bims-medica 2024-01-07 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024‒01‒07
29 papers selected by
Brett Chrest, East Carolina University

Dietary approaches for exploiting metabolic vulnerabilities in cancer.
The KRAS tour: Studying metabolic reprogramming in isogenic pancreatic cancer organoids.
Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer.
Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.
FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia.
Glycine homeostasis requires reverse SHMT flux.
Mitochondrial fusion-fission dynamics and its involvement in colorectal cancer.
Nutritional adjuncts in the management of gliomas: Food for thought.
p32 regulates glycometabolism and TCA cycle to inhibit ccRCC progression via copper-induced DLAT lipoylation oligomerization.
Methionine restriction of glioma does not induce MGMT and greatly improves temozolomide efficacy in an orthotopic nude-mouse model: A potential curable approach to a clinically-incurable disease.
The solute carrier SLC25A17 sustains peroxisomal redox homeostasis in diverse mammalian cell lines.
Western diet-induced obesity results in brain mitochondrial dysfunction in female Ossabaw swine.
Serine synthesis via reversed SHMT2 activity drives glycine depletion and acetaminophen hepatotoxicity in MASLD.
Metabolic reprogramming in skin wound healing.
Feasibility and metabolic outcomes of a well-formulated ketogenic diet as an adjuvant therapeutic intervention for women with stage IV metastatic breast cancer: The Keto-CARE trial.
Mitochondrial Mechanisms in Temozolomide Resistance: Unraveling the Complex Interplay and Therapeutic Strategies in Glioblastoma.
Alterations in mitochondria isolated from peripheral blood mononuclear cells and tumors of patients with epithelial ovarian cancers.
Oleic Acid Activates Mitochondrial Energy Metabolism and Reduces Oxidative Stress Resistance in the Pancreatic β-Cell Line INS-1.
H+-slip correlated to rotor free-wheeling as cause of F1 FO -ATPase dysfunction in primary mitochondrial disorders.
Fast Mimicking Diets and Other Innovative Nutritional Interventions to Treat Patients with Breast Cancer.
Aberrant Lipid Metabolic Signatures in Acute Myeloid Leukemia.
NADPH Oxidase Overexpression and Mitochondrial OxPhos Impairment are More Profound in Human Hearts Donated after Circulatory Death Than Brain Death.
Toolkit for cellular studies of mammalian mitochondrial inorganic polyphosphate.
Tamoxifen induces ferroptosis in MCF-7 organoid.
Basic pathway decomposition of biochemical reaction networks within growing cells.
Hexose phosphorylation for a non-enzymatic glycolysis and pentose phosphate pathway on early Earth.
Empagliflozin improves mitochondrial dysfunction in diabetic cardiomyopathy by modulating ketone body metabolism and oxidative stress.
Excessive Lipid Production Shapes Glioma Tumor Microenvironment.
Investigating the Metabolic Heterogeneity of Cancer Cells Using Functional Single-Cell Selection and nLC Combined with Multinozzle Emitter Mass Spectrometry.

Biochim Biophys Acta Rev Cancer. 2023 Dec 27. pii: S0304-419X(23)00211-1. [Epub ahead of print] 189062

Dietary approaches for exploiting metabolic vulnerabilities in cancer.

Otília Menyhárt, Balázs Győrffy.

  Renewed interest in tumor metabolism sparked an enthusiasm for dietary interventions to prevent and treat cancer. Changes in diet impact circulating nutrient levels in the plasma and the tumor microenvironment, and preclinical studies suggest that dietary approaches, including caloric and nutrient restrictions, can modulate tumor initiation, progression, and metastasis. Cancers are heterogeneous in their metabolic dependencies and preferred energy sources and can be addicted to glucose, fructose, amino acids, or lipids for survival and growth. This dependence is influenced by tumor type, anatomical location, tissue of origin, aberrant signaling, and the microenvironment. This review summarizes nutrient dependencies and the related signaling pathway activations that provide targets for nutritional interventions. We examine popular dietary approaches used as adjuvants to anticancer therapies, encompassing caloric restrictions, including time-restricted feeding, intermittent fasting, fasting-mimicking diets (FMDs), and nutrient restrictions, notably the ketogenic diet. Despite promising results, much of the knowledge on dietary restrictions comes from in vitro and animal studies, which may not accurately reflect real-life situations. Further research is needed to determine the optimal duration, timing, safety, and efficacy of dietary restrictions for different cancers and treatments. In addition, well-designed human trials are necessary to establish the link between specific metabolic vulnerabilities and targeted dietary interventions. However, low patient compliance in clinical trials remains a significant challenge.

Keywords:  Caloric restriction; Dietary intervention; Fasting-mimicking diet; Ketogenic diet; cancer metabolism

DOI:  https://doi.org/10.1016/j.bbcan.2023.189062
Cell Stem Cell. 2024 Jan 04. pii: S1934-5909(23)00440-X. [Epub ahead of print]31(1): 1-2

The KRAS tour: Studying metabolic reprogramming in isogenic pancreatic cancer organoids.

Shree Bose, Xiling Shen.

Using an isogenic organoid platform to model pancreatic cancer, Duan et al. establish an important link between mutant KRAS and cholesterol metabolism and identify perhexiline maleate as a possible therapeutic to target this relationship.

DOI: https://doi.org/10.1016/j.stem.2023.12.010
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
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
Leukemia. 2024 Jan 05.

FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia.

Pamela J Sung, Murugan Selvam, Simone S Riedel, Hongbo M Xie, Katie Bryant, Bryan Manning, Gerald B Wertheim, Katarzyna Kulej, Lucie Pham, Robert L Bowman, Jennifer Peresie, Michael J Nemeth, Ross L Levine, Benjamin A Garcia, Sara E Meyer, Simone Sidoli, Kathrin M Bernt, Martin Carroll.

