017
Nat Commun. 2022 Dec 08. 13(1): 7576

The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction.

Guanlan Hu, Catriona Ling, Lijun Chi, Mehakpreet K Thind, Samuel Furse, Albert Koulman, Jonathan R Swann, Dorothy Lee, Marjolein M Calon, Celine Bourdon, Christian J Versloot, Barbara M Bakker, Gerard Bryan Gonzales, Peter K Kim, Robert H J Bandsma.

Mortality in children with severe malnutrition is strongly related to signs of metabolic dysfunction, such as hypoglycemia. Lower circulating tryptophan levels in children with severe malnutrition suggest a possible disturbance in the tryptophan-nicotinamide adenine dinucleotide (TRP-NAD+) pathway and subsequently in NAD+ dependent metabolism regulator sirtuin1 (SIRT1). Here we show that severe malnutrition in weanling mice, induced by 2-weeks of low protein diet feeding from weaning, leads to an impaired TRP-NAD+ pathway with decreased NAD+ levels and affects hepatic mitochondrial turnover and function. We demonstrate that stimulating the TRP-NAD+ pathway with NAD+ precursors improves hepatic mitochondrial and overall metabolic function through SIRT1 modulation. Activating SIRT1 is sufficient to induce improvement in metabolic functions. Our findings indicate that modulating the TRP-NAD+ pathway can improve liver metabolic function in a mouse model of severe malnutrition. These results could lead to the development of new interventions for children with severe malnutrition.

DOI: https://doi.org/10.1038/s41467-022-35317-y
iScience. 2022 Dec 22. 25(12): 105528

Blockage of lamin-A/C loss diminishes the pro-inflammatory macrophage response.

Johanna L Mehl, Ashley Earle, Jan Lammerding, Musa Mhlanga, Viola Vogel, Nikhil Jain.

  Mutations and defects in nuclear lamins can cause major pathologies, including inflammation and inflammatory diseases. Yet, the underlying molecular mechanisms are not known. We now report that the pro-inflammatory activation of macrophages, as induced by LPS or pathogenic E. coli, reduces Lamin-A/C levels thereby augmenting pro-inflammatory gene expression and cytokine secretion. We show that the activation of bone-marrow-derived macrophages (BMDMs) causes the phosphorylation and degradation of Lamin-A/C, as mediated by CDK1 and Caspase-6, respectively, necessary for upregulating IFN-β expression. Enhanced IFN-β expression subsequently increases pro-inflammatory gene expression via the IFN-β-STAT axis. Pro-inflammatory gene expression was also amplified in the complete absence of Lamin-A/C. Alternatively, pharmacological inhibition of either Lamin-A/C phosphorylation or degradation significantly downregulated pro-inflammatory gene expression, as did the targeting of IFN-β-STAT pathway members, i.e. phospho-STAT1 and phospho-STAT3. As Lamin-A/C is a previously unappreciated regulator of the pro-inflammatory macrophage response, our findings suggest novel opportunities to treat inflammatory diseases.

Keywords:  Cell biology; Functional aspects of cell biology; Immune response; Immunology

DOI:  https://doi.org/10.1016/j.isci.2022.105528
JCI Insight. 2022 Dec 08. pii: e165469. [Epub ahead of print]

Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84.

Ryuji Ohue-Kitano, Hazuki Nonaka, Akari Nishida, Yuki Masujima, Daisuke Takahashi, Takako Ikeda, Akiharu Uwamizu, Miyako Tanaka, Motoyuki Kohjima, Miki Igarashi, Hironori Katoh, Tomohiro Tanaka, Asuka Inoue, Takayoshi Suganami, Koji Hase, Yoshihiro Ogawa, Junken Aoki, Ikuo Kimura.

