bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2023‒01‒29
28 papers selected by
Kelsey Fisher-Wellman
East Carolina University

  1. Science. 2023 Jan 27. 379(6630): 351-357
      The molecular mode of action of biguanides, including the drug metformin, which is widely used in the treatment of diabetes, is incompletely characterized. Here, we define the inhibitory drug-target interaction(s) of a model biguanide with mammalian respiratory complex I by combining cryo-electron microscopy and enzyme kinetics. We interpret these data to explain the selectivity of biguanide binding to different enzyme states. The primary inhibitory site is in an amphipathic region of the quinone-binding channel, and an additional binding site is in a pocket on the intermembrane-space side of the enzyme. An independent local chaotropic interaction, not previously described for any drug, displaces a portion of a key helix in the membrane domain. Our data provide a structural basis for biguanide action and enable the rational design of medicinal biguanides.
  2. Cell Rep. 2023 Jan 27. pii: S2211-1247(23)00052-9. [Epub ahead of print]42(2): 112041
      Succinate dehydrogenase (SDH) is a heterotetrameric enzyme complex belonging to the mitochondrial respiratory chain and uniquely links the tricarboxylic acid (TCA) cycle with oxidative phosphorylation. Cancer-related SDH mutations promote succinate accumulation, which is regarded as an oncometabolite. Post-translational modifications of SDH complex components are known to regulate SDH activity, although the contribution of SUMOylation remains unclear. Here, we show that SDHA is SUMOylated by PIAS3 and deSUMOylated by SENP2, events dictating the assembly and activity of the SDH complex. Moreover, CBP acetylation of SENP2 negatively regulates its deSUMOylation activity. Under glutamine deprivation, CBP levels decrease, and the ensuing SENP2 activation and SDHA deSUMOylation serve to concurrently dampen the TCA cycle and electron transport chain (ETC) activity. Along with succinate accumulation, this mechanism avoids excessive reactive oxygen species (ROS) production to promote cancer cell survival. This study elucidates a major function of mitochondrial-localized SENP2 and expands our understanding of the role of SUMOylation in resolving metabolic stress.
    Keywords:  CP: Cancer; CP: Metabolism; PTMs; SENP2; SUMOylation; TCA cycle; acetylation; metabolic stress; mitochondria; oxidative phosphorylation; succinate dehydrogenase
  3. Cell Death Dis. 2023 Jan 23. 14(1): 54
      The mitochondrial protein IF1 binds to the catalytic domain of the ATP synthase and inhibits ATP hydrolysis in ischemic tissues. Moreover, IF1 is overexpressed in many tumors and has been shown to act as a pro-oncogenic protein, although its mechanism of action is still debated. Here, we show that ATP5IF1 gene disruption in HeLa cells decreases colony formation in soft agar and tumor mass development in xenografts, underlining the role of IF1 in cancer. Notably, the lack of IF1 does not affect proliferation or oligomycin-sensitive mitochondrial respiration, but it sensitizes the cells to the opening of the permeability transition pore (PTP). Immunoprecipitation and proximity ligation analysis show that IF1 binds to the ATP synthase OSCP subunit in HeLa cells under oxidative phosphorylation conditions. The IF1-OSCP interaction is confirmed by NMR spectroscopy analysis of the recombinant soluble proteins. Overall, our results suggest that the IF1-OSCP interaction protects cancer cells from PTP-dependent apoptosis under normoxic conditions.
  4. Trends Biochem Sci. 2023 Jan 24. pii: S0968-0004(22)00334-6. [Epub ahead of print]
      Coenzyme Q (CoQ) is a remarkably hydrophobic, redox-active lipid that empowers diverse cellular processes. Although most known for shuttling electrons between mitochondrial electron transport chain (ETC) complexes, the roles for CoQ are far more wide-reaching and ever-expanding. CoQ serves as a conduit for electrons from myriad pathways to enter the ETC, acts as a cofactor for biosynthetic and catabolic reactions, detoxifies damaging lipid species, and engages in cellular signaling and oxygen sensing. Many open questions remain regarding the biosynthesis, transport, and metabolism of CoQ, which hinders our ability to treat human CoQ deficiency. Here, we recount progress in filling these knowledge gaps, highlight unanswered questions, and underscore the need for novel tools to enable discoveries and improve the treatment of CoQ-related diseases.
