bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024‒06‒16
forty-six papers selected by
Christian Frezza, Universität zu Köln
  1. MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.
  2. Electron transport chain inhibition increases cellular dependence on purine transport and salvage.
  3. Functional implications of fumarate-induced cysteine succination.
  4. The Bioenergetic Landscape of Cancer.
  5. RESPIRATION DEFECTS LIMIT SERINE SYNTHESIS REQUIRED FOR LUNG CANCER GROWTH AND SURVIVAL.
  6. Coenzyme A biosynthesis: mechanisms of regulation, function and disease.
  7. Metabolic Signaling in Cancer.
  8. Reproductive regulation of the mitochondrial stress response in Caenorhabditis elegans.
  9. Metabolic inflexibility promotes mitochondrial health during liver regeneration.
  10. Unique architectural features of mammalian mitochondrial protein synthesis.
  11. Serine Depletion Promotes Anti-Tumor Immunity by Activating Mitochondrial DNA-mediated cGAS-STING Signaling.
  12. ASS1 metabolically contributes to the nuclear and cytosolic p53-mediated DNA damage response.
  13. Understanding mitochondrial potassium channels: 33 years after discovery.
  14. Exploiting ferroptosis vulnerabilities in cancer.
  15. C16ORF70/Mytho promotes healthy ageing in C. elegans and prevents cellular senescence in mammals.
  16. Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease.
  17. Lessons Learned from Cancer Metabolism for Physiology and Disease.
  18. Phosphorylation of mammalian cytosolic and mitochondrial malate dehydrogenase: insights into regulation.
  19. Malate dehydrogenase (MDH) in cancer: a promiscuous enzyme, a redox regulator, and a metabolic co-conspirator.
  20. Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer.
  21. Aging represses lung tumorigenesis and alters tumor suppression.
  22. Regulatory Mechanisms of Aging Through the Nutritional and Metabolic Control of Amino Acid Signaling in Model Organisms.
  23. Molecular mechanism of the ischemia-induced regulatory switch in mammalian complex I.
  24. Mitochondrial membrane synthesis, remodelling and cellular trafficking.
  25. Leucine suppresses α-cell cAMP and glucagon secretion via a combination of cell-intrinsic and islet paracrine signaling.
  26. Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.
  27. CRISPR activation screens identify the SWI/SNF ATPases as suppressors of ferroptosis.
  28. Acetylation of histones and non-histone proteins is not a mere consequence of ongoing transcription.
  29. Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.
  30. Malonate given at reperfusion prevents post-myocardial infarction heart failure by decreasing ischemia/reperfusion injury.
  31. The mitochondrial calcium uniporter: Balancing tumourigenic and anti-tumourigenic responses.
  32. The glutathione S-transferase Gstt1 drives survival and dissemination in metastases.
  33. Endogenous p53 inhibitor TIRR dissociates systemic metabolic health from oncogenic activity.
  34. Unconventional mechanism of action and resistance to rapalogs in renal cancer.
  35. Role of Yme1 in mitochondrial protein homeostasis: from regulation of protein import, OXPHOS function to lipid synthesis and mitochondrial dynamics.
  36. PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway.
  37. Multi-omics profiling of mouse polycystic kidney disease progression at a single cell resolution.
  38. Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes.
  39. Nanobiopsy investigation of the subcellular mtDNA heteroplasmy in human tissues.
  40. Telomeres and the Rate of Living: Linking Biological Clocks of Senescence.
  41. The Space Omics and Medical Atlas (SOMA) and international astronaut biobank.
  42. MYG1 drives glycolysis and colorectal cancer development through nuclear-mitochondrial collaboration.
  43. Tumor Promoters and Opportunities for Molecular Cancer Prevention.
  44. Cosmic kidney disease: an integrated pan-omic, physiological and morphological study into spaceflight-induced renal dysfunction.
  45. Multi-omic Analysis of Human B-cell Activation Reveals a Key Lysosomal BCAT1 Role in mTOR Hyperactivation by B-cell receptor and TLR9.
  46. Spatial multi-omics of human skin reveals KRAS and inflammatory responses to spaceflight.
  1. Cell. 2024 Jun 05. pii: S0092-8674(24)00526-9. [Epub ahead of print]
    MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.
    Luis Carlos Tábara, Stephen P Burr, Michele Frison, Suvagata R Chowdhury, Vincent Paupe, Yu Nie, Mark Johnson, Jara Villar-Azpillaga, Filipa Viegas, Mayuko Segawa, Hanish Anand, Kasparas Petkevicius, Patrick F Chinnery, Julien Prudent.
      Mitochondrial dynamics play a critical role in cell fate decisions and in controlling mtDNA levels and distribution. However, the molecular mechanisms linking mitochondrial membrane remodeling and quality control to mtDNA copy number (CN) regulation remain elusive. Here, we demonstrate that the inner mitochondrial membrane (IMM) protein mitochondrial fission process 1 (MTFP1) negatively regulates IMM fusion. Moreover, manipulation of mitochondrial fusion through the regulation of MTFP1 levels results in mtDNA CN modulation. Mechanistically, we found that MTFP1 inhibits mitochondrial fusion to isolate and exclude damaged IMM subdomains from the rest of the network. Subsequently, peripheral fission ensures their segregation into small MTFP1-enriched mitochondria (SMEM) that are targeted for degradation in an autophagic-dependent manner. Remarkably, MTFP1-dependent IMM quality control is essential for basal nucleoid recycling and therefore to maintain adequate mtDNA levels within the cell.
    Keywords:  IMM quality control; IMM remodeling; MTFP1; autophagy; fission and fusion; mitochondria; mitochondrial dynamics; mitophagy; mtDNA
    DOI:  https://doi.org/10.1016/j.cell.2024.05.017
  2. Cell Metab. 2024 Jun 07. pii: S1550-4131(24)00190-6. [Epub ahead of print]
    Electron transport chain inhibition increases cellular dependence on purine transport and salvage.
    Zheng Wu, Divya Bezwada, Feng Cai, Robert C Harris, Bookyung Ko, Varun Sondhi, Chunxiao Pan, Hieu S Vu, Phong T Nguyen, Brandon Faubert, Ling Cai, Hongli Chen, Misty Martin-Sandoval, Duyen Do, Wen Gu, Yuanyuan Zhang, Yuannyu Zhang, Bailey Brooks, Sherwin Kelekar, Lauren G Zacharias, K Celeste Oaxaca, Joao S Patricio, Thomas P Mathews, Javier Garcia-Bermudez, Min Ni, Ralph J DeBerardinis.
      Mitochondria house many metabolic pathways required for homeostasis and growth. To explore how human cells respond to mitochondrial dysfunction, we performed metabolomics in fibroblasts from patients with various mitochondrial disorders and cancer cells with electron transport chain (ETC) blockade. These analyses revealed extensive perturbations in purine metabolism, and stable isotope tracing demonstrated that ETC defects suppress de novo purine synthesis while enhancing purine salvage. In human lung cancer, tumors with markers of low oxidative mitochondrial metabolism exhibit enhanced expression of the salvage enzyme hypoxanthine phosphoribosyl transferase 1 (HPRT1) and high levels of the HPRT1 product inosine monophosphate. Mechanistically, ETC blockade activates the pentose phosphate pathway, providing phosphoribosyl diphosphate to drive purine salvage supplied by uptake of extracellular bases. Blocking HPRT1 sensitizes cancer cells to ETC inhibition. These findings demonstrate how cells remodel purine metabolism upon ETC blockade and uncover a new metabolic vulnerability in tumors with low respiration.
    Keywords:  HPRT1; NAD(+):NADH ratio; electron transport chain; metabolomics; purine metabolism; stable isotopes
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.014
  3. Trends Biochem Sci. 2024 Jun 13. pii: S0968-0004(24)00113-0. [Epub ahead of print]
    Functional implications of fumarate-induced cysteine succination.
    Iva Guberovic, Christian Frezza.
      Mutations in metabolic enzymes are associated with hereditary and sporadic forms of cancer. For example, loss-of-function mutations affecting fumarate hydratase (FH), the tricarboxylic acid (TCA) cycle enzyme, result in the accumulation of millimolar levels of fumarate that cause an aggressive form of kidney cancer. A distinct feature of fumarate is its ability to spontaneously react with thiol groups of cysteines in a chemical reaction termed succination. Although succination of a few proteins has been causally implicated in the molecular features of FH-deficient cancers, the stoichiometry, wider functional consequences, and contribution of succination to disease development remain largely unexplored. We discuss the functional implications of fumarate-induced succination in FH-deficient cells, the available methodologies, and the current challenges in studying this post-translational modification.
    Keywords:  2-(succino)cysteine (2SC); biomarker; fumarate; hereditary leiomyomatosis and renal cell carcinoma (HLRCC); metabolic rewiring; oncometabolite
    DOI:  https://doi.org/10.1016/j.tibs.2024.05.003
  4. Mol Metab. 2024 Jun 12. pii: S2212-8778(24)00097-8. [Epub ahead of print] 101966
    The Bioenergetic Landscape of Cancer.
    Elizabeth R M Zunica, Christopher L Axelrod, L Anne Gilmore, Erich Gnaiger, John P Kirwan.