  Medium-chain triglycerides (MCTs), which consist of medium-chain fatty acids (MCFAs), are unique forms of dietary fat with various health benefits. GPR84 acts as a receptor for MCFAs (especially C10:0 and C12:0); however, GPR84 is still considered an orphan receptor, and the nutritional signaling of endogenous and dietary MCFAs via GPR84 remains unclear. Here, we showed that endogenous MCFA-mediated GPR84-signaling protected hepatic functions from diet-induced lipotoxicity. Under high-fat diet (HFD) conditions, GPR84-deficient mice exhibited non-alcoholic steatohepatitis (NASH) and the progression of hepatic fibrosis but not steatosis. With markedly increased hepatic MCFA levels under HFD, GPR84 suppressed lipotoxicity-induced macrophage over-activation. Thus, GPR84 is an immunomodulating receptor that suppresses excessive dietary fat intake-induced toxicity by sensing increases in MCFAs. Additionally, administering MCTs, MCFAs (C10:0 or C12:0, but not C8:0), or GPR84 agonists effectively impreoved NASH in mouse models. Exogenous GPR84 stimulation is therefore a potential strategy for treating NASH.

Keywords:  G proteincoupled receptors; Hepatology; Inflammation; Macrophages

DOI:  https://doi.org/10.1172/jci.insight.165469
Immunopharmacol Immunotoxicol. 2022 Dec 08. 1-15

Extracellular vesicle-derived LINC00511 promotes glycolysis and mitochondrial oxidative phosphorylation of pancreatic cancer through macrophage polarization by microRNA-193a-3p-dependent regulation of plasminogen activator urokinase.

Tingting Zhang, Hongyang Yu, Yuxian Bai, Jiaming Song, Jiexin Chen, Yingjie Li, Yue Cui.

   OBJECTIVE: The involvement of tumor-derived extracellular vesicles (EVs) in macrophage polarization has been reported. In our present study, we tried to discuss the regulatory role of LINC00511 encapsulated in pancreatic cancer (PCa) cell-derived EVs in the development and progression of PCa.
METHODS: EVs from PCa cell line BxPC-3 culture medium were collected and subsequently identified by electron microscopy and nanoparticle tracking analysis. The expression pattern of LINC00511 in PCa cell-derived EVs was determined. The interaction among LINC00511, microRNA-193a-3p, and plasminogen activator urokinase (PLAU) was explored. After co-culture of PCa cell-derived EVs with macrophages, the regulatory roles of LINC00511 in macrophage polarization, PCa cell functions, glucose consumption, lactate production, glycolysis, and mitochondrial oxidative phosphorylation were investigated.
RESULTS: PCa cell line BxPC-3 had highly expressed LINC00511 and LINC00511 could be internalized by macrophages. LINC00511 affected macrophage polarization through miR-193a-3p-dependent regulation of PLAU expression. Besides, EV-derived LINC00511 accelerated glycolysis and promoted mitochondrial oxidative phosphorylation of PCa cells through macrophage polarization, thus inducing invasion and migration of PCa cells.
CONCLUSION: LINC00511 encapsulated in PCa cell-derived EVs facilitates glycolysis of PCa cells through regulation of macrophage polarization in the tumor microenvironment.

Keywords:   glycolysis; LINC00511; extracellular vesicles; microRNA-193a-3p; pancreatic cancer; tumor microenvironment

DOI:  https://doi.org/10.1080/08923973.2022.2145968
Cancer Discov. 2022 Dec 09. OF1

Myeloid-Derived Itaconate Suppresses Antitumor Immunity.

Itaconate secreted by MDSCs suppresses CD8+ T-cell effector function and promotes tumor growth.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-213
Cell Rep. 2022 Dec 06. pii: S2211-1247(22)01620-5. [Epub ahead of print]41(10): 111742

Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis.

Alhaji H Janneh, Mohamed Faisal Kassir, F Cansu Atilgan, Han Gyul Lee, Megan Sheridan, Natalia Oleinik, Zdzislaw Szulc, Christina Voelkel-Johnson, Hung Nguyen, Hong Li, Yuri K Peterson, Elisabetta Marangoni, Ozge Saatci, Ozgur Sahin, Michael Lilly, Carl Atkinson, Stephen Tomlinson, Shikhar Mehrotra, Besim Ogretmen.