    Keywords:  coenzyme Q; complex Q; lipids; mitochondria; oxidative phosphorylation; ubiquinone
  5. Cell Death Dis. 2023 Jan 26. 14(1): 61
      LKB1 and KRAS are the third most frequent co-mutations detected in non-small cell lung cancer (NSCLC) and cause aggressive tumor growth. Unfortunately, treatment with RAS-RAF-MEK-ERK pathway inhibitors has minimal therapeutic efficacy in LKB1-mutant KRAS-driven NSCLC. Autophagy, an intracellular nutrient scavenging pathway, compensates for Lkb1 loss to support Kras-driven lung tumor growth. Here we preclinically evaluate the possibility of autophagy inhibition together with MEK inhibition as a treatment for Kras-driven lung tumors. We found that the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and the MEK inhibitor Trametinib displays synergistic anti-proliferative activity in KrasG12D/+;Lkb1-/- (KL) lung cancer cells, but not in KrasG12D/+;p53-/- (KP) lung cancer cells. In vivo studies using tumor allografts, genetically engineered mouse models (GEMMs) and patient-derived xenografts (PDXs) showed anti-tumor activity of the combination of HCQ and Trametinib on KL but not KP tumors. We further found that the combination treatment significantly reduced mitochondrial membrane potential, basal respiration, and ATP production, while also increasing lipid peroxidation, indicative of ferroptosis, in KL tumor-derived cell lines (TDCLs) and KL tumors compared to treatment with single agents. Moreover, the reduced tumor growth by the combination treatment was rescued by ferroptosis inhibitor. Taken together, we demonstrate that autophagy upregulation in KL tumors causes resistance to Trametinib by inhibiting ferroptosis. Therefore, a combination of autophagy and MEK inhibition could be a novel therapeutic strategy to specifically treat NSCLC bearing co-mutations of LKB1 and KRAS.
  6. Nature. 2023 Jan 25.
      Mitochondria have crucial roles in cellular energetics, metabolism, signalling and quality control1-4. They contain around 1,000 different proteins that often assemble into complexes and supercomplexes such as respiratory complexes and preprotein translocases1,3-7. The composition of the mitochondrial proteome has been characterized1,3,5,6; however, the organization of mitochondrial proteins into stable and dynamic assemblies is poorly understood for major parts of the proteome1,4,7. Here we report quantitative mapping of mitochondrial protein assemblies using high-resolution complexome profiling of more than 90% of the yeast mitochondrial proteome, termed MitCOM. An analysis of the MitCOM dataset resolves >5,200 protein peaks with an average of six peaks per protein and demonstrates a notable complexity of mitochondrial protein assemblies with distinct appearance for respiration, metabolism, biogenesis, dynamics, regulation and redox processes. We detect interactors of the mitochondrial receptor for cytosolic ribosomes, of prohibitin scaffolds and of respiratory complexes. The identification of quality-control factors operating at the mitochondrial protein entry gate reveals pathways for preprotein ubiquitylation, deubiquitylation and degradation. Interactions between the peptidyl-tRNA hydrolase Pth2 and the entry gate led to the elucidation of a constitutive pathway for the removal of preproteins. The MitCOM dataset-which is accessible through an interactive profile viewer-is a comprehensive resource for the identification, organization and interaction of mitochondrial machineries and pathways.
  7. EMBO J. 2023 Jan 27. e112309
      Hundreds of nucleus-encoded mitochondrial precursor proteins are synthesized in the cytosol and imported into mitochondria in a post-translational manner. However, the early processes associated with mitochondrial protein targeting remain poorly understood. Here, we show that in Saccharomyces cerevisiae, the cytosol has the capacity to transiently store mitochondrial matrix-destined precursors in dedicated deposits that we termed MitoStores. Competitive inhibition of mitochondrial protein import via clogging of import sites greatly enhances the formation of MitoStores, but they also form during physiological cell growth on nonfermentable carbon sources. MitoStores are enriched for a specific subset of nucleus-encoded mitochondrial proteins, in particular those containing N-terminal mitochondrial targeting sequences. Our results suggest that MitoStore formation suppresses the toxic potential of aberrantly accumulating mitochondrial precursor proteins and is controlled by the heat shock proteins Hsp42 and Hsp104. Thus, the cytosolic protein quality control system plays an active role during the early stages of mitochondrial protein targeting through the coordinated and localized sequestration of mitochondrial precursor proteins.