      Bioenergetic remodeling of core energy metabolism is essential to the initiation, survival, and progression of cancer cells through exergonic supply of adenosine triphosphate (ATP) and metabolic intermediates, as well as control of redox homeostasis. Mitochondria are evolutionarily conserved organelles that mediate cell survival by conferring energetic plasticity and adaptive potential. Mitochondrial ATP synthesis is coupled to the oxidation of a variety of substrates generated through diverse metabolic pathways. As such, inhibition of the mitochondrial bioenergetic system by restricting metabolite availability, direct inhibition of the respiratory Complexes, altering organelle structure, or coupling efficiency may restrict carcinogenic potential and cancer progression. Here, we review the role of bioenergetics as the principal conductor of energetic functions and carcinogenesis while highlighting the therapeutic potential of targeting mitochondrial functions.
    Keywords:  Bioenergetics; Cancer; Cell Survival; Energy Transformation; Mitochondria
    DOI:  https://doi.org/10.1016/j.molmet.2024.101966
  5. bioRxiv. 2024 Jun 02. pii: 2024.05.28.596339. [Epub ahead of print]
    RESPIRATION DEFECTS LIMIT SERINE SYNTHESIS REQUIRED FOR LUNG CANCER GROWTH AND SURVIVAL.
    Eduardo Cararo Lopes, Fuqian Shi, Akshada Sawant, Maria Ibrahim, Maria Gomez-Jenkins, Zhixian Hu, Pranav Manchiraju, Vrushank Bhatt, Wenping Wang, Christian S Hinrichs, Douglas C Wallace, Xiaoyang Su, Joshua D Rabinowitz, Chang S Chan, Jessie Yanxiang Guo, Shridar Ganesan, Edmund C Lattime, Eileen White.
      Mitochondrial function is important for both energetic and anabolic metabolism. Pathogenic mitochondrial DNA (mtDNA) mutations directly impact these functions, resulting in the detrimental consequences seen in human mitochondrial diseases. The role of pathogenic mtDNA mutations in human cancers is less clear; while pathogenic mtDNA mutations are observed in some cancer types, they are almost absent in others. We report here that the proofreading mutant DNA polymerase gamma ( PolG D256A ) induced a high mtDNA mutation burden in non-small-cell lung cancer (NSCLC), and promoted the accumulation of defective mitochondria, which is responsible for decreased tumor cell proliferation and viability and increased cancer survival. In NSCLC cells, pathogenic mtDNA mutations increased glycolysis and caused dependence on glucose. The glucose dependency sustained mitochondrial energetics but at the cost of a decreased NAD+/NADH ratio that inhibited de novo serine synthesis. Insufficient serine synthesis, in turn, impaired the downstream synthesis of GSH and nucleotides, leading to impaired tumor growth that increased cancer survival. Unlike tumors with intact mitochondrial function, NSCLC with pathogenic mtDNA mutations were sensitive to dietary serine and glycine deprivation. Thus, mitochondrial function in NSCLC is required specifically to sustain sufficient serine synthesis for nucleotide production and redox homeostasis to support tumor growth, explaining why these cancers preserve functional mtDNA.In brief: High mtDNA mutation burden in non-small-cell lung cancer (NSCLC) leads to the accumulation of respiration-defective mitochondria and dependency on glucose and glycolytic metabolism. Defective respiratory metabolism causes a massive accumulation of cytosolic nicotinamide adenine dinucleotide + hydrogen (NADH), which impedes serine synthesis and, thereby, glutathione (GSH) and nucleotide synthesis, leading to impaired tumor growth and increased survival.
    Highlights: Proofreading mutations in Polymerase gamma led to a high burden of mitochondrial DNA mutations, promoting the accumulation of mitochondria with respiratory defects in NSCLC.Defective respiration led to reduced proliferation and viability of NSCLC cells increasing survival to cancer.Defective respiration caused glucose dependency to fuel elevated glycolysis.Altered glucose metabolism is associated with high NADH that limits serine synthesis, leading to impaired GSH and nucleotide production.Mitochondrial respiration defects sensitize NSCLC to dietary serine/glycine starvation, further increasing survival.
    Abstract Figure:
    DOI:  https://doi.org/10.1101/2024.05.28.596339
  6. Nat Metab. 2024 Jun 13.
    Coenzyme A biosynthesis: mechanisms of regulation, function and disease.
    Samuel A Barritt, Sarah E DuBois-Coyne, Christian C Dibble.
      The tricarboxylic acid cycle, nutrient oxidation, histone acetylation and synthesis of lipids, glycans and haem all require the cofactor coenzyme A (CoA). Although the sources and regulation of the acyl groups carried by CoA for these processes are heavily studied, a key underlying question is less often considered: how is production of CoA itself controlled? Here, we discuss the many cellular roles of CoA and the regulatory mechanisms that govern its biosynthesis from cysteine, ATP and the essential nutrient pantothenate (vitamin B5), or from salvaged precursors in mammals. Metabolite feedback and signalling mechanisms involving acetyl-CoA, other acyl-CoAs, acyl-carnitines, MYC, p53, PPARα, PINK1 and insulin- and growth factor-stimulated PI3K-AKT signalling regulate the vitamin B5 transporter SLC5A6/SMVT and CoA biosynthesis enzymes PANK1, PANK2, PANK3, PANK4 and COASY. We also discuss methods for measuring CoA-related metabolites, compounds that target CoA biosynthesis and diseases caused by mutations in pathway enzymes including types of cataracts, cardiomyopathy and neurodegeneration (PKAN and COPAN).
    DOI:  https://doi.org/10.1038/s42255-024-01059-y
  7. Cold Spring Harb Perspect Med. 2024 Jun 10. pii: a041544. [Epub ahead of print]
    Metabolic Signaling in Cancer.
    Laura V Pinheiro, Pedro Costa-Pinheiro, Kathryn E Wellen.
      Metabolic reprogramming in cancer allows cells to survive in harsh environments and sustain macromolecular biosynthesis to support proliferation. In addition, metabolites play crucial roles as signaling molecules. Metabolite fluctuations are detected by various sensors in the cell to regulate gene expression, metabolism, and signal transduction. Metabolic signaling mechanisms contribute to tumorigenesis by altering the physiology of cancer cells themselves, as well as that of neighboring cells in the tumor microenvironment. In this review, we discuss principles of metabolic signaling and provide examples of how cancer cells take advantage of metabolic signals to promote cell proliferation and evade the immune system, thereby contributing to tumor growth and progression.
    DOI:  https://doi.org/10.1101/cshperspect.a041544
  8. Cell Rep. 2024 Jun 07. pii: S2211-1247(24)00664-8. [Epub ahead of print]43(6): 114336
    Reproductive regulation of the mitochondrial stress response in Caenorhabditis elegans.
    Nikolaos Charmpilas, Aggeliki Sotiriou, Konstantinos Axarlis, Nektarios Tavernarakis, Thorsten Hoppe.
      Proteome integrity is fundamental for cellular and organismal homeostasis. The mitochondrial unfolded protein response (UPRmt), a key component of the proteostasis network, is activated in a non-cell-autonomous manner in response to mitochondrial stress in distal tissues. However, the importance of inter-tissue communication for UPRmt inducibility under physiological conditions remains elusive. Here, we show that an intact germline is essential for robust UPRmt induction in the Caenorhabditis elegans somatic tissues. A series of nematode mutants with germline defects are unable to respond to genetic or chemical UPRmt inducers. Our genetic analysis suggests that reproductive signals, rather than germline stem cells, are responsible for somatic UPRmt induction. Consistent with this observation, we show that UPRmt is sexually dimorphic, as male nematodes are inherently unresponsive to mitochondrial stress. Our findings highlight a paradigm of germline-somatic communication and suggest that reproductive cessation is a primary cause of age-related UPRmt decline.
    Keywords:  C. elegans; CP: Developmental biology; CP: Molecular biology; aging; germline; mitochondria; proteostasis; unfolded protein response
    DOI:  https://doi.org/10.1016/j.celrep.2024.114336
  9. Science. 2024 Jun 14. 384(6701): eadj4301
    Metabolic inflexibility promotes mitochondrial health during liver regeneration.
    Xun Wang, Cameron J Menezes, Yuemeng Jia, Yi Xiao, Siva Sai Krishna Venigalla, Feng Cai, Meng-Hsiung Hsieh, Wen Gu, Liming Du, Jessica Sudderth, Dohun Kim, Spencer D Shelton, Claire B Llamas, Yu-Hsuan Lin, Min Zhu, Salma Merchant, Divya Bezwada, Sherwin Kelekar, Lauren G Zacharias, Thomas P Mathews, Gerta Hoxhaj, R Max Wynn, Uttam K Tambar, Ralph J DeBerardinis, Hao Zhu, Prashant Mishra.
      Mitochondria are critical for proper organ function and mechanisms to promote mitochondrial health during regeneration would benefit tissue homeostasis. We report that during liver regeneration, proliferation is suppressed in electron transport chain (ETC)-dysfunctional hepatocytes due to an inability to generate acetyl-CoA from peripheral fatty acids through mitochondrial β-oxidation. Alternative modes for acetyl-CoA production from pyruvate or acetate are suppressed in the setting of ETC dysfunction. This metabolic inflexibility forces a dependence on ETC-functional mitochondria and restoring acetyl-CoA production from pyruvate is sufficient to allow ETC-dysfunctional hepatocytes to proliferate. We propose that metabolic inflexibility within hepatocytes can be advantageous by limiting the expansion of ETC-dysfunctional cells.
