bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–04–30
twenty-six papers selected by
Christian Frezza, Universität zu Köln
  1. The Warburg effect: a signature of mitochondrial overload.
  2. Branched-chain amino acid catabolism in muscle affects systemic BCAA levels but not insulin resistance.
  3. Apoptotic cell death in disease-Current understanding of the NCCD 2023.
  4. Human basal metabolic rate has declined over the past 30 years.
  5. MICU1 regulates mitochondrial cristae structure and function independently of the mitochondrial Ca2+ uniporter channel.
  6. Integrative genetic analysis identifies FLVCR1 as a plasma-membrane choline transporter in mammals.
  7. The Hexosamine Biosynthesis Pathway: Regulation and Function.
  8. Multi-omic profiling reveals an RNA processing rheostat that predisposes to prostate cancer.
  9. Biological age is increased by stress and restored upon recovery.
  10. Mitochondrial dynamics define muscle fiber type by modulating cellular metabolic pathways.
  11. Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria.
  12. Cachexia: A systemic consequence of progressive, unresolved disease.
  13. SARM1 deletion delays cerebellar but not spinal cord degeneration in an enhanced mouse model of SPG7 deficiency.
  14. Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction.
  15. Why a good lab website matters.
  16. A metabolic clue for STING suppression.
  17. FGF-21 Conducts a Liver-Brain-Kidney Axis to Promote Renal Cell Carcinoma.
  18. PCK1 is a key regulator of metabolic and mitochondrial functions in renal tubular cells.
  19. Identification of metabolic networks by genetic co-essentiality analysis.
  20. Dysregulated cellular redox status during hyperammonemia causes mitochondrial dysfunction and senescence by inhibiting sirtuin-mediated deacetylation.
  21. HAPLN1 potentiates peritoneal metastasis in pancreatic cancer.
  22. A tissue injury sensing and repair pathway distinct from host pathogen defense.
  23. A druggable copper-signalling pathway that drives inflammation.
  24. Ferroptosis model system by the re-expression of BACH1.
  25. Cellular barcoding tracks heterogeneous clones through selective pressures and phenotypic transitions.
  26. EMT in chemoresistance.
  1. Trends Cell Biol. 2023 Apr 26. pii: S0962-8924(23)00070-3. [Epub ahead of print]
    The Warburg effect: a signature of mitochondrial overload.
    Yahui Wang, Gary J Patti.
      A long-standing question in cancer biology has been why oxygenated tumors ferment the majority of glucose they consume to lactate rather than oxidizing it in their mitochondria, a phenomenon known as the 'Warburg effect.' An abundance of evidence shows not only that most cancer cells have fully functional mitochondria but also that mitochondrial activity is important to proliferation. It is therefore difficult to rationalize the metabolic benefit of cancer cells switching from respiration to fermentation. An emerging perspective is that rather than mitochondrial metabolism being suppressed in tumors, as is often suggested, mitochondrial activity increases to the level of saturation. As such, the Warburg effect becomes a signature of excess glucose being released as lactate due to mitochondrial overload.
    Keywords:  Warburg effect; aerobic fermentation; aerobic glycolysis; cancer metabolism; mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.tcb.2023.03.013
  2. Nat Metab. 2023 Apr;5(4): 589-606
    Branched-chain amino acid catabolism in muscle affects systemic BCAA levels but not insulin resistance.
    Megan C Blair, Michael D Neinast, Cholsoon Jang, Qingwei Chu, Jae Woo Jung, Jessie Axsom, Marc R Bornstein, Chelsea Thorsheim, Kristina Li, Atsushi Hoshino, Steven Yang, Rachel J Roth Flach, Bei B Zhang, Joshua D Rabinowitz, Zoltan Arany.
      Elevated levels of plasma branched-chain amino acids (BCAAs) have been associated with insulin resistance and type 2 diabetes since the 1960s. Pharmacological activation of branched-chain α-ketoacid dehydrogenase (BCKDH), the rate-limiting enzyme of BCAA oxidation, lowers plasma BCAAs and improves insulin sensitivity. Here we show that modulation of BCKDH in skeletal muscle, but not liver, affects fasting plasma BCAAs in male mice. However, despite lowering BCAAs, increased BCAA oxidation in skeletal muscle does not improve insulin sensitivity. Our data indicate that skeletal muscle controls plasma BCAAs, that lowering fasting plasma BCAAs is insufficient to improve insulin sensitivity and that neither skeletal muscle nor liver account for the improved insulin sensitivity seen with pharmacological activation of BCKDH. These findings suggest potential concerted contributions of multiple tissues in the modulation of BCAA metabolism to alter insulin sensitivity.
    DOI:  https://doi.org/10.1038/s42255-023-00794-y
  3. Cell Death Differ. 2023 Apr 26.
    Apoptotic cell death in disease-Current understanding of the NCCD 2023.
