bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–05–07
forty-five papers selected by
Christian Frezza, Universität zu Köln
  1. Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis.
  2. Inter-organelle cross-talk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress.
  3. Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition.
  4. Dynamic protein deacetylation is a limited carbon source for acetyl-CoA-dependent metabolism.
  5. An evolving view of Complex II - non-canonical complexes, megacomplexes, respiration, signaling, and beyond.
  6. Methionine restriction constrains lipoylation and activates mitochondria for nitrogenic synthesis of amino acids.
  7. Mitigating age-related somatic mutation burden.
  8. Metabolic homeostasis and growth in abiotic cells.
  9. The ER-mitochondria interface, where Ca2+ and cell death meet.
  10. MICU1 occludes the mitochondrial calcium uniporter in divalent-free conditions.
  11. Career pathways, part 11.
  12. The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions.
  13. Amino acid metabolism, redox balance and epigenetic regulation in cancer.
  14. Oxaloacetate regulates complex II respiration in brown fat: dependence on UCP1 expression.
  15. AMP-activated protein kinase: An energy sensor and survival mechanism in the reinstatement of metabolic homeostasis.
  16. The Warburg effect modulates DHODH role in ferroptosis: a review.
  17. Air pollution promotes tumorigenesis through pre-existing oncogenic mutations.
  18. Phosphate-storing organelle discovered in fruit flies.
  19. How thought itself can drive tumour growth.
  20. The tricarboxylic acid (TCA) cycle: a malleable metabolic network to counter cellular stress.
  21. Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma.
  22. Mitochondrial protein import clogging as a mechanism of disease.
  23. The secret life of lactate: A novel cell-cycle regulatory mechanism.
  24. PARKIN UBIQUITINATION OF KINDLIN-2 ENABLES MITOCHONDRIA-ASSOCIATED METASTASIS SUPPRESSION.
  25. mTOR inhibition suppresses Myc-driven polyposis by inducing immunogenic cell death.
  26. The expression pattern of pyruvate dehydrogenase kinases predicts prognosis and correlates with immune exhaustion in clear cell renal cell carcinoma.
  27. Organism-wide, cell-type-specific secretome mapping of exercise training in mice.
  28. Systems Immunology Approaches to Metabolism.
  29. Molecular basis of translation termination at noncanonical stop codons in human mitochondria.
  30. Targeting serine-glycine-one-carbon metabolism as a vulnerability in cancers.
  31. Lipid droplets and peroxisomes are co-regulated to drive lifespan extension in response to mono-unsaturated fatty acids.
  32. Acetate regulates GAPDH acetylation and T helper 1 cell differentiation.
  33. Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET.
  34. The mitochondrial unfolded protein response regulates hippocampal neural stem cell aging.
  35. Glioblastoma remodelling of human neural circuits decreases survival.
  36. Termination of STING responses is mediated via ESCRT-dependent degradation.
  37. The biochemistry and physiology of long-chain dicarboxylic acid metabolism.
  38. Mitochondrial and metabolic features of salugenesis and the healing cycle.
  39. A phosphate-sensing organelle regulates phosphate and tissue homeostasis.
  40. Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease.
  41. Stress granule formation inhibits stress-induced apoptosis by selectively sequestering executioner caspases.
  42. Complement, complosome, and complotype: a perspective.
  43. Dissecting metastasis using preclinical models and methods.
  44. Deciphering the role of MitomiRs in cancer: A comprehensive review.
  45. Physiological and pathological roles of lipogenesis.
  1. Sci Adv. 2023 May 03. 9(18): eadf0115
    Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis.
    Luke T Izzo, Sophie Trefely, Christina Demetriadou, Jack M Drummond, Takuya Mizukami, Nina Kuprasertkul, Aimee T Farria, Phuong T T Nguyen, Nivitha Murali, Lauren Reich, Daniel S Kantner, Joshua Shaffer, Hayley Affronti, Alessandro Carrer, Andrew Andrews, Brian C Capell, Nathaniel W Snyder, Kathryn E Wellen.
      The metabolite acetyl-CoA is necessary for both lipid synthesis in the cytosol and histone acetylation in the nucleus. The two canonical precursors to acetyl-CoA in the nuclear-cytoplasmic compartment are citrate and acetate, which are processed to acetyl-CoA by ATP-citrate lyase (ACLY) and acyl-CoA synthetase short-chain 2 (ACSS2), respectively. It is unclear whether other substantial routes to nuclear-cytosolic acetyl-CoA exist. To investigate this, we generated cancer cell lines lacking both ACLY and ACSS2 [double knockout (DKO) cells]. Using stable isotope tracing, we show that both glucose and fatty acids contribute to acetyl-CoA pools and histone acetylation in DKO cells and that acetylcarnitine shuttling can transfer two-carbon units from mitochondria to cytosol. Further, in the absence of ACLY, glucose can feed fatty acid synthesis in a carnitine responsive and carnitine acetyltransferase (CrAT)-dependent manner. The data define acetylcarnitine as an ACLY- and ACSS2-independent precursor to nuclear-cytosolic acetyl-CoA that can support acetylation, fatty acid synthesis, and cell growth.
    DOI:  https://doi.org/10.1126/sciadv.adf0115
  2. Sci Adv. 2023 May 03. 9(18): eadf0138
    Inter-organelle cross-talk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress.
    Ramya S Kuna, Avi Kumar, Karl A Wessendorf-Rodriguez, Hector Galvez, Courtney R Green, Grace H McGregor, Thekla Cordes, Reuben J Shaw, Robert U Svensson, Christian M Metallo.
      Proliferating cells rely on acetyl-CoA to support membrane biogenesis and acetylation. Several organelle-specific pathways are available for provision of acetyl-CoA as nutrient availability fluctuates, so understanding how cells maintain acetyl-CoA homeostasis under such stresses is critically important. To this end, we applied 13C isotope tracing cell lines deficient in these mitochondrial [ATP-citrate lyase (ACLY)]-, cytosolic [acetyl-CoA synthetase (ACSS2)]-, and peroxisomal [peroxisomal biogenesis factor 5 (PEX5)]-dependent pathways. ACLY knockout in multiple cell lines reduced fatty acid synthesis and increased reliance on extracellular lipids or acetate. Knockout of both ACLY and ACSS2 (DKO) severely stunted but did not entirely block proliferation, suggesting that alternate pathways can support acetyl-CoA homeostasis. Metabolic tracing and PEX5 knockout studies link peroxisomal oxidation of exogenous lipids as a major source of acetyl-CoA for lipogenesis and histone acetylation in cells lacking ACLY, highlighting a role for inter-organelle cross-talk in supporting cell survival in response to nutrient fluctuations.
    DOI:  https://doi.org/10.1126/sciadv.adf0138
  3. Nat Chem Biol. 2023 May 01.
    Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition.
    Timothy R Bishop, Chitra Subramanian, Eric M Bilotta, Leopold Garnar-Wortzel, Anissa R Ramos, Yuxiang Zhang, Joshua N Asiaban, Christopher J Ott, Charles O Rock, Michael A Erb.
      Histone acetyltransferases (HATs) are implicated as both oncogene and nononcogene dependencies in diverse human cancers. Acetyl-CoA-competitive HAT inhibitors have emerged as potential cancer therapeutics and the first clinical trial for this class of drugs is ongoing (NCT04606446). Despite these developments, the potential mechanisms of therapeutic response and evolved drug resistance remain poorly understood. Having discovered that multiple regulators of de novo coenzyme A (CoA) biosynthesis can modulate sensitivity to CBP/p300 HAT inhibition (PANK3, PANK4 and SLC5A6), we determined that elevated acetyl-CoA concentrations can outcompete drug-target engagement to elicit acquired drug resistance. This not only affects structurally diverse CBP/p300 HAT inhibitors, but also agents related to an investigational KAT6A/B HAT inhibitor that is currently in Phase 1 clinical trials. Altogether, this work uncovers CoA metabolism as an unexpected liability of anticancer HAT inhibitors and will therefore buoy future efforts to optimize the efficacy of this new form of targeted therapy.
    DOI:  https://doi.org/10.1038/s41589-023-01320-7
  4. J Biol Chem. 2023 May 02. pii: S0021-9258(23)01800-8. [Epub ahead of print] 104772
    Dynamic protein deacetylation is a limited carbon source for acetyl-CoA-dependent metabolism.
    Ioana Soaita, Emily Megill, Daniel Kantner, Adam Chatoff, Yuen Jian Cheong, Philippa Clarke, Zoltan Arany, Nathaniel W Snyder, Kathryn E Wellen, Sophie Trefely.
