bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2021‒04‒04
fifty-one papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit

  1. Nat Cell Biol. 2021 Apr 01.
      Endothelial cells (ECs) adapt their metabolism to enable the growth of new blood vessels, but little is known how ECs regulate metabolism to adopt a quiescent state. Here, we show that the metabolite S-2-hydroxyglutarate (S-2HG) plays a crucial role in the regulation of endothelial quiescence. We find that S-2HG is produced in ECs after activation of the transcription factor forkhead box O1 (FOXO1), where it limits cell cycle progression, metabolic activity and vascular expansion. FOXO1 stimulates S-2HG production by inhibiting the mitochondrial enzyme 2-oxoglutarate dehydrogenase. This inhibition relies on branched-chain amino acid catabolites such as 3-methyl-2-oxovalerate, which increase in ECs with activated FOXO1. Treatment of ECs with 3-methyl-2-oxovalerate elicits S-2HG production and suppresses proliferation, causing vascular rarefaction in mice. Our findings identify a metabolic programme that promotes the acquisition of a quiescent endothelial state and highlight the role of metabolites as signalling molecules in the endothelium.
  2. Front Cell Dev Biol. 2021 ;9 626316
      Interpreting connections between the multiple networks of cell metabolism is indispensable for understanding how cells maintain homeostasis or transform into the decontrolled proliferation phenotype of cancer. Situated at a critical metabolic intersection, citrate, derived via glycolysis, serves as either a combustible fuel for aerobic mitochondrial bioenergetics or as a continuously replenished cytosolic carbon source for lipid biosynthesis, an essentially anaerobic process. Therein lies the paradox: under what conditions do cells control the metabolic route by which they process citrate? The Warburg effect exposes essentially the same dilemma-why do cancer cells, despite an abundance of oxygen needed for energy-generating mitochondrial respiration with citrate as fuel, avoid catabolizing mitochondrial citrate and instead rely upon accelerated glycolysis to support their energy requirements? This review details the genesis and consequences of the metabolic paradigm of a "truncated" Krebs/TCA cycle. Abundant data are presented for substrate utilization and membrane cholesterol enrichment in tumors that are consistent with criteria of the Warburg effect. From healthy cellular homeostasis to the uncontrolled proliferation of tumors, metabolic alterations center upon the loss of regulation of the cholesterol biosynthetic pathway. Deregulated tumor cholesterogenesis at the HMGR locus, generating enhanced carbon flux through the cholesterol synthesis pathway, is an absolute prerequisite for DNA synthesis and cell division. Therefore, expedited citrate efflux from cholesterol-enriched tumor mitochondria via the CTP/SLC25A1 citrate transporter is fundamental for sustaining the constant demand for cytosolic citrate that fuels the elevated flow of carbons from acetyl-CoA through the deregulated pathway of cholesterol biosynthesis.
    Keywords:  Warburg effect; mitochondrial citrate export; truncated Krebs/TCA cycle; tumor cholesterogenesis; tumor membrane cholesterol
  3. Cell Metab. 2021 Mar 26. pii: S1550-4131(21)00113-3. [Epub ahead of print]
      Serine metabolism promotes tumor oncogenesis and regulates immune cell functions, but whether it also contributes to antiviral innate immunity is unknown. Here, we demonstrate that virus-infected macrophages display decreased expression of serine synthesis pathway (SSP) enzymes. Suppressing the SSP key enzyme phosphoglycerate dehydrogenase (PHGDH) by genetic approaches or by treatment with the pharmaceutical inhibitor CBR-5884 and by exogenous serine restriction enhanced IFN-β-mediated antiviral innate immunity in vitro and in vivo. Mechanistic experiments showed that virus infection or serine metabolism deficiency increased the expression of the V-ATPase subunit ATP6V0d2 by inhibiting S-adenosyl methionine-dependent H3K27me3 occupancy at the promoter. ATP6V0d2 promoted YAP lysosomal degradation to relieve YAP-mediated blockade of the TBK1-IRF3 axis and, thus, enhance IFN-β production. These findings implicate critical functions of PHGDH and the key immunometabolite serine in blunting antiviral innate immunity and also suggest manipulation of serine metabolism as a therapeutic strategy against virus infection.
    Keywords:  ATP6V0d2; H3K27me3; PHGDH; SAM; YAP; antiviral; serine metabolism
  4. Nat Commun. 2021 03 29. 12(1): 1940
      Metabolic enzymes and metabolites display non-metabolic functions in immune cell signalling that modulate immune attack ability. However, whether and how a tumour's metabolic remodelling contributes to its immune resistance remain to be clarified. Here we perform a functional screen of metabolic genes that rescue tumour cells from effector T cell cytotoxicity, and identify the embryo- and tumour-specific folate cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2). Mechanistically, MTHFD2 promotes basal and IFN-γ-stimulated PD-L1 expression, which is necessary for tumourigenesis in vivo. Moreover, IFN-γ stimulates MTHFD2 through the AKT-mTORC1 pathway. Meanwhile, MTHFD2 drives the folate cycle to sustain sufficient uridine-related metabolites including UDP-GlcNAc, which promotes the global O-GlcNAcylation of proteins including cMYC, resulting in increased cMYC stability and PD-L1 transcription. Consistently, the O-GlcNAcylation level positively correlates with MTHFD2 and PD-L1 in pancreatic cancer patients. These findings uncover a non-metabolic role for MTHFD2 in cell signalling and cancer biology.
  5. Cancers (Basel). 2021 Mar 24. pii: 1488. [Epub ahead of print]13(7):
      Pyruvate is a key molecule in the metabolic fate of mammalian cells; it is the crossroads from where metabolism proceeds either oxidatively or ends with the production of lactic acid. Pyruvate metabolism is regulated by many enzymes that together control carbon flux. Mitochondrial pyruvate carrier (MPC) is responsible for importing pyruvate from the cytosol to the mitochondrial matrix, where it is oxidatively phosphorylated to produce adenosine triphosphate (ATP) and to generate intermediates used in multiple biosynthetic pathways. MPC activity has an important role in glucose homeostasis, and its alteration is associated with diabetes, heart failure, and neurodegeneration. In cancer, however, controversy surrounds MPC function. In some cancers, MPC upregulation appears to be associated with a poor prognosis. However, most transformed cells undergo a switch from oxidative to glycolytic metabolism, the so-called Warburg effect, which, amongst other possibilities, is induced by MPC malfunction or downregulation. Consequently, impaired MPC function might induce tumors with strong proliferative, migratory, and invasive capabilities. Moreover, glycolytic cancer cells secrete lactate, acidifying the microenvironment, which in turn induces angiogenesis, immunosuppression, and the expansion of stromal cell populations supporting tumor growth. This review examines the latest findings regarding the tumorigenic processes affected by MPC.
    Keywords:  MPC; SLC; Warburg effect; glycolysis; lactate; mitochondrial matrix; oxidative phosphorylation
  6. Redox Biol. 2021 Mar 19. pii: S2213-2317(21)00092-6. [Epub ahead of print]41 101944
      Reactive oxygen species (ROS) are a common product of active mitochondrial respiration carried in mitochondrial cristae, but whether cristae shape influences ROS levels is unclear. Here we report that the mitochondrial fusion and cristae shape protein Opa1 requires mitochondrial ATP synthase oligomers to reduce ROS accumulation. In cells fueled with galactose to force ATP production by mitochondria, cristae are enlarged, ATP synthase oligomers destabilized, and ROS accumulate. Opa1 prevents both cristae remodeling and ROS generation, without impinging on levels of mitochondrial antioxidant defense enzymes that are unaffected by Opa1 overexpression. Genetic and pharmacologic experiments indicate that Opa1 requires ATP synthase oligomerization and activity to reduce ROS levels upon a blockage of the electron transport chain. Our results indicate that the converging effect of Opa1 and mitochondrial ATP synthase on mitochondrial ultrastructure regulate ROS abundance to sustain cell viability.