  Crosstalk between metabolic and signaling events that induce tumor metastasis remains elusive. Here, we determine how oncogenic sphingosine 1-phosphate (S1P) metabolism induces intracellular C3 complement activation to enhance migration/metastasis. We demonstrate that increased S1P metabolism activates C3 complement processing through S1P receptor 1 (S1PR1). S1P/S1PR1-activated intracellular C3b-α'2 is associated with PPIL1 through glutamic acid 156 (E156) and aspartic acid 111 (D111) residues, resulting in NLRP3/inflammasome induction. Inactivation mutations of S1PR1 to prevent S1P signaling or mutations of C3b-α'2 to prevent its association with PPIL1 attenuate inflammasome activation and reduce lung colonization/metastasis in mice. Also, activation of the S1PR1/C3/PPIL1/NLRP3 axis is highly associated with human metastatic melanoma tissues and patient-derived xenografts. Moreover, targeting S1PR1/C3/PPIL1/NLRP3 signaling using molecular, genetic, and pharmacologic tools prevents lung colonization/metastasis of various murine cancer cell lines using WT and C3a-receptor1 knockout (C3aR1-/-) mice. These data provide strategies for treating high-grade/metastatic tumors by targeting the S1PR1/C3/inflammasome axis.

Keywords:  CP: Cancer; CP: Metabolism; S1P; S1P receptor 1; S1PR1; complement signaling; inflammasome; metastasis; sphingolipids; sphingosine 1-phosphate

DOI:  https://doi.org/10.1016/j.celrep.2022.111742
Exp Hematol. 2022 Dec 05. pii: S0301-472X(22)00811-6. [Epub ahead of print]

Heme-dependent induction of mitophagy program during murine erythroid cell differentiation.

Masatoshi Ikeda, Hiroki Kato, Hiroki Shima, Mitsuyo Matsumoto, Eijiro Furukawa, Yan Yan, Ruiqi Liao, Jian Xu, Akihiko Muto, Tohru Fujiwara, Hideo Harigae, Emery H Bresnick, Kazuhiko Igarashi.

  Although establishing and maintaining mitochondria are essential to produce massive amounts of heme in erythroblasts, mitochondria must be degraded upon terminal differentiation to red blood cells, thus creating a bi-phasic regulatory process. Previously, we reported that iron deficiency in mice promotes mitochondria retention in red blood cells, suggesting that the proper amount of iron and/or heme is necessary for the degradation of mitochondria during erythroblast maturation. Since the transcription factor GATA1 regulates autophagy in erythroid cells, which involves mitochondrial clearance (mitophagy), we investigated the relationship between iron, heme and mitophagy by analyzing the expression of genes related to GATA1 and autophagy and the impact of iron or heme restriction on the amount of mitochondria. We found that heme promotes the expression of GATA1-regulated mitophagy-related genes and induction of mitophagy. GATA1 might induce the expression of autophagy-related genes Atg4d and Stk11 for mitophagy through a heme-dependent mechanism in murine erythroleukemia (MEL) cells and in a genetic rescue system with G1E-ER-GATA1 erythroblast cells derived from Gata1-null murine embryonic stem cells. These results provide evidence for a bi-phasic mechanism in which mitochondria are essential for heme generation, and the heme generated during differentiation promotes mitophagy and mitochondria disposal. This mechanism provides a molecular framework for understanding this fundamentally important cell biological process.

Keywords:  GATA transcription factor; autophagy; erythropoiesis; heme; iron; mitochondria

DOI:  https://doi.org/10.1016/j.exphem.2022.11.007
iScience. 2022 Dec 22. 25(12): 105573

Mitochondrial succinate dehydrogenase function is essential for sperm motility and male fertility.

Rachel M Woodhouse, Natalya Frolows, Guoqiang Wang, Azelle Hawdon, Edmund Heng Kin Wong, Linda C Dansereau, Yingying Su, Liam D Adair, Elizabeth J New, Ashleigh M Philp, Wei Kang Tan, Andrew Philp, Alyson Ashe.