      The ability of cells to store and rapidly mobilize energy reserves in response to nutrient availability is essential for survival. Breakdown of carbon stores produces acetyl-coenzyme-A (AcCoA), which fuels essential metabolic pathways and is also the acyl donor for protein lysine acetylation. Histones are abundant and highly acetylated proteins, accounting for 40% - 75% of cellular protein acetylation. Notably, histone acetylation is sensitive to AcCoA availability and nutrient replete conditions induce a substantial accumulation of acetylation on histones. Deacetylation releases acetate, which can be recycled to AcCoA, suggesting that deacetylation could be mobilized as an AcCoA source to feed downstream metabolic processes under nutrient depletion. While the notion of histones as a metabolic reservoir has been frequently proposed, experimental evidence has been lacking. Therefore, to test this concept directly, we used acetate-dependent ATP citrate lyase-deficient fibroblasts (Acly-/- MEFs) and designed a pulse-chase experimental system to trace deacetylation-derived acetate and its incorporation into AcCoA. We found that dynamic protein deacetylation in Acly-/- MEFs contributed carbons to AcCoA and proximal downstream metabolites. However, deacetylation had no significant effect on acyl-CoA pool sizes, and even at maximal acetylation, deacetylation transiently supplied less than 10% of cellular AcCoA. Together, our data reveal that although histone acetylation is dynamic and nutrient-sensitive, its potential for maintaining cellular AcCoA-dependent metabolic pathways is limited compared to cellular demand.
    Keywords:  Acetylation; acetate; acetyl-coenzyme A; histone; metabolism; stable isotope tracing
    DOI:  https://doi.org/10.1016/j.jbc.2023.104772
  5. J Biol Chem. 2023 Apr 27. pii: S0021-9258(23)01789-1. [Epub ahead of print] 104761
    An evolving view of Complex II - non-canonical complexes, megacomplexes, respiration, signaling, and beyond.
    T M Iverson, Prashant K Singh, Gary Cecchini.
      Mitochondrial Complex II is traditionally studied for its participation in two key respiratory processes: the electron transport chain and the Krebs cycle. There is now a rich body of literature explaining how Complex II contributes to respiration. However, more recent research shows that not all of the pathologies associated with altered Complex II activity clearly correlate with this respiratory role. Complex II activity has now been shown to be necessary for a range of biological processes peripherally-related to respiration, including metabolic control, inflammation, and cell fate. Integration of findings from multiple types of studies suggests that Complex II both participates in respiration and controls multiple succinate-dependent signal transduction pathways. Thus, the emerging view is that the true biological function of Complex II is well beyond respiration. This review uses a semi-chronological approach to highlight major paradigm shifts that occurred over time. Special emphasis is given to the more recently identified functions of Complex II and its subunits because these findings have infused new directions into an established field.
    Keywords:  Complex II; Krebs cycle; bacterial chemotaxis; cancer metabolism; hypoxia; inflammation; ischemia-reperfusion; paraganglioma; pheochromocytoma; respirasome; reverse electron transfer; succinate dehydrogenase; succinate signaling
    DOI:  https://doi.org/10.1016/j.jbc.2023.104761
  6. Nat Commun. 2023 May 02. 14(1): 2504
    Methionine restriction constrains lipoylation and activates mitochondria for nitrogenic synthesis of amino acids.
    Wen Fang, Liu Jiang, Yibing Zhu, Sen Yang, Hong Qiu, Jiou Cheng, Qingxi Liang, Zong-Cai Tu, Cunqi Ye.
      Methionine restriction (MR) provides metabolic benefits in many organisms. However, mechanisms underlying the MR-induced effect remain incompletely understood. Here, we show in the budding yeast S. cerevisiae that MR relays a signal of S-adenosylmethionine (SAM) deprivation to adapt bioenergetic mitochondria to nitrogenic anabolism. In particular, decreases in cellular SAM constrain lipoate metabolism and protein lipoylation required for the operation of the tricarboxylic acid (TCA) cycle in the mitochondria, leading to incomplete glucose oxidation with an exit of acetyl-CoA and α-ketoglutarate from the TCA cycle to the syntheses of amino acids, such as arginine and leucine. This mitochondrial response achieves a trade-off between energy metabolism and nitrogenic anabolism, which serves as an effector mechanism promoting cell survival under MR.
    DOI:  https://doi.org/10.1038/s41467-023-38289-9
  7. Trends Mol Med. 2023 Apr 28. pii: S1471-4914(23)00072-2. [Epub ahead of print]
    Mitigating age-related somatic mutation burden.
    Jan Vijg, Björn Schumacher, Abdulkadir Abakir, Michael Antonov, Chris Bradley, Alex Cagan, George Church, Vadim N Gladyshev, Vera Gorbunova, Alexander Y Maslov, Wolf Reik, Samim Sharifi, Yousin Suh, Kenneth Walsh.
      Genomes are inherently unstable and require constant DNA repair to maintain their genetic information. However, selective pressure has optimized repair mechanisms in somatic cells only to allow transmitting genetic information to the next generation, not to maximize sequence integrity long beyond the reproductive age. Recent studies have confirmed that somatic mutations, due to errors during genome repair and replication, accumulate in tissues and organs of humans and model organisms. Here, we describe recent advances in the quantitative analysis of somatic mutations in vivo. We also review evidence for or against a possible causal role of somatic mutations in aging. Finally, we discuss options to prevent, delay or eliminate de novo, random somatic mutations as a cause of aging.
    Keywords:  aging; cancer; chromatin organization; clonal hematopoiesis; germline versus somatic genome; somatic mutations
    DOI:  https://doi.org/10.1016/j.molmed.2023.04.002
  8. Proc Natl Acad Sci U S A. 2023 May 09. 120(19): e2300687120
    Metabolic homeostasis and growth in abiotic cells.
    Amir Akbari, Bernhard O Palsson.
      Metabolism constitutes the core chemistry of life. How it began on the early Earth and whether it had a cellular origin are still uncertain. A leading hypothesis for life's origins postulates that metabolism arose from geochemical CO2-fixing pathways, driven by inorganic catalysts and energy sources, long before enzymes or genes existed. The acetyl-CoA pathway and the reductive tricarboxylic acid cycle are considered ancient reaction networks that hold relics of early carbon-fixing pathways. Although transition metals can promote many steps of these pathways, whether they form a functional metabolic network in abiotic cells has not been demonstrated. Here, we formulate a nonenzymatic carbon-fixing network from these pathways and determine its functional feasibility in abiotic cells by imposing fundamental physicochemical constraints. Using first principles, we show that abiotic cells can sustain a steady carbon-fixing cycle that performs a systemic function over a relatively narrow range of conditions. Furthermore, we find that in all feasible steady states, the operation of the cycle elevates the osmotic pressure, leading to volume expansion. These results suggest that achieving homeostatic metabolic states under prebiotic conditions was possible, but challenging, and volume growth was a fundamental property of early metabolism.
    Keywords:  alkaline hydrothermal vents; carbon-fixing cycles; emergent properties; metabolic homeostasis; origin of metabolism
    DOI:  https://doi.org/10.1073/pnas.2300687120
  9. Cell Calcium. 2023 Apr 25. pii: S0143-4160(23)00055-6. [Epub ahead of print]112 102743
    The ER-mitochondria interface, where Ca2+ and cell death meet.
    Ian de Ridder, Martijn Kerkhofs, Fernanda O Lemos, Jens Loncke, Geert Bultynck, Jan B Parys.
      Endoplasmic reticulum (ER)-mitochondria contact sites are crucial to allow Ca2+ flux between them and a plethora of proteins participate in tethering both organelles together. Inositol 1,4,5-trisphosphate receptors (IP3Rs) play a pivotal role at such contact sites, participating in both ER-mitochondria tethering and as Ca2+-transport system that delivers Ca2+ from the ER towards mitochondria. At the ER-mitochondria contact sites, the IP3Rs function as a multi-protein complex linked to the voltage-dependent anion channel 1 (VDAC1) in the outer mitochondrial membrane, via the chaperone glucose-regulated protein 75 (GRP75). This IP3R-GRP75-VDAC1 complex supports the efficient transfer of Ca2+ from the ER into the mitochondrial intermembrane space, from which the Ca2+ ions can reach the mitochondrial matrix through the mitochondrial calcium uniporter. Under physiological conditions, basal Ca2+ oscillations deliver Ca2+ to the mitochondrial matrix, thereby stimulating mitochondrial oxidative metabolism. However, when mitochondrial Ca2+ overload occurs, the increase in [Ca2+] will induce the opening of the mitochondrial permeability transition pore, thereby provoking cell death. The IP3R-GRP75-VDAC1 complex forms a hub for several other proteins that stabilize the complex and/or regulate the complex's ability to channel Ca2+ into the mitochondria. These proteins and their mechanisms of action are discussed in the present review with special attention for their role in pathological conditions and potential implication for therapeutic strategies.
