bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–02–04
47 papers selected by
Christian Frezza, Universität zu Köln
  1. Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis.
  2. Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.
  3. A RalA between high-fat diet and mitochondrial shape.
  4. The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.
  5. Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.
  6. p53 promotes antiviral innate immunity by driving hexosamine metabolism.
  7. mTORC1 controls murine postprandial hepatic glycogen synthesis via Ppp1r3b.
  8. 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.
  9. The striking differences in the bioenergetics of brain and liver mitochondria are enhanced in mitochondrial disease.
  10. Decreased pyruvate dehydrogenase activity in Tafazzin-deficient cells is caused by dysregulation of pyruvate dehydrogenase phosphatase 1 (PDP1).
  11. OPA1 protects intervertebral disc and knee joint health in aged mice by maintaining the structure and metabolic functions of mitochondria.
  12. A Drosophila model of mitochondrial disease phenotypic heterogeneity.
  13. The inhibitor protein IF1 from mammalian mitochondria inhibits ATP hydrolysis but not ATP synthesis by the ATP synthase complex.
  14. Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation.
  15. The opposite role of lactate dehydrogenase a (LDHA) in cervical cancer under energy stress conditions.
  16. Mitochondrial protein synthesis quality control.
  17. Comprehensive multiscale analysis of lactate metabolic dynamics in vitro and in vivo using highly responsive biosensors.
  18. Pathophysiology of human mitochondrial tRNA metabolism.
  19. Nuclear to cytoplasmic transport is a druggable dependency in MYC-driven hepatocellular carcinoma.
  20. In-vivo tracking of deuterium metabolism in mouse organs using LC-MS/MS.
  21. Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.
  22. Ceramides are Fuel Gauges on the Drive to Cardiometabolic Disease.
  23. 7-Dehydrocholesterol dictates ferroptosis sensitivity.
  24. Tissue-specific profiling of age-dependent miRNAomic changes in Caenorhabditis elegans.
  25. The Sphinx and the egg: Evolutionary enigmas of the (glyco)sphingolipid biosynthetic pathway.
  26. Stress response silencing by an E3 ligase mutated in neurodegeneration.
  27. Mitochondrial-to-nuclear communications through multiple routes regulate cardiomyocyte proliferation.
  28. Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation.
  29. Five years on.
  30. Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation.
  31. Recent insights into the control of mitochondrial fission.
  32. Circadian immunity from bench to bedside: a practical guide.
  33. Malignant tumor cells engender second membrane-lined organelles for self-protection and tumor progression.
  34. Aneuploidy and complex genomic rearrangements in cancer evolution.
  35. Mitochondrial HER2 stimulates respiration and promotes tumorigenicity.
  36. Implications of metabolism on multi-systems healthy aging across the lifespan.
  37. Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver.
  38. Metabolic regulation of the hallmarks of stem cell biology.
  39. Finding the point of no return for cellular senescence.
  40. SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion.
  41. Genetics unravels protein-metabolite relationships.
  42. Should I stay or should I go? Transsulfuration influences invasion and growth in glioblastoma.
  43. Should the standard model of cellular energy metabolism be reconsidered? Possible coupling between the pentose phosphate pathway, glycolysis and extra-mitochondrial oxidative phosphorylation.
  44. A universal metabolite repair enzyme removes a strong inhibitor of the TCA cycle.
  45. Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.
  46. Cell competition and the regulation of protein homeostasis.
  47. Multiplexed screening reveals how cancer-specific alternative polyadenylation shapes tumor growth in vivo.
  1. Sci Adv. 2024 Feb 02. 10(5): eadj9479
    Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis.
    Adam G Maynard, Nancy K Pohl, Annabel P Mueller, Boryana Petrova, Alan Y L Wong, Peng Wang, Andrew J Culhane, Jeannette R Brook, Leah M Hirsch, Ngoc Hoang, Orville Kirkland, Tatum Braun, Sarah Ducamp, Mark D Fleming, Hojun Li, Naama Kanarek.
      Folate, an essential vitamin, is a one-carbon acceptor and donor in key metabolic reactions. Erythroid cells harbor a unique sensitivity to folate deprivation, as revealed by the primary pathological manifestation of nutritional folate deprivation: megaloblastic anemia. To study this metabolic sensitivity, we applied mild folate depletion to human and mouse erythroid cell lines and primary murine erythroid progenitors. We show that folate depletion induces early blockade of purine synthesis and accumulation of the purine synthesis intermediate and signaling molecule, 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR), followed by enhanced heme metabolism, hemoglobin synthesis, and erythroid differentiation. This is phenocopied by inhibition of folate metabolism using the inhibitor SHIN1, and by AICAR supplementation. Mechanistically, the metabolically driven differentiation is independent of mechanistic target of rapamycin complex 1 (mTORC1) and adenosine 5'-monophosphate-activated protein kinase (AMPK) and is instead mediated by protein kinase C. Our findings suggest that folate deprivation-induced premature differentiation of erythroid progenitor cells is a molecular etiology to folate deficiency-induced anemia.
    DOI:  https://doi.org/10.1126/sciadv.adj9479
  2. Nat Cancer. 2024 Jan 29.
    Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.
    Mahnoor Mahmood, Eric Minwei Liu, Amy L Shergold, Elisabetta Tolla, Jacqueline Tait-Mulder, Alejandro Huerta-Uribe, Engy Shokry, Alex L Young, Sergio Lilla, Minsoo Kim, Tricia Park, Sonia Boscenco, Javier L Manchon, Crístina Rodríguez-Antona, Rowan C Walters, Roger J Springett, James N Blaza, Louise Mitchell, Karen Blyth, Sara Zanivan, David Sumpton, Edward W Roberts, Ed Reznik, Payam A Gammage.
      The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.
    DOI:  https://doi.org/10.1038/s43018-023-00721-w
  3. Nat Metab. 2024 Jan 29.
    A RalA between high-fat diet and mitochondrial shape.
    Ludovica Zambello, Luca Scorrano.
      
    DOI:  https://doi.org/10.1038/s42255-023-00969-7
  4. J Biol Chem. 2024 Jan 30. pii: S0021-9258(24)00078-4. [Epub ahead of print] 105702
    The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.
    Aracely Acevedo, Anthony E Jones, Bezawit T Danna, Rory Turner, Katrina P Montales, Cristiane Benincá, Karen Reue, Orian S Shirihai, Linsey Stiles, Martina Wallace, Yibin Wang, Ambre M Bertholet, Ajit S Divakaruni.
      Elevated levels of branched chain amino acids (BCAAs) and branched-chain α-ketoacids (BCKAs) are associated with cardiovascular and metabolic disease, but the molecular mechanisms underlying a putative causal relationship remain unclear. The branched-chain ketoacid dehydrogenase kinase (BCKDK) inhibitor BT2 is often used in preclinical models to increase BCAA oxidation and restore steady-state BCAA and BCKA levels. BT2 administration is protective in various rodent models of heart failure and metabolic disease, but confoundingly, targeted ablation of Bckdk in specific tissues does not reproduce the beneficial effects conferred by pharmacologic inhibition. Here we demonstrate that BT2, a lipophilic weak acid, can act as a mitochondrial uncoupler. Measurements of oxygen consumption, mitochondrial membrane potential, and patch-clamp electrophysiology show BT2 increases proton conductance across the mitochondrial inner membrane independently of its inhibitory effect on BCKDK. BT2 is roughly six-fold less potent than the prototypical uncoupler 2,4-dinitrophenol (DNP), and phenocopies DNP in lowering de novo lipogenesis and mitochondrial superoxide production. The data suggest the therapeutic efficacy of BT2 may be attributable to the well-documented effects of mitochondrial uncoupling in alleviating cardiovascular and metabolic disease.
    Keywords:  BT2; ROS production; branched-chain amino acids; cardiometabolic disease; chemical uncoupling; mitochondria
    DOI:  https://doi.org/10.1016/j.jbc.2024.105702
  5. bioRxiv. 2024 Jan 19. pii: 2024.01.16.575895. [Epub ahead of print]
    Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.
    Megan E Bischoff, Behrouz Shamsaei, Juechen Yang, Dina Secic, Bhargav Vemuri, Julie A Reisz, Angelo D'Alessandro, Caterina Bartolacci, Rafal Adamczak, Lucas Schmidt, Jiang Wang, Amelia Martines, Jacek Biesiada, Katherine E Vest, Pier P Scaglioni, David R Plas, Krushna C Patra, Shuchi Gulati, Julio A Landero Figueroa, Jarek Meller, J Tom Cunningham, Maria F Czyzyk-Krzeska.
