bims-mepmim 2024-01-07 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2024‒01‒07
forty-two papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Glycine homeostasis requires reverse SHMT flux.
Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.
Nutrient uptake strategies shift during mouse epiblast development.
Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance.
H2S serves as the immunoregulatory essence of apoptotic cell death.
SARM1 regulates NAD+-linked metabolism and select immune genes in macrophages.
Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.
ATP citrate lyase (ACLY)-dependent immunometabolism in mucosal T cells drives experimental colitis in vivo.
Amino acid intake strategies define pluripotent cell states.
Mitochondrial isocitrate dehydrogenase impedes CAR T cell function by restraining antioxidant metabolism and histone acetylation.
Dynamic metabolism of endothelial triglycerides protects against atherosclerosis in mice.
Serine synthesis via reversed SHMT2 activity drives glycine depletion and acetaminophen hepatotoxicity in MASLD.
NCOA4 requires a [3Fe-4S] to sense and maintain the iron homeostasis.
Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4-/- mouse.
Ketone bodies promote epididymal white adipose expansion to alleviate liver steatosis in response to a ketogenic diet.
Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis.
MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion.
NOS-like activity of CeO2 nanozymes contributes to diminishing the vascular plaques.
ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis.
Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer.
Fission-independent compartmentalization of mitochondria during budding yeast cell division.
Over-expression of N-acetylaspartate synthase exacerbates pathological energetic deficit and accelerates cognitive decline in the 5xFAD mouse.
NME4 mediates metabolic reprogramming and promotes nonalcoholic fatty liver disease progression.
IL-12 reprograms CAR-expressing natural killer T cells to long-lived Th1-polarized cells with potent antitumor activity.
MCT1-governed pyruvate metabolism is essential for antibody class-switch recombination through H3K27 acetylation.
NAD+ precursors and bile acid sequestration treat preclinical refractory environmental enteric dysfunction.
Vitamin B12 produced by gut bacteria modulates cholinergic signalling.
Myeloid-derived grancalcin instigates obesity-induced insulin resistance and metabolic inflammation in male mice.
TAMC-derived creatine sustains glioblastoma growth.
Macrophage RAGE activation is proinflammatory in NASH.
Metabolic fitness of IgA+ plasma cells in the gut requires DOCK8.
Loss of cardiac mitochondrial complex I persulfidation impairs NAD+ homeostasis in aging.
Human and mouse peritoneal macrophages and dendritic cells compared.
Surplus fatty acid synthesis increases oxidative stress in adipocytes and lnduces lipodystrophy.
Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use.
Acylspermidines are conserved mitochondrial sirtuin-dependent metabolites.
Human inherited CCR2 deficiency underlies progressive polycystic lung disease.
A versatile in situ cofactor enhancing system for meeting cellular demands for engineered metabolic pathways.
Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion.
Mitochondrial-derived vesicles in metabolism, disease, and aging.
The neuronal nitric oxide synthase expression increases during satellite cell-derived primary myoblasts differentiation.
Deciphering the metabolic heterogeneity of hematopoietic stem cells with single-cell resolution.

Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00452-7. [Epub ahead of print]36(1): 103-115.e4

Glycine homeostasis requires reverse SHMT flux.

Matthew J McBride, Craig J Hunter, Zhaoyue Zhang, Tara TeSlaa, Xincheng Xu, Gregory S Ducker, Joshua D Rabinowitz.

  The folate-dependent enzyme serine hydroxymethyltransferase (SHMT) reversibly converts serine into glycine and a tetrahydrofolate-bound one-carbon unit. Such one-carbon unit production plays a critical role in development, the immune system, and cancer. Using rodent models, here we show that the whole-body SHMT flux acts to net consume rather than produce glycine. Pharmacological inhibition of whole-body SHMT1/2 and genetic knockout of liver SHMT2 elevated circulating glycine levels up to eight-fold. Stable-isotope tracing revealed that the liver converts glycine to serine, which is then converted by serine dehydratase into pyruvate and burned in the tricarboxylic acid cycle. In response to diets deficient in serine and glycine, de novo biosynthetic flux was unaltered, but SHMT2- and serine-dehydratase-mediated catabolic flux was lower. Thus, glucose-derived serine synthesis is largely insensitive to systemic demand. Instead, circulating serine and glycine homeostasis is maintained through variable consumption, with liver SHMT2 a major glycine-consuming enzyme.

Keywords:  SHMT; amino acid metabolism; folate cycle; glycine; hepatic clearance; homeostasis; serine

DOI:  https://doi.org/10.1016/j.cmet.2023.12.001
Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00455-2. [Epub ahead of print]36(1): 193-208.e8

Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.

Yingsheng Zhang, Meng-Ju Wu, Wan-Chi Lu, Yi-Chuan Li, Chun Ju Chang, Jer-Yen Yang.

  Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid β-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.

Keywords:  EZH2; PKM2; SLC16A9; induced synthetic lethality; lineage plasticity; metabolic reprogramming

DOI:  https://doi.org/10.1016/j.cmet.2023.12.003
Nat Metab. 2024 Jan 03.

Nutrient uptake strategies shift during mouse epiblast development.

DOI: https://doi.org/10.1038/s42255-023-00941-5
Nat Commun. 2024 Jan 02. 15(1): 79

Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance.

Hyemin Lee, Amber Horbath, Lavanya Kondiparthi, Jitendra Kumar Meena, Guang Lei, Shayani Dasgupta, Xiaoguang Liu, Li Zhuang, Pranavi Koppula, Mi Li, Iqbal Mahmud, Bo Wei, Philip L Lorenzi, Khandan Keyomarsi, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan.

How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on ferroptosis, a form of regulated cell death induced by overwhelming lipid peroxidation at cellular membranes. Mechanistically, cell cycle arrest induces diacylglycerol acyltransferase (DGAT)-dependent lipid droplet formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylglycerols (TAGs), resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from TAGs to phospholipids and re-sensitizes arrested cells to ferroptosis. We show that some slow-cycling antimitotic drug-resistant cancer cells, such as 5-fluorouracil-resistant cells, have accumulation of lipid droplets and that combined treatment with ferroptosis inducers and DGAT inhibitors effectively suppresses the growth of 5-fluorouracil-resistant tumors by inducing ferroptosis. Together, these results reveal a role for cell cycle arrest in driving ferroptosis resistance and suggest a ferroptosis-inducing therapeutic strategy to target slow-cycling therapy-resistant cancers.

DOI: https://doi.org/10.1038/s41467-023-44412-7
Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00457-6. [Epub ahead of print]36(1): 3-5

H2S serves as the immunoregulatory essence of apoptotic cell death.

Christopher Hine, András K Ponti, María Ángeles Cáliz-Molina, Alejandro Martín-Montalvo.

Apoptosis supports tissue homeostasis and prevents immune disorders by removing damaged and functionally aberrant cells. Here, Ou et al. utilized genetic, pharmacological, and proteomic approaches focused on sulfur amino acid catabolism to discover that hydrogen sulfide (H2S) release during apoptosis suppresses Th17 cell differentiation, thus providing therapeutic targets for autoimmune diseases.

DOI: https://doi.org/10.1016/j.cmet.2023.12.006
J Biol Chem. 2024 Jan 02. pii: S0021-9258(23)02649-2. [Epub ahead of print] 105620

SARM1 regulates NAD+-linked metabolism and select immune genes in macrophages.

Katharine A Shanahan, Gavin M Davis, Ciara G Doran, Ryoichi Sugisawa, Gavin P Davey, Andrew G Bowie.

  Sterile alpha and HEAT/Armadillo motif-containing protein (SARM1) was recently described as a NAD+-consuming enzyme, and has previously been shown to regulate immune responses in macrophages. Neuronal SARM1 is known to contribute to axon degeneration due to its NADase activity. However, how SARM1 affects macrophage metabolism has not been explored. Here, we show that macrophages from Sarm1-/- mice display elevated NAD+ concentrations and lower cyclic ADPR, a known product of SARM1-dependent NAD+ catabolism. Further, SARM1-deficient macrophages showed an increase in the reserve capacity of oxidative phosphorylation and glycolysis compared to wild-type cells. Stimulation of macrophages to a pro-inflammatory state by lipopolysaccharide (LPS), revealed that SARM1 restricts the ability of macrophages to upregulate glycolysis and limits the expression of the pro-inflammatory gene Il1b, but boosts expression of anti-inflammatory Il10. In contrast, we show macrophages lacking SARM1 induced to an anti-inflammatory state by IL-4 stimulation display increased oxidative phosphorylation and glycolysis, and reduced expression of the anti-inflammatory gene, Fizz1. Overall, these data show that SARM1 fine-tunes immune gene transcription in macrophages via consumption of NAD+ and altered macrophage metabolism.