    Keywords:  Apoptosis; ER-mitochondria tether; IP(3) receptor; Metabolism; Mitochondria-associated membranes
    DOI:  https://doi.org/10.1016/j.ceca.2023.102743
  10. Proc Natl Acad Sci U S A. 2023 May 09. 120(19): e2218999120
    MICU1 occludes the mitochondrial calcium uniporter in divalent-free conditions.
    Macarena Rodríguez-Prados, Elena Berezhnaya, Maria Teresa Castromonte, Sergio L Menezes-Filho, Melanie Paillard, György Hajnóczky.
      Mitochondrial Ca2+ uptake is mediated by the mitochondrial uniporter complex (mtCU) that includes a tetramer of the pore-forming subunit, MCU, a scaffold protein, EMRE, and the EF-hand regulatory subunit, MICU1 either homodimerized or heterodimerized with MICU2/3. MICU1 has been proposed to regulate Ca2+ uptake via the mtCU by physically occluding the pore and preventing Ca2+ flux at resting cytoplasmic [Ca2+] (free calcium concentration) and to increase Ca2+ flux at high [Ca2+] due to cooperative activation of MICUs EF-hands. However, mtCU and MICU1 functioning when its EF-hands are unoccupied by Ca2+ is poorly studied due to technical limitations. To overcome this barrier, we have studied the mtCU in divalent-free conditions by assessing the Ru265-sensitive Na+ influx using fluorescence-based measurement of mitochondrial matrix [Na+] (free sodium concentration) rise and the ensuing depolarization and swelling. We show an increase in all these measures of Na+ uptake in MICU1KO cells as compared to wild-type (WT) and rescued MICU1KO HEK cells. However, mitochondria in WT cells and MICU1 stable-rescued cells still allowed some Ru265-sensitive Na+ influx that was prevented by MICU1 in excess upon acute overexpression. Thus, MICU1 restricts the cation flux across the mtCU in the absence of Ca2+, but even in cells with high endogenous MICU1 expression such as HEK, some mtCU seem to lack MICU1-dependent gating. We also show rearrangement of the mtCU and altered number of functional channels in MICU1KO and different rescues, and loss of MICU1 during mitoplast preparation, that together might have obscured the pore-blocking function of MICU1 in divalent-free conditions in previous studies.
    Keywords:  EMRE; MICU1; Na+; mitochondrial calcium uniporter; mitoplast
    DOI:  https://doi.org/10.1073/pnas.2218999120
  11. Nat Metab. 2023 May 04.
    Career pathways, part 11.
    Gerta Hoxhaj, Ed Reznik.
      
    DOI:  https://doi.org/10.1038/s42255-023-00788-w
  12. Adv Biol (Weinh). 2023 May 02. e2300095
    The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions.
    Jonathan M Borkum.
      Certain metabolic interventions such as caloric restriction, fasting, exercise, and a ketogenic diet extend lifespan and/or health span. However, their benefits are limited and their connections to the underlying mechanisms of aging are not fully clear. Here, these connections are explored in terms of the tricarboxylic acid (TCA) cycle (Krebs cycle, citric acid cycle) to suggest reasons for the loss of effectiveness and ways of overcoming it. Specifically, the metabolic interventions deplete acetate and likely reduce the conversion of oxaloacetate to aspartate, thereby inhibiting the mammalian target of rapamycin (mTOR) and upregulating autophagy. Synthesis of glutathione may provide a high-capacity sink for amine groups, facilitating autophagy, and prevent buildup of alpha-ketoglutarate, supporting stem cell maintenance. Metabolic interventions also prevent the accumulation of succinate, thereby slowing DNA hypermethylation, facilitating the repair of DNA double-strand breaks, reducing inflammatory and hypoxic signaling, and lowering reliance on glycolysis. In part through these mechanisms, metabolic interventions may decelerate aging, extending lifespan. Conversely, with overnutrition or oxidative stress, these processes function in reverse, accelerating aging and impairing longevity. Progressive damage to aconitase, inhibition of succinate dehydrogenase, and downregulation of hypoxia-inducible factor-1α, and phosphoenolpyruvate carboxykinase (PEPCK) emerge as potentially modifiable reasons for the loss of effectiveness of metabolic interventions.
    Keywords:  DNA methylation; DNA repair; aspartate; autophagy; hypoxia; succinate
    DOI:  https://doi.org/10.1002/adbi.202300095
  13. FEBS J. 2023 May 02.
    Amino acid metabolism, redox balance and epigenetic regulation in cancer.
    Xiang Li, Hong-Sheng Zhang.
      Amino acids act as the versatile nutrients driving cell growth and survival, especially in cancer cells. Amino acid metabolism comprises numerous metabolic networks and is closely linked with intracellular redox balance and epigenetic regulation. Reprogrammed amino acid metabolism has been recognized as a ubiquitous feature in tumor cells. This review outlines the metabolism of several primary amino acids in cancer cells and highlights the pivotal role of amino acid metabolism in sustaining redox homeostasis and regulating epigenetic modification in response to oxidative and genetic stress in cancer cells.
    Keywords:  amino acids; cancer; epigenetic regulation; metabolism; redox balance
    DOI:  https://doi.org/10.1111/febs.16803
  14. Am J Physiol Cell Physiol. 2023 May 01.
    Oxaloacetate regulates complex II respiration in brown fat: dependence on UCP1 expression.
    Ritu Som, Brian D Fink, Liping Yu, William I Sivitz.
      We previously found that skeletal muscle mitochondria incubated at low membrane potential (ΔΨ) or interscapular brown adipose tissue (IBAT) mitochondria, wherein ΔΨ is intrinsically low, accumulate oxaloacetate (OAA) in amounts sufficient to inhibit complex II respiration. We proposed a mechanism wherein low ΔΨ reduces reverse electron transport (RET) to complex I causing a low NADH/NAD+ ratio favoring malate conversion to OAA. To further assess the mechanism and its physiologic relevance we carried out studies of mice with inherently different levels of IBAT mitochondrial inner membrane potential. Isolated complex II (succinate)-energized IBAT mitochondria from obesity resistant 129SVE mice compared to obesity prone C57BL/6J displayed greater UCP1 expression, similar O2 flux despite lower ΔΨ, similar OAA concentrations, and similar NADH/NAD+. When GDP was added to inhibit UCP1, 129SVE IBAT mitochondria, despite their lower ΔΨ, exhibited much lower respiration, 2-fold greater OAA concentrations, much lower RET (as marked by ROS), and much lower NADH and NADH/NAD+ ratios compared to the C57BL/6J IBAT mitochondria. UCP1 knock-out abolished OAA accumulation by succinate-energized mitochondria associated with markedly greater ΔΨ, ROS, and NADH, but equal or greater O2 flux compared to WT mitochondria. GDP addition, compared to no GDP, increased ΔΨ and complex II respiration in wildtype mice associated with much less OAA. Respiration on complex I substrates followed the more classical dynamics of greater respiration at lower ΔΨ. These findings support the above-mentioned mechanism for OAA- and ΔΨ-dependent complex II respiration and support its physiological relevance.
    Keywords:  brown adipose tissue; mitochondria; mitochondrial complex II; oxaloacetate; succinate dehydrogenase
    DOI:  https://doi.org/10.1152/ajpcell.00565.2022
  15. Exp Cell Res. 2023 Apr 29. pii: S0014-4827(23)00161-1. [Epub ahead of print] 113614
    AMP-activated protein kinase: An energy sensor and survival mechanism in the reinstatement of metabolic homeostasis.
    Ankita Sharma, Sumit Kr Anand, Neha Singh, Upendra Nath Dwivedi, Poonam Kakkar.
      Cells are programmed to favorably respond towards the nutrient availability by adapting their metabolism to meet energy demands. AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine energy-sensing kinase. It gets activated upon a decrease in the cellular energy status as reflected by an increased AMP/ATP ratio, ADP, and also during the conditions of glucose starvation without change in the adenine nucelotide ratio. AMPK functions as a centralized regulator of metabolism, acting at cellular and physiological levels to circumvent the metabolic stress by restoring energy balance. This review intricately highlights the integrated signaling pathways by which AMPK gets activated allosterically or by multiple non-canonical upstream kinases. AMPK activates the ATP generating processes (e.g., fatty acid oxidation) and inhibits the ATP consuming processes that are non-critical for survival (e.g., cell proliferation, protein and triglyceride synthesis). An integrated signaling network with AMPK as the central effector regulates all the aspects of enhanced stress resistance, qualified cellular housekeeping, and energy metabolic homeostasis. Importantly, the AMPK mediated amelioration of cellular stress and inflammatory responses are mediated by stimulation of transcription factors such as Nrf2, SIRT1, FoxO and inhibition of NF-κB serving as main downstream effectors. Moreover, many lines of evidence have demonstrated that AMPK controls autophagy through mTOR and ULK1 signaling to fine-tune the metabolic pathways in response to different cellular signals. This review also highlights the critical involvement of AMPK in promoting mitochondrial health, and homeostasis, including mitophagy. Loss of AMPK or ULK1 activity leads to aberrant accumulation of autophagy-related proteins and defective mitophagy thus, connecting cellular energy sensing to autophagy and mitophagy.