    DOI:  https://doi.org/10.1126/science.adj4301
  10. Trends Cell Biol. 2024 Jun 08. pii: S0962-8924(24)00097-7. [Epub ahead of print]
    Unique architectural features of mammalian mitochondrial protein synthesis.
    Oliver Rackham, Martin Saurer, Nenad Ban, Aleksandra Filipovska.
      Mitochondria rely on coordinated expression of their own mitochondrial DNA (mtDNA) with that of the nuclear genome for their biogenesis. The bacterial ancestry of mitochondria has given rise to unique and idiosyncratic features of the mtDNA and its expression machinery that can be specific to different organisms. In animals, the mitochondrial protein synthesis machinery has acquired many new components and mechanisms over evolution. These include several new ribosomal proteins, new stop codons and ways to recognise them, and new mechanisms to deliver nascent proteins into the mitochondrial inner membrane. Here we describe the mitochondrial protein synthesis machinery in mammals and its unique mechanisms of action elucidated to date and highlight the technologies poised to reveal the next generation of discoveries in mitochondrial translation.
    Keywords:  RNA; mitochondria; mitochondrial disease; ribosomes; translation
    DOI:  https://doi.org/10.1016/j.tcb.2024.05.001
  11. Cancer Res. 2024 Jun 11.
    Serine Depletion Promotes Anti-Tumor Immunity by Activating Mitochondrial DNA-mediated cGAS-STING Signaling.
    Suchandrima Saha, Monisankar Ghosh, Jinyu Li, Asher Wen, Lorenzo Galluzzi, Luis A Martinez, David C Montrose.
      Serine is critical for supporting cancer metabolism, and depriving malignant cells of this non-essential amino acid exerts anti-neoplastic effects, in large part, through disrupting metabolic pathways. Given the intricate relationship between cancer metabolism and the immune system, the metabolic defects imposed by serine deprivation might impact tumor-targeting immunity. Here, we demonstrated that restricting endogenous and exogenous sources of serine in colorectal cancer (CRC) cells results in mitochondrial dysfunction, leading to mitochondrial DNA (mtDNA) accumulation in the cytosol and consequent cGAS-STING1-driven type I interferon (IFN) secretion. Depleting mtDNA or blocking its release attenuated cGAS-STING1 activation during serine deprivation. In vivo studies revealed that serine deprivation limits tumor growth, accompanied by enhanced type I IFN signaling and intratumoral infiltration of immune effector cells. Notably, the tumor-suppressive and immune-enhancing effects of serine restriction were impaired by T cell depletion and IFN receptor blockade. Moreover, disrupting cGAS-STING1 signaling in CRC cells limited the immunostimulatory and tumor-suppressive effects of serine deprivation. Lastly, serine depletion increased the sensitivity of tumors to an immune checkpoint inhibitor targeting PD-1. Taken together, these findings reveal a role for serine as a suppressor of anti-tumor immunity, suggesting that serine deprivation may be employed to enhance tumor immunogenicity and improve responsiveness to immune checkpoint inhibitors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-1788
  12. Nat Metab. 2024 Jun 10.
    ASS1 metabolically contributes to the nuclear and cytosolic p53-mediated DNA damage response.
    Lisha Qiu Jin Lim, Lital Adler, Emma Hajaj, Leandro R Soria, Rotem Ben-Tov Perry, Naama Darzi, Ruchama Brody, Noa Furth, Michal Lichtenstein, Elizabeta Bab-Dinitz, Ziv Porat, Tevie Melman, Alexander Brandis, Yael Aylon, Shifra Ben-Dor, Irit Orr, Amir Pri-Or, Rony Seger, Yoav Shaul, Eytan Ruppin, Moshe Oren, Minervo Perez, Jordan Meier, Nicola Brunetti-Pierri, Efrat Shema, Igor Ulitsky, Ayelet Erez, Sergey Malitsky, Maxim Itkin.
      Downregulation of the urea cycle enzyme argininosuccinate synthase (ASS1) in multiple tumors is associated with a poor prognosis partly because of the metabolic diversion of cytosolic aspartate for pyrimidine synthesis, supporting proliferation and mutagenesis owing to nucleotide imbalance. Here, we find that prolonged loss of ASS1 promotes DNA damage in colon cancer cells and fibroblasts from subjects with citrullinemia type I. Following acute induction of DNA damage with doxorubicin, ASS1 expression is elevated in the cytosol and the nucleus with at least a partial dependency on p53; ASS1 metabolically restrains cell cycle progression in the cytosol by restricting nucleotide synthesis. In the nucleus, ASS1 and ASL generate fumarate for the succination of SMARCC1, destabilizing the chromatin-remodeling complex SMARCC1-SNF5 to decrease gene transcription, specifically in a subset of the p53-regulated cell cycle genes. Thus, following DNA damage, ASS1 is part of the p53 network that pauses cell cycle progression, enabling genome maintenance and survival. Loss of ASS1 contributes to DNA damage and promotes cell cycle progression, likely contributing to cancer mutagenesis and, hence, adaptability potential.
    DOI:  https://doi.org/10.1038/s42255-024-01060-5
  13. Acta Biochim Pol. 2024 ;71 13126
    Understanding mitochondrial potassium channels: 33 years after discovery.
    Adam Szewczyk.
      Mitochondrial investigations have extended beyond their traditional functions, covering areas such as ATP synthesis and metabolism. Mitochondria are now implicated in new functional areas such as cytoprotection, cellular senescence, tumor function and inflammation. The basis of these new areas still relies on fundamental biochemical/biophysical mitochondrial functions such as synthesis of reactive oxygen species, mitochondrial membrane potential, and the integrity of the inner mitochondrial membrane i.e., the passage of various molecules through the mitochondrial membranes. In this view transport of potassium cations, known as the potassium cycle, plays an important role. It is believed that K+ influx is mediated by various potassium channels present in the inner mitochondrial membrane. In this article, we present an overview of the key findings and characteristics of mitochondrial potassium channels derived from research of many groups conducted over the past 33 years. We propose a list of six fundamental observations and most important ideas dealing with mitochondrial potassium channels. We also discuss the contemporary challenges and future prospects associated with research on mitochondrial potassium channels.
    Keywords:  cytoprotection; mitochondria; potassium channel openers; potassium channels; reactive oxygen species
    DOI:  https://doi.org/10.3389/abp.2024.13126
  14. Nat Cell Biol. 2024 Jun 10.
    Exploiting ferroptosis vulnerabilities in cancer.
    Toshitaka Nakamura, Marcus Conrad.
      Ferroptosis is a distinct lipid peroxidation-dependent form of necrotic cell death. This process has been increasingly contemplated as a new target for cancer therapy because of an intrinsic or acquired ferroptosis vulnerability in difficult-to-treat cancers and tumour microenvironments. Here we review recent advances in our understanding of the molecular mechanisms that underlie ferroptosis and highlight available tools for the modulation of ferroptosis sensitivity in cancer cells and communication with immune cells within the tumour microenvironment. We further discuss how these new insights into ferroptosis-activating pathways can become new armouries in the fight against cancer.
    DOI:  https://doi.org/10.1038/s41556-024-01425-8
  15. J Clin Invest. 2024 Jun 13. pii: e165814. [Epub ahead of print]
    C16ORF70/Mytho promotes healthy ageing in C. elegans and prevents cellular senescence in mammals.
    Anais Franco-Romero, Valeria Morbidoni, Giulia Milan, Roberta Sartori, Jesper Wulff, Vanina Romanello, Andrea Armani, Leonardo Salviati, Maria Conte, Stefano Salvioli, Claudio Franceschi, Viviana Buonomo, Casey O Swoboda, Paolo Grumati, Luca Pannone, Simone Martinelli, Harold Bj Jefferies, Ivan Dikic, Jennifer van der Laan, Filipe Cabreiro, Douglas P Millay, Sharon A Tooze, Eva Trevisson, Marco Sandri.
      The identification of genes that confer either extension of lifespan or accelerate age-related decline was a step forward in understanding the mechanisms of ageing and revealed that it is partially controlled by genetics and transcriptional programs. Here we discovered that the human DNA sequence C16ORF70 encoded for a protein, named MYTHO (Macroautophagy and YouTH Optimizer), which controls life- and health-span. MYTHO protein is conserved from C. elegans to humans and its mRNA was upregulated in aged mice and elderly people. Deletion of the ortholog myt-1 gene in C. elegans dramatically shortened lifespan and decreased animal survival upon exposure to oxidative stress. Mechanistically, MYTHO is required for autophagy likely because it acts as a scaffold that binds WIPI2 and BCAS3 to recruit and assemble the conjugation system at the phagophore, the nascent autophagosome. We conclude that MYTHO is a transcriptionally regulated initiator of autophagy that is central in promoting stress resistance and healthy ageing.
    Keywords:  Aging; Autophagy; Cell biology; Cellular senescence; Skeletal muscle
    DOI:  https://doi.org/10.1172/JCI165814
  16. Cell Death Dis. 2024 Jun 10. 15(6): 405
    Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease.
    Patricia Morcillo, Khushbu Kabra, Kevin Velasco, Hector Cordero, Sarah Jennings, Taekyung D Yun, Delfina Larrea, H Orhan Akman, Eric A Schon.