    Keywords:  chaperones; mitochondria; proteasome; protein aggregates; protein translocation
  8. Nature. 2023 Jan 25.
    Keywords:  Biochemistry; Cell biology; Metabolism; Proteomics
  9. Nano Lett. 2023 Jan 23.
      The growing knowledge of the links between aberrant mitochondrial gene transcription and human diseases necessitates both an effective and dynamic approach to control mitochondrial DNA (mtDNA) transcription. To address this challenge, we developed a nanoparticle-based synthetic mitochondrial transcription regulator (MitoScript). MitoScript provides great colloidal stability, excellent biocompatibility, efficient cell uptake, and selective mitochondria targeting and can be monitored in live cells using near-infrared fluorescence. Notably, MitoScript controlled mtDNA transcription in a human cell line in an effective and selective manner. MitoScript targeting the light strand promoter region of mtDNA resulted in the downregulation of ND6 gene silencing, which eventually affected cell redox status, with considerably increased reactive oxygen species (ROS) generation. In summary, we developed MitoScript for the efficient, nonviral modification of mitochondrial DNA transcription. Our platform technology can potentially contribute to understanding the fundamental mechanisms of mitochondrial disorders and developing effective treatments for mitochondrial diseases.
    Keywords:  Artificial transcription factors; Mitochondria DNA (mtDNA) manipulations; Mitochondria-targeted delivery; Nanoclusters; Nanomedicine
  10. Exp Biol Med (Maywood). 2023 Jan 23. 15353702221147567
      Succinate dehydrogenase complex subunit C (SDHC) is a subunit of mitochondrial complex II (MCII), which is also known as succinate dehydrogenase (SDH) or succinate: ubiquinone oxidoreductase. Mitochondrial complex II is the smallest respiratory complex in the respiratory chain and contains four subunits. SDHC is a membrane-anchored subunit of SDH, which connects the tricarboxylic acid cycle and the electron transport chain. SDH regulates several physiological processes within cells, plays an important role in generating energy to maintain normal cell growth, and is involved in apoptosis. Currently, SDHC is generally recognized as a tumor-suppressor gene. SDHC mutations can cause oxidative damage in the body. It is closely related to the occurrence and development of cancer, neurodegenerative diseases, and aging-related diseases. Here, we review studies on the structure, biological function, related diseases of SDHC, and the mev-1 Animal Model of SDHC Mutation and its potential use as a therapeutic target of certain human diseases.
    Keywords:  SDHC; animal models; electron transport; mitochondrial complex II; neurodegenerative diseases; oxidative stress; therapeutic target; tumorigenesis
  11. Autophagy. 2023 Jan 24.
      Mitophagy and its variants are considered important salvage pathways to remove dysfunctional mitochondria. Non-canonical mitophagy, independent of autophagosome formation and including endosomal-dependent mitophagy, operate upon specific injury. In a recent paper, we describe a new mechanism where, upon mtDNA damage, mitochondrial nucleoids are eliminated via an endosomal-mitophagy pathway. Using proximity proteomics, we identified the proteins required for elimination of mutated mitochondrial nucleoids from the mitochondrial matrix. Among them, ATAD3 and SAMM50 control cristae architecture and nucleoid interaction, necessary for mtDNA extraction. In the mitochondrial outer membrane, SAMM50 coordinates with the retromer protein VPS35 to sequester mtDNA in endosomes and guide them towards elimination, thus avoiding the activation of an exacerbated immune response. Here, we summarize our findings and examine how this newly described pathway contributes to our understanding of mtDNA quality control.
    Keywords:  - mitophagy; endosomes; mtDNA
  12. Sci Rep. 2023 Jan 27. 13(1): 1483
      Alkaliptosis is a recently discovered type of pH-dependent cell death used for tumor therapy. However, its underlying molecular mechanisms and regulatory networks are largely unknown. Here, we report that the acetate-activating enzyme acetyl-CoA short-chain synthase family member 2 (ACSS2) is a positive regulator of alkaliptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Using qPCR and western blot analysis, we found that the mRNA and protein expression of ACSS2 was upregulated in human PDAC cell lines (PANC1 and MiaPaCa2) in response to the classic alkaliptosis activator JTC801. Consequently, the knockdown of ACSS2 by shRNAs inhibited JTC801-induced cell death in PDAC cells, and was accompanied by an increase in cell clone formation and a decrease in intracellular pH. Mechanically, ACSS2-mediated acetyl-coenzyme A production and subsequent histone acetylation contributed to NF-κB-dependent CA9 downregulation, and this effect was enhanced by the histone deacetylase inhibitor trichostatin A. These findings may provide new insights for understanding the metabolic basis of alkaliptosis and establish a potential strategy for PDAC treatment.