    Keywords:  AMPK; Autophagy; Cellular stress; Metabolic stress; Mitophagy
    DOI:  https://doi.org/10.1016/j.yexcr.2023.113614
  16. Cell Commun Signal. 2023 May 05. 21(1): 100
    The Warburg effect modulates DHODH role in ferroptosis: a review.
    Alvan Amos, Alex Amos, Lirong Wu, He Xia.
      Ferroptosis is an iron-dependent regulated cell death that suppresses tumor growth. It is activated by extensive peroxidation of membrane phospholipids caused by oxidative stress. GPX4, an antioxidant enzyme, reduces these peroxidized membrane phospholipids thereby inhibiting ferroptosis. This enzyme has two distinct subcellular localization; the cytosol and mitochondria. Dihydroorotate dehydrogenase (DHODH) complements mitochondrial GPX4 in reducing peroxidized membrane phospholipids. It is the rate-limiting enzyme in de novo pyrimidine nucleotide biosynthesis. Its role in ferroptosis inhibition suggests that DHODH inhibitors could have two complementary mechanisms of action against tumors; inhibiting de novo pyrimidine nucleotide biosynthesis and enhancing ferroptosis. However, the link between mitochondrial function and ferroptosis, and the involvement of DHODH in the ETC suggests that its role in ferroptosis could be modulated by the Warburg effect. Therefore, we reviewed relevant literature to get an insight into the possible effect of this metabolic reprogramming on the role of DHODH in ferroptosis. Furthermore, an emerging link between DHODH and cellular GSH pool has also been highlighted. These insights could contribute to the rational design of ferroptosis-based anticancer drugs. Video Abstract.
    Keywords:  Dihydroorotate dehydrogenase; Electron transport chain; Ferroptosis; Mitochondria; Ribonucleotide reductase; Superoxide anion
    DOI:  https://doi.org/10.1186/s12964-022-01025-9
  17. Nat Rev Cancer. 2023 May 04.
    Air pollution promotes tumorigenesis through pre-existing oncogenic mutations.
    Gabrielle Brewer.
      
    DOI:  https://doi.org/10.1038/s41568-023-00585-3
  18. Nature. 2023 May 03.
    Phosphate-storing organelle discovered in fruit flies.
    Emily Strachan, Irene Miguel-Aliaga.
      
    Keywords:  Cell biology; Metabolism; Physiology
    DOI:  https://doi.org/10.1038/d41586-023-01410-5
  19. Nature. 2023 May 03.
    How thought itself can drive tumour growth.
    George M Ibrahim, Michael D Taylor.
      
    Keywords:  Cancer; Medical research; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-023-01387-1
  20. Crit Rev Biochem Mol Biol. 2023 Apr 26. 1-17
    The tricarboxylic acid (TCA) cycle: a malleable metabolic network to counter cellular stress.
    Alex MacLean, Felix Legendre, Vasu D Appanna.
      The tricarboxylic acid (TCA) cycle is a primordial metabolic pathway that is conserved from bacteria to humans. Although this network is often viewed primarily as an energy producing engine fueling ATP synthesis via oxidative phosphorylation, mounting evidence reveals that this metabolic hub orchestrates a wide variety of pivotal biological processes. It plays an important part in combatting cellular stress by modulating NADH/NADPH homeostasis, scavenging ROS (reactive oxygen species), producing ATP by substrate-level phosphorylation, signaling and supplying metabolites to quell a range of cellular disruptions. This review elaborates on how the reprogramming of this network prompted by such abiotic stress as metal toxicity, oxidative tension, nutrient challenge and antibiotic insult is critical for countering these conditions in mostly microbial systems. The cross-talk between the stressors and the participants of TCA cycle that results in changes in metabolite and nucleotide concentrations aimed at combatting the abiotic challenge is presented. The fine-tuning of metabolites mediated by disparate enzymes associated with this metabolic hub is discussed. The modulation of enzymatic activities aimed at generating metabolic moieties dedicated to respond to the cellular perturbation is explained. This ancient metabolic network has to be recognized for its ability to execute a plethora of physiological functions beyond its well-established traditional roles.
    Keywords:  NADH; NADPH; TCA cycle; cellular stress; keto-acids; metabolic reprogramming
    DOI:  https://doi.org/10.1080/10409238.2023.2201945
  21. Nat Commun. 2023 May 02. 14(1): 2502
    Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma.
    Emma Martell, Helgi Kuzmychova, Esha Kaul, Harshal Senthil, Subir Roy Chowdhury, Ludivine Coudière Morrison, Agnes Fresnoza, Jamie Zagozewski, Chitra Venugopal, Chris M Anderson, Sheila K Singh, Versha Banerji, Tamra E Werbowetski-Ogilvie, Tanveer Sharif.
      Group 3 medulloblastoma (G3 MB) carries the worst prognosis of all MB subgroups. MYC oncoprotein is elevated in G3 MB tumors; however, the mechanisms that support MYC abundance remain unclear. Using metabolic and mechanistic profiling, we pinpoint a role for mitochondrial metabolism in regulating MYC. Complex-I inhibition decreases MYC abundance in G3 MB, attenuates the expression of MYC-downstream targets, induces differentiation, and prolongs male animal survival. Mechanistically, complex-I inhibition increases inactivating acetylation of antioxidant enzyme SOD2 at K68 and K122, triggering the accumulation of mitochondrial reactive oxygen species that promotes MYC oxidation and degradation in a mitochondrial pyruvate carrier (MPC)-dependent manner. MPC inhibition blocks the acetylation of SOD2 and oxidation of MYC, restoring MYC abundance and self-renewal capacity in G3 MB cells following complex-I inhibition. Identification of this MPC-SOD2 signaling axis reveals a role for metabolism in regulating MYC protein abundance that has clinical implications for treating G3 MB.
    DOI:  https://doi.org/10.1038/s41467-023-38049-9
  22. Elife. 2023 May 02. pii: e84330. [Epub ahead of print]12
    Mitochondrial protein import clogging as a mechanism of disease.
    Liam P Coyne, Xiaowen Wang, Jiyao Song, Ebbing de Jong, Karin Schneider, Paul T Massa, Frank A Middleton, Thomas Becker, Xin Jie Chen.
      Mitochondrial biogenesis requires the import of >1,000 mitochondrial preproteins from the cytosol. Most studies on mitochondrial protein import are focused on the core import machinery. Whether and how the biophysical properties of substrate preproteins affect overall import efficiency is underexplored. Here, we show that protein traffic into mitochondria can be disrupted by amino acid substitutions in a single substrate preprotein. Pathogenic missense mutations in ADP/ATP translocase 1 (ANT1), and its yeast homolog Aac2, cause the protein to accumulate along the protein import pathway, thereby obstructing general protein translocation into mitochondria. This impairs mitochondrial respiration, cytosolic proteostasis and cell viability independent of ANT1's nucleotide transport activity. The mutations act synergistically, as double mutant Aac2/ANT1 cause severe clogging primarily at the Translocase of the Outer Membrane (TOM) complex. This confers extreme toxicity in yeast. In mice, expression of a super-clogger ANT1 variant led to neurodegeneration and an age-dependent dominant myopathy that phenocopy ANT1-induced human disease, suggesting clogging as a mechanism of disease. More broadly, this work implies the existence of uncharacterized amino acid requirements for mitochondrial carrier proteins to avoid clogging and subsequent disease.
    Keywords:  S. cerevisiae; biochemistry; chemical biology; mouse
    DOI:  https://doi.org/10.7554/eLife.84330
  23. Cell Metab. 2023 May 02. pii: S1550-4131(23)00133-X. [Epub ahead of print]35(5): 730-732
    The secret life of lactate: A novel cell-cycle regulatory mechanism.
    Ahmad A Cluntun, Jared Rutter.
      Recently, Liu et al. uncovered an unexpected L-lactate-Zn2+ interaction in the active site of the deSUMOylating enzyme SENP1 that triggers a sequence of events that lead to mitotic exit. This study opens the door to new research avenues of metabolite-metal interactions controlling cellular decisions and functions.