      Copper (Cu) is an essential trace element required for mitochondrial respiration. Late-stage clear cell renal cell carcinoma (ccRCC) accumulates Cu and allocates it to mitochondrial cytochrome c oxidase. We show that Cu drives coordinated metabolic remodeling of bioenergy, biosynthesis and redox homeostasis, promoting tumor growth and progression of ccRCC. Specifically, Cu induces TCA cycle-dependent oxidation of glucose and its utilization for glutathione biosynthesis to protect against H 2 O 2 generated during mitochondrial respiration, therefore coordinating bioenergy production with redox protection. scRNA-seq determined that ccRCC progression involves increased expression of subunits of respiratory complexes, genes in glutathione and Cu metabolism, and NRF2 targets, alongside a decrease in HIF activity, a hallmark of ccRCC. Spatial transcriptomics identified that proliferating cancer cells are embedded in clusters of cells with oxidative metabolism supporting effects of metabolic states on ccRCC progression. Our work establishes novel vulnerabilities with potential for therapeutic interventions in ccRCC. Accumulation of copper is associated with progression and relapse of ccRCC and drives tumor growth.Cu accumulation and allocation to cytochrome c oxidase (CuCOX) remodels metabolism coupling energy production and nucleotide biosynthesis with maintenance of redox homeostasis.Cu induces oxidative phosphorylation via alterations in the mitochondrial proteome and lipidome necessary for the formation of the respiratory supercomplexes. Cu stimulates glutathione biosynthesis and glutathione derived specifically from glucose is necessary for survival of Cu Hi cells. Biosynthesis of glucose-derived glutathione requires activity of glutamyl pyruvate transaminase 2, entry of glucose-derived pyruvate to mitochondria via alanine, and the glutamate exporter, SLC25A22. Glutathione derived from glucose maintains redox homeostasis in Cu-treated cells, reducing Cu-H 2 O 2 Fenton-like reaction mediated cell death. Progression of human ccRCC is associated with gene expression signature characterized by induction of ETC/OxPhos/GSH/Cu-related genes and decrease in HIF/glycolytic genes in subpopulations of cancer cells. Enhanced, concordant expression of genes related to ETC/OxPhos, GSH, and Cu characterizes metabolically active subpopulations of ccRCC cells in regions adjacent to proliferative subpopulations of ccRCC cells, implicating oxidative metabolism in supporting tumor growth.
    DOI:  https://doi.org/10.1101/2024.01.16.575895
  6. Cell Rep. 2024 Jan 30. pii: S2211-1247(24)00052-4. [Epub ahead of print]43(2): 113724
    p53 promotes antiviral innate immunity by driving hexosamine metabolism.
    Wenjun Xia, Peng Jiang.
      The tumor suppressor p53 controls cell fate decisions and prevents malignant transformation, but its functions in antiviral immunity remain unclear. Here, we demonstrate that p53 metabolically promotes antiviral innate immune responses to RNA viral infection. p53-deficient macrophages or mice display reduced expression of glutamine fructose-6-phosphate amidotransferase 2 (GFPT2), a key enzyme of the hexosamine biosynthetic pathway (HBP). Through transcriptional upregulation of GFPT2, p53 drives HBP activity and de novo synthesis of UDP-GlcNAc, which in turn leads to the O-GlcNAcylation of mitochondrial antiviral signaling protein (MAVS) and UBX-domain-containing protein 1 (UBXN1) during virus infection. Moreover, O-GlcNAcylation of UBXN1 blocks its interaction with MAVS, thereby further liberating MAVS for tumor necrosis factor receptor-associated factor 3 binding to activate TANK-binding kinase 1-interferon (IFN) regulatory factor 3 signaling cascades and IFN-β production. Genetic or pharmaceutical inhibition of GFPT efficiently reduces MAVS activation and abrogates the antiviral innate immunity promoted by p53 in vitro and in vivo. Our findings reveal that p53 drives HBP activity and O-GlcNAcylation of UBXN1 and MAVS to enhance IFN-β-mediated antiviral innate immunity.
    Keywords:  CP: Cell biology; CP: Immunology; O-GlcNAcylation; UBXN1-MAVS signaling; antiviral innate immunity; hexosamine metabolism; tumor suppressor p53
    DOI:  https://doi.org/10.1016/j.celrep.2024.113724
  7. J Clin Invest. 2024 Jan 30. pii: e173782. [Epub ahead of print]
    mTORC1 controls murine postprandial hepatic glycogen synthesis via Ppp1r3b.
    Kahealani Uehara, Won Dong Lee, Megan Stefkovich, Dipsikha Biswas, Dominic Santoleri, Anna E Garcia Whitlock, William J Quinn Iii, Talia N Coopersmith, Kate Townsend Creasy, Daniel J Rader, Kei Sakamoto, Joshua D Rabinowitz, Paul M Titchenell.
      In response to a meal, insulin drives hepatic glycogen synthesis to help regulate systemic glucose homeostasis. The mechanistic target of rapamycin complex 1 (mTORC1) is a well-established insulin target and contributes to the postprandial control of liver lipid metabolism, autophagy, and protein synthesis. However, its role in hepatic glucose metabolism is less understood. Here, we used metabolomics, isotope tracing, and mouse genetics to define a role for liver mTORC1 signaling in the control of postprandial glycolytic intermediates and glycogen deposition. We show that mTORC1 is required for glycogen synthase activity and glycogenesis. Mechanistically, hepatic mTORC1 activity promotes the feeding-dependent induction of Ppp1r3b, a gene encoding a phosphatase important for glycogen synthase activity whose polymorphisms are linked to human diabetes. Re-expression of Ppp1r3b in livers lacking mTORC1 signaling enhances glycogen synthase activity and restores postprandial glycogen content. mTORC1-dependent transcriptional control of Ppp1r3b is facilitated by FOXO1, a well characterized transcriptional regulator involved in the hepatic response to nutrient intake. Collectively, we identify a role for mTORC1 signaling in the transcriptional regulation of Ppp1r3b and the subsequent induction of postprandial hepatic glycogen synthesis.
    Keywords:  Endocrinology; Glucose metabolism; Insulin signaling; Metabolism
    DOI:  https://doi.org/10.1172/JCI173782
  8. Nature. 2024 Jan 31.
    7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.
    Florencio Porto Freitas, Hamed Alborzinia, Ancély Ferreira Dos Santos, Palina Nepachalovich, Lohans Pedrera, Omkar Zilka, Alex Inague, Corinna Klein, Nesrine Aroua, Kamini Kaushal, Bettina Kast, Svenja M Lorenz, Viktoria Kunz, Helene Nehring, Thamara N Xavier da Silva, Zhiyi Chen, Sena Atici, Sebastian G Doll, Emily L Schaefer, Ifedapo Ekpo, Werner Schmitz, Aline Horling, Peter Imming, Sayuri Miyamoto, Ann M Wehman, Thiago C Genaro-Mattos, Karoly Mirnics, Lokender Kumar, Judith Klein-Seetharaman, Svenja Meierjohann, Isabel Weigand, Matthias Kroiss, Georg W Bornkamm, Fernando Gomes, Luis Eduardo Soares Netto, Manjima B Sathian, David B Konrad, Douglas F Covey, Bernhard Michalke, Kurt Bommert, Ralf C Bargou, Ana Garcia-Saez, Derek A Pratt, Maria Fedorova, Andreas Trumpp, Marcus Conrad, José Pedro Friedmann Angeli.
      Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation that tumours exploit to counteract phospholipid oxidation1,2. Here, we identify proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation3, we now show that 7-DHC accumulation confers a robust prosurvival function in cancer cells. Because of its far superior reactivity towards peroxyl radicals, 7-DHC effectively shields (phospho)lipids from autoxidation and subsequent fragmentation. We provide validation in neuroblastoma and Burkitt's lymphoma xenografts where we demonstrate that the accumulation of 7-DHC is capable of inducing a shift towards a ferroptosis-resistant state in these tumours ultimately resulting in a more aggressive phenotype. Conclusively, our findings provide compelling evidence of a yet-unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.
    DOI:  https://doi.org/10.1038/s41586-023-06878-9
  9. Biochim Biophys Acta Mol Basis Dis. 2024 Jan 26. pii: S0925-4439(24)00018-8. [Epub ahead of print]1870(3): 167033
    The striking differences in the bioenergetics of brain and liver mitochondria are enhanced in mitochondrial disease.
    Valeria Balmaceda, Timea Komlódi, Marten Szibor, Erich Gnaiger, Anthony L Moore, Erika Fernandez-Vizarra, Carlo Viscomi.
      Mitochondrial disorders are hallmarked by the dysfunction of oxidative phosphorylation (OXPHOS) yet are highly heterogeneous at the clinical and genetic levels. Striking tissue-specific pathological manifestations are a poorly understood feature of these conditions, even if the disease-causing genes are ubiquitously expressed. To investigate the functional basis of this phenomenon, we analyzed several OXPHOS-related bioenergetic parameters, including oxygen consumption rates, electron transfer system (ETS)-related coenzyme Q (mtCoQ) redox state and production of reactive oxygen species (ROS) in mouse brain and liver mitochondria fueled by different substrates. In addition, we determined how these functional parameters are affected by ETS impairment in a tissue-specific manner using pathologically relevant mouse models lacking either Ndufs4 or Ttc19, leading to Complex I (CI) or Complex III (CIII) deficiency, respectively. Detailed OXPHOS analysis revealed striking differences between brain and liver mitochondria in the capacity of the different metabolic substrates to fuel the ETS, reduce the ETS-related mtCoQ, and to induce ROS production. In addition, ETS deficiency due to either CI or CIII dysfunction had a much greater impact on the intrinsic bioenergetic parameters of brain compared with liver mitochondria. These findings are discussed in terms of the still rather mysterious tissue-specific manifestations of mitochondrial disease.