    Ilio Vitale, Federico Pietrocola, Emma Guilbaud, Stuart A Aaronson, John M Abrams, Dieter Adam, Massimiliano Agostini, Patrizia Agostinis, Emad S Alnemri, Lucia Altucci, Ivano Amelio, David W Andrews, Rami I Aqeilan, Eli Arama, Eric H Baehrecke, Siddharth Balachandran, Daniele Bano, Nickolai A Barlev, Jiri Bartek, Nicolas G Bazan, Christoph Becker, Francesca Bernassola, Mathieu J M Bertrand, Marco E Bianchi, Mikhail V Blagosklonny, J Magarian Blander, Giovanni Blandino, Klas Blomgren, Christoph Borner, Carl D Bortner, Pierluigi Bove, Patricia Boya, Catherine Brenner, Petr Broz, Thomas Brunner, Rune Busk Damgaard, George A Calin, Michelangelo Campanella, Eleonora Candi, Michele Carbone, Didac Carmona-Gutierrez, Francesco Cecconi, Francis K-M Chan, Guo-Qiang Chen, Quan Chen, Youhai H Chen, Emily H Cheng, Jerry E Chipuk, John A Cidlowski, Aaron Ciechanover, Gennaro Ciliberto, Marcus Conrad, Juan R Cubillos-Ruiz, Peter E Czabotar, Vincenzo D'Angiolella, Mads Daugaard, Ted M Dawson, Valina L Dawson, Ruggero De Maria, Bart De Strooper, Klaus-Michael Debatin, Ralph J Deberardinis, Alexei Degterev, Giannino Del Sal, Mohanish Deshmukh, Francesco Di Virgilio, Marc Diederich, Scott J Dixon, Brian D Dynlacht, Wafik S El-Deiry, John W Elrod, Kurt Engeland, Gian Maria Fimia, Claudia Galassi, Carlo Ganini, Ana J Garcia-Saez, Abhishek D Garg, Carmen Garrido, Evripidis Gavathiotis, Motti Gerlic, Sourav Ghosh, Douglas R Green, Lloyd A Greene, Hinrich Gronemeyer, Georg Häcker, György Hajnóczky, J Marie Hardwick, Ygal Haupt, Sudan He, David M Heery, Michael O Hengartner, Claudio Hetz, David A Hildeman, Hidenori Ichijo, Satoshi Inoue, Marja Jäättelä, Ana Janic, Bertrand Joseph, Philipp J Jost, Thirumala-Devi Kanneganti, Michael Karin, Hamid Kashkar, Thomas Kaufmann, Gemma L Kelly, Oliver Kepp, Adi Kimchi, Richard N Kitsis, Daniel J Klionsky, Ruth Kluck, Dmitri V Krysko, Dagmar Kulms, Sharad Kumar, Sergio Lavandero, Inna N Lavrik, John J Lemasters, Gianmaria Liccardi, Andreas Linkermann, Stuart A Lipton, Richard A Lockshin, Carlos López-Otín, Tom Luedde, Marion MacFarlane, Frank Madeo, Walter Malorni, Gwenola Manic, Roberto Mantovani, Saverio Marchi, Jean-Christophe Marine, Seamus J Martin, Jean-Claude Martinou, Pier G Mastroberardino, Jan Paul Medema, Patrick Mehlen, Pascal Meier, Gerry Melino, Sonia Melino, Edward A Miao, Ute M Moll, Cristina Muñoz-Pinedo, Daniel J Murphy, Maria Victoria Niklison-Chirou, Flavia Novelli, Gabriel Núñez, Andrew Oberst, Dimitry Ofengeim, Joseph T Opferman, Moshe Oren, Michele Pagano, Theocharis Panaretakis, Manolis Pasparakis, Josef M Penninger, Francesca Pentimalli, David M Pereira, Shazib Pervaiz, Marcus E Peter, Paolo Pinton, Giovanni Porta, Jochen H M Prehn, Hamsa Puthalakath, Gabriel A Rabinovich, Krishnaraj Rajalingam, Kodi S Ravichandran, Markus Rehm, Jean-Ehrland Ricci, Rosario Rizzuto, Nirmal Robinson, Cecilia M P Rodrigues, Barak Rotblat, Carla V Rothlin, David C Rubinsztein, Thomas Rudel, Alessandro Rufini, Kevin M Ryan, Kristopher A Sarosiek, Akira Sawa, Emre Sayan, Kate Schroder, Luca Scorrano, Federico Sesti, Feng Shao, Yufang Shi, Giuseppe S Sica, John Silke, Hans-Uwe Simon, Antonella Sistigu, Anastasis Stephanou, Brent R Stockwell, Flavie Strapazzon, Andreas Strasser, Liming Sun, Erwei Sun, Qiang Sun, Gyorgy Szabadkai, Stephen W G Tait, Daolin Tang, Nektarios Tavernarakis, Carol M Troy, Boris Turk, Nicoletta Urbano, Peter Vandenabeele, Tom Vanden Berghe, Matthew G Vander Heiden, Jacqueline L Vanderluit, Alexei Verkhratsky, Andreas Villunger, Silvia von Karstedt, Anne K Voss, Karen H Vousden, Domagoj Vucic, Daniela Vuri, Erwin F Wagner, Henning Walczak, David Wallach, Ruoning Wang, Ying Wang, Achim Weber, Will Wood, Takahiro Yamazaki, Huang-Tian Yang, Zahra Zakeri, Joanna E Zawacka-Pankau, Lin Zhang, Haibing Zhang, Boris Zhivotovsky, Wenzhao Zhou, Mauro Piacentini, Guido Kroemer, Lorenzo Galluzzi.
      Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
    DOI:  https://doi.org/10.1038/s41418-023-01153-w
  4. Nat Metab. 2023 Apr;5(4): 544-545
    Human basal metabolic rate has declined over the past 30 years.