    Keywords:  Bioenergetics; F(1)F(O)-ATP synthase; Mitochondrial cristae; Opa1; ROS; Ultrastructure
  7. Life (Basel). 2021 Mar 15. pii: 242. [Epub ahead of print]11(3):
      Under aerobic conditions, mitochondrial oxidative phosphorylation (OXPHOS) converts the energy released by nutrient oxidation into ATP, the currency of living organisms. The whole biochemical machinery is hosted by the inner mitochondrial membrane (mtIM) where the protonmotive force built by respiratory complexes, dynamically assembled as super-complexes, allows the F1FO-ATP synthase to make ATP from ADP + Pi. Recently mitochondria emerged not only as cell powerhouses, but also as signaling hubs by way of reactive oxygen species (ROS) production. However, when ROS removal systems and/or OXPHOS constituents are defective, the physiological ROS generation can cause ROS imbalance and oxidative stress, which in turn damages cell components. Moreover, the morphology of mitochondria rules cell fate and the formation of the mitochondrial permeability transition pore in the mtIM, which, most likely with the F1FO-ATP synthase contribution, permeabilizes mitochondria and leads to cell death. As the multiple mitochondrial functions are mutually interconnected, changes in protein composition by mutations or in supercomplex assembly and/or in membrane structures often generate a dysfunctional cascade and lead to life-incompatible diseases or severe syndromes. The known structural/functional changes in mitochondrial proteins and structures, which impact mitochondrial bioenergetics because of an impaired or defective energy transduction system, here reviewed, constitute the main biochemical damage in a variety of genetic and age-related diseases.
    Keywords:  ATP synthase/hydrolase; ROS; cellular signaling; cristae; mitochondrial dysfunction; mitochondrial permeability transition pore; oxidative phosphorylation; respiratory supercomplexes
  8. Int J Mol Sci. 2021 Mar 23. pii: 3245. [Epub ahead of print]22(6):
      Depending on their tissue of origin, genetic and epigenetic marks and microenvironmental influences, cancer cells cover a broad range of metabolic activities that fluctuate over time and space. At the core of most metabolic pathways, mitochondria are essential organelles that participate in energy and biomass production, act as metabolic sensors, control cancer cell death, and initiate signaling pathways related to cancer cell migration, invasion, metastasis and resistance to treatments. While some mitochondrial modifications provide aggressive advantages to cancer cells, others are detrimental. This comprehensive review summarizes the current knowledge about mitochondrial transfers that can occur between cancer and nonmalignant cells. Among different mechanisms comprising gap junctions and cell-cell fusion, tunneling nanotubes are increasingly recognized as a main intercellular platform for unidirectional and bidirectional mitochondrial exchanges. Understanding their structure and functionality is an important task expected to generate new anticancer approaches aimed at interfering with gains of functions (e.g., cancer cell proliferation, migration, invasion, metastasis and chemoresistance) or damaged mitochondria elimination associated with mitochondrial transfer.
    Keywords:  cancer; cancer metabolism; chemoresistance; metastasis; mitochondria; mitochondrial transfer; oxidative phosphorylation (OXPHOS); reactive oxygen species (ROS); tricarboxylic acid (TCA) cycle; tunneling nanotubes (TNT)
  9. FEBS J. 2021 Apr 03.
      Many metabolic phenotypes in cancer cells are also characteristic of proliferating non-transformed mammalian cells, and attempts to distinguish between phenotypes resulting from oncogenic perturbation from those associated with increased proliferation are limited. Here, we examined the extent to which metabolic changes corresponding to oncogenic KRAS expression differed from those corresponding to epidermal growth factor (EGF)-driven proliferation in human mammary epithelial cells (HMECs). Removal of EGF from culture medium reduced growth rates and glucose/glutamine consumption in control HMECs despite limited changes in respiration and fatty acid synthesis, while the relative contribution of branched-chain amino acids to the TCA cycle and lipogenesis increased in the near-quiescent conditions. Most metabolic phenotypes measured in HMECs expressing mutant KRAS were similar to those observed in EGF-stimulated control HMECs that were growing at comparable rates. However, glucose and glutamine consumption as well as lactate and glutamate production were lower in KRAS-expressing cells cultured in media without added EGF, and these changes correlated with reduced sensitivity to GLUT1 inhibitor and phenformin treatment. Our results demonstrate the strong dependence of metabolic behavior on growth rate, and provide a model to distinguish the metabolic influences of oncogenic mutations and non-oncogenic growth.
    Keywords:  Cancer metabolism; KRAS; branched-chain amino acids; cell growth; cell proliferation
  10. Cell Chem Biol. 2021 Mar 30. pii: S2451-9456(21)00143-4. [Epub ahead of print]
      Three limonoid natural products with selective anti-proliferative activity against BRAF(V600E) and NRAS(Q61K)-mutation-dependent melanoma cell lines were identified. Differential transcriptome analysis revealed dependency of compound activity on expression of the mitochondrial cytochrome P450 oxidase CYP27A1, a transcriptional target of melanogenesis-associated transcription factor (MITF). We determined that CYP27A1 activity is necessary for the generation of a reactive metabolite that proceeds to inhibit cellular proliferation. A genome-wide small interfering RNA screen in combination with chemical proteomics experiments revealed gene-drug functional epistasis, suggesting that these compounds target mitochondrial biogenesis and inhibit tumor bioenergetics through a covalent mechanism. Our work suggests a strategy for melanoma-specific targeting by exploiting the expression of MITF target gene CYP27A1 and inhibiting mitochondrial oxidative phosphorylation in BRAF mutant melanomas.
    Keywords:  BRAF; CYP27A1; MITF; cancer metabolism; melanoma; mitochondrial complex I; natural products; oncology; oxidative phosphorylation; prodrug
  11. G3 (Bethesda). 2021 Mar 30. pii: jkab095. [Epub ahead of print]
      Mitochondrial dynamics plays an important role in mitochondrial quality control and the adaptation of metabolic activity in response to environmental changes. The disruption of mitochondrial dynamics has detrimental consequences for mitochondrial and cellular homeostasis and leads to the activation of the mitochondrial unfolded protein response (UPRmt), a quality control mechanism that adjusts cellular metabolism and restores homeostasis. To identify genes involved in the induction of UPRmt in response to a block in mitochondrial fusion, we performed a genome-wide RNAi screen in Caenorhabditis elegans mutants lacking the gene fzo-1, which encodes the ortholog of mammalian Mitofusin, and identified 299 suppressors and 86 enhancers. Approximately 90% of these 385 genes are conserved in humans, and one third of the conserved genes have been implicated in human disease. Furthermore, many have roles in developmental processes, which suggests that mitochondrial function and the response to stress are defined during development and maintained throughout life. Our dataset primarily contains mitochondrial enhancers and non-mitochondrial suppressors of UPRmt, indicating that the maintenance of mitochondrial homeostasis has evolved as a critical cellular function, which, when disrupted, can be compensated for by many different cellular processes. Analysis of the subsets 'non-mitochondrial enhancers' and 'mitochondrial suppressors' suggests that organellar contact sites, especially between the ER and mitochondria, are of importance for mitochondrial homeostasis. In addition, we identified several genes involved in IP3 signaling that modulate UPRmt in fzo-1 mutants and found a potential link between pre-mRNA splicing and UPRmt activation.
    Keywords:  IP3 signaling; Mitoguardin; fzo-1; mitochondrial dynamics; mitochondrial unfolded protein response
  12. Cell Mol Life Sci. 2021 Mar 29.
      Mitochondria are organelles central to myriad cellular processes. To maintain mitochondrial health, various processes co-operate at both the molecular and organelle level. At the molecular level, mitochondria can sense imbalances in their homeostasis and adapt to these by signaling to the nucleus. This mito-nuclear communication leads to the expression of nuclear stress response genes. Upon external stimuli, mitochondria can also alter their morphology accordingly, by inducing fission or fusion. In an extreme situation, mitochondria are degraded by mitophagy. Adequate function and regulation of these mitochondrial quality control pathways are crucial for cellular homeostasis. As we discuss, alterations in these processes have been linked to several pathologies including neurodegenerative diseases and cancer.