  13. Cell Metab. 2023 Jan 14. pii: S1550-4131(22)00577-0. [Epub ahead of print]
      Proteins are secreted from cells to send information to neighboring cells or distant tissues. Because of the highly integrated nature of energy balance systems, there has been particular interest in myokines and adipokines. These are challenging to study through proteomics because serum or plasma contains highly abundant proteins that limit the detection of proteins with lower abundance. We show here that extracellular fluid (EF) from muscle and fat tissues of mice shows a different protein composition than either serum or tissues. Mass spectrometry analyses of EFs from mice with physiological perturbations, like exercise or cold exposure, allowed the quantification of many potentially novel myokines and adipokines. Using this approach, we identify prosaposin as a secreted product of muscle and fat. Prosaposin expression stimulates thermogenic gene expression and induces mitochondrial respiration in primary fat cells. These studies together illustrate the utility of EF isolation as a discovery tool for adipokines and myokines.
    Keywords:  PGC1α; cold adaptation; exercise; extracellular fluid; prosaposin; proteomics; secreted proteins; secretome
  14. Nat Commun. 2023 Jan 25. 14(1): 312
      Aerobic muscle activities predominantly depend on fuel energy supply by mitochondrial respiration, thus, mitochondrial activity enhancement may become a therapeutic intervention for muscle disturbances. The assembly of mitochondrial respiratory complexes into higher-order "supercomplex" structures has been proposed to be an efficient biological process for energy synthesis, although there is controversy in its physiological relevance. We here established Förster resonance energy transfer (FRET) phenomenon-based live imaging of mitochondrial respiratory complexes I and IV interactions using murine myoblastic cells, whose signals represent in vivo supercomplex assembly of complexes I, III, and IV, or respirasomes. The live FRET signals were well correlated with supercomplex assembly observed by blue native polyacrylamide gel electrophoresis (BN-PAGE) and oxygen consumption rates. FRET-based live cell screen defined that the inhibition of spleen tyrosine kinase (SYK), a non-receptor protein tyrosine kinase that belongs to the SYK/ zeta-chain-associated protein kinase 70 (ZAP-70) family, leads to an increase in supercomplex assembly in murine myoblastic cells. In parallel, SYK inhibition enhanced mitochondrial respiration in the cells. Notably, SYK inhibitor administration enhances exercise performance in mice. Overall, this study proves the feasibility of FRET-based respirasome assembly assay, which recapitulates in vivo mitochondrial respiration activities.
  15. Nat Cell Biol. 2023 Jan 23.
      Mitochondria are complex organelles with different compartments, each harbouring their own protein quality control factors. While chaperones of the mitochondrial matrix are well characterized, it is poorly understood which chaperones protect the mitochondrial intermembrane space. Here we show that cytosolic small heat shock proteins are imported under basal conditions into the mitochondrial intermembrane space, where they operate as molecular chaperones. Protein misfolding in the mitochondrial intermembrane space leads to increased recruitment of small heat shock proteins. Depletion of small heat shock proteins leads to mitochondrial swelling and reduced respiration, while aggregation of aggregation-prone substrates is countered in their presence. Charcot-Marie-Tooth disease-causing mutations disturb the mitochondrial function of HSPB1, potentially linking previously observed mitochondrial dysfunction in Charcot-Marie-Tooth type 2F to its role in the mitochondrial intermembrane space. Our results reveal that small heat shock proteins form a chaperone system that operates in the mitochondrial intermembrane space.
  16. Commun Biol. 2023 Jan 23. 6(1): 93
      Mitochondrial DNA (mtDNA) harbors essential genes in most metazoans, yet the regulatory impact of the multiple evolutionary mtDNA rearrangements has been overlooked. Here, by analyzing mtDNAs from ~8000 metazoans we found high gene content conservation (especially of protein and rRNA genes), and codon preferences for mtDNA-encoded tRNAs across most metazoans. In contrast, mtDNA gene order (MGO) was selectively constrained within but not between phyla, yet certain gene stretches (ATP8-ATP6, ND4-ND4L) were highly conserved across metazoans. Since certain metazoans with different MGOs diverge in mtDNA transcription, we hypothesized that evolutionary mtDNA rearrangements affected mtDNA transcriptional patterns. As a first step to test this hypothesis, we analyzed available RNA-seq data from 53 metazoans. Since polycistron mtDNA transcripts constitute a small fraction of the steady-state RNA, we enriched for polycistronic boundaries by calculating RNA-seq read densities across junctions between gene couples encoded either by the same strand (SSJ) or by different strands (DSJ). We found that organisms whose mtDNA is organized in alternating reverse-strand/forward-strand gene blocks (mostly arthropods), displayed significantly reduced DSJ read counts, in contrast to organisms whose mtDNA genes are preferentially encoded by one strand (all chordates). Our findings suggest that mtDNA rearrangements are selectively constrained and likely impact mtDNA regulation.