      
    DOI:  https://doi.org/10.1038/s42255-023-00790-2
  5. Sci Signal. 2023 04 25. 16(782): eabi8948
    MICU1 regulates mitochondrial cristae structure and function independently of the mitochondrial Ca2+ uniporter channel.
    Dhanendra Tomar, Manfred Thomas, Joanne F Garbincius, Devin W Kolmetzky, Oniel Salik, Pooja Jadiya, Suresh K Joseph, April C Carpenter, György Hajnóczky, John W Elrod.
      MICU1 is a calcium (Ca2+)-binding protein that regulates the mitochondrial Ca2+ uniporter channel complex (mtCU) and mitochondrial Ca2+ uptake. MICU1 knockout mice display disorganized mitochondrial architecture, a phenotype that is distinct from that of mice with deficiencies in other mtCU subunits and, thus, is likely not explained by changes in mitochondrial matrix Ca2+ content. Using proteomic and cellular imaging techniques, we found that MICU1 localized to the mitochondrial contact site and cristae organizing system (MICOS) and directly interacted with the MICOS components MIC60 and CHCHD2 independently of the mtCU. We demonstrated that MICU1 was essential for MICOS complex formation and that MICU1 ablation resulted in altered cristae organization, mitochondrial ultrastructure, mitochondrial membrane dynamics, and cell death signaling. Together, our results suggest that MICU1 is an intermembrane space Ca2+ sensor that modulates mitochondrial membrane dynamics independently of matrix Ca2+ uptake. This system enables distinct Ca2+ signaling in the mitochondrial matrix and at the intermembrane space to modulate cellular energetics and cell death in a concerted manner.
    DOI:  https://doi.org/10.1126/scisignal.abi8948
  6. Cell Metab. 2023 Apr 20. pii: S1550-4131(23)00130-4. [Epub ahead of print]
    Integrative genetic analysis identifies FLVCR1 as a plasma-membrane choline transporter in mammals.
    Timothy C Kenny, Artem Khan, Yeeun Son, Lishu Yue, Søren Heissel, Anurag Sharma, H Amalia Pasolli, Yuyang Liu, Eric R Gamazon, Hanan Alwaseem, Richard K Hite, Kıvanç Birsoy.
      Genome-wide association studies (GWASs) of serum metabolites have the potential to uncover genes that influence human metabolism. Here, we combined an integrative genetic analysis that associates serum metabolites to membrane transporters with a coessentiality map of metabolic genes. This analysis revealed a connection between feline leukemia virus subgroup C cellular receptor 1 (FLVCR1) and phosphocholine, a downstream metabolite of choline metabolism. Loss of FLVCR1 in human cells strongly impairs choline metabolism due to the inhibition of choline import. Consistently, CRISPR-based genetic screens identified phospholipid synthesis and salvage machinery as synthetic lethal with FLVCR1 loss. Cells and mice lacking FLVCR1 exhibit structural defects in mitochondria and upregulate integrated stress response (ISR) through heme-regulated inhibitor (HRI) kinase. Finally, Flvcr1 knockout mice are embryonic lethal, which is partially rescued by choline supplementation. Altogether, our findings propose FLVCR1 as a major choline transporter in mammals and provide a platform to discover substrates for unknown metabolite transporters.
    Keywords:  FLVCR1; PCARP; choline; metabolism; mitochondria; phosphatidylcholine
    DOI:  https://doi.org/10.1016/j.cmet.2023.04.003
  7. Genes (Basel). 2023 Apr 18. pii: 933. [Epub ahead of print]14(4):
    The Hexosamine Biosynthesis Pathway: Regulation and Function.
    Alysta Paneque, Harvey Fortus, Julia Zheng, Guy Werlen, Estela Jacinto.
      The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate-N-acetyl glucosamine, UDP-GlcNAc, which is a key metabolite that is used for N- or O-linked glycosylation, a co- or post-translational modification, respectively, that modulates protein activity and expression. The production of hexosamines can occur via de novo or salvage mechanisms that are catalyzed by metabolic enzymes. Nutrients including glutamine, glucose, acetyl-CoA, and UTP are utilized by the HBP. Together with availability of these nutrients, signaling molecules that respond to environmental signals, such as mTOR, AMPK, and stress-regulated transcription factors, modulate the HBP. This review discusses the regulation of GFAT, the key enzyme of the de novo HBP, as well as other metabolic enzymes that catalyze the reactions to produce UDP-GlcNAc. We also examine the contribution of the salvage mechanisms in the HBP and how dietary supplementation of the salvage metabolites glucosamine and N-acetylglucosamine could reprogram metabolism and have therapeutic potential. We elaborate on how UDP-GlcNAc is utilized for N-glycosylation of membrane and secretory proteins and how the HBP is reprogrammed during nutrient fluctuations to maintain proteostasis. We also consider how O-GlcNAcylation is coupled to nutrient availability and how this modification modulates cell signaling. We summarize how deregulation of protein N-glycosylation and O-GlcNAcylation can lead to diseases including cancer, diabetes, immunodeficiencies, and congenital disorders of glycosylation. We review the current pharmacological strategies to inhibit GFAT and other enzymes involved in the HBP or glycosylation and how engineered prodrugs could have better therapeutic efficacy for the treatment of diseases related to HBP deregulation.