Internal tandem duplication mutations in fms-like tyrosine kinase 3 (FLT3-ITD) are recurrent in acute myeloid leukemia (AML) and increase the risk of relapse. Clinical responses to FLT3 inhibitors (FLT3i) include myeloid differentiation of the FLT3-ITD clone in nearly half of patients through an unknown mechanism. We identified enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), as a mediator of this effect using a proteomic-based screen. FLT3i downregulated EZH2 protein expression and PRC2 activity on H3K27me3. FLT3-ITD and loss-of-function mutations in EZH2 are mutually exclusive in human AML. We demonstrated that FLT3i increase myeloid maturation with reduced stem/progenitor cell populations in murine Flt3-ITD AML. Combining EZH1/2 inhibitors with FLT3i increased terminal maturation of leukemic cells and reduced leukemic burden. Our data suggest that reduced EZH2 activity following FLT3 inhibition promotes myeloid differentiation of FLT3-ITD leukemic cells, providing a mechanistic explanation for the clinical observations. These results demonstrate that in addition to its known cell survival and proliferation signaling, FLT3-ITD has a second, previously undefined function to maintain a myeloid stem/progenitor cell state through modulation of PRC2 activity. Our findings support exploring EZH1/2 inhibitors as therapy for FLT3-ITD AML.

DOI: https://doi.org/10.1038/s41375-023-02131-4
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
Mol Oncol. 2023 Dec 29.

Mitochondrial fusion-fission dynamics and its involvement in colorectal cancer.

Zihong Wu, Chong Xiao, Fang Li, Wenbo Huang, Fengming You, Xueke Li.

  The incidence and mortality rates of colorectal cancer have elevated its status as a significant public health concern. Recent research has elucidated the crucial role of mitochondrial fusion-fission dynamics in the initiation and progression of colorectal cancer. Elevated mitochondrial fission or fusion activity can contribute to the metabolic reprogramming of tumor cells, thereby activating oncogenic pathways that drive cell proliferation, invasion, migration, and drug resistance. Nevertheless, excessive mitochondrial fission can induce apoptosis, whereas moderate mitochondrial fusion can protect cells from oxidative stress. This imbalance in mitochondrial dynamics can exert dual roles as both promoters and inhibitors of colorectal cancer progression. This review provides an in-depth analysis of the fusion-fission dynamics and the underlying pathological mechanisms in colorectal cancer cells. Additionally, it offers partial insights into the mitochondrial kinetics in colorectal cancer-associated cells, such as immune and endothelial cells. This review is aimed at identifying key molecular events involved in colorectal cancer progression and highlighting the potential of mitochondrial dynamic proteins as emerging targets for pharmacological intervention.

Keywords:  Colorectal cancer; dynamics; mitochondrial fission; mitochondrial fusion; progression

DOI:  https://doi.org/10.1002/1878-0261.13578
Clin Neurol Neurosurg. 2023 Dec 23. pii: S0303-8467(23)00518-8. [Epub ahead of print]236 108102

Nutritional adjuncts in the management of gliomas: Food for thought.

Ashwin Kumaria, Ahmad Kamaludin, Keyoumars Ashkan.



Keywords:  Brain gut axis; Brain tumours; Glioma; Ketogenic diet; Nutrition

DOI:  https://doi.org/10.1016/j.clineuro.2023.108102
Int J Biol Sci. 2024 ;20(2): 516-536

p32 regulates glycometabolism and TCA cycle to inhibit ccRCC progression via copper-induced DLAT lipoylation oligomerization.

Shaoping Tian, Rui Wang, Yiting Wang, Ruibing Chen, Tianyu Lin, Xuesong Xiao, Xinyu Liu, Justin Eze Ideozu, Hua Geng, Yong Wang, Dan Yue.

  A key player in mitochondrial respiration, p32, often referred to as C1QBP, is mostly found in the mitochondrial matrix. Previously, we showed that p32 interacts with DLAT in the mitochondria. Here, we found that p32 expression was reduced in ccRCC and suppressed progression and metastasis in ccRCC animal models. We observed that increasing p32 expression led to an increase in oxidative phosphorylation by interacting with DLAT, thus, regulating the activation of the pyruvate dehydrogenase complex (PDHc). Mechanistically, reduced p32 expression, in concert with DLAT, suppresses PDHc activity and the TCA cycle. Furthermore, our research discovered that p32 has a direct binding affinity for copper, facilitating the copper-induced oligomerization of lipo-DLAT specifically in ccRCC cells. This finding reveals an innovative function of the p32/DLAT/copper complex in regulating glycometabolism and the TCA cycle in ccRCC. Importantly, our research provides important new understandings of the underlying molecular processes causing the abnormal mitochondrial metabolism linked to this cancer.

Keywords:  Clear cell renal cell carcinoma; Copper; DLAT; glycometabolism; p32; tricarboxylic acid cycle

DOI:  https://doi.org/10.7150/ijbs.84399
Biochem Biophys Res Commun. 2023 Dec 25. pii: S0006-291X(23)01512-7. [Epub ahead of print]695 149418

Methionine restriction of glioma does not induce MGMT and greatly improves temozolomide efficacy in an orthotopic nude-mouse model: A potential curable approach to a clinically-incurable disease.

Yutaro Kubota, Yusuke Aoki, Noriyuki Masaki, Koya Obara, Kazuyuki Hamada, Qinghong Han, Michael Bouvet, Takuya Tsunoda, Robert M Hoffman.