  17. Cancer Treat Res Commun. 2023 Jan 22. pii: S2468-2942(23)00006-0. [Epub ahead of print]35 100685
      A recent phase Ib study investigating the use of reformulated niclosamide in combination with abiraterone and prednisone in patients with castration-resistant prostate cancer (CRPC) demonstrated encouraging preliminary efficacy with low toxicity. Preclinical studies have reported that niclosamide at clinically relevant concentrations inhibits androgen receptor splice variant 7 (AR-V7), a known tumor driver in CRPC. However, the magnitude of anti-tumor effects of niclosamide either used alone or in combination with abiraterone in these experimental models, far exceeded what could have been explained as a simple AR-V7 inhibition. Niclosamide at clinically relevant concentrations also acts as an oxidative phosphorylation (OxPhos) uncoupler in mitochondria. This raises the question whether the observed effects of niclosamide were partly mediated by OxPhos inhibition. Most OxPhos inhibitors did not demonstrate selectivity towards cancer cells and failed to enter clinical practice due to unacceptable toxicity. However, some mitochondrial uncouplers have greater cytotoxicity against cancerous cells compared to non-cancerous. Hyperpolarization of cancer cell mitochondria, or the more alkaline mitochondrial matrix of cancer cells could be potential reasons for this. Niclosamide can also alter Wnt/β-catenin, mTOR, Notch, NF-kB and STAT3 signaling pathways. Hence, the mechanism of action of reformulated niclosamide in CRPC patients requires further investigation. This will potentially lead to new opportunities to develop and investigate even more selective and effective treatments against prostate cancer.
    Keywords:  AR-V7; Inhibitor; Niclosamide; Prostate cancer; Uncouplers
  18. Front Oncol. 2022 ;12 1072739
      Cancer immunotherapy shows durable treatment responses and therapeutic benefits compared to other cancer treatment modalities, but many cancer patients display primary and acquired resistance to immunotherapeutics. Immunosuppressive tumor microenvironment (TME) is a major barrier to cancer immunotherapy. Notably, cancer cells depend on high mitochondrial bioenergetics accompanied with the supply of heme for their growth, proliferation, progression, and metastasis. This excessive mitochondrial respiration increases tumor cells oxygen consumption, which triggers hypoxia and irregular blood vessels formation in various regions of TME, resulting in an immunosuppressive TME, evasion of anti-tumor immunity, and resistance to immunotherapeutic agents. In this review, we discuss the role of heme, heme catabolism, and mitochondrial respiration on mediating immunosuppressive TME by promoting hypoxia, angiogenesis, and leaky tumor vasculature. Moreover, we discuss the therapeutic prospects of targeting heme and mitochondrial respiration in alleviating tumor hypoxia, normalizing tumor vasculature, and TME to restore anti-tumor immunity and resensitize cancer cells to immunotherapy.
    Keywords:  angiogenesis; cancer immunotherapy; heme; hypoxia; mitochondrial respiration; tumor micoenvironment
  19. Front Oncol. 2022 ;12 1054233
      Resistance to drug treatment is a critical barrier in cancer therapy. There is an unmet need to explore cancer hallmarks that can be targeted to overcome this resistance for therapeutic gain. Over time, metabolic reprogramming has been recognised as one hallmark that can be used to prevent therapeutic resistance. With the advent of metabolomics, targeting metabolic alterations in cancer cells and host patients represents an emerging therapeutic strategy for overcoming cancer drug resistance. Driven by technological and methodological advances in mass spectrometry imaging, spatial metabolomics involves the profiling of all the metabolites (metabolomics) so that the spatial information is captured bona fide within the sample. Spatial metabolomics offers an opportunity to demonstrate the drug-resistant tumor profile with metabolic heterogeneity, and also poses a data-mining challenge to reveal meaningful insights from high-dimensional spatial information. In this review, we discuss the latest progress, with the focus on currently available bulk, single-cell and spatial metabolomics technologies and their successful applications in pre-clinical and translational studies on cancer drug resistance. We provide a summary of metabolic mechanisms underlying cancer drug resistance from different aspects; these include the Warburg effect, altered amino acid/lipid/drug metabolism, generation of drug-resistant cancer stem cells, and immunosuppressive metabolism. Furthermore, we propose solutions describing how to overcome cancer drug resistance; these include early detection during cancer initiation, monitoring of clinical drug response, novel anticancer drug and target metabolism, immunotherapy, and the emergence of spatial metabolomics. We conclude by describing the perspectives on how spatial omics approaches (integrating spatial metabolomics) could be further developed to improve the management of drug resistance in cancer patients.