    Keywords:  ISR; Mitochondrial diseases; Mitochondrial dysfunction; Mitochondrial fission; Mitochondrial fusion; Mitophagy; PINK1; Parkin; UPRmt
  13. Nat Cell Biol. 2021 Apr 01.
      Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex that catalyses messenger RNA N6-methyladenosine (m6A) modification. Despite the expanding list of m6A-dependent functions of the methyltransferase complex, the m6A-independent function of the METTL3 and METTL14 complex remains poorly understood. Here we show that genome-wide redistribution of METTL3 and METTL14 transcriptionally drives the senescence-associated secretory phenotype (SASP) in an m6A-independent manner. METTL14 is redistributed to the enhancers, whereas METTL3 is localized to the pre-existing NF-κB sites within the promoters of SASP genes during senescence. METTL3 and METTL14 are necessary for SASP. However, SASP is not regulated by m6A mRNA modification. METTL3 and METTL14 are required for both the tumour-promoting and immune-surveillance functions of senescent cells, which are mediated by SASP in vivo in mouse models. In summary, our results report an m6A-independent function of the METTL3 and METTL14 complex in transcriptionally promoting SASP during senescence.
  14. Proc Natl Acad Sci U S A. 2021 Apr 06. pii: e2020215118. [Epub ahead of print]118(14):
      Autophagy is a catabolic pathway that provides self-nourishment and maintenance of cellular homeostasis. Autophagy is a fundamental cell protection pathway through metabolic recycling of various intracellular cargos and supplying the breakdown products. Here, we report an autophagy function in governing cell protection during cellular response to energy crisis through cell metabolic rewiring. We observe a role of selective type of autophagy in direct activation of cyclic AMP protein kinase A (PKA) and rejuvenation of mitochondrial function. Mechanistically, autophagy selectively degrades the inhibitory subunit RI of PKA holoenzyme through A-kinase-anchoring protein (AKAP) 11. AKAP11 acts as an autophagy receptor that recruits RI to autophagosomes via LC3. Glucose starvation induces AKAP11-dependent degradation of RI, resulting in PKA activation that potentiates PKA-cAMP response element-binding signaling, mitochondria respiration, and ATP production in accordance with mitochondrial elongation. AKAP11 deficiency inhibits PKA activation and impairs cell survival upon glucose starvation. Our results thus expand the view of autophagy cytoprotection mechanism by demonstrating selective autophagy in RI degradation and PKA activation that fuels the mitochondrial metabolism and confers cell resistance to glucose deprivation implicated in tumor growth.
    Keywords:  AKAP11; PKA; autophagy; cell survival; mitochondrial metabolism
  15. Front Cell Dev Biol. 2021 ;9 655889
      Oncogene c-Myc (referred in this report as MYC) promotes tumorigenesis in multiple human cancers. MYC regulates numerous cellular programs involved in cell growth and cell metabolism. Tumor cells exhibit obligatory dependence on cholesterol metabolism, which provides essential membrane components and metabolites to support cell growth. To date, how cholesterol biosynthesis is delicately regulated to promote tumorigenesis remains unclear. Here, we show that MYC enhances cholesterol biosynthesis and promotes cell proliferation. Through transcriptional upregulation of SQLE, a rate-limiting enzyme in cholesterol synthesis pathway, MYC increases cholesterol production and promotes tumor cell growth. SQLE overexpression restores the cellular cholesterol levels in MYC-knockdown cells. More importantly, in SQLE-depleted cells, enforced expression of MYC has no effect on cholesterol levels. Therefore, our findings reveal that SQLE is critical for MYC-mediated cholesterol synthesis, and further demonstrate that SQLE may be a potential therapeutic target in MYC-amplified cancers.
    Keywords:  MYC; SQLE; cancer; cell proliferation; cholesterol synthesis
  16. PLoS Genet. 2021 Mar 29. 17(3): e1009488
      Mitochondria are essential for maintaining skeletal muscle metabolic homeostasis during adaptive response to a myriad of physiologic or pathophysiological stresses. The mechanisms by which mitochondrial function and contractile fiber type are concordantly regulated to ensure muscle function remain poorly understood. Evidence is emerging that the Folliculin interacting protein 1 (Fnip1) is involved in skeletal muscle fiber type specification, function, and disease. In this study, Fnip1 was specifically expressed in skeletal muscle in Fnip1-transgenic (Fnip1Tg) mice. Fnip1Tg mice were crossed with Fnip1-knockout (Fnip1KO) mice to generate Fnip1TgKO mice expressing Fnip1 only in skeletal muscle but not in other tissues. Our results indicate that, in addition to the known role in type I fiber program, FNIP1 exerts control upon muscle mitochondrial oxidative program through AMPK signaling. Indeed, basal levels of FNIP1 are sufficient to inhibit AMPK but not mTORC1 activity in skeletal muscle cells. Gain-of-function and loss-of-function strategies in mice, together with assessment of primary muscle cells, demonstrated that skeletal muscle mitochondrial program is suppressed via the inhibitory actions of FNIP1 on AMPK. Surprisingly, the FNIP1 actions on type I fiber program is independent of AMPK and its downstream PGC-1α. These studies provide a vital framework for understanding the intrinsic role of FNIP1 as a crucial factor in the concerted regulation of mitochondrial function and muscle fiber type that determine muscle fitness.
  17. Front Immunol. 2021 ;12 624919
      Neuroinflammatory and neurodegenerative diseases are a major public health problem worldwide, especially with the increase of life-expectancy observed during the last decades. For many of these diseases, we still lack a full understanding of their etiology and pathophysiology. Nonetheless their association with mitochondrial dysfunction highlights this organelle as an important player during CNS homeostasis and disease. Markers of Parkinson (PD) and Alzheimer (AD) diseases are able to induce innate immune pathways induced by alterations in mitochondrial Ca2+ homeostasis leading to neuroinflammation. Additionally, exacerbated type I IFN responses triggered by mitochondrial DNA (mtDNA), failures in mitophagy, ER-mitochondria communication and mtROS production promote neurodegeneration. On the other hand, regulation of mitochondrial dynamics is essential for CNS health maintenance and leading to the induction of IL-10 and reduction of TNF-α secretion, increased cell viability and diminished cell injury in addition to reduced oxidative stress. Thus, although previously solely seen as power suppliers to organelles and molecular processes, it is now well established that mitochondria have many other important roles, including during immune responses. Here, we discuss the importance of these mitochondrial dynamics during neuroinflammation, and how they correlate either with the amelioration or worsening of CNS disease.
    Keywords:  Alzheimer disease; Parkinson disease; mitochondria; multiple sclerosis; neurodegenerative diseases; neuroinflammation
  18. Antioxidants (Basel). 2021 Mar 26. pii: 520. [Epub ahead of print]10(4):
      Coenzyme Q10 (CoQ10) is classically viewed as an important endogenous antioxidant and key component of the mitochondrial respiratory chain. For this second function, CoQ molecules seem to be dynamically segmented in a pool attached and engulfed by the super-complexes I + III, and a free pool available for complex II or any other mitochondrial enzyme that uses CoQ as a cofactor. This CoQ-free pool is, therefore, used by enzymes that link the mitochondrial respiratory chain to other pathways, such as the pyrimidine de novo biosynthesis, fatty acid β-oxidation and amino acid catabolism, glycine metabolism, proline, glyoxylate and arginine metabolism, and sulfide oxidation metabolism. Some of these mitochondrial pathways are also connected to metabolic pathways in other compartments of the cell and, consequently, CoQ could indirectly modulate metabolic pathways located outside the mitochondria. Thus, we review the most relevant findings in all these metabolic functions of CoQ and their relations with the pathomechanisms of some metabolic diseases, highlighting some future perspectives and potential therapeutic implications.