    Keywords:  Coenzyme Q redox state; Complex I deficiency; Complex III deficiency; Isolated mitochondria; Oxygen consumption; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167033
  10. J Biol Chem. 2024 Jan 30. pii: S0021-9258(24)00073-5. [Epub ahead of print] 105697
    Decreased pyruvate dehydrogenase activity in Tafazzin-deficient cells is caused by dysregulation of pyruvate dehydrogenase phosphatase 1 (PDP1).
    Zhuqing Liang, Tyler Ralph-Epps, Michael W Schmidtke, Vikalp Kumar, Miriam L Greenberg.
      Cardiolipin (CL), the signature lipid of the mitochondrial inner membrane, is critical for maintaining optimal mitochondrial function and bioenergetics. Disruption of CL metabolism, caused by mutations in the CL remodeling enzyme TAFAZZIN, results in the rare and life-threatening disorder Barth syndrome (BTHS). While the clinical manifestations of BTHS, such as dilated cardiomyopathy and skeletal myopathy, point to defects in mitochondrial bioenergetics, the disorder is also characterized by broad metabolic dysregulation, including abnormal levels of metabolites associated with the tricarboxylic acid (TCA) cycle. In line with this, recent studies have identified inhibition of pyruvate dehydrogenase (PDH), the gatekeeper enzyme for TCA cycle carbon influx, as a key deficiency in various BTHS model systems. However, the molecular mechanisms linking aberrant CL remodeling, particularly the primary, direct consequence of reduced tetralinoleoyl-CL (TLCL) levels, to PDH activity deficiency are not yet understood. This knowledge gap has limited our understanding of lipid-mediated metabolic regulation in BTHS and hindered the development of effective treatment strategies. In the current study, we provide evidence that remodeled TLCL promotes PDH function by directly binding to and enhancing the activity of PDH phosphatase 1 (PDP1). This is supported by our findings that TLCL uniquely activates PDH in a dose-dependent manner, TLCL binds to PDP1 in vitro, TLCL-mediated PDH activation is attenuated in the presence of phosphatase inhibitor, and PDP1 activity is decreased in Tafazzin-knockout (TAZ-KO) C2C12 myoblasts. Additionally, we observed decreased mitochondrial calcium levels in TAZ-KO cells, which may affect the calcium-sensitive activity of PDP1. Treating TAZ-KO cells with calcium lactate (CaLac) increases mitochondrial calcium and restores PDH activity and mitochondrial oxygen consumption rate. Based on our findings, we conclude that reduced mitochondrial calcium levels and decreased binding of PDP1 to TLCL contribute to decreased PDP1 activity in TAZ-KO cells.
    DOI:  https://doi.org/10.1016/j.jbc.2024.105697
  11. bioRxiv. 2024 Jan 20. pii: 2024.01.17.576115. [Epub ahead of print]
    OPA1 protects intervertebral disc and knee joint health in aged mice by maintaining the structure and metabolic functions of mitochondria.
    Vedavathi Madhu, Miriam Hernandaz-Meadows, Ashley Coleman, Kimheak Sao, Kameron Inguito, Owen Haslam, Paige K Boneski, Hiromi Sesaki, John A Collins, Makarand V Risbud.
      Due to their glycolytic nature and limited vascularity, nucleus pulposus (NP) cells of the intervertebral disc and articular chondrocytes were long thought to have minimal reliance on mitochondrial function. Recent studies have challenged this long-held view and highlighted the increasingly important role of mitochondria in the physiology of these tissues. We investigated the role of mitochondrial fusion protein OPA1 in maintaining the spine and knee joint health in aging mice. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate without affecting ATP synthesis. OPA1 governed the morphology of multiple organelles, and its loss resulted in the dysregulation of NP cell autophagy. Metabolic profiling and 13 C-flux analyses revealed TCA cycle anaplerosis and altered metabolism in OPA1-deficient NP cells. Noteworthy, Opa1 AcanCreERT2 mice showed age- dependent disc, and cartilage degeneration and vertebral osteopenia. Our findings suggest that OPA1 regulation of mitochondrial dynamics and multi-organelle interactions is critical in preserving metabolic homeostasis of disc and cartilage.
    Teaser: OPA1 is necessary for the maintenance of intervertebral disc and knee joint health in aging mice.
    DOI:  https://doi.org/10.1101/2024.01.17.576115
  12. Biol Open. 2024 Feb 02. pii: bio.060278. [Epub ahead of print]
    A Drosophila model of mitochondrial disease phenotypic heterogeneity.
    Lucy Granat, Debbra Y Knorr, Daniel C Ranson, Ram Prosad Chakrabarty, Navdeep S Chandel, Joseph M Bateman.
      Mutations in genes that affect mitochondrial function cause primary mitochondrial diseases. Mitochondrial diseases are highly heterogeneous and even patients with the same mitochondrial disease can exhibit broad phenotypic heterogeneity, which is poorly understood. Mutations in subunits of mitochondrial respiratory complex I cause complex I deficiency, which can result in severe neurological symptoms and death in infancy. However, some complex I deficiency patients present with much milder symptoms. The most common nuclear gene mutated in complex I deficiency is the highly conserved core subunit NDUFS1. To model the phenotypic heterogeneity in complex I deficiency we used RNAi lines targeting the Drosophila NDUFS1 homolog ND-75 with different efficiencies. Strong knockdown of ND-75 in Drosophila neurons resulted in severe behavioural phenotypes, reduced lifespan, altered mitochondrial morphology, reduced endoplasmic reticulum (ER)-mitochondria contacts and activation of the unfolded protein response (UPR). By contrast, weak ND-75 knockdown caused much milder behavioural phenotypes and changes in mitochondrial morphology. Moreover, weak ND-75 did not alter ER-mitochondria contacts or activate the UPR. Weak and strong ND-75 knockdown resulted in overlapping but distinct transcriptional responses in the brain, with weak knockdown specifically affecting proteosome activity and immune response genes. Metabolism was also differentially affected by weak and strong ND-75 knockdown including gamma-aminobutyric acid (GABA) levels, which may contribute to neuronal dysfunction in ND-75 knockdown flies. Several metabolic processes were only affected by strong ND-75 knockdown including the pentose phosphate pathway and the metabolite 2-hydroxyglutarate (2-HG), suggesting 2-HG as a candidate biomarker of severe neurological mitochondrial disease. Thus, our Drosophila model provides the means to dissect the mechanisms underlying phenotypic heterogeneity in mitochondrial disease.
    Keywords:  Complex I deficiency; Metabolism; Mitochondria; Phenotypic heterogeneity; Signalling
    DOI:  https://doi.org/10.1242/bio.060278
  13. J Biol Chem. 2024 Jan 25. pii: S0021-9258(24)00066-8. [Epub ahead of print] 105690
    The inhibitor protein IF1 from mammalian mitochondria inhibits ATP hydrolysis but not ATP synthesis by the ATP synthase complex.
    Joe Carroll, Ian N Watt, Charlotte J Wright, Shujing Ding, Ian M Fearnley, John E Walker.
      The hydrolytic activity of the ATP synthase in bovine mitochondria is inhibited by a protein called IF1, but bovine IF1 has no effect on the synthetic activity of the bovine enzyme in mitochondrial vesicles in the presence of a proton motive force. In contrast, it has been suggested based on indirect observations that human IFI inhibits both the hydrolytic and synthetic activities of the human ATP synthase, and that the activity of human IF1 is regulated by the phosphorylation of serine-14 of mature IF1. Here, we have made both human and bovine IF1 which are 81 and 84 amino acids long, respectively, and identical in 71.4% of their amino acids, and have investigated their inhibitory effects on the hydrolytic and synthetic activities of ATP synthase in bovine sub-mitochondrial particles. Over a wide range of conditions, including physiological conditions, both human and bovine IF1 are potent inhibitors of ATP hydrolysis, with no effect on ATP synthesis. Also, substitution of serine-14 with phosphomimetic aspartic and glutamic acids had no effect on inhibitory properties, and serine-14 is not conserved throughout mammals. Therefore, it is unlikely that the inhibitory activity of mammalian IF1 is regulated by phosphorylation of this residue.
    Keywords:  ATP synthase; inhibitor protein IF(1); mitochondria; regulation; unidirectional inhibition
    DOI:  https://doi.org/10.1016/j.jbc.2024.105690
  14. Nat Cancer. 2024 Jan 29.
    Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation.