Keywords:  NAD(+); NADase; SARM1; cADPR; cytokine induction; macrophages; metabolism

DOI:  https://doi.org/10.1016/j.jbc.2023.105620
Nat Commun. 2024 Jan 02. 15(1): 168

Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.

Jun Dong, Li Chen, Fei Ye, Junhui Tang, Bing Liu, Jiacheng Lin, Pang-Hu Zhou, Bin Lu, Min Wu, Jia-Hong Lu, Jing-Jing He, Simone Engelender, Qingtao Meng, Zhiyin Song, He He.

Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.

DOI: https://doi.org/10.1038/s41467-023-44057-6
Gut. 2024 Jan 04. pii: gutjnl-2023-330543. [Epub ahead of print]

ATP citrate lyase (ACLY)-dependent immunometabolism in mucosal T cells drives experimental colitis in vivo.

TRR241 IBDome Consortium

  OBJECTIVE: Mucosal T cells play a major role in inflammatory bowel disease (IBD). However, their immunometabolism during intestinal inflammation is poorly understood. Due to its impact on cellular metabolism and proinflammatory immune cell function, we here focus on the enzyme ATP citrate lyase (ACLY) in mucosal T cell immunometabolism and its relevance for IBD.DESIGN: ACLY expression and its immunometabolic impact on colitogenic T cell function were analysed in mucosal T cells from patients with IBD and in two experimental colitis models.
RESULTS: ACLY was markedly expressed in colon tissue under steady-state conditions but was significantly downregulated in lamina propria mononuclear cells in experimental dextran sodium sulfate-induced colitis and in CD4+ and to a lesser extent in CD8+ T cells infiltrating the inflamed gut in patients with IBD. ACLY-deficient CD4+ T cells showed an impaired capacity to induce intestinal inflammation in a transfer colitis model as compared with wild-type T cells. Assessment of T cell immunometabolism revealed that ACLY deficiency dampened the production of IBD-relevant cytokines and impaired glycolytic ATP production but enriched metabolites involved in the biosynthesis of phospholipids and phosphatidylcholine. Interestingly, the short-chain fatty acid butyrate was identified as a potent suppressor of ACLY expression in T cells, while IL-36α and resolvin E1 induced ACLY levels. In a translational approach, in vivo administration of the butyrate prodrug tributyrin downregulated mucosal infiltration of ACLYhigh CD4+ T cells and ameliorated chronic colitis.
CONCLUSION: ACLY controls mucosal T cell immunometabolism and experimental colitis. Therapeutic modulation of ACLY expression in T cells emerges as a novel strategy to promote the resolution of intestinal inflammation.

Keywords:  EXPERIMENTAL COLITIS; INFLAMMATORY BOWEL DISEASE; MUCOSAL IMMUNOLOGY; T LYMPHOCYTES

DOI:  https://doi.org/10.1136/gutjnl-2023-330543
Nat Metab. 2024 Jan 03.

Amino acid intake strategies define pluripotent cell states.

Pavlina K Todorova, Benjamin T Jackson, Vidur Garg, Katrina I Paras, Julia S Brunner, Anna E Bridgeman, Yanyang Chen, Sanjeethan C Baksh, Jielin Yan, Anna-Katerina Hadjantonakis, Lydia W S Finley.

Mammalian preimplantation development is associated with marked metabolic robustness, and embryos can develop under a wide variety of nutrient conditions, including even the complete absence of soluble amino acids. Here we show that mouse embryonic stem cells (ESCs) capture the unique metabolic state of preimplantation embryos and proliferate in the absence of several essential amino acids. Amino acid independence is enabled by constitutive uptake of exogenous protein through macropinocytosis, alongside a robust lysosomal digestive system. Following transition to more committed states, ESCs reduce digestion of extracellular protein and instead become reliant on exogenous amino acids. Accordingly, amino acid withdrawal selects for ESCs that mimic the preimplantation epiblast. More broadly, we find that all lineages of preimplantation blastocysts exhibit constitutive macropinocytic protein uptake and digestion. Taken together, these results highlight exogenous protein uptake and digestion as an intrinsic feature of preimplantation development and provide insight into the catabolic strategies that enable embryos to sustain viability before implantation.

DOI: https://doi.org/10.1038/s42255-023-00940-6
Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00461-8. [Epub ahead of print]36(1): 176-192.e10

Mitochondrial isocitrate dehydrogenase impedes CAR T cell function by restraining antioxidant metabolism and histone acetylation.

Xiaohui Si, Mi Shao, Xinyi Teng, Yue Huang, Ye Meng, Longyuan Wu, Jieping Wei, Lianxuan Liu, Tianning Gu, Junzhe Song, Ruirui Jing, Xingyuan Zhai, Xin Guo, Delin Kong, Xiujian Wang, Bohan Cai, Ying Shen, Zhaoru Zhang, Dongrui Wang, Yongxian Hu, Pengxu Qian, Gang Xiao, He Huang.

  The efficacy of chimeric antigen receptor (CAR) T cell therapy is hampered by relapse in hematologic malignancies and by hyporesponsiveness in solid tumors. Long-lived memory CAR T cells are critical for improving tumor clearance and long-term protection. However, during rapid ex vivo expansion or in vivo tumor eradication, metabolic shifts and inhibitory signals lead to terminal differentiation and exhaustion of CAR T cells. Through a mitochondria-related compound screening, we find that the FDA-approved isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenib enhances memory CAR T cell formation and sustains anti-leukemic cytotoxicity in vivo. Mechanistically, IDH2 impedes metabolic fitness of CAR T cells by restraining glucose utilization via the pentose phosphate pathway, which alleviates oxidative stress, particularly in nutrient-restricted conditions. In addition, IDH2 limits cytosolic acetyl-CoA levels to prevent histone acetylation that promotes memory cell formation. In combination with pharmacological IDH2 inhibition, CAR T cell therapy is demonstrated to have superior efficacy in a pre-clinical model.

Keywords:  chimeric antigen receptor T cell; enasidenib; exhaustion; histone acetylation; isocitrate dehydrogenase 2; memory T cell formation; nutrient-restricted conditions; pentose phosphate pathway

DOI:  https://doi.org/10.1016/j.cmet.2023.12.010
J Clin Invest. 2024 Jan 04. pii: e170453. [Epub ahead of print]

Dynamic metabolism of endothelial triglycerides protects against atherosclerosis in mice.

Nabil E Boutagy, Ana Gamez-Mendez, Joseph Wm Fowler, Hanming Zhang, Bal K Chaube, Enric Esplugues, Sungwoon Lee, Daiki Horikami, Jiasheng Zhang, Kathryn M Citrin, Abhishek K Singh, Brian G Coon, Yajaira Suarez, Carlos Fernandez-Hernando, William C Sessa.

  Blood vessels are continually exposed to circulating lipids and elevations of ApoB containing lipoproteins cause atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level of the capillary endothelium lining metabolically active tissues. How large blood vessels, the site of atherosclerotic vascular disease, regulate the flux of fatty acids (FA) into triglyceride (TG) rich lipid droplets (LD) is not known. In this study, we showed that deletion of the enzyme, adipose triglyceride lipase (ATGL) in the endothelium, led to neutral lipid accumulation in vessels and impaired endothelial dependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL led to endoplasmic reticulum stress-induced inflammation in the endothelium. Consistent with this mechanism, deletion of endothelial ATGL markedly increased lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD impacts endothelial cell homeostasis and consequently large vessel function during normal physiology and in a chronic disease state.

Keywords:  Atherosclerosis; Endothelial cells; Lipoproteins; Vascular Biology

DOI:  https://doi.org/10.1172/JCI170453
Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00464-3. [Epub ahead of print]36(1): 116-129.e7

Serine synthesis via reversed SHMT2 activity drives glycine depletion and acetaminophen hepatotoxicity in MASLD.