    Keywords:  OxPhos; coenzyme Q10; mitochondria; one-carbon metabolism; proline metabolism; sulfide metabolism; super-complexes; ubiquinol-10; ubiquinone-10
  19. Cell Mol Immunol. 2021 Mar 30.
      Mitochondrial stress (mitostress) triggered by viral infection or mitochondrial dysfunction causes the release of mitochondrial DNA (mtDNA) into the cytosol and activates the cGAS-mediated innate immune response. The regulation of mtDNA release upon mitostress remains uncharacterized. Here, we identified mitochondria-associated vaccinia virus-related kinase 2 (VRK2) as a key regulator of this process. VRK2 deficiency inhibited the induction of antiviral genes and caused earlier and higher mortality in mice after viral infection. Upon viral infection, VRK2 associated with voltage-dependent anion channel 1 (VDAC1) and promoted VDAC1 oligomerization and mtDNA release, leading to the cGAS-mediated innate immune response. VRK2 was also required for mtDNA release and cGAS-mediated innate immunity triggered by nonviral factors that cause Ca2+ overload but was not required for the cytosolic nucleic acid-triggered innate immune response. Thus, VRK2 plays a crucial role in the mtDNA-triggered innate immune response and may be a potential therapeutic target for infectious and autoimmune diseases associated with mtDNA release.
    Keywords:  Mita/Sting; cGAS; innate immune response; mitochondrial DNA; mitostress
  20. Sci Adv. 2021 Mar;pii: eabf4148. [Epub ahead of print]7(14):
      Cancer cell-intrinsic programmed cell death protein-1 (PD-1) has emerged as a tumor regulator in an immunity-independent manner, but its precise role in modulating tumor behaviors is complex, and how PD-1 is regulated in cancer cells is largely unknown. Here, we identified PD-1 as a direct target of tumor suppressor p53. Notably, p53 acetylation at K120/164 played a critical role in p53-mediated PD-1 transcription. Acetylated p53 preferentially recruited acetyltransferase cofactors onto PD-1 promoter, selectively facilitating PD-1 transcription by enhancing local chromatin acetylation. Reexpression of PD-1 in cancer cells inhibited tumor growth, whereas depletion of cancer cell-intrinsic PD-1 compromised p53-dependent tumor suppression. Moreover, histone deacetylase inhibitor (HDACi) activated PD-1 in an acetylated p53-dependent manner, supporting a synergistic effect by HDACi and p53 on tumor suppression via stimulating cancer cell-intrinsic PD-1. Our study reveals a mechanism for activating cancer cell-intrinsic PD-1 and indicates that p53-mediated PD-1 activation is critically involved in tumor suppression in an immunity-independent manner.
  21. Curr Stem Cell Rep. 2020 Dec;6(4): 119-125
      Purpose of Review: Diet has profound impacts on health and longevity. Evidence is emerging to suggest that diet impinges upon the metabolic pathways in tissue-specific stem cells to influence health and disease. Here, we review the similarities and differences in the metabolism of stem cells from several tissues, and highlight the mitochondrial metabolic checkpoint in stem cell maintenance and aging. We discuss how diet engages the nutrient sensing metabolic pathways and impacts stem cell maintenance. Finally, we explore the therapeutic implications of dietary and metabolic regulation of stem cells.Recent findings: Stem Cell transition from quiescence to proliferation is associated with a metabolic switch from glycolysis to mitochondrial OXPHOS and the mitochondrial metabolic checkpoint is critically controlled by the nutrient sensors SIRT2, SIRT3, and SIRT7 in hematopoietic stem cells. Intestine stem cell homeostasis during aging and in response to diet is critically dependent on fatty acid metabolism and ketone bodies and is influenced by the niche mediated by the nutrient sensor mTOR.
    Summary: Nutrient sensing metabolic pathways critically regulate stem cell maintenance during aging and in response to diet. Elucidating the molecular mechanisms underlying dietary and metabolic regulation of stem cells provides novel insights for stem cell biology and may be targeted therapeutically to reverse stem cell aging and tissue degeneration.
    Keywords:  SIRT2; SIRT3; SIRT7; calorie restriction; mTOR; stem cell metabolism
  22. Int J Mol Sci. 2021 Mar 25. pii: 3387. [Epub ahead of print]22(7):
      Metabolic plasticity is a hallmark of the ability of metastatic cancer cells to survive under stressful conditions. The intracellular Fer kinase is a selective constituent of the reprogramed mitochondria and metabolic system of cancer cells. In the current work, we deciphered the modulatory roles of Fer in the reprogrammed metabolic systems of metastatic, lung (H358), non-small cell lung cancer (NSCLC), and breast (MDA-MB-231), triple-negative breast cancer (TNBC), carcinoma cells. We show that H358 cells devoid of Fer (H358ΔFer), strictly depend on glucose for their proliferation and growth, and fail to compensate for glucose withdrawal by oxidizing and metabolizing glutamine. Furthermore, glucose deficiency caused increased reactive oxygen species (ROS) production and induction of a DNA damage response (DDR), accompanied by the onset of apoptosis and attenuated cell-cycle progression. Analysis of mitochondrial function revealed impaired respiratory and electron transport chain (ETC) complex 1 (comp. I) activity in the Fer-deficient H358ΔFer cells. This was manifested by decreased levels of NAD+ and ATP and relatively low abundance of tricarboxylic acid (TCA) cycle metabolites. Impaired electron transport chain comp. I activity and dependence on glucose were also confirmed in Fer-deficient, MDA-MB-231ΔFer cells. Although both H358ΔFer and MDA-MB-231ΔFer cells showed a decreased aspartate level, this seemed to be compensated by the predominance of pyrimidines synthesis over the urea cycle progression. Notably, absence of Fer significantly impeded the growth of H358ΔFer and MDA-MB-231ΔFer xenografts in mice provided with a carb-deficient, ketogenic diet. Thus, Fer plays a key role in the sustention of metabolic plasticity of malignant cells. In compliance with this notion, targeting Fer attenuates the progression of H358 and MDA-MB-231 tumors, an effect that is potentiated by a glucose-restrictive diet.
    Keywords:  Fer; Mitochondrial homeostasis; metabolic plasticity; non-small cell lung cancer; triple-negative breast cancer
  23. Cells. 2021 Mar 30. pii: 757. [Epub ahead of print]10(4):
      Mitochondrial F1Fo-ATP-synthase dimers play a critical role in shaping and maintenance of mitochondrial ultrastructure. Previous studies have revealed that ablation of the F1Fo-ATP-synthase assembly factor PaATPE of the ascomycete Podospora anserina strongly affects cristae formation, increases hydrogen peroxide levels, impairs mitochondrial function and leads to premature cell death. In the present study, we investigated the underlying mechanistic basis. Compared to the wild type, we observed a slight increase in non-selective and a pronounced increase in mitophagy, the selective vacuolar degradation of mitochondria. This effect depends on the availability of functional cyclophilin D (PaCYPD), the regulator of the mitochondrial permeability transition pore (mPTP). Simultaneous deletion of PaAtpe and PaAtg1, encoding a key component of the autophagy machinery or of PaCypD, led to a reduction of mitophagy and a partial restoration of the wild-type specific lifespan. The same effect was observed in the PaAtpe deletion strain after inhibition of PaCYPD by its specific inhibitor, cyclosporin A. Overall, our data identify autophagy-dependent cell death (ADCD) as part of the cellular response to impaired F1Fo-ATP-synthase dimerization, and emphasize the crucial role of functional mitochondria in aging.