    Meri Rogava, Tyler J Aprati, Wei-Yu Chi, Johannes C Melms, Clemens Hug, Stephanie H Davis, Ethan M Earlie, Charlie Chung, Sachin K Deshmukh, Sharon Wu, George Sledge, Stephen Tang, Patricia Ho, Amit Dipak Amin, Lindsay Caprio, Carino Gurjao, Somnath Tagore, Bryan Ngo, Michael J Lee, Giorgia Zanetti, Yiping Wang, Sean Chen, William Ge, Luiza Martins Nascentes Melo, Gabriele Allies, Jonas Rösler, Goeffrey T Gibney, Oliver J Schmitz, Megan Sykes, Rémi J Creusot, Thomas Tüting, Dirk Schadendorf, Martin Röcken, Thomas K Eigentler, Andrei Molotkov, Akiva Mintz, Samuel F Bakhoum, Semir Beyaz, Lewis C Cantley, Peter K Sorger, Sven W Meckelmann, Alpaslan Tasdogan, David Liu, Ashley M Laughney, Benjamin Izar.
      Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR-Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms.
    DOI:  https://doi.org/10.1038/s43018-023-00704-x
  15. Free Radic Biol Med. 2024 Jan 31. pii: S0891-5849(24)00051-0. [Epub ahead of print]
    The opposite role of lactate dehydrogenase a (LDHA) in cervical cancer under energy stress conditions.
    Chaoran Jia, Yulun Wu, Feng Gao, Wei Liu, Na Li, Yao Chen, Luguo Sun, Shuyue Wang, Chunlei Yu, Yongli Bao, Zhenbo Song.
      Due to insufficient and defective vascularization, the tumor microenvironment is often nutrient-depleted. LDHA has been demonstrated to play a tumor-promoting role by facilitating the glycolytic process. However, whether and how LDHA regulates cell survival in the nutrient-deficient tumor microenvironment are still unclear. Here, we sought to investigate the role and mechanism of LDHA in regulating cell survival and proliferation under energy stress conditions. Our results showed that the aerobic glycolysis levels, cell survival and proliferation of cervical cancer cells decreased significantly after inhibition of LDHA under normal culture condition while LDHA deficiency greatly inhibited glucose starvation-induced ferroptosis and promoted cell proliferation and tumor formation under energy stress conditions. Mechanistic studies suggested that glucose metabolism shifted from aerobic glycolysis to mitochondrial OXPHOS under energy stress conditions and LDHA knockdown increased accumulation of pyruvate in the cytosol, which entered the mitochondria and upregulated the level of oxaloacetate by phosphoenolpyruvate carboxylase (PC). Importantly, the increase in oxaloacetate production after absence of LDHA remarkably activated AMP-activated protein kinase (AMPK), which increased mitochondrial biogenesis and mitophagy, promoted mitochondrial homeostasis, thereby decreasing ROS level. Moreover, repression of lipogenesis by activation of AMPK led to elevated levels of reduced nicotinamide adenine dinucleotide phosphate (NADPH), which effectively resisted ROS-induced cell ferroptosis and enhanced cell survival under energy stress conditions. These results suggested that LDHA played an opposing role in survival and proliferation of cervical cancer cells under energy stress conditions, and inhibition of LDHA may not be a suitable treatment strategy for cervical cancer.
    Keywords:  AMPK; Cervical cancer; Energy stress; Ferroptosis; LDHA
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.043
  16. Hum Mol Genet. 2024 Jan 27. pii: ddae012. [Epub ahead of print]
    Mitochondrial protein synthesis quality control.
    Lidiia Koludarova, Brendan J Battersby.
      Human mitochondrial DNA is one of the most simplified cellular genomes and facilitates compartmentalized gene expression. Within the organelle, there is no physical barrier to separate transcription and translation, nor is there evidence that quality control surveillance pathways are active to prevent translation on faulty mRNA transcripts. Mitochondrial ribosomes synthesize 13 hydrophobic proteins that require co-translational insertion into the inner membrane of the organelle. To maintain the integrity of the inner membrane, which is essential for organelle function, requires responsive quality control mechanisms to recognize aberrations in protein synthesis. In this review, we explore how defects in mitochondrial protein synthesis can arise due to the culmination of inherent mistakes that occur throughout the steps of gene expression. In turn, we examine the stepwise series of quality control processes that are needed to eliminate any mistakes that would perturb organelle homeostasis. We aim to provide an integrated view on the quality control mechanisms of mitochondrial protein synthesis and to identify promising avenues for future research.
    Keywords:  AFG3L2; MTRFR; OMA1; OPA1; OXA1L; RNA processing; cell stress; co-translational quality control; fusion open reading frames; membrane morphology; mitochondria; non-stop mRNA; post-transcriptional; protein synthesis; proteostasis; ribosome quality control; ribosomes
    DOI:  https://doi.org/10.1093/hmg/ddae012
  17. Nat Protoc. 2024 Feb 02.
    Comprehensive multiscale analysis of lactate metabolic dynamics in vitro and in vivo using highly responsive biosensors.
    Aoxue Wang, Yejun Zou, Shuning Liu, Xiuze Zhang, Ting Li, Lijuan Zhang, Ruwen Wang, Yale Xia, Xie Li, Zhuo Zhang, Tiemin Liu, Zhenyu Ju, Ru Wang, Joseph Loscalzo, Yi Yang, Yuzheng Zhao.
      As a key glycolytic metabolite, lactate has a central role in diverse physiological and pathological processes. However, comprehensive multiscale analysis of lactate metabolic dynamics in vitro and in vivo has remained an unsolved problem until now owing to the lack of a high-performance tool. We recently developed a series of genetically encoded fluorescent sensors for lactate, named FiLa, which illuminate lactate metabolism in cells, subcellular organelles, animals, and human serum and urine. In this protocol, we first describe the FiLa sensor-based strategies for real-time subcellular bioenergetic flux analysis by profiling the lactate metabolic response to different nutritional and pharmacological conditions, which provides a systematic-level view of cellular metabolic function at the subcellular scale for the first time. We also report detailed procedures for imaging lactate dynamics in live mice through a cell microcapsule system or recombinant adeno-associated virus and for the rapid and simple assay of lactate in human body fluids. This comprehensive multiscale metabolic analysis strategy may also be applied to other metabolite biosensors using various analytic platforms, further expanding its usability. The protocol is suited for users with expertise in biochemistry, molecular biology and cell biology. Typically, the preparation of FiLa-expressing cells or mice takes 2 days to 4 weeks, and live-cell and in vivo imaging can be performed within 1-2 hours. For the FiLa-based assay of body fluids, the whole measuring procedure generally takes ~1 min for one sample in a manual assay or ~3 min for 96 samples in an automatic microplate assay.
    DOI:  https://doi.org/10.1038/s41596-023-00948-y
  18. Trends Endocrinol Metab. 2024 Feb 01. pii: S1043-2760(24)00002-X. [Epub ahead of print]
    Pathophysiology of human mitochondrial tRNA metabolism.
    Jian-Hui Zhang, Gilbert Eriani, Xiao-Long Zhou.
      Mitochondria play multiple critical roles in cellular activity. In particular, mitochondrial translation is pivotal in the regulation of mitochondrial and cellular homeostasis. In this forum article, we discuss human mitochondrial tRNA metabolism and highlight its tight connection with various mitochondrial diseases caused by mutations in aminoacyl-tRNA synthetases, tRNAs, and tRNA-modifying enzymes.
    DOI:  https://doi.org/10.1016/j.tem.2024.01.002
  19. Nat Commun. 2024 Feb 01. 15(1): 963
    Nuclear to cytoplasmic transport is a druggable dependency in MYC-driven hepatocellular carcinoma.
    Anja Deutzmann, Delaney K Sullivan, Renumathy Dhanasekaran, Wei Li, Xinyu Chen, Ling Tong, Wadie D Mahauad-Fernandez, John Bell, Adriane Mosley, Angela N Koehler, Yulin Li, Dean W Felsher.
      The MYC oncogene is often dysregulated in human cancer, including hepatocellular carcinoma (HCC). MYC is considered undruggable to date. Here, we comprehensively identify genes essential for survival of MYChigh but not MYClow cells by a CRISPR/Cas9 genome-wide screen in a MYC-conditional HCC model. Our screen uncovers novel MYC synthetic lethal (MYC-SL) interactions and identifies most MYC-SL genes described previously. In particular, the screen reveals nucleocytoplasmic transport to be a MYC-SL interaction. We show that the majority of MYC-SL nucleocytoplasmic transport genes are upregulated in MYChigh murine HCC and are associated with poor survival in HCC patients. Inhibiting Exportin-1 (XPO1) in vivo induces marked tumor regression in an autochthonous MYC-transgenic HCC model and inhibits tumor growth in HCC patient-derived xenografts. XPO1 expression is associated with poor prognosis only in HCC patients with high MYC activity. We infer that MYC may generally regulate and require altered expression of nucleocytoplasmic transport genes for tumorigenesis.