  Mitochondrial health is crucial to sperm quality and male fertility, but the precise role of mitochondria in sperm function remains unclear. SDHA is a component of the succinate dehydrogenase (SDH) complex and plays a critical role in mitochondria. In humans, SDH activity is positively correlated with sperm quality, and mutations in SDHA are associated with Leigh Syndrome. Here we report that the C. elegans SDHA orthologue SDHA-2 is essential for male fertility: sdha-2 mutants produce dramatically fewer offspring due to defective sperm activation and motility, have hyperfused sperm mitochondria, and disrupted redox balance. Similar sperm motility defects in sdha-1 and icl-1 mutant animals suggest an imbalance in metabolites may underlie the fertility defect. Our results demonstrate a role for SDHA-2 in sperm motility and male reproductive health and establish an animal model of SDH deficiency-associated infertility.

Keywords:  Biological sciences; biochemistry; cell biology; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2022.105573
Biochim Biophys Acta Bioenerg. 2022 Dec 06. pii: S0005-2728(22)00419-4. [Epub ahead of print] 148949

Inner mitochondrial membrane structure and fusion dynamics are altered in senescent human iPSC-derived and primary rat cardiomyocytes.

Silke Morris, Isidora Molina-Riquelme, Gonzalo Barrientos, Francisco Bravo, Geraldine Aedo, Wileidy Gómez, Daniel Lagos, Hugo Verdejo, Stefan Peischard, Guiscard Seebohm, Olympia Ekaterini Psathaki, Verónica Eisner, Karin B Busch.

  Dysfunction of the aging heart is a major cause of death in the human population. Amongst other tasks, mitochondria are pivotal to supply the working heart with ATP. The mitochondrial inner membrane (IMM) ultrastructure is tailored to meet these demands and to provide nano-compartments for specific tasks. Thus, function and morphology are closely coupled. Senescent cardiomyocytes from the mouse heart display alterations of the inner mitochondrial membrane. To study the relation between inner mitochondrial membrane architecture, dynamics and function is hardly possible in living organisms. Here, we present two cardiomyocyte senescence cell models that allow in cellular studies of mitochondrial performance. We show that doxorubicin treatment transforms human iPSC-derived cardiomyocytes and rat neonatal cardiomyocytes in an aged phenotype. The treated cardiomyocytes display double-strand breaks in the nDNA, have β-galactosidase activity, possess enlarged nuclei, and show p21 upregulation. Most importantly, they also display a compromised inner mitochondrial structure. This prompted us to test whether the dynamics of the inner membrane was also altered. We found that the exchange of IMM components after organelle fusion was faster in doxorubicin-treated cells than in control cells, with no change in mitochondrial fusion dynamics at the meso-scale. Such altered IMM morphology and dynamics may have important implications for local OXPHOS protein organization, exchange of damaged components, and eventually the mitochondrial bioenergetics function of the aged cardiomyocyte.

Keywords:  Cardiomyocytes; Cristae structure; Doxorubicin; Inner mitochondrial membrane dynamics; Mitochondrial fusion and fission dynamics; Senescence

DOI:  https://doi.org/10.1016/j.bbabio.2022.148949
Cell Rep. 2022 Dec 06. pii: S2211-1247(22)01652-7. [Epub ahead of print]41(10): 111769

Cancer cell-derived type I interferons instruct tumor monocyte polarization.

Dylan Kwart, Jing He, Subhashini Srivatsan, Clarissa Lett, Jacquelynn Golubov, Erin M Oswald, Patrick Poon, Xuan Ye, Janelle Waite, Arielle Glatman Zaretsky, Sokol Haxhinasto, Elsa Au-Yeung, Namita T Gupta, Joyce Chiu, Christina Adler, Samvitha Cherravuru, Evangelia Malahias, Nicole Negron, Kathryn Lanza, Angel Coppola, Min Ni, Hang Song, Yi Wei, Gurinder S Atwal, Lynn Macdonald, Nicole Stokes Oristian, William Poueymirou, Vladimir Jankovic, Matthew Fury, Israel Lowy, Andrew J Murphy, Matthew A Sleeman, Bei Wang, Dimitris Skokos.