    Keywords:  ADCD; F1Fo-ATP-synthase; Podospora anserina; mPTP; mitophagy
  24. Cells. 2021 Mar 12. pii: 634. [Epub ahead of print]10(3):
      BTB domain and CNC homology 1 (BACH1) is a transcription factor that is highly expressed in tumors including breast and lung, relative to their non-tumor tissues. BACH1 is known to regulate multiple physiological processes including heme homeostasis, oxidative stress response, senescence, cell cycle, and mitosis. In a tumor, BACH1 promotes invasion and metastasis of cancer cells, and the expression of BACH1 presents a poor outcome for cancer patients including breast and lung cancer patients. Recent studies identified novel functional roles of BACH1 in the regulation of metabolic pathways in cancer cells. BACH1 inhibits mitochondrial metabolism through transcriptional suppression of mitochondrial membrane genes. In addition, BACH1 suppresses activity of pyruvate dehydrogenase (PDH), a key enzyme that converts pyruvate to acetyl-CoA for the citric acid (TCA) cycle through transcriptional activation of pyruvate dehydrogenase kinase (PDK). Moreover, BACH1 increases glucose uptake and lactate secretion through the expression of metabolic enzymes involved such as hexokinase 2 (HK2) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for aerobic glycolysis. Pharmacological or genetic inhibition of BACH1 could reprogram by increasing mitochondrial metabolism, subsequently rendering metabolic vulnerability of cancer cells against mitochondrial respiratory inhibition. Furthermore, inhibition of BACH1 decreased antioxidant-induced glycolysis rates as well as reduced migration and invasion of cancer cells, suggesting BACH1 as a potentially useful cancer therapeutic target.
    Keywords:  BTB and CNC homology 1 BACH1; Nrf2 (encoded by Nfe2l2); breast cancer; glycolysis; heme oxygenase 1 (HMOX1); hemin; lung cancer; metformin; mitochondrial electron transport chain (ETC); mitochondrial metabolism
  25. Trends Endocrinol Metab. 2021 Mar 29. pii: S1043-2760(21)00049-7. [Epub ahead of print]
      Targeting tumor cell metabolism is an attractive form of therapy, as it may enhance treatment response in therapy resistant cancers as well as mitigate treatment-related toxicities by reducing the need for genotoxic agents. To meet their increased demand for biomass accumulation and energy production and to maintain redox homeostasis, tumor cells undergo profound changes in their metabolism. In addition to the diversion of glucose metabolism, this is achieved by upregulation of amino acid metabolism. Interfering with amino acid availability can be selectively lethal to tumor cells and has proven to be a cancer specific Achilles' heel. Here we review the biology behind such cancer specific amino acid dependencies and discuss how these vulnerabilities can be exploited to improve cancer therapies.
    Keywords:  amino acid depletion therapy; amino acid metabolism; cancer; tumor metabolism
  26. Nat Commun. 2021 Mar 31. 12(1): 1998
      The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.
  27. Dev Biol. 2021 Mar 24. pii: S0012-1606(21)00079-8. [Epub ahead of print]
      Newly emerging transformed cells are often eliminated from the epithelium via cell competition with the surrounding normal cells. A number of recent studies using mammalian cell competition systems have demonstrated that cells with various types of oncogenic insults are extruded from the tissue in a cell death-dependent or -independent manner. Cell competition-mediated elimination of transformed cells, called EDAC (epithelial defense against cancer), represents an intrinsic anti-tumor activity within the epithelial cell society to reduce the risk of oncogenesis. Here we delineate roles and molecular mechanisms of this homeostatic process, especially focusing on mammalian models.
  28. Redox Biol. 2021 Mar 19. pii: S2213-2317(21)00096-3. [Epub ahead of print]41 101948
      Mitochondria harbor a unique fatty acid synthesis pathway (mtFAS) with mysterious functions gaining increasing interest, while its involvement in metabolic regulation is essentially unknown. Here we show that 3-Hydroxyacyl-ACP dehydratase (HTD2), a key enzyme in mtFAS pathway was primarily downregulated in adipocytes of mice under metabolic disorders, accompanied by decreased de novo production of lipoic acid, which is the byproduct of mtFAS pathway. Knockdown of Htd2 in 3T3-L1 preadipocytes or differentiated 3T3-L1 mature adipocytes impaired mitochondrial function via suppression of complex I activity, resulting in enhanced oxidative stress and impaired insulin sensitivity, which were all attenuated by supplement of lipoic acid. Moreover, lipidomic study revealed limited lipid alterations in mtFAS deficient cells which primarily presenting accumulation of triglycerides, attributed to mitochondrial dysfunction. Collectively, the present study highlighted the pivotal role of mtFAS pathway in regulating mitochondrial function and adipocytes insulin sensitivity, demonstrating supportive evidence for lipoic acid being potential effective nutrient for improving insulin resistance and related metabolic disorders.
    Keywords:  3-Hydroxyacyl-ACP dehydratase (HTD2); Insulin resistance; Lipoic acid; Mitochondrial dysfunction; Mitochondrial fatty acid synthesis (mtFAS); Oxidative stress
  29. Sci Rep. 2021 Mar 29. 11(1): 7023
      Natural killer (NK) cells mediate innate host defense against microbial infection and cancer. Hypoxia and low glucose are characteristic for these tissue lesions but do not affect early interferon (IFN) γ and CC chemokine release by interleukin 15 (IL-15) primed human NK cells in vitro. Hypoxia inducible factor 1α (HIF-1α) mediates cellular adaption to hypoxia. Its production is supported by mechanistic target of rapamycin complex 1 (mTORC1) and signal transducer and activator of transcription 3 (STAT3). We used chemical inhibition to probe the importance of mTORC1 and STAT3 for the hypoxia response and of STAT3 for the cytokine response in isolated and IL-15 primed human NK cells. Cellular responses were assayed by magnetic bead array, RT-PCR, western blotting, flow cytometry, and metabolic flux analysis. STAT3 but not mTORC1 activation was essential for HIF-1α accumulation, glycolysis, and oxygen consumption. In both primed normoxic and hypoxic NK cells, STAT3 inhibition reduced the secretion of CCL3, CCL4 and CCL5, and it interfered with IL-12/IL-18 stimulated IFNγ production, but it did not affect cytotoxic granule degranulation up on target cell contact. We conclude that IL-15 priming promotes the HIF-1α dependent hypoxia response and the early cytokine response in NK cells predominantly through STAT3 signaling.
  30. Cell Mol Immunol. 2021 Mar 30.
      The function of lymphocytes is dependent on their plasticity, particularly their adaptation to energy availability and environmental stress, and their protein synthesis machinery. Lymphocytes are constantly under metabolic stress, and macroautophagy/autophagy is the primary metabolic pathway that helps cells overcome stressors. The intrinsic role of autophagy in regulating the metabolism of adaptive immune cells has recently gained increasing attention. In this review, we summarize and discuss the versatile roles of autophagy in regulating cellular metabolism and the implications of autophagy for immune cell function and fate, especially for T and B lymphocytes.
    Keywords:  Immunology; Lysosome; Macroautophagy; Stress
  31. J Clin Med. 2021 Mar 21. pii: 1295. [Epub ahead of print]10(6):
      The mitochondrial quality control network includes several epigenetically-regulated genes involved in mitochondrial dynamics, mitophagy, and mitochondrial biogenesis under physiologic conditions. Dysregulated expression of such genes has been reported in various disease contexts, including cancer. However, their expression pattern and the possible underlying epigenetic modifications remain to be defined within plasma cell (PC) dyscrasias. Herein, we compared the mRNA expression of mitochondrial quality control genes from multiple myeloma, plasma cell leukemia patients and human myeloma cell lines (HMCLs) with healthy plasma cells; moreover, by applying the Sequenom MassARRAY EpiTYPER technology, we performed a pilot investigation of their CpG methylation status in HMCLs. Overall, the results provided indicate dysregulated expression of several mitochondrial network's genes, and alteration of the CpG methylation profile, underscoring novel potential myeloma biomarkers deserving in-depth functional investigation in the future.