    DOI:  https://doi.org/10.1038/s41467-024-45128-y
  20. J Chromatogr A. 2024 Jan 28. pii: S0021-9673(24)00064-5. [Epub ahead of print]1717 464691
    In-vivo tracking of deuterium metabolism in mouse organs using LC-MS/MS.
    Siva Swapna Kasarla, Vera Flocke, Nay Min Thaw Saw, Antonia Fecke, Albert Sickmann, Matthias Gunzer, Ulrich Flögel, Prasad Phapale.
      Mass spectrometry-based metabolomics with stable isotope labeling (SIL) is an established tool for sensitive and precise analyses of tissue metabolism, its flux, and pathway activities in diverse models of physiology and disease. Despite the simplicity and broad applicability of deuterium (2H)-labeled precursors for tracing metabolic pathways with minimal biological perturbations, they are rarely employed in LC-MS/MS-guided metabolomics. In this study, we have developed a LC-MS/MS-guided workflow to trace deuterium metabolism in mouse organs following 2H7 -glucose infusion. The workflow includes isotopically labeled glucose infusion, mouse organ isolation and metabolite extraction, zwitterion-based hydrophilic interaction liquid chromatography (HILIC) coupled to high-resolution tandem mass spectrometry, targeted data acquisition for sensitive detection of deuterated metabolites, a spectral library of over 400 metabolite standards, and multivariate data analysis with pathway mapping. The optimized method was validated for matrix effects, normalization, and quantification to provide both tissue metabolomics and tracking the in-vivo metabolic fate of deuterated glucose through key metabolic pathways. We quantified more than 100 metabolites in five major mouse organ tissues (liver, kidney, brain, brown adipose tissue, and heart). Furthermore, we mapped isotopologues of deuterated metabolites from glycolysis, tricarboxylic acid (TCA) cycle, and amino acid pathways, which are significant for studying both health and various diseases. This study will open new avenues in LC-MS based analysis of 2H-labeled tissue metabolism research in animal models and clinical settings.
    Keywords:  Deuterium tracing; LC-MS; Metabolic flux; Metabolomics; Tissue metabolism
    DOI:  https://doi.org/10.1016/j.chroma.2024.464691
  21. Nat Commun. 2024 Jan 27. 15(1): 830
    Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.
    Juan Ignacio Jiménez-Loygorri, Beatriz Villarejo-Zori, Álvaro Viedma-Poyatos, Juan Zapata-Muñoz, Rocío Benítez-Fernández, María Dolores Frutos-Lisón, Francisco A Tomás-Barberán, Juan Carlos Espín, Estela Area-Gómez, Aurora Gomez-Duran, Patricia Boya.
      Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy is either increased or unchanged in old versus young mice. Transcriptomic analysis shows marked upregulation of the type I interferon response in the retina of old mice, which correlates with increased levels of cytosolic mtDNA and activation of the cGAS/STING pathway. Crucially, these same alterations are replicated in primary human fibroblasts from elderly donors. In old mice, pharmacological induction of mitophagy with urolithin A attenuates cGAS/STING activation and ameliorates deterioration of neurological function. These findings point to mitophagy induction as a strategy to decrease age-associated inflammation and increase healthspan.
    DOI:  https://doi.org/10.1038/s41467-024-45044-1
  22. Physiol Rev. 2024 Feb 01.
    Ceramides are Fuel Gauges on the Drive to Cardiometabolic Disease.
    Joseph L Wilkerson, Sean M Tatum, William L Holland, Scott A Summers.
      Ceramides are signals of fatty acid excess that accumulate when a cell's energetic needs have been met and its nutrient storage has reached capacity. As these sphingolipids accrue, they alter the metabolism and survival of cells throughout the body including in the heart, liver, blood vessels, skeletal muscle, brain, and kidney. These ceramide actions elicit the tissue dysfunction that underlies cardiometabolic diseases such as diabetes, coronary artery disease, metabolic-associated steatohepatitis, and heart failure. Here, we review the biosynthesis and degradation pathways which maintain ceramide levels in normal physiology and discuss how the loss of ceramide homeostasis drives cardiometabolic pathologies. We highlight signaling nodes that sense small changes in ceramides, and in turn reprogram cellular metabolism and stimulate apoptosis. Lastly, we evaluate the emerging therapeutic utility of these unique lipids as biomarkers that forecast disease risk and as targets of ceramide-lowering interventions that ameliorate disease.
    Keywords:  Ceramides; Diabetes; Lipotoxicity; Metabolic Disease; Sphingolipids
    DOI:  https://doi.org/10.1152/physrev.00008.2023
  23. Nature. 2024 Jan 31.
    7-Dehydrocholesterol dictates ferroptosis sensitivity.
    Yaxu Li, Qiao Ran, Qiuhui Duan, Jiali Jin, Yanjin Wang, Lei Yu, Chaojie Wang, Zhenyun Zhu, Xin Chen, Linjun Weng, Zan Li, Jia Wang, Qi Wu, Hui Wang, Hongling Tian, Sihui Song, Zezhi Shan, Qiwei Zhai, Huanlong Qin, Shili Chen, Lan Fang, Huiyong Yin, Hu Zhou, Xuejun Jiang, Ping Wang.
      Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer1-3, degenerative disorders4 and organ ischaemia-reperfusion injury (IRI)5,6. Here, using genome-wide CRISPR-Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)-an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1, CYP51A1, EBP and SC5D, function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI.
    DOI:  https://doi.org/10.1038/s41586-023-06983-9
  24. Nat Commun. 2024 Feb 01. 15(1): 955
    Tissue-specific profiling of age-dependent miRNAomic changes in Caenorhabditis elegans.
    Xueqing Wang, Quanlong Jiang, Hongdao Zhang, Zhidong He, Yuanyuan Song, Yifan Chen, Na Tang, Yifei Zhou, Yiping Li, Adam Antebi, Ligang Wu, Jing-Dong J Han, Yidong Shen.
      Ageing exhibits common and distinct features in various tissues, making it critical to decipher the tissue-specific ageing mechanisms. MiRNAs are essential regulators in ageing and are recently highlighted as a class of intercellular messengers. However, little is known about the tissue-specific transcriptomic changes of miRNAs during ageing. C. elegans is a well-established model organism in ageing research. Here, we profile the age-dependent miRNAomic changes in five isolated worm tissues. Besides the diverse ageing-regulated miRNA expression across tissues, we discover numerous miRNAs in the tissues without their transcription. We further profile miRNAs in the extracellular vesicles and find that worm miRNAs undergo inter-tissue trafficking via these vesicles in an age-dependent manner. Using these datasets, we uncover the interaction between body wall muscle-derived mir-1 and DAF-16/FOXO in the intestine, suggesting mir-1 as a messenger in inter-tissue signalling. Taken together, we systematically investigate worm miRNAs in the somatic tissues and extracellular vesicles during ageing, providing a valuable resource to study tissue-autonomous and nonautonomous functions of miRNAs in ageing.
    DOI:  https://doi.org/10.1038/s41467-024-45249-4
  25. Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Jan 31. pii: S1388-1981(24)00012-X. [Epub ahead of print] 159462
    The Sphinx and the egg: Evolutionary enigmas of the (glyco)sphingolipid biosynthetic pathway.
    Assaf Biran, Tania C B Santos, Tamir Dingjan, Anthony H Futerman.
      In eukaryotes, the de novo synthesis of sphingolipids (SLs) consists of multiple sequential steps which are compartmentalized between the endoplasmic reticulum and the Golgi apparatus. Studies over many decades have identified the enzymes in the pathway, their localization, topology and an array of regulatory mechanisms. However, little is known about the evolutionary forces that underly the generation of this complex pathway or of its anteome, i.e., the metabolic pathways that converge on the SL biosynthetic pathway and are essential for its activity. After briefly describing the pathway, we discuss the mechanisms by which the enzymes of the SL biosynthetic pathway are targeted to their different subcellular locations, how the pathway per se may have evolved, including its compartmentalization, and the relationship of the pathway to eukaryogenesis. We discuss the circular interdependence of the evolution of the SL pathway, and comment on whether current Darwinian evolutionary models are able to provide genuine mechanistic insight into how the pathway came into being.
    Keywords:  Darwinian evolution; Eukaryogenesis; Glycosphingolipids; Golgi apparatus; Membrane trafficking; Metabolic evolution; Sphingolipids; Transmembrane protein
    DOI:  https://doi.org/10.1016/j.bbalip.2024.159462
  26. Nature. 2024 Jan 31.
    Stress response silencing by an E3 ligase mutated in neurodegeneration.
    Diane L Haakonsen, Michael Heider, Andrew J Ingersoll, Kayla Vodehnal, Samuel R Witus, Takeshi Uenaka, Marius Wernig, Michael Rapé.