Alia Ghrayeb, Alexandra C Finney, Bella Agranovich, Daniel Peled, Sumit Kumar Anand, M Peyton McKinney, Mahasen Sarji, Dongshan Yang, Natan Weissman, Shani Drucker, Sara Isabel Fernandes, Jonatan Fernández-García, Kyle Mahan, Zaid Abassi, Lin Tan, Philip L Lorenzi, James Traylor, Jifeng Zhang, Ifat Abramovich, Y Eugene Chen, Oren Rom, Inbal Mor, Eyal Gottlieb.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative stress, enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific ablation of the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated acetaminophen-induced hepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycine availability sensitize mice to xenobiotics even at the reversible stage of this disease.

Keywords:  MASLD; SHMT; acetaminophen hepatotoxicity; glutathione; glycine; one-carbon metabolism; xenobiotic

DOI:  https://doi.org/10.1016/j.cmet.2023.12.013
J Biol Chem. 2023 Dec 28. pii: S0021-9258(23)02641-8. [Epub ahead of print] 105612

NCOA4 requires a [3Fe-4S] to sense and maintain the iron homeostasis.

Hongting Zhao, Yao Lu, Jinghua Zhang, Zichen Sun, Chen Cheng, Yutong Liu, Lin Wu, Meng Zhang, Weijiang He, Shuangying Hao, Kuanyu Li.

  NCOA4 is a selective cargo receptor for ferritinophagy, the autophagic turnover of ferritin (FTH), a process critical for regulating intracellular iron bioavailability. However, how ferritinophagy flux is controlled through NCOA4 in iron-dependent processes needs to be better understood. Here, we show that the C-terminal FTH-binding domain of NCOA4 harbors a [3Fe-4S] binding site with a stoichiometry of approximately one labile [3Fe-4S] cluster per NCOA4 monomer. By analyzing the interaction between NCOA4 and HERC2 ubiquitin ligase or NCOA4 and FTH, we demonstrate that NCOA4 regulates ferritinophagy by sensing the intracellular iron-sulfur-cluster levels. Under iron repletion conditions, HERC2 recognizes and recruits holo-NCOA4 as a substrate for polyubiquitination and degradation, favoring ferritin iron storage. Under iron depletion conditions, NCOA4 exists in the form of apo-protein and binds ferritin to promote the occurrence of ferritinophagy and release iron. Thus, we identify an iron-sulfur cluster [3Fe-4S] as a critical cofactor in determining the fate of NCOA4 in favoring iron storage in ferritin or iron release via ferritinophagy and provide a dual mechanism for selective interaction between HERC2 and [3Fe-4S]-NCOA4 for proteasomal degradation or between ferritin and apo-NCOA4 for ferritinophagy in the control of iron homeostasis.

Keywords:  Iron-sulfur protein; NCOA4; autophagy; ferritin; iron metabolism; protein degradation

DOI:  https://doi.org/10.1016/j.jbc.2023.105612
EMBO J. 2024 Jan 02.

Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4-/- mouse.

Zhan Yin, Ahmed-Noor A Agip, Hannah R Bridges, Judy Hirst.

  Respiratory complex I (NADH:ubiquinone oxidoreductase) is essential for cellular energy production and NAD+ homeostasis. Complex I mutations cause neuromuscular, mitochondrial diseases, such as Leigh Syndrome, but their molecular-level consequences remain poorly understood. Here, we use a popular complex I-linked mitochondrial disease model, the ndufs4-/- mouse, to define the structural, biochemical, and functional consequences of the absence of subunit NDUFS4. Cryo-EM analyses of the complex I from ndufs4-/- mouse hearts revealed a loose association of the NADH-dehydrogenase module, and discrete classes containing either assembly factor NDUFAF2 or subunit NDUFS6. Subunit NDUFA12, which replaces its paralogue NDUFAF2 in mature complex I, is absent from all classes, compounding the deletion of NDUFS4 and preventing maturation of an NDUFS4-free enzyme. We propose that NDUFAF2 recruits the NADH-dehydrogenase module during assembly of the complex. Taken together, the findings provide new molecular-level understanding of the ndufs4-/- mouse model and complex I-linked mitochondrial disease.

Keywords:  Complex I; Cryo-EM; Leigh Syndrome; Mitochondria; NADH:Ubiquinone Oxidoreductase

DOI:  https://doi.org/10.1038/s44318-023-00001-4
J Biol Chem. 2024 Jan 02. pii: S0021-9258(23)02646-7. [Epub ahead of print] 105617

Ketone bodies promote epididymal white adipose expansion to alleviate liver steatosis in response to a ketogenic diet.

Meng-Fei Zhao, Xin-Ge Zhang, Yi-Ping Tang, Ying-Xi Zhu, Hong-Yu Nie, Dan-Dan Bu, Lei Fang, Chao-Jun Li.

  Liver can sense the nutrient status and send signals to other organs to regulate overall metabolic homoeostasis. Herein, we demonstrate that ketone bodies act as signals released from the liver that specifically determine the distribution of excess lipid in epididymal white adipose tissue (eWAT) when exposed to a ketogenic diet (KD). An acute KD can immediately result in excess lipid deposition in the liver. Subsequently, the liver sends the ketone body β-hydroxybutyrate (BHB) to regulate white adipose expansion, including adipogenesis and lipogenesis, to alleviate hepatic lipid accumulation. When ketone bodies are depleted by deleting 3-Hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) gene in liver, the enhanced lipid deposition in eWAT but not in inguinal white adipose tissue (iWAT) is preferentially blocked, while lipid accumulation in liver is not alleviated. Mechanistically, ketone body BHB can significantly decrease lysine acetylation of peroxisome proliferator-activated receptor gamma (PPARγ) in eWAT, causing enhanced activity of PPARγ, the key adipogenic transcription factor. These observations suggest that the liver senses metabolic stress first and sends a corresponding signal, that is, ketone body BHB, to specifically promote eWAT expansion to adapt to metabolic challenges.

Keywords:  adipose remodelling; liver steatosis; liver–adipose signaling axis; peroxisome proliferator-activated receptor gamma; protein acetylation

DOI:  https://doi.org/10.1016/j.jbc.2023.105617
Mol Cell. 2023 Dec 20. pii: S1097-2765(23)01027-4. [Epub ahead of print]

Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis.

Xiaojian Shi, Marisa DeCiucis, Kariona A Grabinska, Jean Kanyo, Adam Liu, Tukiet T Lam, Hongying Shen.

  Organelle transporters define metabolic compartmentalization, and how this metabolite transport process can be modulated is poorly explored. Here, we discovered that human SLC25A39, a mitochondrial transporter critical for mitochondrial glutathione uptake, is a short-lived protein under dual regulation at the protein level. Co-immunoprecipitation mass spectrometry and CRISPR knockout (KO) in mammalian cells identified that mitochondrial m-AAA protease AFG3L2 is responsible for degrading SLC25A39 through the matrix loop 1. SLC25A39 senses mitochondrial iron-sulfur cluster using four matrix cysteine residues and inhibits its degradation. SLC25A39 protein regulation is robust in developing and mature neurons. This dual transporter regulation, by protein quality control and metabolic sensing, allows modulating mitochondrial glutathione level in response to iron homeostasis, opening avenues for exploring regulation of metabolic compartmentalization. Neuronal SLC25A39 regulation connects mitochondrial protein quality control, glutathione, and iron homeostasis, which were previously unrelated biochemical features in neurodegeneration.

Keywords:  AFG3L2; SLC25A39; glutathione; iron; mitochondrial transporter; protein quality control

DOI:  https://doi.org/10.1016/j.molcel.2023.12.008
EMBO Rep. 2023 Dec 14.

MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion.

Andres Goldman, Michael Mullokandov, Yehudit Zaltsman, Limor Regev, Smadar Levin-Zaidman, Atan Gross.