  Monocytes are highly plastic immune cells that modulate antitumor immunity. Therefore, identifying factors that regulate tumor monocyte functions is critical for developing effective immunotherapies. Here, we determine that endogenous cancer cell-derived type I interferons (IFNs) control monocyte functional polarization. Guided by single-cell transcriptomic profiling of human and mouse tumors, we devise a strategy to distinguish and separate immunostimulatory from immunosuppressive tumor monocytes by surface CD88 and Sca-1 expression. Leveraging this approach, we show that cGAS-STING-regulated cancer cell-derived IFNs polarize immunostimulatory monocytes associated with anti-PD-1 immunotherapy response in mice. We also demonstrate that immunosuppressive monocytes convert into immunostimulatory monocytes upon cancer cell-intrinsic cGAS-STING activation. Consistently, we find that human cancer cells can produce type I IFNs that polarize monocytes, and our immunostimulatory monocyte gene signature is enriched in patient tumors that respond to anti-PD-1 immunotherapy. Our work exposes a role for cancer cell-derived IFNs in licensing monocyte functions that influence immunotherapy outcomes.

Keywords:  CP: Cancer; MDSCs; STING; cGAS; cancer immunology; immune checkpoint blockade; innate immunity; macrophages; monocytes; tumor microenvironment; type I interferon

DOI:  https://doi.org/10.1016/j.celrep.2022.111769
Elife. 2022 Dec 05. pii: e78609. [Epub ahead of print]11

Glycine inhibits NINJ1 membrane clustering to suppress plasma membrane rupture in cell death.

Jazlyn P Borges, Ragnhild S R Sætra, Allen Volchuk, Marit Bugge, Pascal Devant, Bjørnar Sporsheim, Bridget R Kilburn, Charles L Evavold, Jonathan C Kagan, Neil M Goldenberg, Trude Helen Flo, Benjamin Ethan Steinberg.

  First recognized more than 30 years ago, glycine protects cells against rupture from diverse types of injury. This robust and widely observed effect has been speculated to target a late downstream process common to multiple modes of tissue injury. The molecular target of glycine that mediates cytoprotection, however, remains elusive. Here, we show that glycine works at the level of NINJ1, a newly identified executioner of plasma membrane rupture in pyroptosis, necrosis, and post-apoptosis lysis. NINJ1 is thought to cluster within the plasma membrane to cause cell rupture. We demonstrate that the execution of pyroptotic cell rupture is similar for human and mouse NINJ1, and that NINJ1 knockout functionally and morphologically phenocopies glycine cytoprotection in macrophages undergoing lytic cell death. Next, we show that glycine prevents NINJ1 clustering by either direct or indirect mechanisms. In pyroptosis, glycine preserves cellular integrity but does not affect upstream inflammasome activities or accompanying energetic cell death. By positioning NINJ1 clustering as a glycine target, our data resolve a long-standing mechanism for glycine-mediated cytoprotection. This new understanding will inform the development of cell preservation strategies to counter pathologic lytic cell death.

Keywords:  cell biology; human; immunology; inflammation; mouse

DOI:  https://doi.org/10.7554/eLife.78609
Nature. 2022 Dec 05.

Dendritic cells direct circadian anti-tumor immune responses.

Chen Wang, Coline Barnoud, Mara Cenerenti, Mengzhu Sun, Irene Caffa, Burak Kizil, Ruben Bill, Yuanlong Liu, Robert Pick, Laure Garnier, Olga A Gkountidi, Louise M Ince, Stephan Holtkamp, Nadine Fournier, Olivier Michielin, Daniel E Speiser, Stéphanie Hugues, Alessio Nencioni, Mikaël J Pittet, Camilla Jandus, Christoph Scheiermann.