    Keywords:  Sequenom MassARRAY; cancer epigenetics; methylation
  32. Semin Cancer Biol. 2021 Mar 27. pii: S1044-579X(21)00060-2. [Epub ahead of print]
      Although the classic activities of p53 including induction of cell-cycle arrest, senescence, and apoptosis are well accepted as critical barriers to cancer development, accumulating evidence suggests that loss of these classic activities is not sufficient to abrogate the tumor suppression activity of p53. Numerous studies suggest that metabolic regulation contributes to tumor suppression, but the mechanisms by which it does so are not completely understood. Cancer cells rewire cellular metabolism to meet the energetic and substrate demands of tumor development. It is well established that p53 suppresses glycolysis and promotes mitochondrial oxidative phosphorylation through a number of downstream targets against the Warburg effect. The role of p53-mediated metabolic regulation in tumor suppression is complexed by its function to promote both cell survival and cell death under different physiological settings. Indeed, p53 can regulate both pro-oxidant and antioxidant target genes for complete opposite effects. In this review, we will summarize the roles of p53 in the regulation of glucose, lipid, amino acid, nucleotide, iron metabolism, and ROS production. We will highlight the mechanisms underlying p53-mediated ferroptosis, AKT/mTOR signaling as well as autophagy and discuss the complexity of p53-metabolic regulation in tumor development.
    Keywords:  ferroptosis; metabolism; p53; transcriptional activation; tumor suppression
  33. Free Radic Biol Med. 2021 Mar 29. pii: S0891-5849(21)00189-1. [Epub ahead of print]
      Early treatment can prevent the occurrence of diabetes; however, there are few pharmacological treatment strategies to date. The liver is a major metabolic organ, and hepatic glucose homeostasis is dysregulated in type 1 and type 2 diabetes mellitus. However, the potential of specifically targeting the liver to prevent diabetes has not been fully exploited. In this study, we found that compartmentally inhibiting hepatic oxidants by nano-MitoPBN, a liver mitochondrial-targeting ROS scavenger, could effectively prevent diabetes. Our results demonstrated that nano-MitoPBN reversed the downregulation of PGC-1α and the enhanced gluconeogenesis in the livers of diabetic mice. PGC-1α, through an AMPK- and SIRT3-mediated mechanism, promoted mitochondrial biogenesis, increased the number of mitochondria, and enhanced the rate of aerobic oxidation, leading to decreased glucose levels in the blood by increasing glucose uptake and catabolism in the liver. Moreover, the increase in PGC-1α activity did not promote the activation of gluconeogenesis. Our study demonstrated that by regulating the redox balance of liver mitochondria in the early stage of diabetes, PGC-1α could selectively inhibit gluconeogenesis in the liver and promote hepatic mitochondrial function, which accelerated the catabolism of hepatic glucose and reduced blood glucose. Thus, glucose tolerance can be normalized through only three weeks of intervention. Our results showed that nano-MitoPBN could effectively prevent diabetes in a short period of time, highlighting the effectiveness and importance of early intervention for diabetes and suggesting the potential advantages of hepatic mitochondrial targeting oxidants nano-inhibitors in the prevention and early treatment of diabetes.
    Keywords:  AMPK/SIRT3-PGC1α axis; Nanoparticle; glucose catabolism; hepatic ROS inhibition; mitochondrial biogenesis; oxidants; prevention of diabetes
  34. Traffic. 2021 Apr 02.
      Intercellular organelle transfer has been documented in several cell types and has been proposed to be important for cell-cell communication and cellular repair. However, the mechanisms by which organelle transfer occurs are uncertain. Recent studies indicate that the gap junction protein, connexin 43 (Cx43), is required for mitochondrial transfer but its specific role is unknown. Using three-dimensional electron microscopy and immunogold labeling of Cx43, this report shows that whole organelles including mitochondria and endosomes are incorporated into double-membrane vesicles, called connexosomes or annular gap junctions, that form as a result of gap junction internalization. These findings demonstrate a novel mechanism for intercellular organelle transfer mediated by Cx43 gap junctions. This article is protected by copyright. All rights reserved.
    Keywords:  Gap junction; internalization; mitochondria; organelle transfer
  35. Nat Commun. 2021 Mar 30. 12(1): 1971
      Most cells constitutively secrete mitochondrial DNA and proteins in extracellular vesicles (EVs). While EVs are small vesicles that transfer material between cells, Mitochondria-Derived Vesicles (MDVs) carry material specifically between mitochondria and other organelles. Mitochondrial content can enhance inflammation under pro-inflammatory conditions, though its role in the absence of inflammation remains elusive. Here, we demonstrate that cells actively prevent the packaging of pro-inflammatory, oxidized mitochondrial proteins that would act as damage-associated molecular patterns (DAMPs) into EVs. Importantly, we find that the distinction between material to be included into EVs and damaged mitochondrial content to be excluded is dependent on selective targeting to one of two distinct MDV pathways. We show that Optic Atrophy 1 (OPA1) and sorting nexin 9 (Snx9)-dependent MDVs are required to target mitochondrial proteins to EVs, while the Parkinson's disease-related protein Parkin blocks this process by directing damaged mitochondrial content to lysosomes. Our results provide insight into the interplay between mitochondrial quality control mechanisms and mitochondria-driven immune responses.
  36. Annu Rev Chem Biomol Eng. 2021 Mar 30.
      Metabolic engineering reprograms cells to synthesize value-added products. In doing so, endogenous genes are altered and heterologous genes can be introduced to achieve the necessary enzymatic reactions. Dynamic regulation of metabolic flux is a powerful control scheme to alleviate and overcome the competing cellular objectives that arise from the introduction of these production pathways. This review explores dynamic regulation strategies that have demonstrated significant production benefits by targeting the metabolic node corresponding to a specific challenge. We summarize the stimulus-responsive control circuits employed in these strategies that determine the criterion for actuating a dynamic response and then examine the points of control that couple the stimulus-responsive circuit to a shift in metabolic flux. Expected final online publication date for the Annual Review of Chemical and Biomolecular Engineering, Volume 12 is June 2021. Please see for revised estimates.
  37. Int J Mol Sci. 2021 Mar 19. pii: 3135. [Epub ahead of print]22(6):
      The study of metabolic deregulation in myeloid malignancies has led to the investigation of metabolic-targeted therapies considering that cells undergoing leukemic transformation have excessive energy demands for growth and proliferation. However, the most difficult challenge in agents targeting metabolism is to determine a window of therapeutic opportunities between normal and neoplastic cells, considering that all or most of the metabolic pathways important for cancer ontogeny may also regulate physiological cell functions. Targeted therapies have used the properties of leukemic cells to produce altered metabolic products when mutated. This is the case of IDH1/2 mutations generating the abnormal conversion of α-ketoglutarate (KG) to 2-hydroxyglutarate, an oncometabolite inhibiting KG-dependent enzymes, such as the TET family of genes (pivotal in characterizing leukemia cells either by mutations, e.g., TET2, or by altered expression, e.g., TET1/2/3). Additional observations derive from the high sensitivity of leukemic cells to oxidative phosphorylation and its amelioration using BCL-2 inhibitors (Venetoclax) or by disrupting the mitochondrial respiration. More recently, nicotinamide metabolism has been described to mediate resistance to Venetoclax in patients with acute myeloid leukemia. Herein, we will provide an overview of the latest research on the link between metabolic pathways interactome and leukemogenesis with a comprehensive analysis of the metabolic consequences of driver genetic lesions and exemplificative druggable pathways.