  Fusion of the outer mitochondrial membrane (OMM) is regulated by mitofusin 1 (MFN1) and 2 (MFN2), yet the differential contribution of each of these proteins is less understood. Mitochondrial carrier homolog 2 (MTCH2) also plays a role in mitochondrial fusion, but its exact function remains unresolved. MTCH2 overexpression enforces MFN2-independent mitochondrial fusion, proposedly by modulating the phospholipid lysophosphatidic acid (LPA), which is synthesized by glycerol-phosphate acyl transferases (GPATs) in the endoplasmic reticulum (ER) and the OMM. Here we report that MTCH2 requires MFN1 to enforce mitochondrial fusion and that fragmentation caused by loss of MTCH2 can be specifically counterbalanced by overexpression of MFN2 but not MFN1, partially independent of its GTPase activity and mitochondrial localization. Pharmacological inhibition of GPATs (GPATi) or silencing ER-resident GPATs suppresses MFN2's ability to compensate for the loss of MTCH2. Loss of either MTCH2, MFN2, or GPATi does not impair stress-induced mitochondrial fusion, whereas the combined loss of MTCH2 and GPATi or the combined loss of MTCH2 and MFN2 does. Taken together, we unmask two cooperative mechanisms that sustain mitochondrial fusion.

Keywords:  LPA; MFN2; MTCH2; Mitochondria-ER Communication; Mitochondrial Fusion

DOI:  https://doi.org/10.1038/s44319-023-00009-1
J Nanobiotechnology. 2024 Jan 03. 22(1): 12

NOS-like activity of CeO2 nanozymes contributes to diminishing the vascular plaques.

Yuxiang Sun, Tianze Xu, Yike Qian, Qiaoyun Chen, Fei Xiong, Wenxian Du, Li Xu.

Ceria nanoparticles (CeO2NPs) exhibit great potential in cardiovascular disease and nonalcoholic fatty liver disease due to its excellent antioxidant capacity. However, the profitable effect of CeO2NPs on many diseases is almost all attributed to the regulation of ROS. Apart from the general antioxidant function, there seems to be no more distinct mechanism to reflect its unique multi-disease improvement effect. Here, we for the first time reveal a new discovery of CeO2NPs in mimicking nitric oxide synthase (NOS) by catalyzing L-arginine (L-Arg) to produce nitric oxide (NO) or the derivatives. NOS-like activity of CeO2NPs is original and associated with multiple factors like substrate concentration, pH, temperature and time, etc. where oxygen vacancy ratio plays a more critical role. Meanwhile, NOS-like activity of CeO2NPs successfully elevates NO secretion in endothelial cells and macrophages without expanding eNOS/iNOS expression. Importantly, NOS-like activity of CeO2NPs and the responsive endogenous NO promote the re-distribution of blood lipids and stabilize eNOS expression but suppress iNOS, thus collectively alleviate the accumulation of vascular plaque. Altogether, we provide a new angle of view to survey the outstanding potential of CeO2NPs, apart from the inevitable antioxidant capacity, the covert but possible and more critical NOS-like enzymatic activity is more noteworthy.

DOI: https://doi.org/10.1186/s12951-023-02276-5
Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00465-5. [Epub ahead of print]

ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis.

Chao Chen, Zhenxing Zhang, Caiyun Liu, Pengkai Sun, Ping Liu, Xinjian Li.

  Itaconate is a metabolite that synthesized from cis-aconitate in mitochondria and transported into the cytosol to exert multiple regulatory effects in macrophages. However, the mechanism by which itaconate exits from macrophages remains unknown. Using a genetic screen, we reveal that itaconate is exported from cytosol to extracellular space by ATP-binding cassette transporter G2 (ABCG2) in an ATPase-dependent manner in human and mouse macrophages. Elevation of transcription factor TFEB-dependent lysosomal biogenesis and antibacterial innate immunity are observed in inflammatory macrophages with deficiency of ABCG2-mediated itaconate export. Furthermore, deficiency of ABCG2-mediated itaconate export in macrophages promotes antibacterial innate immune defense in a mouse model of S. typhimurium infection. Thus, our findings identify ABCG2-mediated itaconate export as a key regulatory mechanism that limits TFEB-dependent lysosomal biogenesis and antibacterial innate immunity in inflammatory macrophages, implying the potential therapeutic utility of blocking itaconate export in treating human bacterial infections.

Keywords:  ABCG2; TFEB; exporter; innate immunity; itaconate; lysosomal biogenesis; macrophages

DOI:  https://doi.org/10.1016/j.cmet.2023.12.015
Nat Cancer. 2024 Jan 02.

Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer.

Fuming Li, Pingyu Liu, Wen Mi, Liucheng Li, Nicole M Anderson, Nicholas P Lesner, Michelle Burrows, Jacqueline Plesset, Ariana Majer, Guanlin Wang, Jinyang Li, Lingzhi Zhu, Brian Keith, M Celeste Simon.

Availability of the essential amino acid methionine affects cellular metabolism and growth, and dietary methionine restriction has been implicated as a cancer therapeutic strategy. Nevertheless, how liver cancer cells respond to methionine deprivation and underlying mechanisms remain unclear. Here we find that human liver cancer cells undergo irreversible cell cycle arrest upon methionine deprivation in vitro. Blocking methionine adenosyl transferase 2A (MAT2A)-dependent methionine catabolism induces cell cycle arrest and DNA damage in liver cancer cells, resulting in cellular senescence. A pharmacological screen further identified GSK3 inhibitors as senolytics that selectively kill MAT2A-inhibited senescent liver cancer cells. Importantly, combined treatment with MAT2A and GSK3 inhibitors therapeutically blunts liver tumor growth in vitro and in vivo across multiple models. Together, methionine catabolism is essential for liver tumor growth, and its inhibition can be exploited as an improved pro-senescence strategy for combination with senolytic agents to treat liver cancer.

DOI: https://doi.org/10.1038/s43018-023-00671-3
J Cell Biol. 2024 Mar 04. pii: e202211048. [Epub ahead of print]223(3):

Fission-independent compartmentalization of mitochondria during budding yeast cell division.

Saori R Yoshii, Yves Barral.

Lateral diffusion barriers compartmentalize membranes to generate polarity or asymmetrically partition membrane-associated macromolecules. Budding yeasts assemble such barriers in the endoplasmic reticulum (ER) and the outer nuclear envelope at the bud neck to retain aging factors in the mother cell and generate naïve and rejuvenated daughter cells. However, little is known about whether other organelles are similarly compartmentalized. Here, we show that the membranes of mitochondria are laterally compartmentalized at the bud neck and near the cell poles. The barriers in the inner mitochondrial membrane are constitutive, whereas those in the outer membrane form in response to stresses. The strength of mitochondrial diffusion barriers is regulated positively by spatial cues from the septin axis and negatively by retrograde (RTG) signaling. These data indicate that mitochondria are compartmentalized in a fission-independent manner. We propose that these diffusion barriers promote mitochondrial polarity and contribute to mitochondrial quality control.

DOI: https://doi.org/10.1083/jcb.202211048
J Neurochem. 2024 Jan 05.

Over-expression of N-acetylaspartate synthase exacerbates pathological energetic deficit and accelerates cognitive decline in the 5xFAD mouse.

Jeremy S Francis, Quy Nguyen, Vladimir Markov, Paola Leone.

  N-acetylaspartate (NAA) is an abundant central nervous system amino acid derivative that is tightly coupled to mitochondria and energy metabolism in neurons. A reduced NAA signature is a prominent early pathological biomarker in multiple neurodegenerative diseases and becomes progressively more pronounced as disease advances. Because NAA synthesis requires aspartate drawn directly from mitochondria, we argued that this process is in direct competition with oxidative phosphorylation for substrate and that sustained high levels of NAA synthesis would be incompatible with pathological energy crisis. We show here that over-expression of the rate-limiting NAA synthetic enzyme in the hippocampus of the 5x familial Alzheimer's disease (5xFAD) mouse results in an exaggerated pathological ATP deficit and accelerated cognitive decline. Over-expression of NAA synthase did not increase amyloid burden or result in cell loss but did significantly deplete mitochondrial aspartate and impair the ability of mitochondria to oxidize glutamate for adenosine triphosphate (ATP) synthesis. These results define NAA as a sink for energetic substrate and suggest initial pathological reductions in NAA are part of a response to energetic crisis designed to preserve substrate bioavailability for mitochondrial ATP synthesis.

Keywords:  N-acetylaspartate; Neurodegenerative disease; metabolic decline

DOI:  https://doi.org/10.1111/jnc.16044
EMBO Rep. 2023 Dec 14.

NME4 mediates metabolic reprogramming and promotes nonalcoholic fatty liver disease progression.