    Keywords:  GFAT1; GFAT2; Gfpt1; O-GlcNAcylation; UDP-GlcNAc; glucosamine; glycosylation; hexosamine biosynthesis pathway; metabolism; protein folding
    DOI:  https://doi.org/10.3390/genes14040933
  8. EMBO Mol Med. 2023 Apr 24. e17463
    Multi-omic profiling reveals an RNA processing rheostat that predisposes to prostate cancer.
    Maike Stentenbach, Judith A Ermer, Danielle L Rudler, Kara L Perks, Samuel A Raven, Richard G Lee, Tim McCubbin, Esteban Marcellin, Stefan J Siira, Oliver Rackham, Aleksandra Filipovska.
      Prostate cancer is the most commonly diagnosed malignancy and the third leading cause of cancer deaths. GWAS have identified variants associated with prostate cancer susceptibility; however, mechanistic and functional validation of these mutations is lacking. We used CRISPR-Cas9 genome editing to introduce a missense variant identified in the ELAC2 gene, which encodes a dually localised nuclear and mitochondrial RNA processing enzyme, into the mouse Elac2 gene as well as to generate a prostate-specific knockout of Elac2. These mutations caused enlargement and inflammation of the prostate and nodule formation. The Elac2 variant or knockout mice on the background of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model show that Elac2 mutation with a secondary genetic insult exacerbated the onset and progression of prostate cancer. Multiomic profiling revealed defects in energy metabolism that activated proinflammatory and tumorigenic pathways as a consequence of impaired noncoding RNA processing and reduced protein synthesis. Our physiologically relevant models show that the ELAC2 variant is a predisposing factor for prostate cancer and identify changes that underlie the pathogenesis of this cancer.
    Keywords:  RNA processing; gene expression; mitochondria; prostate cancer susceptibility
    DOI:  https://doi.org/10.15252/emmm.202317463
  9. Cell Metab. 2023 Apr 04. pii: S1550-4131(23)00093-1. [Epub ahead of print]
    Biological age is increased by stress and restored upon recovery.
    Jesse R Poganik, Bohan Zhang, Gurpreet S Baht, Alexander Tyshkovskiy, Amy Deik, Csaba Kerepesi, Sun Hee Yim, Ake T Lu, Amin Haghani, Tong Gong, Anna M Hedman, Ellika Andolf, Göran Pershagen, Catarina Almqvist, Clary B Clish, Steve Horvath, James P White, Vadim N Gladyshev.
      Aging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies have raised the possibility of age reversal. Here, we report that biological age is fluid and exhibits rapid changes in both directions. At epigenetic, transcriptomic, and metabolomic levels, we find that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment. We also identify transient changes in biological age during major surgery, pregnancy, and severe COVID-19 in humans and/or mice. Together, these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress. Our study uncovers a new layer of aging dynamics that should be considered in future studies. The elevation of biological age by stress may be a quantifiable and actionable target for future interventions.
    Keywords:  aging; biological age; dynamics; epigenetic aging clocks; recovery; stress
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.015
  10. Cell Rep. 2023 Apr 24. pii: S2211-1247(23)00445-X. [Epub ahead of print]42(5): 112434
    Mitochondrial dynamics define muscle fiber type by modulating cellular metabolic pathways.
    Tatsuki Yasuda, Takaya Ishihara, Ayaka Ichimura, Naotada Ishihara.
      Skeletal muscle is highly developed after birth, consisting of glycolytic fast-twitch and oxidative slow-twitch fibers; however, the mechanisms of fiber-type-specific differentiation are poorly understood. Here, we found an unexpected role of mitochondrial fission in the differentiation of fast-twitch oxidative fibers. Depletion of the mitochondrial fission factor dynamin-related protein 1 (Drp1) in mouse skeletal muscle and cultured myotubes results in specific reduction of fast-twitch muscle fibers independent of respiratory function. Altered mitochondrial fission causes activation of the Akt/mammalian target of rapamycin (mTOR) pathway via mitochondrial accumulation of mTOR complex 2 (mTORC2), and rapamycin administration rescues the reduction of fast-twitch fibers in vivo and in vitro. Under Akt/mTOR activation, the mitochondria-related cytokine growth differentiation factor 15 is upregulated, which represses fast-twitch fiber differentiation. Our findings reveal a crucial role of mitochondrial dynamics in the activation of mTORC2 on mitochondria, resulting in the differentiation of muscle fibers.
    Keywords:  Akt; CP: Metabolism; Drp1; GDF-15; mTOR; mitochondria; mitochondrial dynamics; muscle atrophy; muscle differentiation
    DOI:  https://doi.org/10.1016/j.celrep.2023.112434
  11. Nat Commun. 2023 Apr 24. 14(1): 2356
    Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria.
    Janne Purhonen, Rishi Banerjee, Vilma Wanne, Nina Sipari, Matthias Mörgelin, Vineta Fellman, Jukka Kallijärvi.