  Glioma is a highly recalcitrant disease with a 5-year survival of 6.8 %. Temozolomide (TMZ), first-line therapy for glioma, is more effective in O6-methylguanine-DNA methyltransferase (MGMT)-negative gliomas than in MGMT-positive gliomas as MGMT confers resistance to TMZ. Methionine restriction is effective for many cancers in mouse models including glioma. The concern is that methionine restriction could induce MGMT by decreasing DNA methylation and confer resistance to TMZ. In the present study, we investigated the efficacy of combining methionine restriction with TMZ for the treatment of MGMT-negative glioma, and whether methionine restriction induced MGMT. Human MGMT-negative U87 glioma cells were used to determine the efficacy of TMZ combined with methionine restriction. Recombinant methioninase (rMETase) inhibited U87 glioma growth without induction of MGMT in vitro. The combination of rMETase and TMZ inhibited U87 cell proliferation more than either agent alone in vitro. In the orthotopic nude-mouse model, the combination of TMZ and a methionine-deficient diet was much more effective than TMZ alone: two mice out of five were cured of glioma by the combination. No mice died during the treatment period. Methionine restriction enhanced the efficacy of TMZ in MGMT-negative glioma without inducing MGMT, demonstrating potential clinical promise for improved outcome of a currently incurable disease.

Keywords:  Combination therapy; Efficacy; Glioma; MGMT; Methionine restriction; Nude mice; Orthotopic; Temozolomide

DOI:  https://doi.org/10.1016/j.bbrc.2023.149418
Free Radic Biol Med. 2023 Dec 29. pii: S0891-5849(23)01191-7. [Epub ahead of print]212 241-254

The solute carrier SLC25A17 sustains peroxisomal redox homeostasis in diverse mammalian cell lines.

Cláudio F Costa, Celien Lismont, Serhii Chornyi, Janet Koster, Hongli Li, Mohamed A F Hussein, Paul P Van Veldhoven, Hans R Waterham, Marc Fransen.

  Despite the crucial role of peroxisomes in cellular redox maintenance, little is known about how these organelles transport redox metabolites across their membrane. In this study, we sought to assess potential associations between the cellular redox landscape and the human peroxisomal solute carrier SLC25A17, also known as PMP34. This carrier has been reported to function as a counter-exchanger of adenine-containing cofactors such as coenzyme A (CoA), dephospho-CoA, flavin adenine dinucleotide, nicotinamide adenine dinucleotide (NAD+), adenosine 3',5'-diphosphate, flavin mononucleotide, and adenosine monophosphate. We found that inactivation of SLC25A17 resulted in a shift toward a more reductive state in the glutathione redox couple (GSSG/GSH) across HEK-293 cells, HeLa cells, and SV40-transformed mouse embryonic fibroblasts, with variable impact on the NADPH levels and the NAD+/NADH redox couple. This phenotype could be rescued by the expression of Candida boidinii Pmp47, a putative SLC25A17 orthologue reported to be essential for the metabolism of medium-chain fatty acids in yeast peroxisomes. In addition, we provide evidence that the alterations in the redox state are not caused by changes in peroxisomal antioxidant enzyme expression, catalase activity, H2O2 membrane permeability, or mitochondrial fitness. Furthermore, treating control and ΔSLC25A17 cells with dehydroepiandrosterone, a commonly used glucose-6-phosphate dehydrogenase inhibitor affecting NADPH regeneration, revealed a kinetic disconnection between the peroxisomal and cytosolic glutathione pools. Additionally, these experiments underscored the impact of SLC25A17 loss on peroxisomal NADPH metabolism. The relevance of these findings is discussed in the context of the still ambiguous substrate specificity of SLC25A17 and the recent observation that the mammalian peroxisomal membrane is readily permeable to both GSH and GSSG.

Keywords:  CoA; Glutathione; Metabolite transport; NADPH; PMP34; Peroxisomes; Redox compartmentalization; SLC25A17

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.035
Front Mol Neurosci. 2023 ;16 1320879

Western diet-induced obesity results in brain mitochondrial dysfunction in female Ossabaw swine.

Taylor J Kelty, Chris L Taylor, Nicole E Wieschhaus, Pamela K Thorne, Amira R Amin, Christina M Mueller, T Dylan Olver, Darla L Tharp, Craig A Emter, Alexander W Caulk, R Scott Rector.

  Diet-induced obesity is implicated in the development of a variety of neurodegenerative disorders. Concurrently, the loss of mitochondrial Complex I protein or function is emerging as a key phenotype across an array of neurodegenerative disorders. Therefore, the objective of this study was to determine if Western diet (WD) feeding in swine [carbohydrate = 40.8% kCal (17.8% of total calories from high fructose corn syrup), protein = 16.2% kcal, fat = 42.9% kCal, and 2% cholesterol] would result in Complex I syndrome pathology. To characterize the effects of WD-induced obesity on brain mitochondria in swine, high resolution respirometry measurements from isolated brain mitochondria, oxidative phosphorylation Complex expression, and indices of oxidative stress and mitochondrial biogenesis were assessed in female Ossabaw swine fed a WD for 6-months. In line with Complex I syndrome, WD feeding severely reduced State 3 Complex I, State 3 Complex I and II, and uncoupled mitochondrial respiration in the hippocampus and prefrontal cortex (PFC). State 3 Complex I mitochondrial respiration in the PFC inversely correlated with serum total cholesterol. WD feeding also significantly reduced protein expression of oxidative phosphorylation Complexes I-V in the PFC. WD feeding significantly increased markers of antioxidant defense and mitochondrial biogenesis in the hippocampi and PFC. These data suggest WD-induced obesity may contribute to Complex I syndrome pathology by increasing oxidative stress, decreasing oxidative phosphorylation Complex protein expression, and reducing brain mitochondrial respiration. Furthermore, these findings provide mechanistic insight into the clinical link between obesity and mitochondrial Complex I related neurodegenerative disorders.