      Genetic mutations causing primary mitochondrial disease (i.e those compromising oxidative phosphorylation [OxPhos]) resulting in reduced bioenergetic output display great variability in their clinical features, but the reason for this is unknown. We hypothesized that disruption of the communication between endoplasmic reticulum (ER) and mitochondria at mitochondria-associated ER membranes (MAM) might play a role in this variability. To test this, we assayed MAM function and ER-mitochondrial communication in OxPhos-deficient cells, including cybrids from patients with selected pathogenic mtDNA mutations. Our results show that each of the various mutations studied indeed altered MAM functions, but notably, each disorder presented with a different MAM "signature". We also found that mitochondrial membrane potential is a key driver of ER-mitochondrial connectivity. Moreover, our findings demonstrate that disruption in ER-mitochondrial communication has consequences for cell survivability that go well beyond that of reduced ATP output. The findings of a "MAM-OxPhos" axis, the role of mitochondrial membrane potential in controlling this process, and the contribution of MAM dysfunction to cell death, reveal a new relationship between mitochondria and the rest of the cell, as well as providing new insights into the diagnosis and treatment of these devastating disorders.
    DOI:  https://doi.org/10.1038/s41419-024-06781-9
  17. Cold Spring Harb Perspect Med. 2024 Jun 10. pii: a041554. [Epub ahead of print]
    Lessons Learned from Cancer Metabolism for Physiology and Disease.
    Sydney L Campbell, Heather R Christofk.
      Tumor cells divide rapidly and dramatically alter their metabolism to meet biosynthetic and bioenergetic needs. Through studying the aberrant metabolism of cancer cells, other contexts in which metabolism drives cell state transitions become apparent. In this work, we will discuss how principles established by the field of cancer metabolism have led to discoveries in the contexts of physiology and tissue injury, mammalian embryonic development, and virus infection. We present specific examples of findings from each of these fields that have been shaped by the study of cancer metabolism. We also discuss the next important scientific questions facing these subject areas collectively. Altogether, these examples demonstrate that the study of "cancer metabolism" is indeed the study of cell metabolism in the context of a tumor, and undoubtedly discoveries from each of the fields discussed here will continue to build on each other in the future.
    DOI:  https://doi.org/10.1101/cshperspect.a041554
  18. Essays Biochem. 2024 Jun 12. pii: EBC20230079. [Epub ahead of print]
    Phosphorylation of mammalian cytosolic and mitochondrial malate dehydrogenase: insights into regulation.
    Joseph J Provost, Kathleen A Cornely, Pamela S Mertz, Celeste N Peterson, Sophie G Riley, Harrison J Tarbox, Shree R Narasimhan, Andrew J Pulido, Amy L Springer.
      Malate dehydrogenase (MDH) is a key enzyme in mammalian metabolic pathways in cytosolic and mitochondrial compartments. Regulation of MDH through phosphorylation remains an underexplored area. In this review we consolidate evidence supporting the potential role of phosphorylation in modulating the function of mammalian MDH. Parallels are drawn with the phosphorylation of lactate dehydrogenase, a homologous enzyme, to reveal its regulatory significance and to suggest a similar regulatory strategy for MDH. Comprehensive mining of phosphorylation databases, provides substantial experimental (primarily mass spectrometry) evidence of MDH phosphorylation in mammalian cells. Experimentally identified phosphorylation sites are overlaid with MDH's functional domains, offering perspective on how these modifications could influence enzyme activity. Preliminary results are presented from phosphomimetic mutations (serine/threonine residues changed to aspartate) generated in recombinant MDH proteins serving as a proof of concept for the regulatory impact of phosphorylation. We also examine and highlight several approaches to probe the structural and cellular impact of phosphorylation. This review highlights the need to explore the dynamic nature of MDH phosphorylation and calls for identifying the responsible kinases and the physiological conditions underpinning this modification. The synthesis of current evidence and experimental data aims to provide insights for future research on understanding MDH regulation, offering new avenues for therapeutic interventions in metabolic disorders and cancer.
    Keywords:  MDH; kinase; malate dehydrogenase; metabolism; phosphorylation; post translational modification
    DOI:  https://doi.org/10.1042/EBC20230079
  19. Essays Biochem. 2024 Jun 12. pii: EBC20230088. [Epub ahead of print]
    Malate dehydrogenase (MDH) in cancer: a promiscuous enzyme, a redox regulator, and a metabolic co-conspirator.
    Betsy Leverett, Shane Austin, Jason Tan-Arroyo.
      Malate dehydrogenase (MDH) is an essential enzyme in the tricarboxylic acid cycle that functions in cellular respiration and redox homeostasis. Recent studies indicate that MDH facilitates metabolic plasticity in tumor cells, catalyzing the formation of an oncometabolite, contributing to altered epigenetics, and maintaining redox capacity to support the rewired energy metabolism and biosynthesis that enables cancer progression. This minireview summarizes current findings on the unique supporting roles played by MDH in human cancers and provides an update on targeting MDH in cancer chemotherapy.
    Keywords:  cancer; malate dehydrogenase; metabolomics; oncometabolism; redox balance
    DOI:  https://doi.org/10.1042/EBC20230088
  20. Nat Metab. 2024 Jun 14.
    Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer.
    Hyun Min Lee, Nefertiti Muhammad, Elizabeth L Lieu, Feng Cai, Jiawei Mu, Yun-Sok Ha, Guoshen Cao, Chamey Suchors, Kenneth Joves, Constantinos Chronis, Kailong Li, Gregory S Ducker, Kellen Olszewski, Ling Cai, Derek B Allison, Sara E Bachert, William R Ewing, Harvey Wong, Hyosun Seo, Isaac Y Kim, Brandon Faubert, James Kim, Jiyeon Kim.
      Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine-glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)-NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies.
    DOI:  https://doi.org/10.1038/s42255-024-01066-z
  21. bioRxiv. 2024 May 31. pii: 2024.05.28.596319. [Epub ahead of print]
    Aging represses lung tumorigenesis and alters tumor suppression.
    Emily G Shuldiner, Saswati Karmakar, Min K Tsai, Jess D Hebert, Yuning J Tang, Laura Andrejka, Minwei Wang, Colin R Detrick, Hongchen Cai, Rui Tang, Dmitri A Petrov, Monte M Winslow.
      Most cancers are diagnosed in persons over the age of sixty, but little is known about how age impacts tumorigenesis. While aging is accompanied by mutation accumulation - widely understood to contribute to cancer risk - it is also associated with numerous other cellular and molecular changes likely to impact tumorigenesis. Moreover, cancer incidence decreases in the oldest part of the population, suggesting that very old age may reduce carcinogenesis. Here we show that aging represses tumor initiation and growth in genetically engineered mouse models of human lung cancer. Moreover, aging dampens the impact of inactivating many, but not all, tumor suppressor genes with the impact of inactivating PTEN, a negative regulator of the PI3K/AKT pathway, weakened to a disproportionate extent. Single-cell transcriptomic analysis revealed that neoplastic cells from tumors in old mice retain many age-related transcriptomic changes, showing that age has an enduring impact that persists through oncogenic transformation. Furthermore, the consequences of PTEN inactivation were strikingly age-dependent, with PTEN deficiency reducing signatures of aging in cancer cells and the tumor microenvironment. Our findings suggest that the relationship between age and lung cancer incidence may reflect an integration of the competing effects of driver mutation accumulation and tumor suppressive effects of aging.
    DOI:  https://doi.org/10.1101/2024.05.28.596319
  22. Annu Rev Genet. 2024 Jun 10.
    Regulatory Mechanisms of Aging Through the Nutritional and Metabolic Control of Amino Acid Signaling in Model Organisms.
    Fumiaki Obata, Masayuki Miura.
      Life activities are supported by the intricate metabolic network that is fueled by nutrients. Nutritional and genetic studies in model organisms have determined that dietary restriction and certain mutations in the insulin signaling pathway lead to lifespan extension. Subsequently, the detailed mechanisms of aging as well as various nutrient signaling pathways and their relationships have been investigated in a wide range of organisms, from yeast to mammals. This review summarizes the roles of nutritional and metabolic signaling in aging and lifespan with a focus on amino acids, the building blocks of organisms. We discuss how lifespan is affected by the sensing, transduction, and metabolism of specific amino acids and consider the influences of life stage, sex, and genetic background on the nutritional control of aging. Our goal is to enhance our understanding of how nutrients affect aging and thus contribute to the biology of aging and lifespan.
    DOI:  https://doi.org/10.1146/annurev-genet-111523-102042
  23. Science. 2024 Jun 14. 384(6701): 1247-1253
    Molecular mechanism of the ischemia-induced regulatory switch in mammalian complex I.
    Daniel N Grba, John J Wright, Zhan Yin, William Fisher, Judy Hirst.
      Respiratory complex I is an efficient driver for oxidative phosphorylation in mammalian mitochondria, but its uncontrolled catalysis under challenging conditions leads to oxidative stress and cellular damage. Ischemic conditions switch complex I from rapid, reversible catalysis into a dormant state that protects upon reoxygenation, but the molecular basis for the switch is unknown. We combined precise biochemical definition of complex I catalysis with high-resolution cryo-electron microscopy structures in the phospholipid bilayer of coupled vesicles to reveal the mechanism of the transition into the dormant state, modulated by membrane interactions. By implementing a versatile membrane system to unite structure and function, attributing catalytic and regulatory properties to specific structural states, we define how a conformational switch in complex I controls its physiological roles.