      Accumulating evidence suggests mitochondria as key modulators of normal and premature aging, yet whether primary oxidative phosphorylation (OXPHOS) deficiency can cause progeroid disease remains unclear. Here, we show that mice with severe isolated respiratory complex III (CIII) deficiency display nuclear DNA damage, cell cycle arrest, aberrant mitoses, and cellular senescence in the affected organs such as liver and kidney, and a systemic phenotype resembling juvenile-onset progeroid syndromes. Mechanistically, CIII deficiency triggers presymptomatic cancer-like c-MYC upregulation followed by excessive anabolic metabolism and illicit cell proliferation against lack of energy and biosynthetic precursors. Transgenic alternative oxidase dampens mitochondrial integrated stress response and the c-MYC induction, suppresses the illicit proliferation, and prevents juvenile lethality despite that canonical OXPHOS-linked functions remain uncorrected. Inhibition of c-MYC with the dominant-negative Omomyc protein relieves the DNA damage in CIII-deficient hepatocytes in vivo. Our results connect primary OXPHOS deficiency to genomic instability and progeroid pathogenesis and suggest that targeting c-MYC and aberrant cell proliferation may be therapeutic in mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s41467-023-38027-1
  12. Cell. 2023 Apr 27. pii: S0092-8674(23)00325-2. [Epub ahead of print]186(9): 1824-1845
    Cachexia: A systemic consequence of progressive, unresolved disease.
    Miriam Ferrer, Tracy G Anthony, Janelle S Ayres, Giulia Biffi, Justin C Brown, Bette J Caan, Elizabeth M Cespedes Feliciano, Anthony P Coll, Richard F Dunne, Marcus D Goncalves, Jonas Grethlein, Steven B Heymsfield, Sheng Hui, Mariam Jamal-Hanjani, Jie Min Lam, David Y Lewis, David McCandlish, Karen M Mustian, Stephen O'Rahilly, Norbert Perrimon, Eileen P White, Tobias Janowitz.
      Cachexia, a systemic wasting condition, is considered a late consequence of diseases, including cancer, organ failure, or infections, and contributes to significant morbidity and mortality. The induction process and mechanistic progression of cachexia are incompletely understood. Refocusing academic efforts away from advanced cachexia to the etiology of cachexia may enable discoveries of new therapeutic approaches. Here, we review drivers, mechanisms, organismal predispositions, evidence for multi-organ interaction, model systems, clinical research, trials, and care provision from early onset to late cachexia. Evidence is emerging that distinct inflammatory, metabolic, and neuro-modulatory drivers can initiate processes that ultimately converge on advanced cachexia.
    DOI:  https://doi.org/10.1016/j.cell.2023.03.028
  13. Brain. 2023 Apr 22. pii: awad136. [Epub ahead of print]
    SARM1 deletion delays cerebellar but not spinal cord degeneration in an enhanced mouse model of SPG7 deficiency.
    Carolina Montoro-Gámez, Hendrik Nolte, Thibaut Molinié, Giovanna Evangelista, Simon Tröder, Esther Barth, Milica Popovic, Aleksandra Trifunovic, Branko Zevnik, Thomas Langer, Elena I Rugarli.
      Hereditary spastic paraplegia is a neurological condition characterized by predominant axonal degeneration in long spinal tracts, leading to weakness and spasticity in the lower limbs. The NAD + -consuming enzyme SARM1 has emerged as a key executioner of axonal degeneration upon nerve transection and in some neuropathies. An increase in the nicotinamide mononucleotide/NAD+ ratio activates SARM1, causing catastrophic NAD+ depletion and axonal degeneration. However, the role of SARM1 in the pathogenesis of hereditary spastic paraplegia has not been investigated. Here, we report an enhanced mouse model for hereditary spastic paraplegia caused by mutations in SPG7. eSpg7 knock-out mice carry a deletion in both Spg7 and Afg3l1, a redundant homologue expressed in mice but not in humans. eSpg7 knock-out mice recapitulate the phenotypic features of human patients, showing progressive symptoms of spastic-ataxia and degeneration of axons in the spinal cord as well as the cerebellum. We show that the lack of SPG7 rewires the mitochondrial proteome in both tissues, leading to an early onset decrease in mitoribosomal subunits and a remodelling of mitochondrial solute carriers and transporters. To interrogate mechanisms leading to axonal degeneration in this mouse model, we explored the involvement of SARM1. Deletion of SARM1 delays the appearance of ataxic signs, rescues mitochondrial swelling and axonal degeneration of cerebellar granule cells and dampens neuroinflammation in the cerebellum. The loss of SARM1 also prevents endoplasmic reticulum abnormalities in long spinal cord axons, but does not halt the degeneration of these axons. Our data thus reveal a neuron-specific interplay between SARM1 and mitochondrial dysfunction caused by lack of SPG7 in hereditary spastic paraplegia.
    Keywords:  axonal degeneration; cerebellum; mitochondria; paraplegin; spinal cord
    DOI:  https://doi.org/10.1093/brain/awad136
  14. Nat Metab. 2023 Apr;5(4): 546-562
    Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction.
    Anna S Monzel, José Antonio Enríquez, Martin Picard.
      Mitochondria have cell-type specific phenotypes, perform dozens of interconnected functions and undergo dynamic and often reversible physiological recalibrations. Given their multifunctional and malleable nature, the frequently used terms 'mitochondrial function' and 'mitochondrial dysfunction' are misleading misnomers that fail to capture the complexity of mitochondrial biology. To increase the conceptual and experimental specificity in mitochondrial science, we propose a terminology system that distinguishes between (1) cell-dependent properties, (2) molecular features, (3) activities, (4) functions and (5) behaviours. A hierarchical terminology system that accurately captures the multifaceted nature of mitochondria will achieve three important outcomes. It will convey a more holistic picture of mitochondria as we teach the next generations of mitochondrial biologists, maximize progress in the rapidly expanding field of mitochondrial science, and also facilitate synergy with other disciplines. Improving specificity in the language around mitochondrial science is a step towards refining our understanding of the mechanisms by which this unique family of organelles contributes to cellular and organismal health.