    DOI:  https://doi.org/10.1016/j.cmet.2023.04.006
  24. J Biol Chem. 2023 May 02. pii: S0021-9258(23)01802-1. [Epub ahead of print] 104774
    PARKIN UBIQUITINATION OF KINDLIN-2 ENABLES MITOCHONDRIA-ASSOCIATED METASTASIS SUPPRESSION.
    Minjeong Yeon, Irene Bertolini, Ekta Agarwal, Jagadish C Ghosh, Hsin-Yao Tang, David W Speicher, Frederick Keeney, Khalid Sossey-Alaoui, Elzbieta Pluskota, Katarzyna Bialkowska, Edward F Plow, Lucia R Languino, Emmanuel Skordalakes, M Cecilia Caino, Dario C Altieri.
      Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitin ligase altered in Parkinson's Disease (PD), forms a complex with the regulator of cell motility, Kindlin-2 (K2) at mitochondria of tumor cells. In turn, Parkin ubiquitinates Lys581 and Lys582 using Lys48 linkages, resulting in proteasomal degradation of K2 and shortened half-life from ∼5 h to ∼1.5 h. Loss of K2 inhibits focal adhesion turnover and β1 integrin activation, impairs membrane lamellipodia size and frequency, and inhibits mitochondrial dynamics, altogether suppressing tumor cell-ECM interactions, migration, and invasion. Conversely, Parkin does not affect tumor cell proliferation, cell cycle transitions or apoptosis. Expression of a Parkin ubiquitination-resistant K2 Lys581Ala/Lys582Ala double mutant is sufficient to restore membrane lamellipodia dynamics, correct mitochondrial fusion/fission, and preserve single-cell migration and invasion. In a 3D model of mammary gland developmental morphogenesis, impaired K2 ubiquitination drives multiple oncogenic traits of EMT, increased cell proliferation, reduced apoptosis and disrupted basal-apical polarity. Therefore, deregulated K2 is a potent oncogene and its ubiquitination by Parkin enables mitochondria-associated metastasis suppression.
    Keywords:  Kindlin-2; Parkin; metastasis suppression; tumor cell motility; ubiquitination
    DOI:  https://doi.org/10.1016/j.jbc.2023.104774
  25. Oncogene. 2023 May 03.
    mTOR inhibition suppresses Myc-driven polyposis by inducing immunogenic cell death.
    Brian J Leibowitz, Guangyi Zhao, Wenxin Xia, Yuhan Wang, Hang Ruan, Lin Zhang, Jian Yu.
      Myc is a key driver of colorectal cancer initiation and progression, but remains a difficult drug target. In this study, we show that mTOR inhibition potently suppresses intestinal polyp formation, regresses established polyps, and prolongs lifespan of APCMin/+ mice. Everolimus in diet strongly reduces p-4EBP1, p-S6, and Myc levels, and induces apoptosis of cells with activated β-catenin (p-S552) in the polyps on day 3. The cell death is accompanied by ER stress, activation of the extrinsic apoptotic pathway, innate immune cell recruitment, and followed by T-cell infiltration on day 14 persisting for months thereafter. These effects are absent in normal intestinal crypts with physiologic levels of Myc and a high rate of proliferation. Using normal human colonic epithelial cells, EIF4E S209A knockin and BID knockout mice, we found that local inflammation and antitumor efficacy of Everolimus requires Myc-dependent induction of ER stress and apoptosis. These findings demonstrate mTOR and deregulated Myc as a selective vulnerability of mutant APC-driven intestinal tumorigenesis, whose inhibition disrupts metabolic and immune adaptation and reactivates immune surveillance necessary for long-term tumor control.
    DOI:  https://doi.org/10.1038/s41388-023-02706-6
  26. Sci Rep. 2023 May 05. 13(1): 7339
    The expression pattern of pyruvate dehydrogenase kinases predicts prognosis and correlates with immune exhaustion in clear cell renal cell carcinoma.
    Caroline E Nunes-Xavier, Maite Emaldi, Janire Mingo, Tove Øyjord, Gunhild M Mælandsmo, Øystein Fodstad, Peio Errarte, Gorka Larrinaga, Roberto Llarena, José I López, Rafael Pulido.
      Renal cancer cells constitute a paradigm of tumor cells with a glycolytic reprogramming which drives metabolic alterations favouring cell survival and transformation. We studied the expression and activity of pyruvate dehydrogenase kinases (PDK1-4), key enzymes of the energy metabolism, in renal cancer cells. We analysed the expression, subcellular distribution and clinicopathological correlations of PDK1-4 by immunohistochemistry of tumor tissue microarray samples from a cohort of 96 clear cell renal cell carcinoma (ccRCC) patients. Gene expression analysis was performed on whole tumor tissue sections of a subset of ccRCC samples. PDK2 and PDK3 protein expression in tumor cells correlated with lower patient overall survival, whereas PDK1 protein expression correlated with higher patient survival. Gene expression analysis revealed molecular association of PDK2 and PDK3 expression with PI3K signalling pathway, as well as with T cell infiltration and exhausted CD8 T cells. Inhibition of PDK by dichloroacetate in human renal cancer cell lines resulted in lower cell viability, which was accompanied by an increase in pAKT. Together, our findings suggest a differential role for PDK enzymes in ccRCC progression, and highlight PDK as actionable metabolic proteins in relation with PI3K signalling and exhausted CD8 T cells in ccRCC.
    DOI:  https://doi.org/10.1038/s41598-023-34087-x
  27. Cell Metab. 2023 Apr 28. pii: S1550-4131(23)00138-9. [Epub ahead of print]
    Organism-wide, cell-type-specific secretome mapping of exercise training in mice.
    Wei Wei, Nicholas M Riley, Xuchao Lyu, Xiaotao Shen, Jing Guo, Steffen H Raun, Meng Zhao, Maria Dolores Moya-Garzon, Himanish Basu, Alan Sheng-Hwa Tung, Veronica L Li, Wentao Huang, Amanda L Wiggenhorn, Katrin J Svensson, Michael P Snyder, Carolyn R Bertozzi, Jonathan Z Long.
      There is a significant interest in identifying blood-borne factors that mediate tissue crosstalk and function as molecular effectors of physical activity. Although past studies have focused on an individual molecule or cell type, the organism-wide secretome response to physical activity has not been evaluated. Here, we use a cell-type-specific proteomic approach to generate a 21-cell-type, 10-tissue map of exercise training-regulated secretomes in mice. Our dataset identifies >200 exercise training-regulated cell-type-secreted protein pairs, the majority of which have not been previously reported. Pdgfra-cre-labeled secretomes were the most responsive to exercise training. Finally, we show anti-obesity, anti-diabetic, and exercise performance-enhancing activities for proteoforms of intracellular carboxylesterases whose secretion from the liver is induced by exercise training.
    Keywords:  CES2; cell type; energy metabolism; exercise; exercise performance; hepatokine; obesity; secretome; tissue crosstalk
    DOI:  https://doi.org/10.1016/j.cmet.2023.04.011
  28. Annu Rev Immunol. 2023 04 26. 41 317-342
    Systems Immunology Approaches to Metabolism.
    Denis A Mogilenko, Alexey Sergushichev, Maxim N Artyomov.
      Over the last decade, immunometabolism has emerged as a novel interdisciplinary field of research and yielded significant fundamental insights into the regulation of immune responses. Multiple classical approaches to interrogate immunometabolism, including bulk metabolic profiling and analysis of metabolic regulator expression, paved the way to appreciating the physiological complexity of immunometabolic regulation in vivo. Studying immunometabolism at the systems level raised the need to transition towards the next-generation technology for metabolic profiling and analysis. Spatially resolved metabolic imaging and computational algorithms for multi-modal data integration are new approaches to connecting metabolism and immunity. In this review, we discuss recent studies that highlight the complex physiological interplay between immune responses and metabolism and give an overview of technological developments that bear the promise of capturing this complexity most directly and comprehensively.
    Keywords:  computational biology; immunometabolism; metabolic imaging; metabolomics; systems immunology; transcriptomics
    DOI:  https://doi.org/10.1146/annurev-immunol-101220-031513
  29. Science. 2023 May 05. 380(6644): 531-536
    Molecular basis of translation termination at noncanonical stop codons in human mitochondria.
    Martin Saurer, Marc Leibundgut, Hima Priyanka Nadimpalli, Alain Scaiola, Tanja Schönhut, Richard G Lee, Stefan J Siira, Oliver Rackham, René Dreos, Tea Lenarčič, Eva Kummer, David Gatfield, Aleksandra Filipovska, Nenad Ban.