      Stress response pathways detect and alleviate adverse conditions to safeguard cell and tissue homeostasis, yet their prolonged activation induces apoptosis and disrupts organismal health1-3. How stress responses are turned off at the right time and place remains poorly understood. Here we report a ubiquitin-dependent mechanism that silences the cellular response to mitochondrial protein import stress. Crucial to this process is the silencing factor of the integrated stress response (SIFI), a large E3 ligase complex mutated in ataxia and in early-onset dementia that degrades both unimported mitochondrial precursors and stress response components. By recognizing bifunctional substrate motifs that equally encode protein localization and stability, the SIFI complex turns off a general stress response after a specific stress event has been resolved. Pharmacological stress response silencing sustains cell survival even if stress resolution failed, which underscores the importance of signal termination and provides a roadmap for treating neurodegenerative diseases caused by mitochondrial import defects.
    DOI:  https://doi.org/10.1038/s41586-023-06985-7
  27. Cell Regen. 2024 Jan 31. 13(1): 2
    Mitochondrial-to-nuclear communications through multiple routes regulate cardiomyocyte proliferation.
    Xinhang Li, Yalin Zhu, Pilar Ruiz-Lozano, Ke Wei.
      The regenerative capacity of the adult mammalian heart remains a formidable challenge in biological research. Despite extensive investigations into the loss of regenerative potential during evolution and development, unlocking the mechanisms governing cardiomyocyte proliferation remains elusive. Two recent groundbreaking studies have provided fresh perspectives on mitochondrial-to-nuclear communication, shedding light on novel factors that regulate cardiomyocyte proliferation. The studies identified two mitochondrial processes, fatty acid oxidation and protein translation, as key players in restricting cardiomyocyte proliferation. Inhibition of these processes led to increased cell cycle activity in cardiomyocytes, mediated by reduction in H3k4me3 levels through accumulated α-ketoglutarate (αKG), and activation of the mitochondrial unfolded protein response (UPRmt), respectively. In this research highlight, we discuss the novel insights into mitochondrial-to-nuclear communication presented in these studies, the broad implications in cardiomyocyte biology and cardiovascular diseases, as well as the intriguing scientific questions inspired by the studies that may facilitate future investigations into the detailed molecular mechanisms of cardiomyocyte metabolism, proliferation, and mitochondrial-to-nuclear communications.
    Keywords:  ATF4; Cardiomyocyte; Cpt1b; FAO; H3k4me3; Mitochondria; Mrps5; Proliferation; UPRmt; αKG
    DOI:  https://doi.org/10.1186/s13619-024-00186-x
  28. Elife. 2024 Feb 02. pii: RP92420. [Epub ahead of print]12
    Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation.
    Rabina Mainali, Nancy Buechler, Cristian Otero, Laken Edwards, Chia-Chi Key, Cristina Furdui, Matthew A Quinn.
      One primary metabolic manifestation of inflammation is the diversion of cis-aconitate within the tricarboxylic acid (TCA) cycle to synthesize the immunometabolite itaconate. Itaconate is well established to possess immunomodulatory and metabolic effects within myeloid cells and lymphocytes, however, its effects in other organ systems during sepsis remain less clear. Utilizing Acod1 knockout mice that are deficient in synthesizing itaconate, we aimed to understand the metabolic role of itaconate in the liver and systemically during sepsis. We find itaconate aids in lipid metabolism during sepsis. Specifically, Acod1 KO mice develop a heightened level of hepatic steatosis when induced with polymicrobial sepsis. Proteomics analysis reveals enhanced expression of enzymes involved in fatty acid oxidation in following 4-octyl itaconate (4-OI) treatment in vitro. Downstream analysis reveals itaconate stabilizes the expression of the mitochondrial fatty acid uptake enzyme CPT1a, mediated by its hypoubiquitination. Chemoproteomic analysis revealed itaconate interacts with proteins involved in protein ubiquitination as a potential mechanism underlying its stabilizing effect on CPT1a. From a systemic perspective, we find itaconate deficiency triggers a hypothermic response following endotoxin stimulation, potentially mediated by brown adipose tissue (BAT) dysfunction. Finally, by use of metabolic cage studies, we demonstrate Acod1 KO mice rely more heavily on carbohydrates versus fatty acid sources for systemic fuel utilization in response to endotoxin treatment. Our data reveal a novel metabolic role of itaconate in modulating fatty acid oxidation during polymicrobial sepsis.
    Keywords:  fatty acid oxidation; immunology; inflammation; itaconate; mouse
    DOI:  https://doi.org/10.7554/eLife.92420
  29. Nat Metab. 2024 Jan;6(1): 1
    Five years on.
      
    DOI:  https://doi.org/10.1038/s42255-024-00982-4
  30. Nat Metab. 2024 Jan 29.
    Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation.
    Wenmin Xia, Preethi Veeragandham, Yu Cao, Yayun Xu, Torrey E Rhyne, Jiaxin Qian, Chao-Wei Hung, Peng Zhao, Ying Jones, Hui Gao, Christopher Liddle, Ruth T Yu, Michael Downes, Ronald M Evans, Mikael Rydén, Martin Wabitsch, Zichen Wang, Hiroyuki Hakozaki, Johannes Schöneberg, Shannon M Reilly, Jianfeng Huang, Alan R Saltiel.
      Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction.
    DOI:  https://doi.org/10.1038/s42255-024-00978-0
  31. Biochem Soc Trans. 2024 Jan 30. pii: BST20230220. [Epub ahead of print]
    Recent insights into the control of mitochondrial fission.
    Jiajia He, Ke Liu, Chuanhai Fu.
      Mitochondria are the powerhouse of the cell. They undergo fission and fusion to maintain cellular homeostasis. In this review, we explore the intricate regulation of mitochondrial fission at various levels, including the protein level, the post-translational modification level, and the organelle level. Malfunctions in mitochondrial fission can have detrimental effects on cells. Therefore, we also examine the association between mitochondrial fission with diseases such as breast cancer and cardiovascular disorders. We anticipate that a comprehensive investigation into the control of mitochondrial fission will pave the way for the development of innovative therapeutic strategies.
    Keywords:  mitochondria; organelles; phosphorylation/dephosphorylation; transmembrane proteins
    DOI:  https://doi.org/10.1042/BST20230220
  32. J Clin Invest. 2024 Feb 01. pii: e175706. [Epub ahead of print]134(3):
    Circadian immunity from bench to bedside: a practical guide.
    Huram Mok, Elaine Ostendorf, Alex Ganninger, Avi J Adler, Guy Hazan, Jeffrey A Haspel.
      The immune system is built to counteract unpredictable threats, yet it relies on predictable cycles of activity to function properly. Daily rhythms in immune function are an expanding area of study, and many originate from a genetically based timekeeping mechanism known as the circadian clock. The challenge is how to harness these biological rhythms to improve medical interventions. Here, we review recent literature documenting how circadian clocks organize fundamental innate and adaptive immune activities, the immunologic consequences of circadian rhythm and sleep disruption, and persisting knowledge gaps in the field. We then consider the evidence linking circadian rhythms to vaccination, an important clinical realization of immune function. Finally, we discuss practical steps to translate circadian immunity to the patient's bedside.
    DOI:  https://doi.org/10.1172/JCI175706
  33. Proc Natl Acad Sci U S A. 2024 Feb 06. 121(6): e2317141121
    Malignant tumor cells engender second membrane-lined organelles for self-protection and tumor progression.
    Tingfang Yi, Gerhard Wagner.
      Cancer is a leading cause of mortality in humans, but the efficacy of current treatments for many cancers is limited, as they lack unique mechanistically defined targets. Here, we show that, upon malignant transformation, aggressive oncocells generate a second membrane exterior to their plasma membrane to form cytocapsulas (CCs) and cytocapsular tubes (CCTs), which all together constitute cytocapsular oncocells with pleotropic biological functions in cancer patient tissues in vivo. Proteomic and biochemical analyses revealed that the PMCA2 calcium pump is highly up-regulated in CCs and CCTs in malignant tumors but not in normal tissues, thus identifying a unique cancer biomarker and target for cancer therapy. Cytocapsular oncocells are universally present in solid cancers and appear in hematologic cancers in immune organs. Multi-cell malignant tumors are also enveloped by protective CC membranes. These cytocapsular tumors (CTs) generate numerous CCTs that form freeways for cancer cell metastasis to both neighboring and distant destinations. Entire cytocapsular tumor networks (CTNs) dominate physical cancer metastasis pathways in cancer patients in vivo. Later, CCTs invade micro blood vessels and release cytocapsular oncocells into the blood, providing a source of circulating tumor cells. CTNs interconnect cytocapsular tumors in primary and secondary cancer niches, creating larger cytocapsular tumor network systems (CTNSs). Primary and secondary CTNSs are in turn interconnected, forming dynamic and integrated CTNSs. Thus, interconnected cytocapsular oncocells, CTNs, and CTNSs coordinate cancer progression via the integrated cytocapsular membrane systems.
    Keywords:  PMCA2; cancer; cytocapsular oncocell; cytocapsular tube; cytocapsular tumor
    DOI:  https://doi.org/10.1073/pnas.2317141121
  34. Nat Cancer. 2024 Jan 29.
    Aneuploidy and complex genomic rearrangements in cancer evolution.