The process of cancer immunosurveillance is a mechanism of tumor suppression that can protect the host from cancer development throughout its lifetime1,2. Yet, it is unknown whether its effectiveness fluctuates over a single day. Here, we demonstrate that the initial time-of-day of tumor engraftment dictates ensuing tumor size across murine cancer models. Using immunodeficient mice and animals lacking lineage-specific circadian functions, we show that dendritic cells (DCs) and CD8+ T cells exert circadian anti-tumor functions that control melanoma volume. Specifically, we find that rhythmic trafficking of DCs to the tumor draining lymph node (dLN) governs a circadian response of tumor antigen-specific CD8+ T cells, which is dependent on circadian expression of the co-stimulatory molecule CD80. Consequently, cancer immunotherapy is more effective when synchronized with DC functions, shows circadian outcomes in mice and suggests similar effects in humans. These data demonstrate that circadian rhythms of anti-tumor immune components are not only critical for the control of tumor size but can also be exploited therapeutically.

DOI: https://doi.org/10.1038/s41586-022-05605-0
Nature. 2022 Dec 07.

A plant-derived natural photosynthetic system for improving cell anabolism.

Pengfei Chen, Xin Liu, Chenhui Gu, Peiyu Zhong, Nan Song, Mobai Li, Zhanqiu Dai, Xiangqian Fang, Zhaoming Liu, Jianfeng Zhang, Ruikang Tang, Shunwu Fan, Xianfeng Lin.

Insufficient intracellular anabolism is a crucial factor involved in many pathological processes in the body1,2. The anabolism of intracellular substances requires the consumption of sufficient intracellular energy and the production of reducing equivalents. ATP acts as an 'energy currency' for biological processes in cells3,4, and the reduced form of NADPH is a key electron donor that provides reducing power for anabolism5. Under pathological conditions, it is difficult to correct impaired anabolism and to increase insufficient levels of ATP and NADPH to optimum concentrations1,4,6-8. Here we develop an independent and controllable nanosized plant-derived photosynthetic system based on nanothylakoid units (NTUs). To enable cross-species applications, we use a specific mature cell membrane (the chondrocyte membrane (CM)) for camouflage encapsulation. As proof of concept, we demonstrate that these CM-NTUs enter chondrocytes through membrane fusion, avoid lysosome degradation and achieve rapid penetration. Moreover, the CM-NTUs increase intracellular ATP and NADPH levels in situ following exposure to light and improve anabolism in degenerated chondrocytes. They can also systemically correct energy imbalance and restore cellular metabolism to improve cartilage homeostasis and protect against pathological progression of osteoarthritis. Our therapeutic strategy for degenerative diseases is based on a natural photosynthetic system that can controllably enhance cell anabolism by independently providing key energy and metabolic carriers. This study also provides an enhanced understanding of the preparation and application of bioorganisms and composite biomaterials for the treatment of disease.

DOI: https://doi.org/10.1038/s41586-022-05499-y
J Clin Invest. 2022 Dec 08. pii: e159498. [Epub ahead of print]

Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction.

Shanshan Cai, Mingyue Zhao, Bo Zhou, Akira Yoshii, Darrian Bugg, Outi Villet, Anita Sahu, Gregory S Olson, Jennifer Davis, Rong Tian.

  Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found myeloid specific deletion of mitochondrial Complex I protein Ndufs4 (mKO) reproduced the proinflammatory metabolic profile in macrophages and exaggerated the response to lipopolysacharride. Moreover, mKO mice showed increased mortality, poor scar formation and worsened cardiac function 30 days post-MI. We observed a greater inflammatory response in mKO on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to reparative phase during day 3-7 post-MI. Efferocytosis is markedly impaired in mKO macrophages leading to lower expression of anti-inflammatory cytokine and tissue repair factors, which suppressed the proliferation/activation of myofibroblasts in the infarct area. Mitochondria-targeted ROS scavenging rescued these impairments and improved myofibroblast function in vivo and reduced post-MI mortality in mKO mice. Together these results reveal a novel role of mitochondria in inflammation resolution and tissue repair via modulating efferocytosis and crosstalk with fibroblasts. The findings are significant for post-MI recovery as well as for other inflammatory conditions.

Keywords:  Cardiology; Cardiovascular disease; Macrophages; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/JCI159498