Keywords:  Complex I syndrome; Western diet; hippocampus; mitochondrial dysfunction; obesity; prefrontal cortex; swine

DOI:  https://doi.org/10.3389/fnmol.2023.1320879
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
Burns Trauma. 2024 ;12 tkad047

Metabolic reprogramming in skin wound healing.

Zitong Wang, Feng Zhao, Chengcheng Xu, Qiqi Zhang, Haiyue Ren, Xing Huang, Cai He, Jiajie Ma, Zhe Wang.

  Metabolic reprogramming refers to the ability of a cell to alter its metabolism in response to different stimuli and forms of pressure. It helps cells resist external stress and provides them with new functions. Skin wound healing involves the metabolic reprogramming of nutrients, such as glucose, lipids, and amino acids, which play vital roles in the proliferation, differentiation, and migration of multiple cell types. During the glucose metabolic process in wounds, glucose transporters and key enzymes cause elevated metabolite levels. Glucose-mediated oxidative stress drives the proinflammatory response and promotes wound healing. Reprogramming lipid metabolism increases the number of fibroblasts and decreases the number of macrophages. It enhances local neovascularization and improves fibrin stability to promote extracellular matrix remodelling, accelerates wound healing, and reduces scar formation. Reprogramming amino acid metabolism affects wound re-epithelialization, collagen deposition, and angiogenesis. However, comprehensive reviews on the role of metabolic reprogramming in skin wound healing are lacking. Therefore, we have systematically reviewed the metabolic reprogramming of glucose, lipids, and amino acids during skin wound healing. Notably, we identified their targets with potential therapeutic value and elucidated their mechanisms of action.

Keywords:  Metabolic reprogramming; Molecular mechanism; Skin; Therapeutic potential; Wound healing

DOI:  https://doi.org/10.1093/burnst/tkad047
PLoS One. 2024 ;19(1): e0296523

Feasibility and metabolic outcomes of a well-formulated ketogenic diet as an adjuvant therapeutic intervention for women with stage IV metastatic breast cancer: The Keto-CARE trial.

Alex Buga, David G Harper, Teryn N Sapper, Parker N Hyde, Brandon Fell, Ryan Dickerson, Justen T Stoner, Madison L Kackley, Christopher D Crabtree, Drew D Decker, Bradley T Robinson, Gerald Krystal, Katherine Binzel, Maryam B Lustberg, Jeff S Volek.

PURPOSE: Ketogenic diets may positively influence cancer through pleiotropic mechanisms, but only a few small and short-term studies have addressed feasibility and efficacy in cancer patients. The primary goals of this study were to evaluate the feasibility and the sustained metabolic effects of a personalized well-formulated ketogenic diet (WFKD) designed to achieve consistent blood beta-hydroxybutyrate (βHB) >0.5 mM in women diagnosed with stage IV metastatic breast cancer (MBC) undergoing chemotherapy.METHODS: Women (n = 20) were enrolled in a six month, two-phase, single-arm WFKD intervention (NCT03535701). Phase I was a highly-supervised, ad libitum, personalized WFKD, where women were provided with ketogenic-appropriate food daily for three months. Phase II transitioned women to a self-administered WFKD with ongoing coaching for an additional three months. Fasting capillary βHB and glucose were collected daily; weight, body composition, plasma insulin, and insulin resistance were collected at baseline, three and six months.
RESULTS: Capillary βHB indicated women achieved nutritional ketosis (Phase I mean: 0.8 mM (n = 15); Phase II mean: 0.7 mM (n = 9)). Body weight decreased 10% after three months, primarily from body fat. Fasting plasma glucose, plasma insulin, and insulin resistance also decreased significantly after three months (p < 0.01), an effect that persisted at six months.
CONCLUSIONS: Women diagnosed with MBC undergoing chemotherapy can safely achieve and maintain nutritional ketosis, while improving body composition and insulin resistance, out to six months.

DOI: https://doi.org/10.1371/journal.pone.0296523
Mitochondrion. 2023 Dec 27. pii: S1567-7249(23)00116-2. [Epub ahead of print]75 101836

Mitochondrial Mechanisms in Temozolomide Resistance: Unraveling the Complex Interplay and Therapeutic Strategies in Glioblastoma.

Hao-Yi Li, Yin-Hsun Feng, Chien-Liang Lin, Tsung-I Hsu.

  Glioblastoma (GBM) is a highly aggressive and lethal brain tumor, with temozolomide (TMZ) being the standard chemotherapeutic agent for its treatment. However, TMZ resistance often develops, limiting its therapeutic efficacy and contributing to poor patient outcomes. Recent evidence highlights the crucial role of mitochondria in the development of TMZ resistance through various mechanisms, including alterations in reactive oxygen species (ROS) production, metabolic reprogramming, apoptosis regulation, biogenesis, dynamics, stress response, and mtDNA mutations. This review article aims to provide a comprehensive overview of the mitochondrial mechanisms involved in TMZ resistance and discuss potential therapeutic strategies targeting these mechanisms to overcome resistance in GBM. We explore the current state of clinical trials targeting mitochondria or related pathways in primary GBM or recurrent GBM, as well as the challenges and future perspectives in this field. Understanding the complex interplay between mitochondria and TMZ resistance will facilitate the development of more effective therapeutic strategies and ultimately improve the prognosis for GBM patients.

Keywords:  Glioblastoma; Mitochondria; TMZ resistance

DOI:  https://doi.org/10.1016/j.mito.2023.101836
Sci Rep. 2024 01 02. 14(1): 15

Alterations in mitochondria isolated from peripheral blood mononuclear cells and tumors of patients with epithelial ovarian cancers.