Shaofang Xie, Lei Yuan, Yue Sui, Shan Feng, Hengle Li, Xu Li.

  Nonalcoholic fatty liver disease (NAFLD) is mainly characterized by excessive fat accumulation in the liver, and it is associated with liver-related complications and adverse systemic diseases. NAFLD has become the most prevalent liver disease; however, effective therapeutic agents for NAFLD are still lacking. We combined clinical data with proteomics and metabolomics data, and found that the mitochondrial nucleoside diphosphate kinase NME4 plays a central role in mitochondrial lipid metabolism. Nme4 is markedly upregulated in mice fed with high-fat diet, and its expression is positively correlated with the level of steatosis. Hepatic deletion of Nme4 suppresses the progression of hepatic steatosis. Further studies demonstrated that NME4 interacts with several key enzymes in coenzyme A (CoA) metabolism and increases the level of acetyl-CoA and malonyl-CoA, which are the major lipid components of the liver in NAFLD. Increased level of acetyl-CoA and malonyl-CoA lead to increased triglyceride levels and lipid accumulation in the liver. Taken together, these findings reveal that NME4 is a critical regulator of NAFLD progression and a potential therapeutic target for NAFLD.

Keywords:  Coenzyme A Metabolism; Lipid Accumulation; NAFLD; NME4

DOI:  https://doi.org/10.1038/s44319-023-00012-6
Nat Commun. 2024 Jan 02. 15(1): 89

IL-12 reprograms CAR-expressing natural killer T cells to long-lived Th1-polarized cells with potent antitumor activity.

Elisa Landoni, Mark G Woodcock, Gabriel Barragan, Gabriele Casirati, Vincenzo Cinella, Simone Stucchi, Leah M Flick, Tracy A Withers, Hanna Hudson, Giulia Casorati, Paolo Dellabona, Pietro Genovese, Barbara Savoldo, Leonid S Metelitsa, Gianpietro Dotti.

Human natural killer T cells (NKTs) are innate-like T lymphocytes increasingly used for cancer immunotherapy. Here we show that human NKTs expressing the pro-inflammatory cytokine interleukin-12 (IL-12) undergo extensive and sustained molecular and functional reprogramming. Specifically, IL-12 instructs and maintains a Th1-polarization program in NKTs in vivo without causing their functional exhaustion. Furthermore, using CD62L as a marker of memory cells in human NKTs, we observe that IL-12 maintains long-term CD62L-expressing memory NKTs in vivo. Notably, IL-12 initiates a de novo programming of memory NKTs in CD62L-negative NKTs indicating that human NKTs circulating in the peripheral blood possess an intrinsic differentiation hierarchy, and that IL-12 plays a role in promoting their differentiation to long-lived Th1-polarized memory cells. Human NKTs engineered to co-express a Chimeric Antigen Receptor (CAR) coupled with the expression of IL-12 show enhanced antitumor activity in leukemia and neuroblastoma tumor models, persist long-term in vivo and conserve the molecular signature driven by the IL-12 expression. Thus IL-12 reveals an intrinsic plasticity of peripheral human NKTs that may play a crucial role in the development of cell therapeutics.

DOI: https://doi.org/10.1038/s41467-023-44310-y
Nat Commun. 2024 Jan 02. 15(1): 163

MCT1-governed pyruvate metabolism is essential for antibody class-switch recombination through H3K27 acetylation.

Wenna Chi, Na Kang, Linlin Sheng, Sichen Liu, Lei Tao, Xizhi Cao, Ye Liu, Can Zhu, Yuming Zhang, Bolong Wu, Ruiqun Chen, Lili Cheng, Jing Wang, Xiaolin Sun, Xiaohui Liu, Haiteng Deng, Jinliang Yang, Zhanguo Li, Wanli Liu, Ligong Chen.

Monocarboxylate transporter 1 (MCT1) exhibits essential roles in cellular metabolism and energy supply. Although MCT1 is highly expressed in activated B cells, it is not clear how MCT1-governed monocarboxylates transportation is functionally coupled to antibody production during the glucose metabolism. Here, we report that B cell-lineage deficiency of MCT1 significantly influences the class-switch recombination (CSR), rendering impaired IgG antibody responses in Mct1f/fMb1Cre mice after immunization. Metabolic flux reveals that glucose metabolism is significantly reprogrammed from glycolysis to oxidative phosphorylation in Mct1-deficient B cells upon activation. Consistently, activation-induced cytidine deaminase (AID), is severely suppressed in Mct1-deficient B cells due to the decreased level of pyruvate metabolite. Mechanistically, MCT1 is required to maintain the optimal concentration of pyruvate to secure the sufficient acetylation of H3K27 for the elevated transcription of AID in activated B cells. Clinically, we found that MCT1 expression levels are significantly upregulated in systemic lupus erythematosus patients, and Mct1 deficiency can alleviate the symptoms of bm12-induced murine lupus model. Collectively, these results demonstrate that MCT1-mediated pyruvate metabolism is required for IgG antibody CSR through an epigenetic dependent AID transcription, revealing MCT1 as a potential target for vaccine development and SLE disease treatment.

DOI: https://doi.org/10.1038/s41467-023-44540-0
Sci Transl Med. 2024 Jan 03. 16(728): eabq4145

NAD+ precursors and bile acid sequestration treat preclinical refractory environmental enteric dysfunction.

Atika Malique, Shengxiang Sun, Kanta Chandwe, Beatrice Amadi, Talin Haritunians, Umang Jain, Brian D Muegge, Jennifer Frein, Yo Sasaki, Amanda Foster, Chad E Storer, Emebet Mengesha, Justin Kern, Dermot P B McGovern, Richard D Head, Paul Kelly, Ta-Chiang Liu.

Environmental enteric dysfunction (EED) is a diffuse small bowel disorder associated with poor growth, inadequate responses to oral vaccines, and nutrient malabsorption in millions of children worldwide. We identify loss of the small intestinal Paneth and goblet cells that are critical for innate immunity, reduced villous height, increased bile acids, and dysregulated nicotinamide adenine dinucleotide (NAD+) synthesis signaling as potential mechanisms underlying EED and which also correlated with diminished length-for-age z score. Isocaloric low-protein diet (LPD) consumption in mice recapitulated EED histopathology and transcriptomic changes in a microbiota-independent manner, as well as increases in serum and fecal bile acids. Children with refractory EED harbor single-nucleotide polymorphisms in key enzymes involved in NAD+ synthesis. In mice, deletion of Nampt, the gene encoding the rate-limiting enzyme in the NAD+ salvage pathway, from intestinal epithelium also reduced Paneth cell function, a deficiency that was further aggravated by LPD. Separate supplementation with NAD+ precursors or bile acid sequestrant partially restored LPD-associated Paneth cell defects and, when combined, fully restored all histopathology defects in LPD-fed mice. Therapeutic regimens that increase protein and NAD+ contents while reducing excessive bile acids may benefit children with refractory EED.

DOI: https://doi.org/10.1126/scitranslmed.abq4145
Nat Cell Biol. 2024 Jan 02.

Vitamin B12 produced by gut bacteria modulates cholinergic signalling.

Woo Kyu Kang, Jeremy T Florman, Antonia Araya, Bennett W Fox, Andrea Thackeray, Frank C Schroeder, Albertha J M Walhout, Mark J Alkema.

A growing body of evidence indicates that gut microbiota influence brain function and behaviour. However, the molecular basis of how gut bacteria modulate host nervous system function is largely unknown. Here we show that vitamin B12-producing bacteria that colonize the intestine can modulate excitatory cholinergic signalling and behaviour in the host Caenorhabditis elegans. Here we demonstrate that vitamin B12 reduces cholinergic signalling in the nervous system through rewiring of the methionine (Met)/S-adenosylmethionine cycle in the intestine. We identify a conserved metabolic crosstalk between the methionine/S-adenosylmethionine cycle and the choline-oxidation pathway. In addition, we show that metabolic rewiring of these pathways by vitamin B12 reduces cholinergic signalling by limiting the availability of free choline required by neurons to synthesize acetylcholine. Our study reveals a gut-brain communication pathway by which enteric bacteria modulate host behaviour and may affect neurological health.