      The genetic code that specifies the identity of amino acids incorporated into proteins during protein synthesis is almost universally conserved. Mitochondrial genomes feature deviations from the standard genetic code, including the reassignment of two arginine codons to stop codons. The protein required for translation termination at these noncanonical stop codons to release the newly synthesized polypeptides is not currently known. In this study, we used gene editing and ribosomal profiling in combination with cryo-electron microscopy to establish that mitochondrial release factor 1 (mtRF1) detects noncanonical stop codons in human mitochondria by a previously unknown mechanism of codon recognition. We discovered that binding of mtRF1 to the decoding center of the ribosome stabilizes a highly unusual conformation in the messenger RNA in which the ribosomal RNA participates in specific recognition of the noncanonical stop codons.
    DOI:  https://doi.org/10.1126/science.adf9890
  30. Biomark Res. 2023 May 05. 11(1): 48
    Targeting serine-glycine-one-carbon metabolism as a vulnerability in cancers.
    Wei Sun, Ruochen Liu, Xinyue Gao, Zini Lin, Hongao Tang, Hongjuan Cui, Erhu Zhao.
      The serine-glycine-one-carbon (SGOC) metabolic pathway is critical for DNA methylation, histone methylation, and redox homeostasis, in addition to protein, lipid, and nucleotide biosynthesis. The SGOC pathway is a crucial metabolic network in tumorigenesis, wherein the outputs are required for cell survival and proliferation and are particularly likely to be co-opted by aggressive cancers. SGOC metabolism provides an integration point in cell metabolism and is of crucial clinical significance. The mechanism of how this network is regulated is the key to understanding tumor heterogeneity and overcoming the potential mechanism of tumor recurrence. Herein, we review the role of SGOC metabolism in cancer by focusing on key enzymes with tumor-promoting functions and important products with physiological significance in tumorigenesis. In addition, we introduce the ways in which cancer cells acquire and use one-carbon unit, and discuss the recently clarified role of SGOC metabolic enzymes in tumorigenesis and development, as well as their relationship with cancer immunotherapy and ferroptosis. The targeting of SGOC metabolism may be a potential therapeutic strategy to improve clinical outcomes in cancers.
    Keywords:  Ferroptosis; Immunotherapy; Metabolic enzyme inhibitors; Serine-glycine-one-carbon metabolism; Vulnerability
    DOI:  https://doi.org/10.1186/s40364-023-00487-4
  31. Nat Cell Biol. 2023 May 01.
    Lipid droplets and peroxisomes are co-regulated to drive lifespan extension in response to mono-unsaturated fatty acids.
    Katharina Papsdorf, Jason W Miklas, Amir Hosseini, Matias Cabruja, Christopher S Morrow, Marzia Savini, Yong Yu, Carlos G Silva-García, Nicole R Haseley, Luke Meraz Murphy, Pallas Yao, Elisa de Launoit, Scott J Dixon, Michael P Snyder, Meng C Wang, William B Mair, Anne Brunet.
      Dietary mono-unsaturated fatty acids (MUFAs) are linked to longevity in several species. But the mechanisms by which MUFAs extend lifespan remain unclear. Here we show that an organelle network involving lipid droplets and peroxisomes is critical for MUFA-induced longevity in Caenorhabditis elegans. MUFAs upregulate the number of lipid droplets in fat storage tissues. Increased lipid droplet number is necessary for MUFA-induced longevity and predicts remaining lifespan. Lipidomics datasets reveal that MUFAs also modify the ratio of membrane lipids and ether lipids-a signature associated with decreased lipid oxidation. In agreement with this, MUFAs decrease lipid oxidation in middle-aged individuals. Intriguingly, MUFAs upregulate not only lipid droplet number but also peroxisome number. A targeted screen identifies genes involved in the co-regulation of lipid droplets and peroxisomes, and reveals that induction of both organelles is optimal for longevity. Our study uncovers an organelle network involved in lipid homeostasis and lifespan regulation, opening new avenues for interventions to delay aging.
    DOI:  https://doi.org/10.1038/s41556-023-01136-6
  32. Mol Biol Cell. 2023 May 03. mbcE23020070
    Acetate regulates GAPDH acetylation and T helper 1 cell differentiation.
    Xizhong Jing, Junfang Lyu, Jianhua Xiong.
      The short-chain fatty acid metabolite acetyl-coenzyme A (acetyl-CoA) has emerged as a major signal transducer that can broadly affect cell fate and function at least partly by influencing acetylation of key proteins. The mechanism by which acetyl-CoA regulates CD4+ T cell fate determination remains poorly understood. Herein, we report that acetate modulates glyceraldehyde-3-phosphate dehydrogenase (GAPDH) acetylation and CD4+ T helper 1 (Th1) cell differentiation by altering acetyl-CoA levels. Our transcriptome profiling shows that acetate is a robust positive regulator of CD4+ T cell gene expression typical of glycolysis. We further show that acetate potentiates GAPDH activity, aerobic glycolysis and Th1 polarization through regulation of GAPDH acetylation levels. This acetate-dependent GAPDH acetylation occurs in a dose- and time-dependent manner, while decreasing acetyl-CoA levels by fatty acid oxidation (FAO) inhibition results in a decline in acetyl-GAPDH levels. Thus, acetate functions as a potent metabolic regulator in CD4+ T cells by promoting GAPDH acetylation and Th1 cell fate decision.
    DOI:  https://doi.org/10.1091/mbc.E23-02-0070
  33. Cell Death Differ. 2023 May 04.
    Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET.
    Dimitris C Kanellis, Asimina Zisi, Zdenek Skrott, Bennie Lemmens, Jaime A Espinoza, Martin Kosar, Andrea Björkman, Xuexin Li, Stefanos Arampatzis, Jirina Bartkova, Miguel Andújar-Sánchez, Oscar Fernandez-Capetillo, Martin Mistrik, Mikael S Lindström, Jiri Bartek.
      Drug repurposing is a versatile strategy to improve current therapies. Disulfiram has long been used in the treatment of alcohol dependency and multiple clinical trials to evaluate its clinical value in oncology are ongoing. We have recently reported that the disulfiram metabolite diethyldithiocarbamate, when combined with copper (CuET), targets the NPL4 adapter of the p97VCP segregase to suppress the growth of a spectrum of cancer cell lines and xenograft models in vivo. CuET induces proteotoxic stress and genotoxic effects, however important issues concerning the full range of the CuET-evoked tumor cell phenotypes, their temporal order, and mechanistic basis have remained largely unexplored. Here, we have addressed these outstanding questions and show that in diverse human cancer cell models, CuET causes a very early translational arrest through the integrated stress response (ISR), later followed by features of nucleolar stress. Furthermore, we report that CuET entraps p53 in NPL4-rich aggregates leading to elevated p53 protein and its functional inhibition, consistent with the possibility of CuET-triggered cell death being p53-independent. Our transcriptomics profiling revealed activation of pro-survival adaptive pathways of ribosomal biogenesis (RiBi) and autophagy upon prolonged exposure to CuET, indicating potential feedback responses to CuET treatment. The latter concept was validated here by simultaneous pharmacological inhibition of RiBi and/or autophagy that further enhanced CuET's tumor cytotoxicity, using both cell culture and zebrafish in vivo preclinical models. Overall, these findings expand the mechanistic repertoire of CuET's anti-cancer activity, inform about the temporal order of responses and identify an unorthodox new mechanism of targeting p53. Our results are discussed in light of cancer-associated endogenous stresses as exploitable tumor vulnerabilities and may inspire future clinical applications of CuET in oncology, including combinatorial treatments and focus on potential advantages of using certain validated drug metabolites, rather than old, approved drugs with their, often complex, metabolic profiles.
    DOI:  https://doi.org/10.1038/s41418-023-01167-4
  34. Cell Metab. 2023 Apr 28. pii: S1550-4131(23)00139-0. [Epub ahead of print]
    The mitochondrial unfolded protein response regulates hippocampal neural stem cell aging.
    Chih-Ling Wang, Rika Ohkubo, Wei-Chieh Mu, Wei Chen, Jiang Lan Fan, Zehan Song, Ayane Maruichi, Peter H Sudmant, Angela O Pisco, Dena B Dubal, Na Ji, Danica Chen.
      Aging results in a decline in neural stem cells (NSCs), neurogenesis, and cognitive function, and evidence is emerging to demonstrate disrupted adult neurogenesis in the hippocampus of patients with several neurodegenerative disorders. Here, single-cell RNA sequencing of the dentate gyrus of young and old mice shows that the mitochondrial protein folding stress is prominent in activated NSCs/neural progenitors (NPCs) among the neurogenic niche, and it increases with aging accompanying dysregulated cell cycle and mitochondrial activity in activated NSCs/NPCs in the dentate gyrus. Increasing mitochondrial protein folding stress results in compromised NSC maintenance and reduced neurogenesis in the dentate gyrus, neural hyperactivity, and impaired cognitive function. Reducing mitochondrial protein folding stress in the dentate gyrus of old mice improves neurogenesis and cognitive function. These results establish the mitochondrial protein folding stress as a driver of NSC aging and suggest approaches to improve aging-associated cognitive decline.