    Toby M Baker, Sara Waise, Maxime Tarabichi, Peter Van Loo.
      Mutational processes that alter large genomic regions occur frequently in developing tumors. They range from simple copy number gains and losses to the shattering and reassembly of entire chromosomes. These catastrophic events, such as chromothripsis, chromoplexy and the formation of extrachromosomal DNA, affect the expression of many genes and therefore have a substantial effect on the fitness of the cells in which they arise. In this review, we cover large genomic alterations, the mechanisms that cause them and their effect on tumor development and evolution.
    DOI:  https://doi.org/10.1038/s43018-023-00711-y
  35. Eur J Clin Invest. 2024 Jan 30. e14174
    Mitochondrial HER2 stimulates respiration and promotes tumorigenicity.
    Eliska Novotna, Mirko Milosevic, Dana Prukova, Silvia Magalhaes-Novais, Sarka Dvorakova, Kristina Dmytruk, Jakub Gemperle, Dagmar Zudova, Tereza Nickl, Marek Vrbacky, Daniel Rosel, Vlada Filimonenko, Jan Prochazka, Jan Brabek, Jiri Neuzil, Katerina Rohlenova, Jakub Rohlena.
       BACKGROUND: Amplification of HER2, a receptor tyrosine kinase and a breast cancer-linked oncogene, is associated with aggressive disease. HER2 protein is localised mostly at the cell membrane, but a fraction translocates to mitochondria. Whether and how mitochondrial HER2 contributes to tumorigenicity is currently unknown.
    METHODS: We enriched the mitochondrial (mt-)HER2 fraction in breast cancer cells using an N-terminal mitochondrial targeting sequence and analysed how this manipulation impacts bioenergetics and tumorigenic properties. The role of the tyrosine kinase activity of mt-HER2 was assessed in wild type, kinase-dead (K753M) and kinase-enhanced (V659E) mtHER2 constructs.
    RESULTS: We document that mt-HER2 associates with the oxidative phosphorylation system, stimulates bioenergetics and promotes larger respiratory supercomplexes. mt-HER2 enhances proliferation and invasiveness in vitro and tumour growth and metastatic potential in vivo, in a kinase activity-dependent manner. On the other hand, constitutively active mt-HER2 provokes excessive mitochondria ROS generation, sensitises to cell death, and restricts growth of primary tumours, suggesting that regulation of HER2 activity in mitochondria is required for the maximal pro-tumorigenic effect.
    CONCLUSIONS: mt-HER2 promotes tumorigenicity by supporting bioenergetics and optimal redox balance.
    Keywords:  HER2; cancer; electron transport chain; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1111/eci.14174
  36. Aging Cell. 2024 Jan 29. e14090
    Implications of metabolism on multi-systems healthy aging across the lifespan.
    Shanshan Yao, Laura A Colangelo, Andrew S Perry, Megan M Marron, Kristine Yaffe, Sanaz Sedaghat, Joao A C Lima, Qu Tian, Clary B Clish, Anne B Newman, Ravi V Shah, Venkatesh L Murthy.
      Aging is increasingly thought to involve dysregulation of metabolism in multiple organ systems that culminate in decreased functional capacity and morbidity. Here, we seek to understand complex interactions among metabolism, aging, and systems-wide phenotypes across the lifespan. Among 2469 adults (mean age 74.7 years; 38% Black) in the Health, Aging and Body Composition study we identified metabolic cross-sectionally correlates across 20 multi-dimensional aging-related phenotypes spanning seven domains. We used LASSO-PCA and bioinformatic techniques to summarize metabolome-phenome relationships and derive metabolic scores, which were subsequently linked to healthy aging, mortality, and incident outcomes (cardiovascular disease, disability, dementia, and cancer) over 9 years. To clarify the relationship of metabolism in early adulthood to aging, we tested association of these metabolic scores with aging phenotypes/outcomes in 2320 participants (mean age 32.1, 44% Black) of the Coronary Artery Risk Development in Young Adults (CARDIA) study. We observed significant overlap in metabolic correlates across the seven aging domains, specifying pathways of mitochondrial/cellular energetics, host-commensal metabolism, inflammation, and oxidative stress. Across four metabolic scores (body composition, mental-physical performance, muscle strength, and physical activity), we found strong associations with healthy aging and incident outcomes, robust to adjustment for risk factors. Metabolic scores for participants four decades younger in CARDIA were related to incident cardiovascular, metabolic, and neurocognitive performance, as well as long-term cardiovascular disease and mortality over three decades. Conserved metabolic states are strongly related to domain-specific aging and outcomes over the life-course relevant to energetics, host-commensal interactions, and mechanisms of innate immunity.
    Keywords:  aging; mechanisms; metabolomics
    DOI:  https://doi.org/10.1111/acel.14090
  37. Nature. 2024 Jan 31.
    Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver.
    Weiguo Fan, Kolade Adebowale, Lóránd Váncza, Yuan Li, Md Foysal Rabbi, Koshi Kunimoto, Dongning Chen, Gergely Mozes, David Kung-Chun Chiu, Yisi Li, Junyan Tao, Yi Wei, Nia Adeniji, Ryan L Brunsing, Renumathy Dhanasekaran, Aatur Singhi, David Geller, Su Hao Lo, Louis Hodgson, Edgar G Engleman, Gregory W Charville, Vivek Charu, Satdarshan P Monga, Taeyoon Kim, Rebecca G Wells, Ovijit Chaudhuri, Natalie J Török.
      Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development1,2, and increased stiffness is known to promote HCC progression in cirrhotic conditions3,4. Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic β-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-β1-tensin-1-YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.
    DOI:  https://doi.org/10.1038/s41586-023-06991-9
  38. Cell Stem Cell. 2024 Feb 01. pii: S1934-5909(24)00003-1. [Epub ahead of print]31(2): 161-180
    Metabolic regulation of the hallmarks of stem cell biology.
    Benjamin T Jackson, Lydia W S Finley.
      Stem cells perform many different functions, each of which requires specific metabolic adaptations. Over the past decades, studies of pluripotent and tissue stem cells have uncovered a range of metabolic preferences and strategies that correlate with or exert control over specific cell states. This review aims to describe the common themes that emerge from the study of stem cell metabolism: (1) metabolic pathways supporting stem cell proliferation, (2) metabolic pathways maintaining stem cell quiescence, (3) metabolic control of cellular stress responses and cell death, (4) metabolic regulation of stem cell identity, and (5) metabolic requirements of the stem cell niche.
    DOI:  https://doi.org/10.1016/j.stem.2024.01.003
  39. Nat Cell Biol. 2024 Feb 02.
    Finding the point of no return for cellular senescence.
    Eiji Hara.
      
    DOI:  https://doi.org/10.1038/s41556-023-01306-6
  40. Cell. 2024 Jan 25. pii: S0092-8674(24)00010-2. [Epub ahead of print]
    SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion.
    Giuseppe Leuzzi, Alessandro Vasciaveo, Angelo Taglialatela, Xiao Chen, Tessa M Firestone, Allison R Hickman, Wendy Mao, Tanay Thakar, Alina Vaitsiankova, Jen-Wei Huang, Raquel Cuella-Martin, Samuel B Hayward, Jordan S Kesner, Ali Ghasemzadeh, Tarun S Nambiar, Patricia Ho, Alexander Rialdi, Maxime Hebrard, Yinglu Li, Jinmei Gao, Saarang Gopinath, Oluwatobi A Adeleke, Bryan J Venters, Charles G Drake, Richard Baer, Benjamin Izar, Ernesto Guccione, Michael-Christopher Keogh, Raphael Guerois, Lu Sun, Chao Lu, Andrea Califano, Alberto Ciccia.
      Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 limits endogenous DNA damage, thereby suppressing cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a PD-L1 transcriptional regulatory element, thereby promoting PD-L1 expression in cancer cells. SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a promising target for cancer immunotherapy.
    Keywords:  AP-1; CRISPR-Cas9 screens; DNA damage response; JUN; PD-L1 regulation; SMARCAL1; cGAS-STING pathway; cancer immunotherapy; cancer-intrinsic innate immunity
    DOI:  https://doi.org/10.1016/j.cell.2024.01.008
  41. Trends Endocrinol Metab. 2024 Jan 31. pii: S1043-2760(24)00022-5. [Epub ahead of print]
    Genetics unravels protein-metabolite relationships.
    James R Hilser, Aldons J Lusis, Hooman Allayee.
      Integrating molecular traits into genetic studies enhances our understanding of how DNA variation influences complex clinical and physiological phenotypes. In a recent article, Benson and colleagues apply this systems genetics approach with proteomics and metabolomics data in plasma from humans to identify and validate several previously unrecognized causal protein-metabolite associations.