Kittipat Charoenkwan, Nattayaporn Apaijai, Sirawit Sriwichaiin, Nipon Chattipakorn, Siriporn C Chattipakorn.

Metabolic alterations play an essential role in ovarian carcinogenesis. The flexibility of mitochondrial functions facilitates cellular adaptation to the tough environment associated with carcinogenesis. An understanding of the differences in mitochondrial functions in normal ovaries and cancers could provide a basis for further exploration of future mitochondria-based screening, diagnosis, prognostic prediction, and targeted therapy for epithelial ovarian cancers. The main objective of this study was to assess mitochondrial function profiles measured from PBMCs and ovarian tissues of epithelial ovarian cancers in comparison with normal ovaries. A total of 36 patients were recruited for the study, all of whom underwent primary surgical treatment for malignant epithelial ovarian neoplasm. Of these, 20 patients were in the early stage and 16 patients were in the advanced stage. Additionally, 21 patients who had pelvic surgery for benign gynecologic conditions, with normal ovaries incidentally removed, were recruited as controls. At the time of surgery, a blood sample was collected from each participant for PBMC isolation, and ovarian tissue was retained for molecular studies. These studies included the examination of oxidative stress, mitochondrial mass, mitochondrial respiration, mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP) changes, and mitochondrial swelling. Clinical and histopathological data were also collected and compared between different stages of epithelial ovarian cancers: early-stage (group 1), advanced-stage (group 2), and normal ovaries (group 3). The levels of cellular oxidative stress, mitochondrial mass, and mitochondrial biogenesis in the peripheral blood mononuclear cells (PBMCs) of participants with ovarian cancer were significantly lower than those of the control group. However, the mitochondrial respiratory parameters measured from the PBMCs were similar across all three groups. Furthermore, mitochondrial membrane depolarization and mitochondrial swelling were observed in ovarian tissues of both early-stage and advanced-stage cancer groups. We demonstrated the dynamic nature of mitochondrial ROS production, biogenesis, and respiratory function in response to epithelial ovarian carcinogenesis. The flexibility of mitochondrial functions under diverse conditions may make it a challenging therapeutic target for ovarian cancer.

DOI: https://doi.org/10.1038/s41598-023-51009-z
Biol Pharm Bull. 2024 ;47(1): 145-153

Oleic Acid Activates Mitochondrial Energy Metabolism and Reduces Oxidative Stress Resistance in the Pancreatic β-Cell Line INS-1.

Mariko Suzuki, Kaoruko Endo, Riko Nagata, Naoko Iida-Tanaka.

  Elevated concentration of saturated fatty acids in plasma adversely affects pancreatic β-cells, but the effects of unsaturated fatty acids are controversial. In this study, we examined the effects of oleic acid (OA), a monounsaturated fatty acid, on mitochondrial function, which is important for insulin secretion, using INS-1 cells, a pancreatic β-cell line derived from rats. Observations of mitochondrial membrane potential and intracellular ATP concentration showed that the electron transport chain was enhanced and ATP production increased in cells treated with OA, indicating that the response that occurs from sensing an increase in glucose concentration to the production of ATP was accelerated. Measurements of intracellular reactive oxygen species (ROS) indicated that the rate of increase in ROS after glucose stimulation was significantly higher in OA-treated cells. The mRNA expression levels of superoxide dismutase 1 and 2, which are responsive to ROS and other substances, were significantly increased in OA 1-d treated cells, but decreased in OA 7-d treated cells. It can be inferred that continued exposure to high concentrations of OA reduced ROS processing capacity and increased intracellular ROS levels. The mRNA expression of apoptosis-inducing enzyme Caspase-3 was significantly increased in OA-treated cells, although its activity was not high. However, the apoptosis induction rate after H2O2 stimulation was significantly higher in OA-treated cells. The high OA environment was shown to promote mitochondrial energy metabolism, leading to an increase in glucose sensitivity and a decrease in oxidative stress resistance.

Keywords:  mitochondrial function; oleic acid; oxidative stress resistance; pancreatic β-cell

DOI:  https://doi.org/10.1248/bpb.b23-00559
Med Res Rev. 2024 Jan 03.

H+-slip correlated to rotor free-wheeling as cause of F1 FO -ATPase dysfunction in primary mitochondrial disorders.

Salvatore Nesci, Giovanni Romeo.

  Inborn errors of metabolism are related to mitochondrial disorders caused by dysfunction of the oxidative phosphorylation (OXPHOS) system. Congenital hypermetabolism in the infant is a rare disease belonging to Luft syndrome, nonthyroidal hypermetabolism, arising from a singular example of a defect in OXPHOS. The mitochondria lose coupling of mitochondrial substrates oxidation from the ADP phosphorylation. Since Luft syndrome is due to uncoupled cell respiration responsible for deficient in ATP production that originates in the respiratory complexes, a de novo heterozygous variant in the catalytic subunit of mitochondrial F1 FO -ATPase arises as the main cause of an autosomal dominant syndrome of hypermetabolism associated with dysfunction in ATP production, which does not involve the respiratory complexes. The F1 FO -ATPase works as an embedded molecular machine with a rotary action using two different motor engines. The FO , which is an integral domain in the membrane, dissipates the chemical potential difference for H+ , a proton motive force (Δp), across the inner membrane to generate a torsion. The F1 domain-the hydrophilic portion responsible for ATP turnover-is powered by the molecular rotary action to synthesize ATP. The structural and functional coupling of F1 and FO domains support the energy transduction for ATP synthesis. The dissipation of Δp by means of an H+ slip correlated to rotor free-wheeling of the F1 FO -ATPase has been discovered to cause enzyme dysfunction in primary mitochondrial disorders. In this insight, we try to offer commentary and analysis of the molecular mechanism in these impaired mitochondria.