    Keywords:  SIRT1; SIRT2; SIRT3; SIRT6; SIRT7; cognitive aging; mitochondrial unfolded protein response; neural stem cell aging; sirtuin; stem cell aging
    DOI:  https://doi.org/10.1016/j.cmet.2023.04.012
  35. Nature. 2023 May 03.
    Glioblastoma remodelling of human neural circuits decreases survival.
    Saritha Krishna, Abrar Choudhury, Michael B Keough, Kyounghee Seo, Lijun Ni, Sofia Kakaizada, Anthony Lee, Alexander Aabedi, Galina Popova, Benjamin Lipkin, Caroline Cao, Cesar Nava Gonzales, Rasika Sudharshan, Andrew Egladyous, Nyle Almeida, Yalan Zhang, Annette M Molinaro, Humsa S Venkatesh, Andy G S Daniel, Kiarash Shamardani, Jeanette Hyer, Edward F Chang, Anne Findlay, Joanna J Phillips, Srikantan Nagarajan, David R Raleigh, David Brang, Michelle Monje, Shawn L Hervey-Jumper.
      Gliomas synaptically integrate into neural circuits1,2. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth1-4 and gliomas increasing neuronal excitability2,5-8. Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition.
    DOI:  https://doi.org/10.1038/s41586-023-06036-1
  36. EMBO J. 2023 May 04. e112712
    Termination of STING responses is mediated via ESCRT-dependent degradation.
    Katherine R Balka, Rajan Venkatraman, Tahnee L Saunders, Angus Shoppee, Ee Shan Pang, Zoe Magill, Jihane Homman-Ludiye, Cheng Huang, Rachael M Lane, Harrison M York, Peck Tan, Ralf B Schittenhelm, Senthil Arumugam, Benjamin T Kile, Meredith O'Keeffe, Dominic De Nardo.
      cGAS-STING signalling is induced by detection of foreign or mislocalised host double-stranded (ds)DNA within the cytosol. STING acts as the major signalling hub, where it controls production of type I interferons and inflammatory cytokines. Basally, STING resides on the ER membrane. Following activation STING traffics to the Golgi to initiate downstream signalling and subsequently to endolysosomal compartments for degradation and termination of signalling. While STING is known to be degraded within lysosomes, the mechanisms controlling its delivery remain poorly defined. Here we utilised a proteomics-based approach to assess phosphorylation changes in primary murine macrophages following STING activation. This identified numerous phosphorylation events in proteins involved in intracellular and vesicular transport. We utilised high-temporal microscopy to track STING vesicular transport in live macrophages. We subsequently identified that the endosomal complexes required for transport (ESCRT) pathway detects ubiquitinated STING on vesicles, which facilitates the degradation of STING in murine macrophages. Disruption of ESCRT functionality greatly enhanced STING signalling and cytokine production, thus characterising a mechanism controlling effective termination of STING signalling.
    Keywords:  ESCRT; cGAS-STING; innate immunity; lysosomal degradation; vesicular trafficking
    DOI:  https://doi.org/10.15252/embj.2022112712
  37. Biochem J. 2023 May 15. 480(9): 607-627
    The biochemistry and physiology of long-chain dicarboxylic acid metabolism.
    Pablo Ranea-Robles, Sander M Houten.
      Mitochondrial β-oxidation is the most prominent pathway for fatty acid oxidation but alternative oxidative metabolism exists. Fatty acid ω-oxidation is one of these pathways and forms dicarboxylic acids as products. These dicarboxylic acids are metabolized through peroxisomal β-oxidation representing an alternative pathway, which could potentially limit the toxic effects of fatty acid accumulation. Although dicarboxylic acid metabolism is highly active in liver and kidney, its role in physiology has not been explored in depth. In this review, we summarize the biochemical mechanism of the formation and degradation of dicarboxylic acids through ω- and β-oxidation, respectively. We will discuss the role of dicarboxylic acids in different (patho)physiological states with a particular focus on the role of the intermediates and products generated through peroxisomal β-oxidation. This review is expected to increase the understanding of dicarboxylic acid metabolism and spark future research.
    DOI:  https://doi.org/10.1042/BCJ20230041
  38. Mitochondrion. 2023 Apr 27. pii: S1567-7249(23)00035-1. [Epub ahead of print]
    Mitochondrial and metabolic features of salugenesis and the healing cycle.
    Robert K Naviaux.
      Pathogenesis and salugenesis are the first and second stages of the two-stage problem of disease production and health recovery. Salugenesis is the automatic, evolutionarily conserved, ontogenetic sequence of molecular, cellular, organ system, and behavioral changes that is used by living systems to heal. It is a whole-body process that begins with mitochondria and the cell. The stages of salugenesis define a circle that is energy- and resource-consuming, genetically programmed, and environmentally responsive. Energy and metabolic resources are provided by mitochondrial and metabolic transformations that drive the cell danger response (CDR) and create the three phases of the healing cycle: Phase 1-Inflammation, Phase 2-Proliferation, and Phase 3-Differentiation. Each phase requires a different mitochondrial phenotype. Without different mitochondria there can be no healing. The rise and fall of extracellular ATP (eATP) signaling is a key driver of the mitochondrial and metabolic reprogramming required to progress through the healing cycle. Sphingolipid and cholesterol-enriched membrane lipid rafts act as rheostats for tuning cellular sensitivity to purinergic signaling. Abnormal persistence of any phase of the CDR inhibits the healing cycle, creates dysfunctional cellular mosaics, causes the symptoms of chronic disease, and accelerates the process of aging. New research reframes the rising tide of chronic disease around the world as a systems problem caused by the combined action of pathogenic triggers and anthropogenic factors that interfere with the mitochondrial functions needed for healing. Once chronic pain, disability, or disease is established, salugenesis-based therapies will start where pathogenesis-based therapies end.
    Keywords:  Anthropocene; aging; allostatic load; cell danger response; chronic disease; ecoalleles; healing cycle; integrated stress response; metabolic memory; metabolic reprogramming; mitochondria; mitotypes; phenomics; pluricausal disease; polyvagal theory; purinergic signaling; purinosis; pónos; salugenesis; synthetic phenotypes
    DOI:  https://doi.org/10.1016/j.mito.2023.04.003
  39. Nature. 2023 May 03.
    A phosphate-sensing organelle regulates phosphate and tissue homeostasis.
    Chiwei Xu, Jun Xu, Hong-Wen Tang, Maria Ericsson, Jui-Hsia Weng, Jonathan DiRusso, Yanhui Hu, Wenzhe Ma, John M Asara, Norbert Perrimon.
      Inorganic phosphate (Pi) is one of the essential molecules for life. However, little is known about intracellular Pi metabolism and signalling in animal tissues1. Following the observation that chronic Pi starvation causes hyperproliferation in the digestive epithelium of Drosophila melanogaster, we determined that Pi starvation triggers the downregulation of the Pi transporter PXo. In line with Pi starvation, PXo deficiency caused midgut hyperproliferation. Interestingly, immunostaining and ultrastructural analyses showed that PXo specifically marks non-canonical multilamellar organelles (PXo bodies). Further, by Pi imaging with a Förster resonance energy transfer (FRET)-based Pi sensor2, we found that PXo restricts cytosolic Pi levels. PXo bodies require PXo for biogenesis and undergo degradation following Pi starvation. Proteomic and lipidomic characterization of PXo bodies unveiled their distinct feature as an intracellular Pi reserve. Therefore, Pi starvation triggers PXo downregulation and PXo body degradation as a compensatory mechanism to increase cytosolic Pi. Finally, we identified connector of kinase to AP-1 (Cka), a component of the STRIPAK complex and JNK signalling3, as the mediator of PXo knockdown- or Pi starvation-induced hyperproliferation. Altogether, our study uncovers PXo bodies as a critical regulator of cytosolic Pi levels and identifies a Pi-dependent PXo-Cka-JNK signalling cascade controlling tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41586-023-06039-y
  40. Nat Commun. 2023 May 04. 14(1): 2573
    Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease.
    Jialiu Zeng, Rebeca Acin-Perez, Essam A Assali, Andrew Martin, Alexandra J Brownstein, Anton Petcherski, Lucía Fernández-Del-Rio, Ruiqing Xiao, Chih Hung Lo, Michaël Shum, Marc Liesa, Xue Han, Orian S Shirihai, Mark W Grinstaff.
      Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux, mitochondrial function, and insulin sensitivity. Here, we report the synthesis of novel biodegradable acid-activated acidifying nanoparticles (acNPs) as a lysosome targeting treatment to restore lysosomal acidity and autophagy. The acNPs, composed of fluorinated polyesters, remain inactive at plasma pH, and only become activated in lysosomes after endocytosis. Specifically, they degrade at pH of ~6 characteristic of dysfunctional lysosomes, to further acidify and enhance the function of lysosomes. In established in vivo high fat diet mouse models of NAFLD, re-acidification of lysosomes via acNP treatment restores autophagy and mitochondria function to lean, healthy levels. This restoration, concurrent with reversal of fasting hyperglycemia and hepatic steatosis, indicates the potential use of acNPs as a first-in-kind therapeutic for NAFLD.
    DOI:  https://doi.org/10.1038/s41467-023-38165-6
  41. Curr Biol. 2023 Apr 21. pii: S0960-9822(23)00460-8. [Epub ahead of print]
    Stress granule formation inhibits stress-induced apoptosis by selectively sequestering executioner caspases.
    Daichi Fujikawa, Takanori Nakamura, Daisuke Yoshioka, Zizheng Li, Hisashi Moriizumi, Mari Taguchi, Noriko Tokai-Nishizumi, Hiroko Kozuka-Hata, Masaaki Oyama, Mutsuhiro Takekawa.
      Cytoplasmic stress granules (SGs) are phase-separated membrane-less organelles that form in response to various stress stimuli. SGs are mainly composed of non-canonical stalled 48S preinitiation complexes. In addition, many other proteins also accumulate into SGs, but the list is still incomplete. SG assembly suppresses apoptosis and promotes cell survival under stress. Furthermore, hyperformation of SGs is frequently observed in various human cancers and accelerates tumor development and progression by reducing stress-induced damage of cancer cells. Therefore, they are of clinical importance. However, the precise mechanism underlying SG-mediated inhibition of apoptosis remains ill-defined. Here, using a proximity-labeling proteomic approach, we comprehensively analyzed SG-resident proteins and identified the executioner caspases, caspase-3 and -7, as SG components. We demonstrate that accumulation of caspase-3/7 into SGs is mediated by evolutionarily conserved amino acid residues within their large catalytic domains and inhibits caspase activities and consequent apoptosis induced by various stresses. Expression of an SG-localization-deficient caspase-3 mutant in cells largely counteracted the anti-apoptotic effect of SGs, whereas enforced relocalization of the caspase-3 mutant to SGs restored it. Thus, SG-mediated sequestration of executioner caspases is a mechanism underlying the broad cytoprotective function of SGs. Furthermore, using a mouse xenograft tumor model, we show that this mechanism prevents cancer cells from apoptosis in tumor tissues, thereby promoting cancer progression. Our results reveal the functional crosstalk between SG-mediated cell survival and caspase-mediated cell death signaling pathways and delineate a molecular mechanism that dictates cell-fate decisions under stress and promotes tumorigenesis.
    Keywords:  G3BP; TIA-1; apoptosis; cancer; caspase; liquid-liquid phase separation; stress granules; stress response
    DOI:  https://doi.org/10.1016/j.cub.2023.04.012
  42. Eur J Immunol. 2023 Apr 30. e2250042
    Complement, complosome, and complotype: a perspective.
    Parul Singh, Claudia Kemper.
      Recent rapid progress in key technological advances, including the broader accessibility of single cell 'omic' approaches, allowed immunologists to gain important novel insights into the contributions of individual immune cells in protective immunity and immunopathologies. These insights also taught us that there is still much to uncover about the (cellular) networks underlying immune responses. For example, in the last decade, studies on a key component of innate immunity, the complement system, have defined intracellularly active complement (the complosome) as a key orchestrator of normal cell physiology. This added an unexpected facet to the biology of complement which was long considered fully explored. Here, we will summarize succinctly the known activation modes and functions of the complosome and provide a perspective on the origins of intracellular complement. We will also make a case for extending assessments of the complotype, the individual inherited landscape of common variants in complement genes, to the complosome and for re-assessing patients with known serum complement deficiencies for complosome perturbations. Finally, we will discuss where we see current opportunities and hurdles for dissecting the compartmentalization of complement activities towards a better understanding of its contributions to cellular function in health and disease. This article is protected by copyright. All rights reserved.
    Keywords:  Intracellular complement ⋅ Complosome ⋅ Complotype ⋅ Metabolism ⋅ Non-canonical complement
    DOI:  https://doi.org/10.1002/eji.202250042
  43. Nat Rev Cancer. 2023 May 03.
    Dissecting metastasis using preclinical models and methods.
    Jess D Hebert, Joel W Neal, Monte M Winslow.
      Metastasis has long been understood to lead to the overwhelming majority of cancer-related deaths. However, our understanding of the metastatic process, and thus our ability to prevent or eliminate metastases, remains frustratingly limited. This is largely due to the complexity of metastasis, which is a multistep process that likely differs across cancer types and is greatly influenced by many aspects of the in vivo microenvironment. In this Review, we discuss the key variables to consider when designing assays to study metastasis: which source of metastatic cancer cells to use and where to introduce them into mice to address different questions of metastasis biology. We also examine methods that are being used to interrogate specific steps of the metastatic cascade in mouse models, as well as emerging techniques that may shed new light on previously inscrutable aspects of metastasis. Finally, we explore approaches for developing and using anti-metastatic therapies, and how mouse models can be used to test them.
    DOI:  https://doi.org/10.1038/s41568-023-00568-4
  44. Mitochondrion. 2023 Apr 27. pii: S1567-7249(23)00036-3. [Epub ahead of print]
    Deciphering the role of MitomiRs in cancer: A comprehensive review.
    Dimple Patel, Sanu Thankachan, Abu Fawaz P P, Thejaswini Venkatesh, Shama Prasada Kabekkodu, Padmanaban S Suresh.
      MicroRNAs (miRNAs) are short non-coding RNAs that regulate many metabolic and signal transduction pathways. The role of miRNAs, usually found in the cytoplasm, in regulating gene expression and cancer progression has been extensively studied in the last few decades. However, very recently, miRNAs were found to localize in the mitochondria. MiRNAs that specifically localize in the mitochondria and the cytoplasmic miRNAs associated with mitochondria that directly or indirectly modulate specific mitochondrial functions are termed as "mitomiRs". Although it is not clear about the origin of mitomiRs that are situated within mitochondria (nuclear or mitochondrial origin), it is evident that they have specific functions in modulating gene expression and regulating important mitochondrial metabolic pathways. Through this review, we aim to delineate the mechanisms by which mitomiRs alter mitochondrial metabolic pathways and influence the initiation and progression of cancer. We further discuss the functions of particular mitomiRs, which have been widely studied in the context of mitochondrial metabolism and oncogenic signaling pathways. Based on the current knowledge, we can conclude that mitomiRs contribute significantly to mitochondrial function and metabolic regulation, and that dysregulation of mitomiRs can aid the proliferation of cancer cells. Therefore, the less explored area of mitomiRs' biology can be an important topic of research investigation in the future for targeting cancer cells.
    Keywords:  Mitochondria; cancer; metabolism; mitomiRs
    DOI:  https://doi.org/10.1016/j.mito.2023.04.004
  45. Nat Metab. 2023 May 04.
    Physiological and pathological roles of lipogenesis.
    Yong Geun Jeon, Ye Young Kim, Gung Lee, Jae Bum Kim.
      Lipids are essential metabolites, which function as energy sources, structural components and signalling mediators. Most cells are able to convert carbohydrates into fatty acids, which are often converted into neutral lipids for storage in the form of lipid droplets. Accumulating evidence suggests that lipogenesis plays a crucial role not only in metabolic tissues for systemic energy homoeostasis but also in immune and nervous systems for their proliferation, differentiation and even pathophysiological roles. Thus, excessive or insufficient lipogenesis is closely associated with aberrations in lipid homoeostasis, potentially leading to pathological consequences, such as dyslipidaemia, diabetes, fatty liver, autoimmune diseases, neurodegenerative diseases and cancers. For systemic energy homoeostasis, multiple enzymes involved in lipogenesis are tightly controlled by transcriptional and post-translational modifications. In this Review, we discuss recent findings regarding the regulatory mechanisms, physiological roles and pathological importance of lipogenesis in multiple tissues such as adipose tissue and the liver, as well as the immune and nervous systems. Furthermore, we briefly introduce the therapeutic implications of lipogenesis modulation.
    DOI:  https://doi.org/10.1038/s42255-023-00786-y
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