    DOI:  https://doi.org/10.1126/science.ado2075
  24. J Inherit Metab Dis. 2024 Jun 14.
    Mitochondrial membrane synthesis, remodelling and cellular trafficking.
    Martina Messina, Frédéric M Vaz, Shamima Rahman.
      Mitochondria are dynamic cellular organelles with complex roles in metabolism and signalling. Primary mitochondrial disorders are a group of approximately 400 monogenic disorders arising from pathogenic genetic variants impacting mitochondrial structure, ultrastructure and/or function. Amongst these disorders, defects of complex lipid biosynthesis, especially of the unique mitochondrial membrane lipid cardiolipin, and membrane biology are an emerging group characterised by clinical heterogeneity, but with recurrent features including cardiomyopathy, encephalopathy, neurodegeneration, neuropathy and 3-methylglutaconic aciduria. This review discusses lipid synthesis in the mitochondrial membrane, the mitochondrial contact site and cristae organising system (MICOS), mitochondrial dynamics and trafficking, and the disorders associated with defects of each of these processes. We highlight overlapping functions of proteins involved in lipid biosynthesis and protein import into the mitochondria, pointing to an overarching coordination and synchronisation of mitochondrial functions. This review also focuses on membrane interactions between mitochondria and other organelles, namely the endoplasmic reticulum, peroxisomes, lysosomes and lipid droplets. We signpost disorders of these membrane interactions that may explain the observation of secondary mitochondrial dysfunction in heterogeneous pathological processes. Disruption of these organellar interactions ultimately impairs cellular homeostasis and organismal health, highlighting the central role of mitochondria in human health and disease.
    Keywords:  MAM; MERC; MICOS; cardiolipin; cell trafficking; mitochondrial lipid biosynthesis; organellar crosstalk; primary mitochondrial disease
    DOI:  https://doi.org/10.1002/jimd.12766
  25. Diabetes. 2024 Jun 13. pii: db231013. [Epub ahead of print]
    Leucine suppresses α-cell cAMP and glucagon secretion via a combination of cell-intrinsic and islet paracrine signaling.
    Emily R Knuth, Hannah R Foster, Erli Jin, Maia H Ekstrand, Jakob G Knudsen, Matthew J Merrins.
      Glucagon is critical for the maintenance of blood glucose, however nutrient regulation of pancreatic α-cells remains poorly understood. Here, we identified a role for leucine, a well-known β-cell fuel, in the α-cell intrinsic regulation of glucagon release. In islet perifusion assays, physiological concentrations of leucine strongly inhibited alanine and arginine-stimulated glucagon secretion from human and mouse islets under hypoglycemic conditions. Mechanistically, leucine dose-dependently reduced α-cell cAMP, independently of Ca2+, ATP/ADP, or fatty acid oxidation. Leucine also reduced α-cell cAMP in islets treated with Sstr2 antagonists or diazoxide, compounds that limit paracrine signaling from β/δ-cells. Studies in dispersed mouse islets confirmed an α-cell intrinsic effect. The inhibitory effect of leucine on cAMP was mimicked by glucose, α-ketoisocaproate, succinate, and the glutamate dehydrogenase activator BCH, and blocked by cyanide, indicating a mechanism dependent on mitochondrial metabolism. Glucose dose-dependently reduced the impact of leucine on α-cell cAMP, indicating an overlap in function, however leucine was still effective at suppressing glucagon secretion in the presence of elevated glucose, amino acids, and the incretin GIP. Taken together, these findings show that leucine plays an intrinsic role in limiting α-cell secretory tone across the physiological range of glucose levels, complementing the inhibitory paracrine actions of β/δ-cells.
    DOI:  https://doi.org/10.2337/db23-1013
  26. Nat Commun. 2024 Jun 13. 15(1): 4871
    Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.
    TRACERx consortium
      The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-024-47606-9
  27. Cell Rep. 2024 Jun 11. pii: S2211-1247(24)00673-9. [Epub ahead of print]43(6): 114345
    CRISPR activation screens identify the SWI/SNF ATPases as suppressors of ferroptosis.
    Kamakoti P Bhat, Jinchu Vijay, Caroline K Vilas, Jyoti Asundi, Jun Zou, Ted Lau, Xiaoyu Cai, Musaddeque Ahmed, Michal Kabza, Julie Weng, Jean-Philippe Fortin, Aaron Lun, Steffen Durinck, Marc Hafner, Michael R Costa, Xin Ye.
      Ferroptosis is an iron-dependent cell death mechanism characterized by the accumulation of toxic lipid peroxides and cell membrane rupture. GPX4 (glutathione peroxidase 4) prevents ferroptosis by reducing these lipid peroxides into lipid alcohols. Ferroptosis induction by GPX4 inhibition has emerged as a vulnerability of cancer cells, highlighting the need to identify ferroptosis regulators that may be exploited therapeutically. Through genome-wide CRISPR activation screens, we identify the SWI/SNF (switch/sucrose non-fermentable) ATPases BRM (SMARCA2) and BRG1 (SMARCA4) as ferroptosis suppressors. Mechanistically, they bind to and increase chromatin accessibility at NRF2 target loci, thus boosting NRF2 transcriptional output to counter lipid peroxidation and confer resistance to GPX4 inhibition. We further demonstrate that the BRM/BRG1 ferroptosis connection can be leveraged to enhance the paralog dependency of BRG1 mutant cancer cells on BRM. Our data reveal ferroptosis induction as a potential avenue for broadening the efficacy of BRM degraders/inhibitors and define a specific genetic context for exploiting GPX4 dependency.
    Keywords:  CP: Cancer; CP: Molecular biology
    DOI:  https://doi.org/10.1016/j.celrep.2024.114345
  28. Nat Commun. 2024 Jun 11. 15(1): 4962
    Acetylation of histones and non-histone proteins is not a mere consequence of ongoing transcription.
    Tim Liebner, Sinan Kilic, Jonas Walter, Hitoshi Aibara, Takeo Narita, Chunaram Choudhary.
      In all eukaryotes, acetylation of histone lysine residues correlates with transcription activation. Whether histone acetylation is a cause or consequence of transcription is debated. One model suggests that transcription promotes the recruitment and/or activation of acetyltransferases, and histone acetylation occurs as a consequence of ongoing transcription. However, the extent to which transcription shapes the global protein acetylation landscapes is not known. Here, we show that global protein acetylation remains virtually unaltered after acute transcription inhibition. Transcription inhibition ablates the co-transcriptionally occurring ubiquitylation of H2BK120 but does not reduce histone acetylation. The combined inhibition of transcription and CBP/p300 further demonstrates that acetyltransferases remain active and continue to acetylate histones independently of transcription. Together, these results show that histone acetylation is not a mere consequence of transcription; acetyltransferase recruitment and activation are uncoupled from the act of transcription, and histone and non-histone protein acetylation are sustained in the absence of ongoing transcription.
    DOI:  https://doi.org/10.1038/s41467-024-49370-2
  29. Nature. 2024 Jun 12.
    Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.
    Jackie E Bader, Melissa M Wolf, Gian Luca Lupica-Tondo, Matthew Z Madden, Bradley I Reinfeld, Emily N Arner, Emma S Hathaway, KayLee K Steiner, Gabriel A Needle, Zaid Hatem, Madelyn D Landis, Eden E Faneuff, Amondrea Blackman, Elysa M Wolf, Matthew A Cottam, Xiang Ye, Madison E Bates, Kyra Smart, Wenjun Wang, Laura V Pinheiro, Anthos Christofides, DuPreez Smith, Vassiliki A Boussiotis, Scott M Haake, Kathryn E Beckermann, Kathryn E Wellen, Cynthia A Reinhart-King, C Henrique Serezani, Cheng-Han Lee, Christa Aubrey, Heidi Chen, W Kimryn Rathmell, Alyssa H Hasty, Jeffrey C Rathmell.
      Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3-5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6-8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19-12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.
    DOI:  https://doi.org/10.1038/s41586-024-07529-3
  30. Basic Res Cardiol. 2024 Jun 12.
    Malonate given at reperfusion prevents post-myocardial infarction heart failure by decreasing ischemia/reperfusion injury.
    Jiro Abe, Ana Vujic, Hiran A Prag, Michael P Murphy, Thomas Krieg.
      The mitochondrial metabolite succinate is a key driver of ischemia/reperfusion injury (IRI). Targeting succinate metabolism by inhibiting succinate dehydrogenase (SDH) upon reperfusion using malonate is an effective therapeutic strategy to achieve cardioprotection in the short term (< 24 h reperfusion) in mouse and pig in vivo myocardial infarction (MI) models. We aimed to assess whether inhibiting IRI with malonate given upon reperfusion could prevent post-MI heart failure (HF) assessed after 28 days. Male C57BL/6 J mice were subjected to 30 min left anterior coronary artery (LAD) occlusion, before reperfusion for 28 days. Malonate or without-malonate control was infused as a single dose upon reperfusion. Cardiac function was assessed by echocardiography and fibrosis by Masson's trichrome staining. Reperfusion without malonate significantly reduced ejection fraction (~ 47%), fractional shortening (~ 23%) and elevated collagen deposition 28 days post-MI. Malonate, administered as a single infusion (16 mg/kg/min for 10 min) upon reperfusion, gave a significant cardioprotective effect, with ejection fraction (~ 60%) and fractional shortening (~ 30%) preserved and less collagen deposition. Using an acidified malonate formulation, to enhance its uptake into cardiomyocytes via the monocarboxylate transporter 1, both 1.6 and 16 mg/kg/min 10 min infusion led to robust long-term cardioprotection with preserved ejection fraction (> 60%) and fractional shortening (~ 30%), as well as significantly less collagen deposition than control hearts. Malonate administration upon reperfusion prevents post-MI HF. Acidification of malonate enables lower doses of malonate to also achieve long-term cardioprotection post-MI. Therefore, the administration of acidified malonate upon reperfusion is a promising therapeutic strategy to prevent IRI and post-MI HF.