    Keywords:  cancer drug resistance; metabolic reprogramming; metabolomics; single-cell metabolomics; spatial metabolomics
  20. Front Genet. 2022 ;13 1081262
      Background: Acute myeloid leukemia (AML) is a heterogeneous malignant disease. SLC25A1, the gene encoding mitochondrial carrier subfamily of solute carrier proteins, was reported to be overexpressed in certain solid tumors. However, its expression and value as prognostic marker has not been assessed in AML. Methods: We retrieved RNA profile and corresponding clinical data of AML patients from the Beat AML, TCGA, and TARGET databases (TARGET_AML). Patients in the TCGA cohort were well-grouped into two group based on SLC25A1 and differentially expressed genes were determined between the SLC25A1 high and low group. The expression of SLC25A1 was validated with clinical samples. The survival and apoptosis of two AML cell lines were analyzed with SLC25A1 inhibitor (CTPI-2) treatment. Cox and the least absolute shrinkage and selection operator (LASSO) regression analyses were applied to Beat AML database to identify SLC25A1-associated genes for the construction of a prognostic risk-scoring model. Survival analysis was performed by Kaplan-Meier and receiver operator characteristic curves. Results: Our analysis revealed that high expressed level of SLC25A1 in AML patients correlates with unfavorable prognosis. Moreover, SLC25A1 expression was positively associated with metabolism activity. We further demonstrated that the inhibition of SLC25A1 could inhibit the proliferation and increase the apoptosis of AML cells. In addition, a panel of SLC25A1-associated genes, was identified to construct a prognostic risk-scoring model. This SLC25A1-associated prognostic signature (SPS) is an independent risk factor with high area under curve (AUC) values of receiver operating characteristic (ROC) curves. A high SPS in leukemia patients is associated with poor survival. A Prognostic nomogram including the SPS and other clinical parameters, was constructed and its predictive efficiency was confirmed. Conclusion: We have successfully established a SPS prognostic model that predict outcome and risk stratification in AML. This risk model can be used as an independent biomarker to assess prognosis of AML.
    Keywords:  SLC25A1; acute myeloid leukemia; metabolism; prognosis; target therapy
  21. J Transl Med. 2023 Jan 26. 21(1): 50
      BACKGROUND: Although β-catenin signaling cascade is frequently altered in human cancers, targeting this pathway has not been approved for cancer treatment.METHODS: High-throughput screening of an FDA-approved drug library was conducted to identify therapeutics that selectively inhibited the cells with activated β-catenin. Efficacy of iron chelator and mitochondrial inhibitor was evaluated for suppression of cell proliferation and tumorigenesis. Cellular chelatable iron levels were measured to gain insight into the potential vulnerability of β-catenin-activated cells to iron deprivation. Extracellular flux analysis of mitochondrial function was conducted to evaluate the downstream events of iron deprivation. Chromatin immunoprecipitation, real-time quantitative PCR and immunoblotting were performed to identify β-catenin targets. Depletion of iron-regulatory protein 2 (IRP2), a key regulator of cellular iron homeostasis, was carried out to elucidate its significance in β-catenin-activated cells. Online databases were analyzed for correlation between β-catenin activity and IRP2-TfR1 axis in human cancers.
    RESULTS: Iron chelators were identified as selective inhibitors against β-catenin-activated cells. Deferoxamine mesylate, an iron chelator, preferentially repressed β-catenin-activated cell proliferation and tumor formation in mice. Mechanically, β-catenin stimulated the transcription of IRP2 to increase labile iron level. Depletion of IRP2-sequered iron impaired β-catenin-invigorated mitochondrial function. Moreover, mitochondrial inhibitor S-Gboxin selectively reduced β-catenin-associated cell viability and tumor formation.
    CONCLUSIONS: β-catenin/IRP2/iron stimulation of mitochondrial energetics is targetable vulnerability of β-catenin-potentiated cancer.