Keywords:  ATP synthase; bioenergetic failure; congenital hypermetabolism; de novo mutation; mitochondria

DOI:  https://doi.org/10.1002/med.22013
Cancer Treat Res. 2023 ;188 199-218

Fast Mimicking Diets and Other Innovative Nutritional Interventions to Treat Patients with Breast Cancer.

Federica Giugliano, Laura Boldrini, Jacopo Uliano, Edoardo Crimini, Ida Minchella, Giuseppe Curigliano.

  The impact of nutritional patterns on the risk of breast cancer (BC) is well investigated in the oncology literature, including the type of diets and caloric intake. While obesity and elevated body mass index are well-reported critical risk factors of BC occurrence, there is an expanding area of oncology assessing the impact of caloric intake and nutritional patterns in patients with cancer. Caloric restriction and fast mimicking alimentary regimens have been consistently reported to improve survival outcomes based on preclinical models. Moreover, emerging clinical evidence has paved the way for new metabolic approaches for the treatment of BC, in addition to the established therapeutic arsenal or as alternative options. In this chapter, our aim is to discuss the principal strategies of metabolic manipulation through nutritional interventions for patients with BC as an innovative area of cancer therapy.

Keywords:  Breast cancer; Caloric restriction; Fast mimicking diet; Metabolism

DOI:  https://doi.org/10.1007/978-3-031-33602-7_8
Stem Cells. 2024 Jan 03. pii: sxad095. [Epub ahead of print]

Aberrant Lipid Metabolic Signatures in Acute Myeloid Leukemia.

Pooja Singh, Roopak Murali, Sri Gayathri Shanmugam, Steve Thomas, Julius Scott, Sudha Warrier, Frank Arfuso, Arun Dharmarajan, Rajesh Kumar Gandhirajan.

  Leukemogenesis is a complex process that involves multiple stages of mutation in either hematopoietic stem or progenitor cells, leading to cancer development over time. Acute myeloid leukemia (AML) is an aggressive malignancy that affects myeloid cells. The major disease burden is caused by immature blast cells, which are eliminated using conventional chemotherapies. Unfortunately, relapse is a leading cause of death in AML patients, with 30 to 80% experiencing it within two years of initial treatment. The dominant cause of relapse in leukemia is the presence of therapy-resistant Leukemic Stem Cells (LSCs). These cells express genes related to stemness are frequently difficult to eradicate and tend to survive standard treatments. Studies have demonstrated that by targeting the metabolic pathways of LSCs, it is possible to improve outcomes and extend the survival of those afflicted by leukemia. The overwhelming evidence suggests that lipid metabolism is reprogrammed in LSCs, leading to an increase in fatty acid uptake and de novo lipogenesis. Genes regulating this process also play a crucial role in therapy evasion. In this concise review, we summarize the lipid metabolism in normal hematopoietic cells, AML blast cells, and AML LSCs. We also compare the lipid metabolic signatures in de novo versus therapy resistant AML blast and LSCs. We further discuss the metabolic switches, cellular cross talk, potential targets, and inhibitors of lipid metabolism that could alleviate treatment resistance and relapse.

Keywords:  Acute Myeloid Leukemia; hematopoietic stem cells; leukemic blast cells; leukemic stem cells; lipid metabolism; relapse

DOI:  https://doi.org/10.1093/stmcls/sxad095
Am J Physiol Heart Circ Physiol. 2024 Jan 05.

NADPH Oxidase Overexpression and Mitochondrial OxPhos Impairment are More Profound in Human Hearts Donated after Circulatory Death Than Brain Death.

Nandan K Mondal, Shiyi Li, Abdussalam E Elsenousi, Aladdein Mattar, Katherine V Nordick, Harveen K Lamba, Camila Hochman-Mendez, Todd K Rosengart, Kenneth K Liao.

  This study investigated cardiac stress and mitochondrial oxidative phosphorylation in human DCD (donation after circulatory death) hearts regarding warm ischemic time (WIT) and subsequent cold storage and compared them to that of human DBD (brain death donor) hearts. A total of 24 human hearts were procured for the research study-six in the DBD group and eighteen in the DCD group. DCD group was divided into three groups (n=6) based on different WITs (20, 40, and 60 minutes). All hearts received del Nido cardioplegia before being placed in normal saline cold storage for 6 hours. Left ventricular biopsies were performed at hours 0,2,4, and 6. Cardiac stress (NADPH oxidase subunits: p47phox, gp91phox) and mitochondrial oxidative phosphorylation (OxPhos: CI-CV) proteins were measured in cardiac tissue and mitochondria respectively. Modulation of cardiac stress and mitochondrial dysfunction were observed in both DCD and DBD hearts. However, DCD hearts suffered more cardiac stress (overexpressed NADPH oxidase subunits) and diminished mitochondrial OxPhos than DBD hearts. The severity of cardiac stress and impaired oxidative phosphorylation in DCD hearts correlated with the longer WIT and subsequent cold storage time. More drastic changes were evident in DCD hearts with a WIT of 60 minutes or more. Activation of NADPH oxidase via overproduction of p47phox and gp91phox proteins in cardiac tissue may be responsible for cardiac stress leading to diminished mitochondrial oxidative phosphorylation. These protein changes can be used as biomarkers for myocardium damage, and might help assess DCD and DBD heart transplant suitability.

Keywords:  Cardiac Stress; Cold Static Storage; Human Donor Heart; Mitochondrial Oxidative Phosphorylation; Warm Ischemic Time

DOI:  https://doi.org/10.1152/ajpheart.00616.2023
Front Cell Dev Biol. 2023 ;11 1302585

Toolkit for cellular studies of mammalian mitochondrial inorganic polyphosphate.