    Keywords:  Heart failure with reduced ejection fraction; Ischemia/reperfusion injury; Malonate; Mitochondria; Reactive oxygen species; Succinate
    DOI:  https://doi.org/10.1007/s00395-024-01063-z
  31. J Physiol. 2024 Jun 10.
    The mitochondrial calcium uniporter: Balancing tumourigenic and anti-tumourigenic responses.
    Danielle M Colussi, Peter B Stathopulos.
      Increased malignancy and poor treatability associated with solid tumour cancers have commonly been attributed to mitochondrial calcium (Ca2+) dysregulation. The mitochondrial Ca2+ uniporter complex (mtCU) is the predominant mode of Ca2+ uptake into the mitochondrial matrix. The main components of mtCU are the pore-forming mitochondrial Ca2+ uniporter (MCU) subunit, MCU dominant-negative beta (MCUb) subunit, essential MCU regulator (EMRE) and the gatekeeping mitochondrial Ca2+ uptake 1 and 2 (MICU1 and MICU2) proteins. In this review, we describe mtCU-mediated mitochondrial Ca2+ dysregulation in solid tumour cancer types, finding enhanced mtCU activity observed in colorectal cancer, breast cancer, oral squamous cell carcinoma, pancreatic cancer, hepatocellular carcinoma and embryonal rhabdomyosarcoma. By contrast, decreased mtCU activity is associated with melanoma, whereas the nature of mtCU dysregulation remains unclear in glioblastoma. Furthermore, we show that numerous polymorphisms associated with cancer may alter phosphorylation sites on the pore forming MCU and MCUb subunits, which cluster at interfaces with EMRE. We highlight downstream/upstream biomolecular modulators of MCU and MCUb that alter mtCU-mediated mitochondrial Ca2+ uptake and may be used as biomarkers or to aid in the development of novel cancer therapeutics. Additionally, we provide an overview of the current small molecule inhibitors of mtCU that interact with the Asp residue of the critical Asp-Ile-Met-Glu motif or through other allosteric regulatory mechanisms to block Ca2+ permeation. Finally, we describe the relationship between MCU- and MCUb-mediating microRNAs and mitochondrial Ca2+ uptake that should be considered in the discovery of new treatment approaches for cancer.
    Keywords:  MCU; MCU dominant negative beta subunit; MCUb; cancer; miRNA; mitochondrial calcium uniporter; mutation; phosphorylation
    DOI:  https://doi.org/10.1113/JP285515
  32. Nat Cell Biol. 2024 Jun;26(6): 975-990
    The glutathione S-transferase Gstt1 drives survival and dissemination in metastases.
    Christina M Ferrer, Hyo Min Cho, Ruben Boon, Tiziano Bernasocchi, Lai Ping Wong, Murat Cetinbas, Elizabeth R Haggerty, Irene Mitsiades, Gregory R Wojtkiewicz, Daniel E McLoughlin, Reem Aboushousha, Hend Abdelhamid, Sita Kugel, Esther Rheinbay, Ruslan Sadreyev, Dejan Juric, Yvonne M W Janssen-Heininger, Raul Mostoslavsky.
      Identifying the adaptive mechanisms of metastatic cancer cells remains an elusive question in the treatment of metastatic disease, particularly in pancreatic cancer (pancreatic adenocarcinoma, PDA). A loss-of-function shRNA targeted screen in metastatic-derived cells identified Gstt1, a member of the glutathione S-transferase superfamily, as uniquely required for dissemination and metastasis, but dispensable for primary tumour growth. Gstt1 is expressed in latent disseminated tumour cells (DTCs), is retained within a subpopulation of slow-cycling cells within existing metastases, and its inhibition leads to complete regression of macrometastatic tumours. This distinct Gstt1high population is highly metastatic and retains slow-cycling phenotypes, epithelial-mesenchymal transition features and DTC characteristics compared to the Gstt1low population. Mechanistic studies indicate that in this subset of cancer cells, Gstt1 maintains metastases by binding and glutathione-modifying intracellular fibronectin, in turn promoting its secretion and deposition into the metastatic microenvironment. We identified Gstt1 as a mediator of metastasis, highlighting the importance of heterogeneity and its influence on the metastatic tumour microenvironment.
    DOI:  https://doi.org/10.1038/s41556-024-01426-7
  33. Cell Rep. 2024 Jun 09. pii: S2211-1247(24)00665-X. [Epub ahead of print]43(6): 114337
    Endogenous p53 inhibitor TIRR dissociates systemic metabolic health from oncogenic activity.
    Eva Tsaousidou, Jędrzej Chrzanowski, Pascal Drané, Grace Y Lee, Nadine Bahour, Zeqiu Branden Wang, Shijun Deng, Zhe Cao, Kaimeng Huang, Yizhou He, Mateusz Kaminski, Dominika Michalek, Ekin Güney, Kalindi Parmar, Wojciech Fendler, Dipanjan Chowdhury, Gökhan S Hotamışlıgil.
      It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53HET) mouse survival and correlates with enhanced progression-free survival in patients with various p53HET carcinomas. Finally, TIRR's oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.
    Keywords:  CP: Cancer; CP: Metabolism; cancer metabolism; cancer mouse model of p53 activation; cancer protection; in vivo physiology in cancer; mevalonate pathway suppression; obesity and cancer; overweight and cancer; p53 activation; p53 derepression; p53 inhibitor; type 2 diabetes and cancer
    DOI:  https://doi.org/10.1016/j.celrep.2024.114337
  34. Proc Natl Acad Sci U S A. 2024 Jun 18. 121(25): e2310793121
    Unconventional mechanism of action and resistance to rapalogs in renal cancer.
    Juan Yang, Ramesh Butti, Shannon Cohn, Vanina Toffessi-Tcheuyap, Arijit Mal, Mylinh Nguyen, Christina Stevens, Alana Christie, Akhilesh Mishra, Yuanqing Ma, Jiwoong Kim, Robert Abraham, Payal Kapur, Robert E Hammer, James Brugarolas.
      mTORC1 is aberrantly activated in renal cell carcinoma (RCC) and is targeted by rapalogs. As for other targeted therapies, rapalogs clinical utility is limited by the development of resistance. Resistance often results from target mutation, but mTOR mutations are rarely found in RCC. As in humans, prolonged rapalog treatment of RCC tumorgrafts (TGs) led to resistance. Unexpectedly, explants from resistant tumors became sensitive both in culture and in subsequent transplants in mice. Notably, resistance developed despite persistent mTORC1 inhibition in tumor cells. In contrast, mTORC1 became reactivated in the tumor microenvironment (TME). To test the role of the TME, we engineered immunocompromised recipient mice with a resistance mTOR mutation (S2035T). Interestingly, TGs became resistant to rapalogs in mTORS2035T mice. Resistance occurred despite mTORC1 inhibition in tumor cells and could be induced by coculturing tumor cells with mutant fibroblasts. Thus, enforced mTORC1 activation in the TME is sufficient to confer resistance to rapalogs. These studies highlight the importance of mTORC1 inhibition in nontumor cells for rapalog antitumor activity and provide an explanation for the lack of mTOR resistance mutations in RCC patients.
    Keywords:  Cancer-associated fibroblasts (CAFs); everolimus; kinase inhibitors; patient-derived xenograft (PDX); temsirolimus
    DOI:  https://doi.org/10.1073/pnas.2310793121
  35. Biochem Soc Trans. 2024 Jun 12. pii: BST20240450. [Epub ahead of print]
    Role of Yme1 in mitochondrial protein homeostasis: from regulation of protein import, OXPHOS function to lipid synthesis and mitochondrial dynamics.
    Kwan Ting Kan, Joel Wilcock, Hui Lu.
      Mitochondria are essential organelles of eukaryotic cells and thus mitochondrial proteome is under constant quality control and remodelling. Yme1 is a multi-functional protein and subunit of the homo-hexametric complex i-AAA proteinase. Yme1 plays vital roles in the regulation of mitochondrial protein homeostasis and mitochondrial plasticity, ranging from substrate degradation to the regulation of protein functions involved in mitochondrial protein biosynthesis, energy production, mitochondrial dynamics, and lipid biosynthesis and signalling. In this mini review, we focus on discussing the current understanding of the roles of Yme1 in mitochondrial protein import via TIM22 and TIM23 pathways, oxidative phosphorylation complex function, as well as mitochondrial lipid biosynthesis and signalling, as well as a brief discussion of the role of Yme1 in modulating mitochondrial dynamics.