DOI: https://doi.org/10.1038/s41556-023-01299-2
Nat Commun. 2024 Jan 02. 15(1): 97

Myeloid-derived grancalcin instigates obesity-induced insulin resistance and metabolic inflammation in male mice.

Tian Su, Yue He, Yan Huang, Mingsheng Ye, Qi Guo, Ye Xiao, Guangping Cai, Linyun Chen, Changjun Li, Haiyan Zhou, Xianghang Luo.

The crosstalk between the bone and adipose tissue is known to orchestrate metabolic homeostasis, but the underlying mechanisms are largely unknown. Herein, we find that GCA + (grancalcin) immune cells accumulate in the bone marrow and release a considerable amount of GCA into circulation during obesity. Genetic deletion of Gca in myeloid cells attenuates metabolic dysfunction in obese male mice, whereas injection of recombinant GCA into male mice causes adipose tissue inflammation and insulin resistance. Mechanistically, we found that GCA binds to the Prohibitin-2 (PHB2) receptor on adipocytes and activates the innate and adaptive immune response of adipocytes via the PAK1-NF-κB signaling pathway, thus provoking the infiltration of inflammatory immune cells. Moreover, we show that GCA-neutralizing antibodies improve adipose tissue inflammation and insulin sensitivity in obese male mice. Together, these observations define a mechanism whereby bone marrow factor GCA initiates adipose tissue inflammation and insulin resistance, showing that GCA could be a potential target to treat metainflammation.

DOI: https://doi.org/10.1038/s41467-023-43787-x
Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00463-1. [Epub ahead of print]36(1): 1-3

TAMC-derived creatine sustains glioblastoma growth.

Huiwen Yan, Pengcheng Bu.

Tumor-associated myeloid cells (TAMCs) are the predominant immune population in glioblastoma (GBM), but the definite role of TAMCs in GBM tumorigenicity remains uncertain. In this issue of Cell Metabolism, Rashidi et al. identify a specific population of TAMCs surrounding hypoxic regions of GBM. These TAMCs provide creatine to nearby tumor cells to promote GBM progression.

DOI: https://doi.org/10.1016/j.cmet.2023.12.012
JCI Insight. 2024 Jan 04. pii: e169138. [Epub ahead of print]

Macrophage RAGE activation is proinflammatory in NASH.

Gopanandan Parthasarathy, Amy S Mauer, Naresh Golla, P Vineeth Daniel, Lily H Kim, Guneet S Sidhu, George W Marek Rd, Emilien Loeuillard, Anuradha Krishnan, Hyun Se Kim Lee, Kevin D Pavelko, Michael Charlton, Petra Hirsova, Sumera I Ilyas, Harmeet Malhi.

  Intrahepatic macrophages in nonalcoholic steatohepatitis (NASH) are heterogenous and include proinflammatory recruited monocyte derived macrophages. The receptor for advanced glycation end products (RAGE) is expressed on macrophages and can be activated by damage associated molecular patterns (DAMPs) upregulated in NASH, yet the role of macrophage-specific RAGE signaling in NASH is unclear. Therefore, we hypothesized that RAGE expressing macrophages are proinflammatory and mediate liver inflammation in NASH. Compared to healthy controls, RAGE expression was increased in liver biopsies from human NASH patients. In a high -fat, -fructose, and -cholesterol (FFC)-induced murine model of NASH, RAGE expression was increased, specifically on recruited macrophages. FFC mice that received a pharmacological inhibitor of RAGE (TTP488), and myeloid-specific RAGE knockout mice (RAGE-MKO) had attenuated liver injury associated with a reduced accumulation of RAGE+ recruited macrophages. Transcriptomic analysis suggested that pathways of macrophage and T-cell activation were upregulated by FFC diet, inhibited by TTP488 treatment, and reduced in RAGE-MKO mice. Correspondingly, the secretome of ligand-stimulated bone marrow derived macrophages from RAGE-MKO mice had an attenuated capacity to activate CD8+ T cells. Our data implicate RAGE as what we propose to be a novel and potentially targetable mediator of the proinflammatory signaling of recruited macrophages in NASH.

Keywords:  Drug therapy; Hepatitis; Hepatology; Inflammation; Macrophages

DOI:  https://doi.org/10.1172/jci.insight.169138
Mucosal Immunol. 2023 Dec 28. pii: S1933-0219(23)00097-1. [Epub ahead of print]

Metabolic fitness of IgA+ plasma cells in the gut requires DOCK8.

Biyan Zhang, Shuting Chen, Xiangyun Yin, Caleb D McBride, Jake A Gertie, Marina Yurieva, Agata A Bielecka, Brian Hoffmann, J Travis Hinson, Jessica Grassmann, Lan Xu, Emily R Siniscalco, Arielle Soldatenko, Laura Hoyt, Julie Joseph, Elizabeth B Norton, Gowthaman Uthaman, Noah W Palm, Elise Liu, Stephanie C Eisenbarth, Adam Williams.

  Dedicator of cytokinesis 8 (DOCK8) mutations lead to a primary immunodeficiency associated with recurrent gastrointestinal infections and poor antibody responses but paradoxically, heightened IgE to food antigens, suggesting that DOCK8 is central to immune homeostasis in the gut. Using Dock8-deficient mice, we found that DOCK8 was necessary for mucosal IgA production to multiple T cell-dependent antigens, including peanut and cholera toxin. Yet DOCK8 was not necessary in T cells for this phenotype. Instead, B cell intrinsic DOCK8 was required for maintenance of antigen-specific IgA secreting plasma cells (PCs) in the gut lamina propria. Unexpectedly, DOCK8 was not required for early B cell activation, migration, or IgA class switching. An unbiased interactome screen revealed novel protein partners involved in metabolism and apoptosis. Dock8-deficient IgA+ B cells had impaired cellular respiration and failed to engage glycolysis appropriately. These results demonstrate that maintenance of the IgA+ PC compartment requires DOCK8 and suggests that gut IgA+ PCs have unique metabolic requirements for long-term survival in the lamina propria.

Keywords:  DOCK8; IgA; Metabolism; Mucosal Immunity; Plasma Cell

DOI:  https://doi.org/10.1016/j.mucimm.2023.12.001
Redox Biol. 2023 Dec 25. pii: S2213-2317(23)00415-9. [Epub ahead of print]69 103014

Loss of cardiac mitochondrial complex I persulfidation impairs NAD+ homeostasis in aging.

Maria-Kyriaki Drekolia, Christina Karantanou, Ilka Wittig, Yuanyuan Li, Dominik C Fuhrmann, Bernhard Brüne, Antonia Katsouda, Jiong Hu, Andreas Papapetropoulos, Sofia-Iris Bibli.

  Protein persulfidation is a significant post-translational modification that involves addition of a sulfur atom to the cysteine thiol group and is facilitated by sulfide species. Persulfidation targets reactive cysteine residues within proteins, influencing their structure and/or function across various biological systems. This modification is evolutionarily conserved and plays a crucial role in preventing irreversible cysteine overoxidation, a process that becomes prominent with aging. While, persulfidation decreases with age, its levels in the aged heart and the functional implications of such a reduction in cardiac metabolism remain unknown. Here we interrogated the cardiac persulfydome in wild-type adult mice and age-matched mice lacking the two sulfide generating enzymes, namely cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3MST). Our findings revealed that cardiac persulfidated proteins in wild type hearts are less abundant compared to those in other organs, with a primary involvement in mitochondrial metabolic processes. We further focused on one specific target, NDUFB7, which undergoes persulfidation by both CSE and 3MST derived sulfide species. In particular, persulfidation of cysteines C80 and C90 in NDUFB7 protects the protein from overoxidation and maintains the complex I activity in cardiomyocytes. As the heart ages, the levels of CSE and 3MST in cardiomyocytes decline, leading to reduced NDUFB7 persulfidation and increased cardiac NADH/NAD+ ratio. Collectively, our data provide compelling evidence for a direct link between cardiac persulfidation and mitochondrial complex I activity, which is compromised in aging.

Keywords:  3MST; CSE; Cardiac aging; NDUFB7; Persulfidation

DOI:  https://doi.org/10.1016/j.redox.2023.103014
Nat Immunol. 2024 Jan;25(1): 17-18

Human and mouse peritoneal macrophages and dendritic cells compared.