    Keywords:  IRP2; Iron chelator; Labile iron pool; Mitochondrial function; β-catenin
  22. Cancer Res. 2023 Jan 25. pii: CAN-22-3083. [Epub ahead of print]
      Radiotherapy is a major component of standard-of-care treatment for gliomas, the most prevalent type of brain tumor. However, resistance to radiotherapy remains a major concern. Identification of mechanisms governing radioresistance in gliomas could reveal improved therapeutic strategies for treating patients. Here, we report that mitochondrial metabolic pathways are suppressed in radioresistant gliomas through integrated analyses of transcriptomic data from glioma specimens and cell lines. Decreased expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α), the key regulator of mitochondrial biogenesis and metabolism, correlated with glioma recurrence and predicted poor prognosis and response to radiation therapy of glioma patients. The subpopulation of glioma cells with low-mitochondrial-mass exhibited reduced expression of PGC-1α and enhanced resistance to radiation treatment. Mechanistically, PGC-1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase (DNA-PK) in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC-1α by facilitating its binding to the E3 ligase RNF34. Restoring PGC-1α activity with expression of PGC-1α S636A, a phosphorylation-resistant mutant, or a small molecule PGC-1α activator ZLN005 increased radiosensitivity of resistant glioma cells by reactivating mitochondria-related ROS production and inducing apoptotic effects both in vitro and in vivo. In summary, this study identified a self-protective mechanism in glioma cells in which radiation-induced degradation of PGC-1α and suppression of mitochondrial biogenesis play a central role. Targeted activation of PGC-1α could help improve response to radiation therapy in glioma patients.
  23. Heliyon. 2023 Jan;9(1): e12515
      Metabolic reprogramming is one of the essential features of tumor that may dramatically contribute to metastasis and collapse. The metabolic profiling is investigated on the patient derived tissue and cancer cell line derived mouse metastasis xenograft. As well-recognized "seeds" for remote metastasis of tumor, role of circulating tumor cells (CTCs) in the study of metabolic reprogramming feature of tumor is yet to be elucidated. More specifically, whether there is difference of metabolic features of liver metastasis in colorectal cancer (CRC) derived from either CTCs or cancer cell line is still unknown. In this study, comprehensive untargeted metabolomics was performed using high performance liquid chromatography-mass spectrometry (HPLC-MS) in liver metastasis tissues from CT26 cells and CTCs derived mouse models. We identified 288 differential metabolites associated with the pathways such as one carbon pool by folate, folate biosynthesis and histidine metabolism through bioinformation analysis. Multiple gene expression was upregulated in the CTCs derived liver metastasis, specifically some specific enzymes. These results indicated that the metabolite phenotype and corresponding gene expression in the CTCs derived liver metastasis tissues was different from the parental CT26 cells, displaying a specific up-regulation of mRNAs involved in the above metabolism-related pathways. The metabolic profile of CTCs was characterized on the liver metastatic process in colorectal cancer. The invasion ability and chemo drug tolerance of the CTCs derived tumor and metastasis was found to be overwhelming higher than cell line derived counterpart. Identification of the differential metabolites will lead to a better understanding of the hallmarks of the cancer progression and metastasis, which may suggest potential attractive target for treating metastatic CRC.
    Keywords:  Circulating tumor cell; Colorectal cancer; Liver metastasis; Metabolomics; Mouse models
  24. FEMS Yeast Res. 2023 Jan 24. pii: foad008. [Epub ahead of print]
      Microbial growth requires energy for maintaining the existing cells and producing components for the new ones. Microbes therefore invest a considerable amount of their resources into proteins needed for energy harvesting. Growth in different environments is associated with different energy demands for growth of yeast Saccharomyces cerevisiae, although the cross-condition differences remain poorly characterized. Furthermore, a direct comparison of the energy costs for the biosynthesis of the new biomass across conditions is not feasible experimentally; computational models, on the contrary, allow comparing the optimal metabolic strategies and quantify the respective costs of energy and nutrients. Thus in this study, we used a resource allocation model of S. cerevisiae to compare the optimal metabolic strategies between different conditions. We found that S. cerevisiae with respiratory-impaired mitochondria required additional energetic investments for growth, while growth on amino acid-rich media was not affected. Amino acid supplementation in anaerobic conditions also was predicted to rescue the growth reduction in mitochondrial respiratory shuttle-deficient mutants of S. cerevisiae. Collectively, these results point to elevated costs of resolving the redox imbalance caused by de novo biosynthesis of amino acids in mitochondria. To sum up, our study provides an example of how resource allocation modeling can be used to address and suggest explanations to open questions in microbial physiology.