    DOI:  https://doi.org/10.1038/s42255-023-00783-1
  15. Nat Metab. 2023 Apr;5(4): 533
    Why a good lab website matters.
      
    DOI:  https://doi.org/10.1038/s42255-023-00797-9
  16. Trends Cell Biol. 2023 Apr 24. pii: S0962-8924(23)00077-6. [Epub ahead of print]
    A metabolic clue for STING suppression.
    Yifan Zhang, Ming-Zhu Lei, Miao Yin, Qun-Ying Lei.
      A recent report by Heath et al. reveals that obesity could impair cancer immunogenicity and foster a type I interferon (IFN-I)-deprived tumor microenvironment through saturated fatty acid-mediated stimulator of interferon genes (STING) inhibition.
    Keywords:  STING; antitumor immunity; fatty acids; obesity
    DOI:  https://doi.org/10.1016/j.tcb.2023.04.003
  17. bioRxiv. 2023 Apr 13. pii: 2023.04.12.536558. [Epub ahead of print]
    FGF-21 Conducts a Liver-Brain-Kidney Axis to Promote Renal Cell Carcinoma.
    Zongyu Li, Xinyi Zhang, Wanling Zhu, Cuiling Zhang, Katherine Sadak, Alexandra A Halberstam, Jason R Brown, Curtis J Perry, Azia Bunn, David A Braun, Adebowale Adeniran, Sangwon Lee, Andrew Wang, Rachel J Perry.
      Metabolic homeostasis is one of the most exquisitely tuned systems in mammalian physiology. Metabolic homeostasis requires multiple redundant systems to cooperate to maintain blood glucose concentrations in a narrow range, despite a multitude of physiological and pathophysiological pressures. Cancer is one of the canonical pathophysiological settings in which metabolism plays a key role. In this study, we utilized REnal Gluconeogenesis Analytical Leads (REGAL), a liquid chromatography-mass spectrometry/mass spectrometry-based stable isotope tracer method that we developed to show that in conditions of metabolic stress, the fasting hepatokine fibroblast growth factor-21 (FGF-21) 1, 2 coordinates a liver-brain-kidney axis to promote renal gluconeogenesis. FGF-21 promotes renal gluconeogenesis by enhancing β2 adrenergic receptor (Adrb2)-driven, adipose triglyceride lipase (ATGL)-mediated intrarenal lipolysis. Further, we show that this liver-brain-kidney axis promotes gluconeogenesis in the renal parenchyma in mice and humans with renal cell carcinoma (RCC). This increased gluconeogenesis is, in turn, associated with accelerated RCC progression. We identify Adrb2 blockade as a new class of therapy for RCC in mice, with confirmatory data in human patients. In summary, these data reveal a new metabolic function of FGF-21 in driving renal gluconeogenesis, and demonstrate that inhibition of renal gluconeogenesis by FGF-21 antagonism deserves attention as a new therapeutic approach to RCC.
    DOI:  https://doi.org/10.1101/2023.04.12.536558
  18. Am J Physiol Renal Physiol. 2023 Apr 27.
    PCK1 is a key regulator of metabolic and mitochondrial functions in renal tubular cells.
    Thomas Verissimo, Delal Dalga, Grégoire Arnoux, Imene Sakhi, Anna Faivre, Hannah Auwerx, Soline Bourgeois, Deborah Paolucci, Quentin Gex, Joseph M Rutkowski, David Legouis, Carsten A Wagner, Andrew M Hall, Sophie de Seigneux.
      Phosphoenolpyruvate Carboxykinase 1 (PCK1, PEPCK-C) is a cytosolic enzyme converting oxaloacetate to phosphoenolpyruvate, with a potential role in gluconeogenesis, ammoniagenesis and cataplerosis in the liver. Kidney proximal tubule cells display a high expression of this enzyme, which importance is currently not well defined. We generated PCK1 kidney specific knock-out and knock-in mice under the tubular cell specific PAX8 promoter. We studied the effect of PCK1 deletion and overexpression at the renal level on tubular physiology under normal condition and during metabolic acidosis and proteinuric renal disease. PCK1 deletion led to hyperchloremic metabolic acidosis characterized by reduced but not abolished ammoniagenesis. PCK1 deletion also resulted in glycosuria, lactaturia and altered systemic glucose and lactate metabolism at baseline and during metabolic acidosis. Metabolic acidosis resulted in kidney injury in PCK1 deficient animals with decreased creatinine clearance and albuminuria. PCK1 further regulated energy production by the proximal tubule and PCK1 deletion decreased ATP generation. In proteinuric chronic kidney disease, mitigating PCK1 downregulation led to better renal function preservation. PCK1 is essential for kidney tubular cell acid base control, mitochondrial function and glucose/lactate homeostasis. Loss of PCK1 increases tubular injury during acidosis. Mitigating kidney tubular PCK1 downregulation during proteinuric renal disease improves renal function.
    Keywords:  Acid-base; Chronic kidney disease; Gluconeogenesis; PCK1
    DOI:  https://doi.org/10.1152/ajprenal.00038.2023
  19. Nat Rev Mol Cell Biol. 2023 Apr 26.
    Identification of metabolic networks by genetic co-essentiality analysis.