DOI: https://doi.org/10.1038/s41590-023-01709-5
Nat Commun. 2024 Jan 02. 15(1): 133

Surplus fatty acid synthesis increases oxidative stress in adipocytes and lnduces lipodystrophy.

Li Weng, Wen-Shuai Tang, Xu Wang, Yingyun Gong, Changqin Liu, Ni-Na Hong, Ying Tao, Kuang-Zheng Li, Shu-Ning Liu, Wanzi Jiang, Ying Li, Ke Yao, Li Chen, He Huang, Yu-Zheng Zhao, Ze-Ping Hu, Youli Lu, Haobin Ye, Xingrong Du, Hongwen Zhou, Peng Li, Tong-Jin Zhao.

Adipocytes are the primary sites for fatty acid storage, but the synthesis rate of fatty acids is very low. The physiological significance of this phenomenon remains unclear. Here, we show that surplus fatty acid synthesis in adipocytes induces necroptosis and lipodystrophy. Transcriptional activation of FASN elevates fatty acid synthesis, but decreases NADPH level and increases ROS production, which ultimately leads to adipocyte necroptosis. We identify MED20, a subunit of the Mediator complex, as a negative regulator of FASN transcription. Adipocyte-specific male Med20 knockout mice progressively develop lipodystrophy, which is reversed by scavenging ROS. Further, in a murine model of HIV-associated lipodystrophy and a human patient with acquired lipodystrophy, ROS neutralization significantly improves metabolic disorders, indicating a causal role of ROS in disease onset. Our study well explains the low fatty acid synthesis rate in adipocytes, and sheds light on the management of acquired lipodystrophy.

DOI: https://doi.org/10.1038/s41467-023-44393-7
Nat Commun. 2024 Jan 02. 15(1): 45

Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use.

Anna Worthmann, Julius Ridder, Sharlaine Y L Piel, Ioannis Evangelakos, Melina Musfeldt, Hannah Voß, Marie O'Farrell, Alexander W Fischer, Sangeeta Adak, Monica Sundd, Hasibullah Siffeti, Friederike Haumann, Katja Kloth, Tatjana Bierhals, Markus Heine, Paul Pertzborn, Mira Pauly, Julia-Josefine Scholz, Suman Kundu, Marceline M Fuh, Axel Neu, Klaus Tödter, Maja Hempel, Uwe Knippschild, Clay F Semenkovich, Hartmut Schlüter, Joerg Heeren, Ludger Scheja, Christian Kubisch, Christian Schlein.

Dietary polyunsaturated fatty acids (PUFA) are increasingly recognized for their health benefits, whereas a high production of endogenous fatty acids - a process called de novo lipogenesis (DNL) - is closely linked to metabolic diseases. Determinants of PUFA incorporation into complex lipids are insufficiently understood and may influence the onset and progression of metabolic diseases. Here we show that fatty acid synthase (FASN), the key enzyme of DNL, critically determines the use of dietary PUFA in mice and humans. Moreover, the combination of FASN inhibition and PUFA-supplementation decreases liver triacylglycerols (TAG) in mice fed with high-fat diet. Mechanistically, FASN inhibition causes higher PUFA uptake via the lysophosphatidylcholine transporter MFSD2A, and a diacylglycerol O-acyltransferase 2 (DGAT2)-dependent incorporation of PUFA into TAG. Overall, the outcome of PUFA supplementation may depend on the degree of endogenous DNL and combining PUFA supplementation and FASN inhibition might be a promising approach to target metabolic disease.

DOI: https://doi.org/10.1038/s41467-023-44364-y
Nat Chem Biol. 2024 Jan 02.

Acylspermidines are conserved mitochondrial sirtuin-dependent metabolites.

Bingsen Zhang, James Mullmann, Andreas H Ludewig, Irma R Fernandez, Tyler R Bales, Robert S Weiss, Frank C Schroeder.

Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent protein lysine deacylases regulating metabolism and stress responses; however, characterization of the removed acyl groups and their downstream metabolic fates remains incomplete. Here we employed untargeted comparative metabolomics to reinvestigate mitochondrial sirtuin biochemistry. First, we identified N-glutarylspermidines as metabolites downstream of the mitochondrial sirtuin SIR-2.3 in Caenorhabditis elegans and demonstrated that SIR-2.3 functions as a lysine deglutarylase and that N-glutarylspermidines can be derived from O-glutaryl-ADP-ribose. Subsequent targeted analysis of C. elegans, mouse and human metabolomes revealed a chemically diverse range of N-acylspermidines, and formation of N-succinylspermidines and/or N-glutarylspermidines was observed downstream of mammalian mitochondrial sirtuin SIRT5 in two cell lines, consistent with annotated functions of SIRT5. Finally, N-glutarylspermidines were found to adversely affect C. elegans lifespan and mammalian cell proliferation. Our results indicate that N-acylspermidines are conserved metabolites downstream of mitochondrial sirtuins that facilitate annotation of sirtuin enzymatic activities in vivo and may contribute to sirtuin-dependent phenotypes.

DOI: https://doi.org/10.1038/s41589-023-01511-2
Cell. 2023 Dec 20. pii: S0092-8674(23)01323-5. [Epub ahead of print]

Human inherited CCR2 deficiency underlies progressive polycystic lung disease.

Anna-Lena Neehus, Brenna Carey, Marija Landekic, Patricia Panikulam, Gail Deutsch, Masato Ogishi, Carlos A Arango-Franco, Quentin Philippot, Mohammadreza Modaresi, Iraj Mohammadzadeh, Melissa Corcini Berndt, Darawan Rinchai, Tom Le Voyer, Jérémie Rosain, Mana Momenilandi, Marta Martin-Fernandez, Taushif Khan, Jonathan Bohlen, Ji Eun Han, Alexandre Deslys, Mathilde Bernard, Tania Gajardo-Carrasco, Camille Soudée, Corentin Le Floc'h, Mélanie Migaud, Yoann Seeleuthner, Mi-Sun Jang, Eirini Nikolouli, Simin Seyedpour, Hugues Begueret, Jean-François Emile, Pierre Le Guen, Guido Tavazzi, Costanza Natalia Julia Colombo, Federico Capra Marzani, Micol Angelini, Francesca Trespidi, Stefano Ghirardello, Nasrin Alipour, Anne Molitor, Raphael Carapito, Mohsen Mazloomrezaei, Hassan Rokni-Zadeh, Majid Changi-Ashtiani, Chantal Brouzes, Pablo Vargas, Alessandro Borghesi, Nico Lachmann, Seiamak Bahram, Bruno Crestani, Susanta Pahari, Larry S Schlesinger, Nico Marr, Dusan Bugonovic, Stéphanie Boisson-Dupuis, Vivien Béziat, Laurent Abel, Raphael Borie, Lisa R Young, Robin Deterding, Mohammad Shahrooei, Nima Rezaei, Nima Parvaneh, Daniel Craven, Philippe Gros, Danielle Malo, Fernando E Sepulveda, Lawrence M Nogee, Nathalie Aladjidi, Bruce C Trapnell, Jean-Laurent Casanova, Jacinta Bustamante.

  We describe a human lung disease caused by autosomal recessive, complete deficiency of the monocyte chemokine receptor C-C motif chemokine receptor 2 (CCR2). Nine children from five independent kindreds have pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including bacillus Calmette Guérin (BCG) disease. The CCR2 variants are homozygous in six patients and compound heterozygous in three, and all are loss-of-expression and loss-of-function. They abolish CCR2-agonist chemokine C-C motif ligand 2 (CCL-2)-stimulated Ca2+ signaling in and migration of monocytic cells. All patients have high blood CCL-2 levels, providing a diagnostic test for screening children with unexplained lung or mycobacterial disease. Blood myeloid and lymphoid subsets and interferon (IFN)-γ- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated immunity are unaffected. CCR2-deficient monocytes and alveolar macrophage-like cells have normal gene expression profiles and functions. By contrast, alveolar macrophage counts are about half. Human complete CCR2 deficiency is a genetic etiology of PAP, polycystic lung disease, and recurrent infections caused by impaired CCL2-dependent monocyte migration to the lungs and infected tissues.

Keywords:  PAP; chemotaxis; cystic lung disease; macrophage; monocyte; recurrent infection

DOI:  https://doi.org/10.1016/j.cell.2023.11.036
J Biol Chem. 2023 Dec 28. pii: S0021-9258(23)02627-3. [Epub ahead of print] 105598

A versatile in situ cofactor enhancing system for meeting cellular demands for engineered metabolic pathways.