    Keywords:  Energy requirements; anaerobic growth; metabolic modeling; mitochondria; resource allocation
  25. Mol Metab. 2023 Jan 21. pii: S2212-8778(23)00011-X. [Epub ahead of print] 101677
      OBJECTIVE: Mitochondria fuel most animal cells with ATP, ensuring proper energetic metabolism of organs. Early and extensive mitochondrial dysfunction often leads to severe disorders through multiorgan failure. Hacd2 gene encodes an enzyme involved in very long chain fatty acid (C ≥ 18) synthesis, yet its roles in vivo remain poorly understood. Since mitochondria function relies on specific properties of their membranes conferred by a particular phospholipid composition, we investigated if Hacd2 gene participates to mitochondrial integrity.METHODS: We generated two mouse models, the first one leading to a partial knockdown of Hacd2 expression and the second one, to a complete knockout of Hacd2 expression. We performed an in-depth analysis of the associated phenotypes, from whole organism to molecular scale.
    RESULTS: Thanks to these models, we show that Hacd2 displays an early and broad expression, and that its deficiency in mice is lethal. Specifically, partial knockdown of Hacd2 expression leads to death within one to four weeks after birth, from a sudden growth arrest followed by cachexia and lethargy. The total knockout of Hacd2 is even more severe, characterized by embryonic lethality around E9.5 following developmental arrest and pronounced cardiovascular malformations. In-depth mechanistic analysis revealed that Hacd2 deficiency causes altered mitochondrial efficiency and ultrastructure, as well as accumulation of oxidized cardiolipin.
    CONCLUSIONS: Altogether, these data indicate that the Hacd2 gene is essential for energetic metabolism during embryonic and postnatal development, acting through the control of proper mitochondrial organization and function.
    Keywords:  ELOVL; Fatty acid; Heart development; OXPHOS coupling; Phospholipid; VLCFA
  26. Cancer Metastasis Rev. 2023 Jan 25.
      While anti-cancer drug treatments are often effective for the clinical management of cancer, these treatments frequently leave behind drug-tolerant persister cancer cells that can ultimately give rise to recurrent disease. Such persistent cancer cells can lie dormant for extended periods of time, going undetected by conventional clinical means. Understanding the mechanisms that such dormant cancer cells use to survive, and the mechanisms that drive emergence from dormancy, is critical to the development of improved therapeutic strategies to prevent and manage disease recurrence. Cancer cells often exhibit metabolic alterations compared to their non-transformed counterparts. An emerging body of evidence supports the notion that dormant cancer cells also have unique metabolic adaptations that may offer therapeutically targetable vulnerabilities. Herein, we review mechanisms through which cancer cells metabolically adapt to persist during drug treatments and develop drug resistance. We also highlight emerging therapeutic strategies to target dormant cancer cells via their metabolic features.
    Keywords:  Cancer; Energy; Fatty acid; Glucose; Metabolism; Tumor
  27. Immunology. 2023 Jan 28.
      The NLRP3 inflammasome plays a crucial role in innate immunity and is involved in the pathogenesis of autoinflammatory diseases. Glycolysis regulates NLRP3 inflammasome activation in macrophages. However, how lactic acid fermentation and pyruvate oxidation controlled by the mitochondrial pyruvate carrier (MPC) affect NLRP3 inflammasome activation and autoinflammatory disease remains elusive. We found that inactivation of MPC with genetic depletion or pharmacological inhibitors, MSDC-0160 or pioglitazone, increased NLRP3 inflammasome activation and IL-1β secretion in macrophages. Glycolytic reprogramming induced by MPC inhibition skewed mitochondrial ATP-associated oxygen consumption into cytosolic lactate production, which enhanced NLRP3 inflammasome activation in response to monosodium urate (MSU) crystals. As pioglitazone is an insulin sensitizer used for diabetes, its MPC inhibitory effect in diabetic individuals was investigated. The results showed that MPC inhibition exacerbated MSU-induced peritonitis in diabetic mice and increased the risk of gout in patients with diabetes. Altogether, we found that glycolysis controlled by MPC regulated NLRP3 inflammasome activation and gout development. Accordingly, prescriptions for medications targeting MPC should consider the increased risk of NLRP3-related autoinflammatory diseases. This article is protected by copyright. All rights reserved.
    Keywords:  Gout; Mitochondrial pyruvate carrier; NLRP3 inflammasome; Pioglitazone