    Keywords:  IDH1/2 mutations; TET2 mutations; myeloid malignancies; nicotinamide; venetoclax
  38. JCI Insight. 2021 Mar 30. pii: 144341. [Epub ahead of print]
      Perilipin 2 (PLIN2) is the lipid droplet (LD) protein in β cells that increases under nutritional stress. Down-regulation of PLIN2 is often sufficient to reduce LD accumulation. To determine whether PLIN2 positively or negatively affects β cell function under nutritional stress, PLIN2 was down-regulated in mouse β cells, INS1 cells, and human islet cells. β cell specific deletion of PLIN2 in mice on a high fat diet reduced glucose-stimulated insulin secretion (GSIS) in vivo and in vitro. Down-regulation of PLIN2 in INS1 cells blunted GSIS after 24 h incubation with 0.2 mM palmitic acids. Down-regulation of PLIN2 in human pseudoislets cultured at 5.6 mM glucose impaired both phases of GSIS, indicating that PLIN2 is critical for GSIS. Down-regulation of PLIN2 decreased specific OXPHOS proteins in all three models and reduced oxygen consumption rates in INS1 cells and mouse islets. Moreover, we found that PLIN2 deficient INS1 cells increased the distribution of a fluorescent oleic acid analog to mitochondria and showed signs of mitochondrial stress as indicated by susceptibility to fragmentation and alterations of acyl-carnitines and glucose metabolites. Collectively, PLIN2 in β cells have an important role in preserving insulin secretion, β cell metabolism, and mitochondrial function under nutritional stress.
    Keywords:  Diabetes; Endocrinology; Islet cells; Metabolism
  39. J Biol Chem. 2021 Mar 26. pii: S0021-9258(21)00380-X. [Epub ahead of print] 100600
      Ceramide-1-phosphate transfer proteins (CPTPs) are members of the glycolipid transfer protein (GLTP) superfamily that shuttle ceramide-1-phosphate (C1P) between membranes. CPTPs regulate cellular sphingolipid homeostasis in ways that impact programmed cell death and inflammation. CPTP downregulation specifically alters C1P levels in the plasma and trans-Golgi membranes, stimulating pro-inflammatory eicosanoid production and autophagy-dependent inflammasome-mediated cytokine release. However, the mechanism(s) used by CPTP to target the trans-Golgi and plasma membrane are not well understood. Here, we monitored C1P intervesicular transfer using fluorescence energy transfer (FRET), and showed that certain phosphoinositides (phosphatidylinositol 4,5 bisphosphate (PI-(4,5)P2) and phosphatidylinositol 4-phosphate (PI-4P)) increased CPTP transfer activity, whereas others (phosphatidylinositol 3-phosphate (PI-3P) and PI) did not. PIPs that stimulated CPTP did not stimulate GLTP, another superfamily member. Short-chain, PI-(4,5)P2, which is soluble and does not remain membrane-embedded, failed to activate CPTP. CPTP stimulation by physiologically-relevant PI-(4,5)P2 levels surpassed that of phosphatidylserine (PS), the only known non-PIP stimulator of CPTP, despite PI-(4,5)P2 increasing membrane equilibrium binding affinity less effectively than PS. Functional mapping of mutations that led to altered FRET lipid transfer and assessment of CPTP membrane interaction by surface plasmon resonance indicated that di-arginine motifs located in the α-6 helix and the α3-α4 helix regulatory loop of the membrane-interaction region serve as PI-(4,5)P2 headgroup-specific interaction sites. Haddock modeling revealed specific interactions involving the PI-(4,5)P2 headgroup that left the acyl chains oriented favorably for membrane embedding. We propose that PI-(4,5)P2 interaction sites enhance CPTP activity by serving as preferred membrane targeting/docking sites that favorably orient the protein for function.
    Keywords:  Arabidopsis accelerated cell death (ACD11) protein; GLTP-fold; Human ceramide-1-phosphate transfer protein (CPTP); ceramide-1-phosphate (C1P); di-Arg motif; human glycolipid transfer protein (GLTP); membrane interaction; phosphatidylinositol; phosphatidylinositol-4,5-phosphate; phosphatidylinositol-4-phosphate; phosphoinositide regulation
  40. FEBS J. 2021 Mar 27.
      Cysteine is a conditionally essential amino acid that contributes to the synthesis of proteins and many important intracellular metabolites. Cysteine depletion can trigger iron-dependent non-apoptotic cell death-ferroptosis. Despite this, cysteine itself is normally maintained at relatively low levels within the cell, and many mechanisms that could act to buffer cysteine depletion do not appear to be especially effective or active, at least in cancer cells. How do we reconcile these seemingly paradoxical features? Here we describe the regulation of cysteine and contribution to ferroptosis and speculate about how the levels of this amino acid are controlled to govern non-apoptotic cell death.
    Keywords:  Cysteine; Ferroptosis; Glutathione; Iron; Metabolism
  41. Int J Mol Sci. 2021 Mar 24. pii: 3315. [Epub ahead of print]22(7):
      Chemo-resistance hinders treatment of patients with hepatocellular carcinoma. Although there are many models that can be found in the literature, the root mechanism to explain chemo-resistance is still not fully understood. To gain a better understanding of this phenomenon, a chemo-resistant line, R-HepG2, was developed from a chemo-sensitive HepG2 line through an exposure of doxorubicin (DOX). The R-HepG2 exhibited a cancer stem cell (CSC) phenotype with an over-expression of P-glycoprotein (P-gp), conferring it a significant enhancement in drug efflux and survival. With these observations, we hypothesize that metabolic alteration in this drug-resistant CSC is the root cause of chemo-resistance. Our results show that, unlike other metabolic-reprogrammed CSCs that exhibit glycolytic phenotype described by the "Warburg effect", the R-HepG2 was metabolically quiescent with glucose independence, high metabolic plasticity, and relied on glutamine metabolism via the mitochondria for its chemo-resistance Intriguingly, drug efflux by P-gp in R-HepG2 depended on the mitochondrial ATP fueled by glutamine instead of glycolytic ATP. Armed with these observations, we blocked the glutamine metabolism in the R-HepG2 and a significant reduction of DOX efflux was obtained. We exploited this metabolic vulnerability using a combination of DOX and metformin in a glutamine-free condition to target the R-HepG2, resulting in a significant DOX sensitization. In conclusion, our findings highlight the metabolic modulation of chemo-resistance in CSCs. We delineate the altered metabolism that drives chemo-resistance and offer a new approach to target this CSC through metabolic interventions.
    Keywords:  P-glycoprotein; cancer cell metabolism; cancer stem cells; chemo-resistance; hepatocellular carcinoma; metabolic alteration; mitochondria
  42. Neurosurg Clin N Am. 2021 Apr;pii: S1042-3680(20)30113-3. [Epub ahead of print]32(2): 159-169
      Glioblastomas (GBMs) exhibit altered metabolism to support a variety of bioenergetic and biosynthetic demands for tumor growth, invasion, and drug resistance. Changes in glycolytic flux, oxidative phosphorylation, the pentose phosphate pathway, fatty acid biosynthesis and oxidation, and nucleic acid biosynthesis are observed in GBMs to help drive tumorigenesis. Both the genetic landscape of GBMs and the unique brain tumor microenvironment shape metabolism; therefore, an understanding of how both intrinsic and extrinsic factors modulate metabolism is becoming increasingly important for finding effect targets and therapeutics for GBM.
    Keywords:  GBM; Metabolism; Oncogene; Tumor microenvironment
  43. Cell Metab. 2021 Mar 24. pii: S1550-4131(21)00122-4. [Epub ahead of print]
      The molecular circadian clock and symbiotic host-microbe relationships both evolved as mechanisms that enhance metabolic responses to environmental challenges. The gut microbiome benefits the host by breaking down diet-derived nutrients indigestible by the host and generating microbiota-derived metabolites that support host metabolism. Similarly, cellular circadian clocks optimize organismal physiology to the environment by influencing the timing and coordination of metabolic processes. Host-microbe interactions are influenced by dietary quality and timing, as well as daily light/dark cycles that entrain circadian rhythms in the host. Together, the gut microbiome and the molecular circadian clock play a coordinated role in neural processing, metabolism, adipogenesis, inflammation, and disease initiation and progression. This review examines the bidirectional interactions between the circadian clock, gut microbiota, and host metabolic systems and their effects on obesity and energy homeostasis. Directions for future research and the development of therapies that leverage these systems to address metabolic disease are highlighted.