Vedangi Hambardikar, Yaw A Akosah, Ernest R Scoma, Mariona Guitart-Mampel, Pedro Urquiza, Renata T Da Costa, Matheus M Perez, Lindsey M Riggs, Rajesh Patel, Maria E Solesio.

  Introduction: Inorganic polyphosphate (polyP) is an ancient polymer which is extremely well-conserved throughout evolution, and found in every studied organism. PolyP is composed of orthophosphates linked together by high-energy bonds, similar to those found in ATP. The metabolism and the functions of polyP in prokaryotes and simple eukaryotes are well understood. However, little is known about its physiological roles in mammalian cells, mostly due to its unknown metabolism and lack of systematic methods and effective models for the study of polyP in these organisms. Methods: Here, we present a comprehensive set of genetically modified cellular models to study mammalian polyP. Specifically, we focus our studies on mitochondrial polyP, as previous studies have shown the potent regulatory role of mammalian polyP in the organelle, including bioenergetics, via mechanisms that are not yet fully understood. Results: Using SH-SY5Y cells, our results show that the enzymatic depletion of mitochondrial polyP affects the expression of genes involved in the maintenance of mitochondrial physiology, as well as the structure of the organelle. Furthermore, this depletion has deleterious effects on mitochondrial respiration, an effect that is dependent on the length of polyP. Our results also show that the depletion of mammalian polyP in other subcellular locations induces significant changes in gene expression and bioenergetics; as well as that SH-SY5Y cells are not viable when the amount and/or the length of polyP are increased in mitochondria. Discussion: Our findings expand on the crucial role of polyP in mammalian mitochondrial physiology and place our cell lines as a valid model to increase our knowledge of both mammalian polyP and mitochondrial physiology.

Keywords:  bioenergetics; inorganic polyphosphate; mammalian cells; mitochondria; polyP; toolkit

DOI:  https://doi.org/10.3389/fcell.2023.1302585
J Cancer Res Ther. 2023 Dec 01. 19(6): 1627-1635

Tamoxifen induces ferroptosis in MCF-7 organoid.

Lei Ye, Fei Zhong, Shishen Sun, Xiaowei Ou, Jie Yuan, Jintao Zhu, Zhiqiang Zeng.

BACKGROUND: Breast cancer is the most common female malignant tumor type globally. The occurrence and development of breast cancer involve ferroptosis, which is closely related to its treatment. The development of breast cancer organoids facilitates the analysis of breast cancer molecular background and tumor biological behavior, including clinical pathological characteristics, drug response, or drug resistance relationship, and promotes the advancement of precision treatment for breast cancer. The three-dimensional (3D) cell culture of breast cancer MCF-7 organoid is more similar to the in vivo environment and thus obtains more realistic results than 2D cell culture. Our study examined the new mechanism of tamoxifen in treating breast cancer through breast cancer MCF-7 organoids.METHODS: We used 3D cells to culture breast cancer MCF-7 organoid, as well as tamoxifen-treated MCF-7 and tamoxifen-resistant MCF-7 (MCF-7 TAMR) cells. We used transcriptome sequencing. We detected GPX4 and SLC7A11 protein levels using Western blotting and the content of ATP, glutathione, and ferrous ions using the Cell Counting Lite 3D Kit. We assessed cell viability using the Cell Counting Kit-8 (CCK-8) assay.
RESULTS: Tamoxifen significantly inhibited the growth of MCF-7 organoids and significantly induced ferroptosis in MCF-7 organoids. The ferroptosis inhibitor reversed the significant tamoxifen-induced MCF-7 organoid inhibition activity. Moreover, the ferroptosis activator enhanced the tamoxifen-induced MCF-7 TAMR cell activity inhibition.
CONCLUSION: Our study revealed that ferroptosis plays an important role in tamoxifen-induced MCF-7 organoid cell death and provides a new research idea for precise treatment of breast cancer through an organoid model.

DOI: https://doi.org/10.4103/jcrt.jcrt_608_23
iScience. 2024 Jan 19. 27(1): 108506

Basic pathway decomposition of biochemical reaction networks within growing cells.

Jay R Walton, Paul A Lindahl.

  This contribution treats linear, steady-state dynamics for a metabolic network within a growing cell. Admissible steady-state reaction fluxes are assumed to form a pointed, convex, polyhedral, conical subset of the stoichiometric null-space. A solution of the problem is defined to consist of a linear basis for the stoichiometric null-space consisting of admissible fluxes called basic pathways. The algorithm used to construct the set of basic pathways scales as a polynomial of the system size in contrast to the NP-hard algorithms employed in the traditional notions of solution named extreme pathways, elementary flux modes, MEMos, and MinSpan, and that therefore suffer from the curse of dimensionality. The basic pathways approach is applied to a metabolic network consisting of a simplified version of the TCA cycle coupled to glycolysis highlighting that each basic pathway has a readily understood chemical interpretation. Generic admissible pathways are simply expressed in terms of basic pathways.

Keywords:  Biological sciences; Metabolic engineering; Network

DOI:  https://doi.org/10.1016/j.isci.2023.108506
Sci Rep. 2024 01 02. 14(1): 264

Hexose phosphorylation for a non-enzymatic glycolysis and pentose phosphate pathway on early Earth.

Yuta Hirakawa, Takeshi Kakegawa, Yoshihiro Furukawa.