    Benjamin T Jackson.
      
    DOI:  https://doi.org/10.1038/s41580-023-00608-9
  20. Aging Cell. 2023 Apr 26. e13852
    Dysregulated cellular redox status during hyperammonemia causes mitochondrial dysfunction and senescence by inhibiting sirtuin-mediated deacetylation.
    Saurabh Mishra, Nicole Welch, Manikandan Karthikeyan, Annette Bellar, Ryan Musich, Shashi Shekhar Singh, Dongmei Zhang, Jinendiran Sekar, Amy H Attaway, Aruna Chelluboyina, Shuhui Wang Lorkowski, Sanjoy Roychowdhary, Ling Li, Belinda Willard, Jonathan D Smith, Charles L Hoppel, Vidula Vachharajani, Avinash Kumar, Srinivasan Dasarathy.
      Perturbed metabolism of ammonia, an endogenous cytotoxin, causes mitochondrial dysfunction, reduced NAD+ /NADH (redox) ratio, and postmitotic senescence. Sirtuins are NAD+ -dependent deacetylases that delay senescence. In multiomics analyses, NAD metabolism and sirtuin pathways are enriched during hyperammonemia. Consistently, NAD+ -dependent Sirtuin3 (Sirt3) expression and deacetylase activity were decreased, and protein acetylation was increased in human and murine skeletal muscle/myotubes. Global acetylomics and subcellular fractions from myotubes showed hyperammonemia-induced hyperacetylation of cellular signaling and mitochondrial proteins. We dissected the mechanisms and consequences of hyperammonemia-induced NAD metabolism by complementary genetic and chemical approaches. Hyperammonemia inhibited electron transport chain components, specifically complex I that oxidizes NADH to NAD+ , that resulted in lower redox ratio. Ammonia also caused mitochondrial oxidative dysfunction, lower mitochondrial NAD+ -sensor Sirt3, protein hyperacetylation, and postmitotic senescence. Mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX), but not NAD+ precursor nicotinamide riboside, reversed ammonia-induced oxidative dysfunction, electron transport chain supercomplex disassembly, lower ATP and NAD+ content, protein hyperacetylation, Sirt3 dysfunction and postmitotic senescence in myotubes. Even though Sirt3 overexpression reversed ammonia-induced hyperacetylation, lower redox status or mitochondrial oxidative dysfunction were not reversed. These data show that acetylation is a consequence of, but is not the mechanism of, lower redox status or oxidative dysfunction during hyperammonemia. Targeting NADH oxidation is a potential approach to reverse and potentially prevent ammonia-induced postmitotic senescence in skeletal muscle. Since dysregulated ammonia metabolism occurs with aging, and NAD+ biosynthesis is reduced in sarcopenia, our studies provide a biochemical basis for cellular senescence and have relevance in multiple tissues.
    Keywords:  acetylation; human inducible pluripotent stem cells; mitochondria; multiomics; redox; sirtuin; skeletal muscle; systems biology
    DOI:  https://doi.org/10.1111/acel.13852
  21. Nat Commun. 2023 Apr 24. 14(1): 2353
    HAPLN1 potentiates peritoneal metastasis in pancreatic cancer.
    Lena Wiedmann, Francesca De Angelis Rigotti, Nuria Vaquero-Siguero, Elisa Donato, Elisa Espinet, Iris Moll, Elisenda Alsina-Sanchis, Hanibal Bohnenberger, Elena Fernandez-Florido, Ronja Mülfarth, Margherita Vacca, Jennifer Gerwing, Lena-Christin Conradi, Philipp Ströbel, Andreas Trumpp, Carolin Mogler, Andreas Fischer, Juan Rodriguez-Vita.
      Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes into the peritoneum, which contributes to poor prognosis. Metastatic spreading is promoted by cancer cell plasticity, yet its regulation by the microenvironment is incompletely understood. Here, we show that the presence of hyaluronan and proteoglycan link protein-1 (HAPLN1) in the extracellular matrix enhances tumor cell plasticity and PDAC metastasis. Bioinformatic analysis showed that HAPLN1 expression is enriched in the basal PDAC subtype and associated with worse overall patient survival. In a mouse model for peritoneal carcinomatosis, HAPLN1-induced immunomodulation favors a more permissive microenvironment, which accelerates the peritoneal spread of tumor cells. Mechanistically, HAPLN1, via upregulation of tumor necrosis factor receptor 2 (TNFR2), promotes TNF-mediated upregulation of Hyaluronan (HA) production, facilitating EMT, stemness, invasion and immunomodulation. Extracellular HAPLN1 modifies cancer cells and fibroblasts, rendering them more immunomodulatory. As such, we identify HAPLN1 as a prognostic marker and as a driver for peritoneal metastasis in PDAC.
    DOI:  https://doi.org/10.1038/s41467-023-38064-w
  22. Cell. 2023 Apr 24. pii: S0092-8674(23)00328-8. [Epub ahead of print]
    A tissue injury sensing and repair pathway distinct from host pathogen defense.