    Keywords:  i-AAA proteinase; mitochondrial protein homeostasis; mitochondrial protein import; oxidative phosphorylation complex; protein function
    DOI:  https://doi.org/10.1042/BST20240450
  36. J Exp Med. 2024 Jul 01. pii: e20221721. [Epub ahead of print]221(7):
    PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway.
    Jonathan J Hodgins, John Abou-Hamad, Colin Edward O'Dwyer, Ash Hagerman, Edward Yakubovich, Christiano Tanese de Souza, Marie Marotel, Ariel Buchler, Saleh Fadel, Maria M Park, Claire Fong-McMaster, Mathieu F Crupi, Olivia Joan Makinson, Reem Kurdieh, Reza Rezaei, Harkirat Singh Dhillon, Carolina S Ilkow, John C Bell, Mary-Ellen Harper, Benjamin H Rotstein, Rebecca C Auer, Barbara C Vanderhyden, Luc A Sabourin, Marie-Claude Bourgeois-Daigneault, David P Cook, Michele Ardolino.
      While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 promoted a metabolic shift characterized by enhanced glycolysis rate that resulted in increased lactate production. In turn, lactate inhibited type I IFN responses. In addition to adding mechanistic insight into PD-L1 intrinsic function, our results will also help guide the numerous ongoing efforts to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.
    DOI:  https://doi.org/10.1084/jem.20221721
  37. bioRxiv. 2024 May 31. pii: 2024.05.27.595830. [Epub ahead of print]
    Multi-omics profiling of mouse polycystic kidney disease progression at a single cell resolution.
    Yoshiharu Muto, Yasuhiro Yoshimura, Haojia Wu, Monica Chang-Panesso, Nicolas Ledru, Owen M Woodward, Patricia Outeda, Tao Cheng, Moe R Mahjoub, Terry J Watnick, Benjamin D Humphreys.
      Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to end-stage kidney disease. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single nucleus multimodal atlas of an orthologous mouse PKD model at early, mid and late timepoints, consisting of 125,434 single-nucleus transcriptomic and epigenetic multiomes. We catalogue differentially expressed genes and activated epigenetic regions in each cell type during PKD progression, characterizing cell-type-specific responses to Pkd1 deletion. We describe heterogeneous, atypical collecting duct cells as well as proximal tubular cells that constitute cyst epithelia in PKD. The transcriptional regulation of the cyst lining cell marker GPRC5A is conserved between mouse and human PKD cystic epithelia, suggesting shared gene regulatory pathways. Our single nucleus multiomic analysis of mouse PKD provides a foundation to understand the earliest changes molecular deregulation in a mouse model of PKD at a single-cell resolution.
    DOI:  https://doi.org/10.1101/2024.05.27.595830
  38. Nat Metab. 2024 Jun 13.
    Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes.
    Hüsün S Kizilkaya, Kimmie V Sørensen, Jakob S Madsen, Peter Lindquist, Jonathan D Douros, Jette Bork-Jensen, Alessandro Berghella, Peter A Gerlach, Lærke S Gasbjerg, Jacek Mokrosiński, Stephanie A Mowery, Patrick J Knerr, Brian Finan, Jonathan E Campbell, David A D'Alessio, Diego Perez-Tilve, Felix Faas, Signe Mathiasen, Jørgen Rungby, Henrik T Sørensen, Allan Vaag, Jens S Nielsen, Jens-Christian Holm, Jeannet Lauenborg, Peter Damm, Oluf Pedersen, Allan Linneberg, Bolette Hartmann, Jens J Holst, Torben Hansen, Shane C Wright, Volker M Lauschke, Niels Grarup, Alexander S Hauser, Mette M Rosenkilde.
      Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR-GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.
    DOI:  https://doi.org/10.1038/s42255-024-01061-4
  39. Sci Rep. 2024 Jun 14. 14(1): 13789
    Nanobiopsy investigation of the subcellular mtDNA heteroplasmy in human tissues.
    Alexander Bury, Angela Pyle, Amy E Vincent, Paolo Actis, Gavin Hudson.
      Mitochondrial function is critical to continued cellular vitality and is an important contributor to a growing number of human diseases. Mitochondrial dysfunction is typically heterogeneous, mediated through the clonal expansion of mitochondrial DNA (mtDNA) variants in a subset of cells in a given tissue. To date, our understanding of the dynamics of clonal expansion of mtDNA variants has been technically limited to the single cell-level. Here, we report the use of nanobiopsy for subcellular sampling from human tissues, combined with next-generation sequencing to assess subcellular mtDNA mutation load in human tissue from mitochondrial disease patients. The ability to map mitochondrial mutation loads within individual cells of diseased tissue samples will further our understanding of mitochondrial genetic diseases.
    DOI:  https://doi.org/10.1038/s41598-024-64455-0
  40. Ecol Evol Physiol. 2024 May-Jun;97(3):97(3): 157-163
    Telomeres and the Rate of Living: Linking Biological Clocks of Senescence.
    James F Gillooly, Emily S Khazan.
      AbstractTwo prominent theories of aging, one based on telomere dynamics and the other on mass-specific energy flux, propose biological time clocks of senescence. The relationship between these two theories, and the biological clocks proposed by each, remains unclear. Here, we examine the relationships between telomere shortening rate, mass-specific metabolic rate, and lifespan among vertebrates (mammals, birds, fishes). Results show that telomere shortening rate increases linearly with mass-specific metabolic rate and decreases nonlinearly with increasing body mass in the same way as mass-specific metabolic rate. Results also show that both telomere shortening rate and mass-specific metabolic rate are similarly related to lifespan and that both strongly predict differences in lifespan, although the slopes of the relationships are less than linear. On average, then, telomeres shorten a fixed amount per unit of mass-specific energy flux. So the mitotic clock of telomere shortening and the energetics-based clock described by metabolic rate can be viewed as alternative measures of the same biological clock. These two processes may be linked, we speculate, through the process of cell division.
    Keywords:  aging; energetics; longevity; scaling; telomere dynamics
    DOI:  https://doi.org/10.1086/730588
  41. Nature. 2024 Jun 11.
    The Space Omics and Medical Atlas (SOMA) and international astronaut biobank.
    Eliah G Overbey, JangKeun Kim, Braden T Tierney, Jiwoon Park, Nadia Houerbi, Alexander G Lucaci, Sebastian Garcia Medina, Namita Damle, Deena Najjar, Kirill Grigorev, Evan E Afshin, Krista A Ryon, Karolina Sienkiewicz, Laura Patras, Remi Klotz, Veronica Ortiz, Matthew MacKay, Annalise Schweickart, Christopher R Chin, Maria A Sierra, Matias F Valenzuela, Ezequiel Dantas, Theodore M Nelson, Egle Cekanaviciute, Gabriel Deards, Jonathan Foox, S Anand Narayanan, Caleb M Schmidt, Michael A Schmidt, Julian C Schmidt, Sean Mullane, Seth Stravers Tigchelaar, Steven Levitte, Craig Westover, Chandrima Bhattacharya, Serena Lucotti, Jeremy Wain Hirschberg, Jacqueline Proszynski, Marissa Burke, Ashley Kleinman, Daniel J Butler, Conor Loy, Omary Mzava, Joan Lenz, Doru Paul, Christopher Mozsary, Lauren M Sanders, Lynn E Taylor, Chintan O Patel, Sharib A Khan, Mir Suhail, Syed G Byhaqui, Burhan Aslam, Aaron S Gajadhar, Lucy Williamson, Purvi Tandel, Qiu Yang, Jessica Chu, Ryan W Benz, Asim Siddiqui, Daniel Hornburg, Kelly Blease, Juan Moreno, Andrew Boddicker, Junhua Zhao, Bryan Lajoie, Ryan T Scott, Rachel R Gilbert, San-Huei Lai Polo, Andrew Altomare, Semyon Kruglyak, Shawn Levy, Ishara Ariyapala, Joanne Beer, Bingqing Zhang, Briana M Hudson, Aric Rininger, Sarah E Church, Afshin Beheshti, George M Church, Scott M Smith, Brian E Crucian, Sara R Zwart, Irina Matei, David C Lyden, Francine Garrett-Bakelman, Jan Krumsiek, Qiuying Chen, Dawson Miller, Joe Shuga, Stephen Williams, Corey Nemec, Guy Trudel, Martin Pelchat, Odette Laneuville, Iwijn De Vlaminck, Steven Gross, Kelly L Bolton, Susan M Bailey, Richard Granstein, David Furman, Ari M Melnick, Sylvain V Costes, Bader Shirah, Min Yu, Anil S Menon, Jaime Mateus, Cem Meydan, Christopher E Mason.
      Spaceflight induces molecular, cellular, and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space1-6. Yet, current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools, and protocols. Here, we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular, and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study7, JAXA CFE study8,9, SpaceX Inspiration4 crew10-12, plus Axiom and Polaris. The SOMA resource represents a >10-fold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiome data sets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation, and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific murine data sets. Leveraging the datasets, tools, and resources in SOMA can help accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation, and countermeasures data for upcoming lunar, Mars, and exploration-class missions.
    DOI:  https://doi.org/10.1038/s41586-024-07639-y
  42. Nat Commun. 2024 Jun 11. 15(1): 4969
    MYG1 drives glycolysis and colorectal cancer development through nuclear-mitochondrial collaboration.