Glycolysis and pentose phosphate pathways play essential roles in cellular processes and are assumed to be among the most ancient metabolic pathways. Non-enzymatic metabolism-like reactions might have occurred on the prebiotic Earth and been inherited by the biological reactions. Previous research has identified a part of the non-enzymatic glycolysis and the non-enzymatic pentose phosphate pathway from glucose 6-phosphate and 6-phosphogluconate, which are intermediates of these reactions. However, how these phosphorylated molecules were formed on the prebiotic Earth remains unclear. Herein, we demonstrate the synthesis of glucose and gluconate from simple aldehydes in alkaline solutions and the formation of glucose 6-phosphate and 6-phosphogluconate with borate using thermal evaporation. These results imply that the initial stages of glycolysis-like and pentose phosphate pathway-like reactions were achieved in borate-rich evaporative environments on prebiotic Earth, suggesting that non-enzymatic metabolism provided biomolecules and their precursors on prebiotic Earth.

DOI: https://doi.org/10.1038/s41598-023-50743-8
Redox Biol. 2023 Dec 27. pii: S2213-2317(23)00411-1. [Epub ahead of print]69 103010

Empagliflozin improves mitochondrial dysfunction in diabetic cardiomyopathy by modulating ketone body metabolism and oxidative stress.

Weijuan Cai, Kunying Chong, Yunfei Huang, Chun Huang, Liang Yin.

  Ketone bodies are considered as an alternative energy source for diabetic cardiomyopathy (DCM) and can improve the energy supply of the heart muscle, suggesting that it may be an important area of research and development as a therapeutic target for DCM. Cumulative cardiovascular trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in diabetic populations. Whether SGLT2 inhibitors improve DCM by enhancing ketone body metabolism remains and whether they help prevent oxidative damage remains to be clarified. Here, we present the combined results of nine GSE datasets for diabetic cardiomyopathy (GSE215979, GSE161931, GSE145294, GSE161052, GSE173384, GSE123975, GSE161827, GSE210612, and GSE5606). We found significant up-regulated gene 3-hydroxymethylglutaryl CoA synthetase 2 (HMGCS2) and down-regulated gene 3-hydroxybutyrate dehydrogenase (BDH1) and 3-oxoacid CoA-transferase1 (OXCT1), respectively. Based on the analysis of the constructed protein interaction network, it was found that HMGCS2 was in the core position of the interaction network. In addition, Gene ontology (GO) enrichment analysis mainly focused on redox process, acyl-CoA metabolic process, catalytic activity, redox enzyme activity and mitochondria. The activity of HMGCS2 in DCM heart was increased, while the expression of ketolysis enzymes BDH1 and OXCT1 was inhibited. In vivo, Empagliflozin (Emp) treated DCM group significantly decreased ventricular weight, myocardial cell cross-sectional area, and myocardial fibrosis. In addition, Emp further promoted the activity of BDH1 and OXCT1, increased the utilization of ketone bodies, further promoted the activity of HMGCS2 in DCM, and increased the synthesis of ketone bodies, prevented mitochondrial breakage and dysfunction, increased myocardial ATP to provide sufficient energy, inhibited oxidative stress and apoptosis of cardiac cells ex vivo, and improved the myocardial dysfunction of DCM. Emp can improve mitochondrial dysfunction in diabetic cardiomyopathy by regulating ketone body metabolism and oxidative stress. These findings provide a theoretical basis for evaluating Emp as a treatment for DCM.

Keywords:  Diabetic cardiomyopathy; Ketone body metabolism; Mitochondrial dysfunction; Oxidative stress; SGLT2 inhibitor

DOI:  https://doi.org/10.1016/j.redox.2023.103010
Res Sq. 2023 Dec 12. pii: rs.3.rs-3694185. [Epub ahead of print]

Excessive Lipid Production Shapes Glioma Tumor Microenvironment.

Haitham Maraqah, John Paul Aboubechara, Mones Abu-Asab, Han Sung Lee, Orwa Aboud.

Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n = 18) and IDH1 mutant (IDH1-mt) astrocytoma (n = 12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical membraneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vasculature have lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Lipid excess in gliomas stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune responses, non-lipophilic drugs, and free radicals.

DOI: https://doi.org/10.21203/rs.3.rs-3694185/v1
Anal Chem. 2023 Dec 29.

Investigating the Metabolic Heterogeneity of Cancer Cells Using Functional Single-Cell Selection and nLC Combined with Multinozzle Emitter Mass Spectrometry.

Kai-Wen Cheng, Pin-Rui Su, Kate Jo-Ann Feller, Miao-Ping Chien, Cheng-Chih Hsu.

Tumor metastasis and cancer recurrence are often a result of cell heterogeneity, where specific subpopulations of tumor cells may be resistant to radio- or chemotherapy. To investigate this physiological and phenotypic diversity, single-cell metabolomics provides a powerful approach at the chemical level, where distinct lipid profiles can be found in different tumor cells. Here, we established a highly sensitive platform using nanoflow liquid chromatography (nLC) combined with multinozzle emitter electrospray ionization mass spectrometry for more in-depth metabolomics profiling. Our platform identified 15 and 17 lipids from individual osteosarcoma (U2OS) and glioblastoma (GBM) cells when analyzing single-cell samples. Additionally, we used the functional single-cell selection (fSCS) pipeline to analyze the subpopulations of cells with a DNA damage response (DDR) in U2OS cells and fast migration in GBM cells. Specifically, we observed a down-regulation of polyunsaturated fatty acids (PUFAs) in U2OS cells undergoing DDR, such as fatty acids FA 20:3; O2 and FA 17:4; O3. Furthermore, ceramides (Cer 38:0; O3) and triglycerides (TG 36:0) were found to be down-regulated in fast-migrating GBM cells compared to the slow-migrating subpopulation. These findings suggest the potential roles of these metabolites and/or lipids in the cellular behavior of the subpopulations.

DOI: https://doi.org/10.1021/acs.analchem.3c03688