    Keywords:  Mendelian randomization; metabolomics; proteomics; systems genetics
    DOI:  https://doi.org/10.1016/j.tem.2024.01.008
  42. J Clin Invest. 2024 Feb 01. pii: e176879. [Epub ahead of print]134(3):
    Should I stay or should I go? Transsulfuration influences invasion and growth in glioblastoma.
    András K Ponti, Daniel J Silver, Christopher Hine, Justin D Lathia.
      A major challenge in treating patients with glioblastoma is the inability to eliminate highly invasive cells with chemotherapy, radiation, or surgical resection. As cancer cells face the issue of replicating or invading neighboring tissue, they rewire their metabolism in a concerted effort to support necessary cellular processes and account for altered nutrient abundance. In this issue of the JCI, Garcia et al. compared an innovative 3D hydrogel-based invasion device to regional patient biopsies through a comprehensive multiomics-based approach paired with a CRISPR knockout screen. Their findings elucidate a role for cystathionine γ-lyase (CTH), an enzyme in the transsulfuration pathway, as a means of regulating the cellular response to oxidative stress. CTH-mediated conversion of cystathionine to cysteine was necessary for regulating reactive oxygen species to support invasion. Meanwhile, inhibition of CTH suppressed the invasive glioblastoma phenotype. However, inhibiting CTH resulted in a larger overall tumor mass. These findings suggest that targeting the transsulfuration pathway may serve as a means of redirecting glioblastoma to proliferate or invade.
    DOI:  https://doi.org/10.1172/JCI176879
  43. Biochimie. 2024 Jan 31. pii: S0300-9084(24)00036-1. [Epub ahead of print]
    Should the standard model of cellular energy metabolism be reconsidered? Possible coupling between the pentose phosphate pathway, glycolysis and extra-mitochondrial oxidative phosphorylation.
    Alessandro Maria Morelli, Felix Scholkmann.
      The process of cellular respiration occurs for energy production through catabolic reactions, generally with glucose as the first process step. In the present work, we introduce a novel concept for understanding this process, based on our conclusion that glucose metabolism is coupled to the pentose phosphate pathway (PPP) and extra-mitochondrial oxidative phosphorylation in a closed-loop process. According to the current standard model of glycolysis, glucose is first converted to glucose 6-phosphate (glucose 6-P) and then to fructose 6-phosphate, glyceraldehyde 3-phosphate and pyruvate, which then enters the Krebs cycle in the mitochondria. However, it is more likely that the pyruvate will be converted to lactate. In the PPP, glucose 6-P is branched off from glycolysis and used to produce NADPH and ribulose 5-phosphate (ribulose 5-P). Ribulose 5-P can be converted to fructose 6-P and glyceraldehyde 3-P. In our view, a circular process can take place in which the ribulose 5-P produced by the PPP enters the glycolysis pathway and is then retrogradely converted to glucose 6-P. This process is repeated several times until the complete degradation of glucose 6-P. The role of mitochondria in this process is to degrade lipids by beta-oxidation and produce acetyl-CoA; the function of producing ATP appears to be only secondary. This proposed new concept of cellular bioenergetics allows the resolution of some previously unresolved controversies related to cellular respiration and provides a deeper understanding of metabolic processes in the cell, including a new insights into the Warburg effect.
    Keywords:  Cancer metabolism; Cellular respiration; Endoplasmic reticulum; Extra-mitochondrial OXPHOS; Glycolysis; Pentose phosphate pathway
    DOI:  https://doi.org/10.1016/j.biochi.2024.01.018
  44. Nat Commun. 2024 Jan 29. 15(1): 846
    A universal metabolite repair enzyme removes a strong inhibitor of the TCA cycle.
    Anthony J Zmuda, Xiaojun Kang, Katie B Wissbroecker, Katrina Freund Saxhaug, Kyle C Costa, Adrian D Hegeman, Thomas D Niehaus.
      A prevalent side-reaction of succinate dehydrogenase oxidizes malate to enol-oxaloacetate (OAA), a metabolically inactive form of OAA that is a strong inhibitor of succinate dehydrogenase. We purified from cow heart mitochondria an enzyme (OAT1) with OAA tautomerase (OAT) activity that converts enol-OAA to the physiological keto-OAA form, and determined that it belongs to the highly conserved and previously uncharacterized Fumarylacetoacetate_hydrolase_domain-containing protein family. From all three domains of life, heterologously expressed proteins were shown to have strong OAT activity, and ablating the OAT1 homolog caused significant growth defects. In Escherichia coli, expression of succinate dehydrogenase was necessary for OAT1-associated growth defects to occur, and ablating OAT1 caused a significant increase in acetate and other metabolites associated with anaerobic respiration. OAT1 increased the succinate dehydrogenase reaction rate by 35% in in vitro assays with physiological concentrations of both succinate and malate. Our results suggest that OAT1 is a universal metabolite repair enzyme that is required to maximize aerobic respiration efficiency by preventing succinate dehydrogenase inhibition.
    DOI:  https://doi.org/10.1038/s41467-024-45134-0
  45. Nat Commun. 2024 Jan 31. 15(1): 937
    Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.
    Stanley C Xie, Yinuo Wang, Craig J Morton, Riley D Metcalfe, Con Dogovski, Charisse Flerida A Pasaje, Elyse Dunn, Madeline R Luth, Krittikorn Kumpornsin, Eva S Istvan, Joon Sung Park, Kate J Fairhurst, Nutpakal Ketprasit, Tomas Yeo, Okan Yildirim, Mathamsanqa N Bhebhe, Dana M Klug, Peter J Rutledge, Luiz C Godoy, Sumanta Dey, Mariana Laureano De Souza, Jair L Siqueira-Neto, Yawei Du, Tanya Puhalovich, Mona Amini, Gerry Shami, Duangkamon Loesbanluechai, Shuai Nie, Nicholas Williamson, Gouranga P Jana, Bikash C Maity, Patrick Thomson, Thomas Foley, Derek S Tan, Jacquin C Niles, Byung Woo Han, Daniel E Goldberg, Jeremy Burrows, David A Fidock, Marcus C S Lee, Elizabeth A Winzeler, Michael D W Griffin, Matthew H Todd, Leann Tilley.
      Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.
    DOI:  https://doi.org/10.1038/s41467-024-45224-z
  46. Curr Opin Cell Biol. 2024 Jan 31. pii: S0955-0674(24)00002-4. [Epub ahead of print]87 102323
    Cell competition and the regulation of protein homeostasis.
    Shruthi Krishnan, Pranab K Paul, Tristan A Rodriguez.
      The process of embryonic development involves remarkable cellular plasticity, which governs the coordination between cells necessary to build an organism. One role of this plasticity is to ensure that when aberrant cells are eliminated, growth adjustment occurs so that the size of the tissue is maintained. An important regulator of cellular plasticity that ensures cellular cooperation is a fitness-sensing mechanism termed cell competition. During cell competition, cells with defects that lower fitness but do not affect viability, such as those that cause impaired signal transduction, slower cellular growth, mitochondrial dysregulation or impaired protein homeostasis, are killed when surrounded by fitter cells. This is accompanied by the compensatory proliferation of the surviving cells. The underlying factors and mechanisms that demarcate certain cells as less fit than their neighbouring cells and losers of cell competition are still relatively unknown. Recent evidence has pointed to mitochondrial defects and proteotoxic stress as important hallmarks of these loser cells. Here, we review recent advances in this area, focussing on the role of mitochondrial activity and protein homeostasis as major mechanisms determining competitive cell fitness during development and the importance of cell proteostasis in determining cell fitness.
    Keywords:  Cell competition; Cell fitness; Losers; Mitochondrial dysregulation; Proteostasis; Winners
    DOI:  https://doi.org/10.1016/j.ceb.2024.102323
  47. Nat Commun. 2024 Feb 01. 15(1): 959
    Multiplexed screening reveals how cancer-specific alternative polyadenylation shapes tumor growth in vivo.
    Austin M Gabel, Andrea E Belleville, James D Thomas, Siegen A McKellar, Taylor R Nicholas, Toshihiro Banjo, Edie I Crosse, Robert K Bradley.
      Alternative polyadenylation (APA) is strikingly dysregulated in many cancers. Although global APA dysregulation is frequently associated with poor prognosis, the importance of most individual APA events is controversial simply because few have been functionally studied. Here, we address this gap by developing a CRISPR-Cas9-based screen to manipulate endogenous polyadenylation and systematically quantify how APA events contribute to tumor growth in vivo. Our screen reveals individual APA events that control mouse melanoma growth in an immunocompetent host, with concordant associations in clinical human cancer. For example, forced Atg7 3' UTR lengthening in mouse melanoma suppresses ATG7 protein levels, slows tumor growth, and improves host survival; similarly, in clinical human melanoma, a long ATG7 3' UTR is associated with significantly prolonged patient survival. Overall, our study provides an easily adaptable means to functionally dissect APA in physiological systems and directly quantifies the contributions of recurrent APA events to tumorigenic phenotypes.
    DOI:  https://doi.org/10.1038/s41467-024-44931-x
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