    Jianxiong Chen, Shiyu Duan, Yulu Wang, Yuping Ling, Xiaotao Hou, Sijing Zhang, Xunhua Liu, Xiaoli Long, Jiawen Lan, Miao Zhou, Huimeng Xu, Haoxuan Zheng, Jun Zhou.
      Metabolic remodeling is a strategy for tumor survival under stress. However, the molecular mechanisms during the metabolic remodeling of colorectal cancer (CRC) remain unclear. Melanocyte proliferating gene 1 (MYG1) is a 3'-5' RNA exonuclease and plays a key role in mitochondrial functions. Here, we uncover that MYG1 expression is upregulated in CRC progression and highly expressed MYG1 promotes glycolysis and CRC progression independent of its exonuclease activity. Mechanistically, nuclear MYG1 recruits HSP90/GSK3β complex to promote PKM2 phosphorylation, increasing its stability. PKM2 transcriptionally activates MYC and promotes MYC-medicated glycolysis. Conversely, c-Myc also transcriptionally upregulates MYG1, driving the progression of CRC. Meanwhile, mitochondrial MYG1 on the one hand inhibits oxidative phosphorylation (OXPHOS), and on the other hand blocks the release of Cyt c from mitochondria and inhibits cell apoptosis. Clinically, patients with KRAS mutation show high expression of MYG1, indicating a high level of glycolysis and a poor prognosis. Targeting MYG1 may disturb metabolic balance of CRC and serve as a potential target for the diagnosis and treatment of CRC.
    DOI:  https://doi.org/10.1038/s41467-024-49221-0
  43. Cancer Discov. 2024 Jun 12. OF1-OF7
    Tumor Promoters and Opportunities for Molecular Cancer Prevention.
    William Hill, Clare E Weeden, Charles Swanton.
      Environmental carcinogens increase cancer incidence via both mutagenic and non-mutagenic mechanisms. There are over 500 known or suspected carcinogens classified by the International Agency for Research on Cancer. Sequencing of both cancerous and histologically non-cancerous tissue has been instrumental in improving our understanding of how environmental carcinogens cause cancer. Understanding how and defining which environmental or lifestyle exposures drive cancer will support cancer prevention. Recent research is revisiting the mechanisms of early tumorigenesis, paving the way for an era of molecular cancer prevention. Significance: Recent data have improved our understanding of how carcinogens cause cancer, which may reveal novel opportunities for molecular cancer prevention.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0128
  44. Nat Commun. 2024 Jun 11. 15(1): 4923
    Cosmic kidney disease: an integrated pan-omic, physiological and morphological study into spaceflight-induced renal dysfunction.
    Keith Siew, Kevin A Nestler, Charlotte Nelson, Viola D'Ambrosio, Chutong Zhong, Zhongwang Li, Alessandra Grillo, Elizabeth R Wan, Vaksha Patel, Eliah Overbey, JangKeun Kim, Sanghee Yun, Michael B Vaughan, Chris Cheshire, Laura Cubitt, Jessica Broni-Tabi, Maneera Yousef Al-Jaber, Valery Boyko, Cem Meydan, Peter Barker, Shehbeel Arif, Fatemeh Afsari, Noah Allen, Mohammed Al-Maadheed, Selin Altinok, Nourdine Bah, Samuel Border, Amanda L Brown, Keith Burling, Margareth Cheng-Campbell, Lorianna M Colón, Lovorka Degoricija, Nichola Figg, Rebecca Finch, Jonathan Foox, Pouya Faridi, Alison French, Samrawit Gebre, Peter Gordon, Nadia Houerbi, Hossein Valipour Kahrood, Frederico C Kiffer, Aleksandra S Klosinska, Angela Kubik, Han-Chung Lee, Yinghui Li, Nicholas Lucarelli, Anthony L Marullo, Irina Matei, Colleen M McCann, Sayat Mimar, Ahmed Naglah, Jérôme Nicod, Kevin M O'Shaughnessy, Lorraine Christine De Oliveira, Leah Oswalt, Laura Ioana Patras, San-Huei Lai Polo, María Rodríguez-Lopez, Candice Roufosse, Omid Sadeghi-Alavijeh, Rebekah Sanchez-Hodge, Anindya S Paul, Ralf Bernd Schittenhelm, Annalise Schweickart, Ryan T Scott, Terry Chin Choy Lim Kam Sian, Willian A da Silveira, Hubert Slawinski, Daniel Snell, Julio Sosa, Amanda M Saravia-Butler, Marshall Tabetah, Erwin Tanuwidjaya, Simon Walker-Samuel, Xiaoping Yang, Yasmin, Haijian Zhang, Jasminka Godovac-Zimmermann, Pinaki Sarder, Lauren M Sanders, Sylvain V Costes, Robert A A Campbell, Fathi Karouia, Vidya Mohamed-Alis, Samuel Rodriques, Steven Lynham, Joel Ricky Steele, Sergio Baranzini, Hossein Fazelinia, Zhongquan Dai, Akira Uruno, Dai Shiba, Masayuki Yamamoto, Eduardo A C Almeida, Elizabeth Blaber, Jonathan C Schisler, Amelia J Eisch, Masafumi Muratani, Sara R Zwart, Scott M Smith, Jonathan M Galazka, Christopher E Mason, Afshin Beheshti, Stephen B Walsh.
      Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts' increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR.
    DOI:  https://doi.org/10.1038/s41467-024-49212-1
  45. Res Sq. 2024 May 30. pii: rs.3.rs-4413958. [Epub ahead of print]
    Multi-omic Analysis of Human B-cell Activation Reveals a Key Lysosomal BCAT1 Role in mTOR Hyperactivation by B-cell receptor and TLR9.
    Benjamin Gewurz, Rui Guo, Matthew Lim, Hardik Shah, Joao Paulo, Yuchen Zhang, Haopeng Yang, Liang Wei Wang, Daniel Strebinger, Nicolas Smith, Meng Li, Merrin Leong, Michael Lutchenkov, Jin-Hua Liang, Zhixuan Li, Yin Wang, Rishi Puri, Ari Melnick, Michael Green, John Asara, Adonia Papathanassiu, Steven Gygi, Vamsi Mootha.
      B-lymphocytes play major adaptive immune roles, producing antibody and driving T-cell responses. However, how immunometabolism networks support B-cell activation and differentiation in response to distinct receptor stimuli remains incompletely understood. To gain insights, we systematically investigated acute primary human B-cell transcriptional, translational and metabolomic responses to B-cell receptor (BCR), Toll-like receptor 9 (TLR9), CD40-ligand (CD40L), interleukin-4 (IL4) or combinations thereof. T-independent BCR/TLR9 co-stimulation, which drives malignant and autoimmune B-cell states, jointly induced PD-L1 plasma membrane expression, supported by NAD metabolism and oxidative phosphorylation. BCR/TLR9 also highly induced the transaminase BCAT1, which localized to lysosomal membranes to support branched chain amino acid synthesis and mTORC1 hyperactivation. BCAT1 inhibition blunted BCR/TLR9, but not CD40L/IL4-triggered B-cell proliferation, IL10 expression and BCR/TLR pathway-driven lymphoma xenograft outgrowth. These results provide a valuable resource, reveal receptor-mediated immunometabolism remodeling to support key B-cell phenotypes including PD-L1 checkpoint signaling, and identify BCAT1 as a novel B-cell therapeutic target.
    DOI:  https://doi.org/10.21203/rs.3.rs-4413958/v1
  46. Nat Commun. 2024 Jun 11. 15(1): 4773
    Spatial multi-omics of human skin reveals KRAS and inflammatory responses to spaceflight.
    Jiwoon Park, Eliah G Overbey, S Anand Narayanan, JangKeun Kim, Braden T Tierney, Namita Damle, Deena Najjar, Krista A Ryon, Jacqueline Proszynski, Ashley Kleinman, Jeremy Wain Hirschberg, Matthew MacKay, Evan E Afshin, Richard Granstein, Justin Gurvitch, Briana M Hudson, Aric Rininger, Sean Mullane, Sarah E Church, Cem Meydan, George Church, Afshin Beheshti, Jaime Mateus, Christopher E Mason.
      Spaceflight can change metabolic, immunological, and biological homeostasis and cause skin rashes and irritation, yet the molecular basis remains unclear. To investigate the impact of short-duration spaceflight on the skin, we conducted skin biopsies on the Inspiration4 crew members before (L-44) and after (R + 1) flight. Leveraging multi-omics assays including GeoMx™ Digital Spatial Profiler, single-cell RNA/ATAC-seq, and metagenomics/metatranscriptomics, we assessed spatial gene expressions and associated microbial and immune changes across 95 skin regions in four compartments: outer epidermis, inner epidermis, outer dermis, and vasculature. Post-flight samples showed significant up-regulation of genes related to inflammation and KRAS signaling across all skin regions. These spaceflight-associated changes mapped to specific cellular responses, including altered interferon responses, DNA damage, epithelial barrier disruptions, T-cell migration, and hindered regeneration were located primarily in outer tissue compartments. We also linked epithelial disruption to microbial shifts in skin swab and immune cell activity to PBMC single-cell data from the same crew and timepoints. Our findings present the inaugural collection and examination of astronaut skin, offering insights for future space missions and response countermeasures.
    DOI:  https://doi.org/10.1038/s41467-024-48625-2
This page is being maintained by Thomas Krichel. It was last updated on 2024‒06‒16 at 5:41.