Juthamas Jaroensuk, Chalermroj Sutthaphirom, Jittima Phonbuppha, Wachirawit Chinantuya, Chatchai Kesornpun, Nattanon Akeratchatapan, Narongyot Kittipanukul, Kamonwan Phatinuwat, Sopapan Atichartpongkul, Mayuree Fuangthong, Thunyarat Pongtharangkul, Frank Hollmann, Pimchai Chaiyen.

  Cofactor imbalance obstructs the productivities of metabolically engineered cells. Herein, we employed a minimally perturbing system, xylose reductase and lactose (XR/lactose), to increase levels of a pool of sugar-phosphates which are connected to the biosynthesis of NAD(P)H, FAD, FMN and ATP in Escherichia coli. The XR/lactose system could increase the amounts of the precursors of these cofactors and was tested with three different metabolically engineered cell systems (fatty alcohol biosynthesis, bioluminescence light generation and alkane biosynthesis) with different cofactor demands. Productivities of these cells were increased 2-4-fold by the XR/lactose system. Untargeted metabolomic analysis revealed different metabolite patterns among these cells; demonstrating that only metabolites involved in relevant cofactor biosynthesis were altered. The results were also confirmed by transcriptomic analysis. Another sugar reducing system (glucose dehydrogenase, GDH) could also be used to increase fatty alcohol production but resulted in less yield enhancement than XR. This work demonstrates that the approach of increasing cellular sugar phosphates can be a generic tool to increase in vivo cofactor generation upon cellular demand for synthetic biology.

Keywords:  Alkane; Bioluminescence; Fatty alcohol; Metabolic engineering; Sugar phosphate; Synthetic Biology; Xylose reductase

DOI:  https://doi.org/10.1016/j.jbc.2023.105598
Nat Immunol. 2024 Jan 04.

Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion.

Ronghui Yan, Pinggen Zhang, Shengqi Shen, Yu Zeng, Ting Wang, Zhaolin Chen, Wenhao Ma, Junru Feng, Caixia Suo, Tong Zhang, Haoran Wei, Zetan Jiang, Rui Chen, Shi-Ting Li, Xiuying Zhong, Weidong Jia, Linchong Sun, Chunlei Cang, Huafeng Zhang, Ping Gao.

Tumor cells and surrounding immune cells undergo metabolic reprogramming, leading to an acidic tumor microenvironment. However, it is unclear how tumor cells adapt to this acidic stress during tumor progression. Here we show that carnosine, a mobile buffering metabolite that accumulates under hypoxia in tumor cells, regulates intracellular pH homeostasis and drives lysosome-dependent tumor immune evasion. A previously unrecognized isoform of carnosine synthase, CARNS2, promotes carnosine synthesis under hypoxia. Carnosine maintains intracellular pH (pHi) homeostasis by functioning as a mobile proton carrier to accelerate cytosolic H+ mobility and release, which in turn controls lysosomal subcellular distribution, acidification and activity. Furthermore, by maintaining lysosomal activity, carnosine facilitates nuclear transcription factor X-box binding 1 (NFX1) degradation, triggering galectin-9 and T-cell-mediated immune escape and tumorigenesis. These findings indicate an unconventional mechanism for pHi regulation in cancer cells and demonstrate how lysosome contributes to immune evasion, thus providing a basis for development of combined therapeutic strategies against hepatocellular carcinoma that exploit disrupted pHi homeostasis with immune checkpoint blockade.

DOI: https://doi.org/10.1038/s41590-023-01719-3
Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00446-1. [Epub ahead of print]36(1): 21-35

Mitochondrial-derived vesicles in metabolism, disease, and aging.

Tim König, Heidi M McBride.

Mitochondria are central hubs of cellular metabolism and are tightly connected to signaling pathways. The dynamic plasticity of mitochondria to fuse, divide, and contact other organelles to flux metabolites is central to their function. To ensure bona fide functionality and signaling interconnectivity, diverse molecular mechanisms evolved. An ancient and long-overlooked mechanism is the generation of mitochondrial-derived vesicles (MDVs) that shuttle selected mitochondrial cargoes to target organelles. Just recently, we gained significant insight into the mechanisms and functions of MDV transport, ranging from their role in mitochondrial quality control to immune signaling, thus demonstrating unexpected and diverse physiological aspects of MDV transport. This review highlights the origin of MDVs, their biogenesis, and their cargo selection, with a specific focus on the contribution of MDV transport to signaling across cell and organ barriers. Additionally, the implications of MDVs in peroxisome biogenesis, neurodegeneration, metabolism, aging, and cancer are discussed.

DOI: https://doi.org/10.1016/j.cmet.2023.11.014
Cell Mol Biol (Noisy-le-grand). 2023 Dec 10. 69(13): 128-133

The neuronal nitric oxide synthase expression increases during satellite cell-derived primary myoblasts differentiation.

Masaki Kusano, Kazuya Sakai, Yuki Tomiga, Ai Ito, Shihoko Nakashima, Yoshinari Uehara, Kentaro Kawanaka, Yasuo Kitajima, Yasuki Higaki.

The neuronal nitric oxide synthase (nNOS; encoded by NOS1)-derived nitric oxide (NO) plays an important role in maintaining skeletal muscle mass. In adult skeletal muscle, nNOS localizes to the cell membrane, cytosol, and nucleus, and regulates muscle hypertrophy and atrophy in various subcellular fractions. However, its role in muscle stem cells (also known as muscle satellite cells), which provide myonuclei for postnatal muscle growth, maintenance, and regeneration, remains unclear. The present study aimed to determine nNOS expression in muscle satellite cell-derived primary myoblasts during differentiation and its DNA methylation levels, an epigenetic modification that controls gene expression. Undifferentiated and differentiated satellite cell-derived primary myoblasts were found to express nNOS. Immunohistochemical analysis revealed that nNOS colocalized with Pax7 (satellite cell marker) only in the undifferentiated myoblasts. Furthermore, nNOS immunoreactivity spread to the cytosol of Pax7-negative differentiated myotube-like cells. The level of Nos1µ mRNA, the main isoform of skeletal muscle nNOS, was increased in differentiated satellite cell-derived primary myoblasts compared to that in the undifferentiated cells. However, Nos1 methylation levels remained unchanged during differentiation. These findings suggest that nNOS induction and the appropriate transition of its subcellular localization may contribute to muscle differentiation.

DOI: https://doi.org/10.14715/cmb/2023.69.13.20
Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00456-4. [Epub ahead of print]36(1): 209-221.e6

Deciphering the metabolic heterogeneity of hematopoietic stem cells with single-cell resolution.

Jing Cao, Qi Jason Yao, Jiao Wu, Xiaonan Chen, Lin Huang, Wanshan Liu, Kun Qian, Jing-Jing Wan, Bo O Zhou.

  Metabolic status is crucial for stem cell functions; however, the metabolic heterogeneity of endogenous stem cells has never been directly assessed. Here, we develop a platform for high-throughput single-cell metabolomics (hi-scMet) of hematopoietic stem cells (HSCs). By combining flow cytometric isolation and nanoparticle-enhanced laser desorption/ionization mass spectrometry, we routinely detected >100 features from single cells. We mapped the single-cell metabolomes of all hematopoietic cell populations and HSC subpopulations with different division times, detecting 33 features whose levels exhibited trending changes during HSC proliferation. We found progressive activation of the oxidative pentose phosphate pathway (OxiPPP) from dormant to active HSCs. Genetic or pharmacological interference with OxiPPP increased reactive oxygen species level in HSCs, reducing HSC self-renewal upon oxidative stress. Together, our work uncovers the metabolic dynamics during HSC proliferation, reveals a role of OxiPPP for HSC activation, and illustrates the utility of hi-scMet in dissecting metabolic heterogeneity of immunophenotypically defined cell populations.

Keywords:  6-phosphogluconic acid; HSC; MALDI-MS; hematopoietic stem cell; hi-scMet; metabolism; metabolomic heterogeneity; nanoparticle; pentose phosphate pathway; single-cell metabolomics

DOI:  https://doi.org/10.1016/j.cmet.2023.12.005