    Keywords:  diet; energy balance; microbiota; rhythmicity
  44. Cell Stem Cell. 2021 Apr 01. pii: S1934-5909(21)00114-4. [Epub ahead of print]28(4): 589-591
      The response of adipose progenitors to metabolic states is a crucial, but poorly understood, determinant of metabolic health. The back-to-back papers by Joffin et al. (2021) and Shao et al. (2021) in this issue of Cell Stem Cell reveal how adipose-tissue-resident PDGFRβ+precursor cell fate is regulated by mitochondrial bioenergetic state and how such processes go wrong in obesity.
  45. Cells. 2021 Mar 22. pii: 705. [Epub ahead of print]10(3):
      Cancer is a redox disease. Low levels of reactive oxygen species (ROS) are beneficial for cells and have anti-cancer effects. ROS are produced in the mitochondria during ATP production by oxidative phosphorylation (OXPHOS). In the present review, we describe ATP production in primary brain tumors, glioblastoma, in relation to ROS production. Differentiated glioblastoma cells mainly use glycolysis for ATP production (aerobic glycolysis) without ROS production, whereas glioblastoma stem cells (GSCs) in hypoxic periarteriolar niches use OXPHOS for ATP and ROS production, which is modest because of the hypoxia and quiescence of GSCs. In a significant proportion of glioblastoma, isocitrate dehydrogenase 1 (IDH1) is mutated, causing metabolic rewiring, and all cancer cells use OXPHOS for ATP and ROS production. Systemic therapeutic inhibition of glycolysis is not an option as clinical trials have shown ineffectiveness or unwanted side effects. We argue that systemic therapeutic inhibition of OXPHOS is not an option either because the anti-cancer effects of ROS production in healthy cells is inhibited as well. Therefore, we advocate to remove GSCs out of their hypoxic niches by the inhibition of their binding to niches to enable their differentiation and thus increase their sensitivity to radiotherapy and/or chemotherapy.
    Keywords:  IDH1-mutation; energy metabolism; glioblastoma stem cells
  46. Nat Commun. 2021 Mar 31. 12(1): 1980
      The majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these 'SLE-like' conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.
  47. Nature. 2021 Apr;592(7852): S7-S9
    Keywords:  Cell biology; Physiology
  48. Adv Exp Med Biol. 2021 ;1280 161-172
      Gain-of-function mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) were demonstrated to induce the production and accumulation of oncometabolite 2-hydroxyglutarate (2HG). 2HG is a potent competitor of α-ketoglutarate (α-KG) and can inhibit multiple α-KG-dependent dioxygenases that are critical for regulating the metabolic and epigenetic state of cells. The accumulation of 2HG contributes to elevated risk of malignant tumors. 2HG carries an asymmetric carbon atom in its carbon backbone and therefore occurs in two enantiomers, D-2-hydroxyglutarate (D-2HG) and L-2-hydroxyglutarate (L-2HG). Each enantiomer is produced and metabolized in independent biochemical pathway and catalyzed by different enzymes. The accurate diagnosis of 2HG-related diseases relies on determining the configuration of the two enantiomers. Quantitative methods for analysis of D-2HG and L-2HG have been well developed. These analytical strategies mainly include the use of chiral chromatography medium to facilitate chromatographic separation of enantiomers prior to spectroscopy or mass spectrometry analysis and the use of chiral derivatization reagents to convert the enantiomers to diastereomers with differential physical and chemical properties that can improve their chromatographic separation. Here, we summarize and discuss these established methods for analysis of total 2HG as well as the determination of the enantiomers of D-2HG and L-2HG.
    Keywords:  2-Hydroxyglutarate; Chiral derivatization; Enantiomer; Gas chromatography-mass spectrometry; Liquid chromatography-mass spectrometry; Oncometabolite
  49. Int J Mol Sci. 2021 Mar 15. pii: 2974. [Epub ahead of print]22(6):
      The circadian clock driven by the daily light-dark and temperature cycles of the environment regulates fundamental physiological processes and perturbations of these sophisticated mechanisms may result in pathological conditions, including cancer. While experimental evidence is building up to unravel the link between circadian rhythms and tumorigenesis, it is becoming increasingly apparent that the response to antitumor agents is similarly dependent on the circadian clock, given the dependence of each drug on the circadian regulation of cell cycle, DNA repair and apoptosis. However, the molecular mechanisms that link the circadian machinery to the action of anticancer treatments is still poorly understood, thus limiting the application of circadian rhythms-driven pharmacological therapy, or chronotherapy, in the clinical practice. Herein, we demonstrate the circadian protein period 1 (PER1) and the tumor suppressor p53 negatively cross-regulate each other's expression and activity to modulate the sensitivity of cancer cells to anticancer treatments. Specifically, PER1 physically interacts with p53 to reduce its stability and impair its transcriptional activity, while p53 represses the transcription of PER1. Functionally, we could show that PER1 reduced the sensitivity of cancer cells to drug-induced apoptosis, both in vitro and in vivo in NOD scid gamma (NSG) mice xenotransplanted with a lung cancer cell line. Therefore, our results emphasize the importance of understanding the relationship between the circadian clock and tumor regulatory proteins as the basis for the future development of cancer chronotherapy.
    Keywords:  chronotherapy; circadian rhythm; p53; period
  50. Cells. 2021 Mar 16. pii: 657. [Epub ahead of print]10(3):
      The maintenance of cellular homeostasis involves the participation of multiple organelles. These organelles are associated in space and time, and either cooperate or antagonize each other with regards to cell function. Crosstalk between organelles has become a significant topic in research over recent decades. We believe that signal transduction between organelles, especially the endoplasmic reticulum (ER) and mitochondria, is a factor that can influence the cell fate. As the cellular center for protein folding and modification, the endoplasmic reticulum can influence a range of physiological processes by regulating the quantity and quality of proteins. Mitochondria, as the cellular "energy factory," are also involved in cell death processes. Some researchers regard the ER as the sensor of cellular stress and the mitochondria as an important actuator of the stress response. The scientific community now believe that bidirectional communication between the ER and the mitochondria can influence cell death. Recent studies revealed that the death signals can shuttle between the two organelles. Mitochondria-associated membranes (MAMs) play a vital role in the complex crosstalk between the ER and mitochondria. MAMs are known to play an important role in lipid synthesis, the regulation of Ca2+ homeostasis, the coordination of ER-mitochondrial function, and the transduction of death signals between the ER and the mitochondria. Clarifying the structure and function of MAMs will provide new concepts for studying the pathological mechanisms associated with neurodegenerative diseases, aging, and cancers. Here, we review the recent studies of the structure and function of MAMs and its roles involved in cell death, especially in apoptosis.
    Keywords:  Ca2+; MAMs; apoptosis; endoplasmic reticulum; mitochondria
  51. Adv Exp Med Biol. 2021 ;1280 231-241
      Although normal cells depend on exogenous lipids to function and survive, excessive amount of body fat has been associated with increased risk for certain human cancers. Cancer cells can redirect metabolic pathways to meet energy demands through the regulation of fatty acid metabolism. The importance of de novo fatty acid synthesis and fatty acid oxidation in cancer cells suggests fatty acid metabolism may be targeted for anticancer treatment through the use of pharmacological blockade to limit cell proliferation, growth, and transformation. However, our current knowledge about fatty acid metabolism in cancer cells remains limited, and the investigations of such processes and related pathways are certainly warranted to reveal the clinical relevance of fatty acid metabolism in cancer diagnosis and therapy.
    Keywords:  Cancer metabolism; Fatty acid oxidation; Fatty acid synthesis