    Siqi Liu, Yun Ha Hur, Xin Cai, Qian Cong, Yihao Yang, Chiwei Xu, Angelina M Bilate, Kevin Andrew Uy Gonzales, S Martina Parigi, Christopher J Cowley, Brian Hurwitz, Ji-Dung Luo, Tiffany Tseng, Shiri Gur-Cohen, Megan Sribour, Tatiana Omelchenko, John Levorse, Hilda Amalia Pasolli, Craig B Thompson, Daniel Mucida, Elaine Fuchs.
      Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces cytokines/chemokines to activate resistance mechanisms. Here, we show that, in contrast to most pathogen-induced cytokines, interleukin-24 (IL-24) is predominately induced by barrier epithelial progenitors after tissue injury and is independent of microbiome or adaptive immunity. Moreover, Il24 ablation in mice impedes not only epidermal proliferation and re-epithelialization but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic IL-24 induction in the homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, Il24 expression depends upon both epithelial IL24-receptor/STAT3 signaling and hypoxia-stabilized HIF1α, which converge following injury to trigger autocrine and paracrine signaling involving IL-24-mediated receptor signaling and metabolic regulation. Thus, parallel to innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL-24-mediated tissue repair.
    Keywords:  STAT3; angiogenesis; coordinated tissue repair; epithelial stem cells; hypoxia; innate immune signaling; interferons; interleukin-24; microbiome-independent responses; tissue injury
    DOI:  https://doi.org/10.1016/j.cell.2023.03.031
  23. Nature. 2023 Apr 26.
    A druggable copper-signalling pathway that drives inflammation.
    Stéphanie Solier, Sebastian Müller, Tatiana Cañeque, Antoine Versini, Arnaud Mansart, Fabien Sindikubwabo, Leeroy Baron, Laila Emam, Pierre Gestraud, G Dan Pantoș, Vincent Gandon, Christine Gaillet, Ting-Di Wu, Florent Dingli, Damarys Loew, Sylvain Baulande, Sylvère Durand, Valentin Sencio, Cyril Robil, François Trottein, David Péricat, Emmanuelle Näser, Céline Cougoule, Etienne Meunier, Anne-Laure Bègue, Hélène Salmon, Nicolas Manel, Alain Puisieux, Sarah Watson, Mark A Dawson, Nicolas Servant, Guido Kroemer, Djillali Annane, Raphaël Rodriguez.
      Inflammation is a complex physiological process triggered in response to harmful stimuli1. It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases2-4. The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper(II) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.
    DOI:  https://doi.org/10.1038/s41586-023-06017-4
  24. J Biochem. 2023 Apr 24. pii: mvad036. [Epub ahead of print]
    Ferroptosis model system by the re-expression of BACH1.
    Riko Irikura, Hironari Nishizawa, Kazuma Nakajima, Mie Yamanaka, Guan Chen, Kozo Tanaka, Masafumi Onodera, Mitsuyo Matsumoto, Kazuhiko Igarashi.
      Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation. The heme-responsive transcription factor BTB and CNC homology 1 (BACH1) promotes ferroptosis by repressing the transcription of genes involved in glutathione (GSH) synthesis and intracellular labile iron metabolism, which are key regulatory pathways in ferroptosis. We found that BACH1 re-expression in Bach1-/- immortalized mouse embryonic fibroblasts (iMEFs) can induce ferroptosis upon 2-mercaptoethanol removal, without any ferroptosis inducers. In these iMEFs, GSH synthesis was reduced, and intracellular labile iron levels were increased upon BACH1 re-expression. We used this system to investigate whether the major ferroptosis regulators glutathione peroxidase 4 (Gpx4) and apoptosis-inducing factor mitochondria-associated 2 (Aifm2), the gene for ferroptosis suppressor protein 1, are target genes of BACH1. Neither Gpx4 nor Aifm2 was regulated by BACH1 in the iMEFs. However, we found that BACH1 represses AIFM2 transcription in human pancreatic cancer cells. These results suggest that the ferroptosis regulators targeted by BACH1 may vary across different cell types and animal species. Furthermore, we confirmed that the ferroptosis induced by BACH1 re-expression exhibited a propagating effect. BACH1 re-expression represents a new strategy for inducing ferroptosis after GPX4 or system Xc- suppression, and is expected to contribute to future ferroptosis research.
    Keywords:  BACH1; Ferroptosis; extracellular signal; fibroblasts; transcription
    DOI:  https://doi.org/10.1093/jb/mvad036
  25. Trends Cancer. 2023 Apr 25. pii: S2405-8033(23)00040-7. [Epub ahead of print]
    Cellular barcoding tracks heterogeneous clones through selective pressures and phenotypic transitions.
    Kennedy K Howland, Amy Brock.
      Genomic DNA barcoding has emerged as a sensitive and flexible tool to measure the fates of clonal subpopulations within a heterogeneous cancer cell population. Coupling cellular barcoding with single-cell transcriptomics permits the longitudinal analysis of molecular mechanisms with detailed clone-level resolution. Numerous recent studies have employed these tools to track clonal cell states in cancer progression and treatment response. With these new technologies comes the opportunity to examine longstanding questions about the origins and contributions of tumor cell heterogeneity and the roles of selection and phenotypic plasticity in disease progression and treatment.
    Keywords:  barcoding; drug resistance; phenotypic plasticity; tumor evolution; tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.trecan.2023.03.008
  26. Nat Rev Cancer. 2023 Apr 27.
    EMT in chemoresistance.
    Anna Dart.
      
    DOI:  https://doi.org/10.1038/s41568-023-00581-7
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