bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2023–11–05
eightteen papers selected by
Marc Segarra Mondejar, University of Cologne
  1. Mitochondrial complexome and import network.
  2. DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress.
  3. Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma.
  4. Systems-level analyses dissociate genetic regulators of reactive oxygen species and energy production.
  5. Real-time resolution studies of the regulation of pyruvate-dependent lactate metabolism by hexokinases in single cells.
  6. Metabolic pathway analysis using stable isotopes in patients with cancer.
  7. Mitochondrial hydrogen peroxide production by pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGDH) in oxidative eustress and oxidative distress.
  8. Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer.
  9. Autoregulatory control of mitochondrial glutathione homeostasis.
  10. PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy.
  11. Mitochondrial regulation in stem cells.
  12. Biodistribution of Intravenously Transplanted Mitochondria Conjugated with Graphene Quantum Dots in Diabetic Rats.
  13. Minorities drive growth resumption in cross-feeding microbial communities.
  14. A practical perspective on how to develop, implement, execute, and reproduce high-resolution respirometry experiments: The physiologist's guide to an Oroboros O2k.
  15. A carbon-nitrogen negative feedback loop underlies the repeated evolution of cnidarian-Symbiodiniaceae symbioses.
  16. Tumor Metabolism-Rewriting Nanomedicines for Cancer Immunotherapy.
  17. Super-resolution microscopy: Insights into mitochondria-lysosome crosstalk in health and disease.
  18. Hepatic conversion of acetyl-CoA to acetate plays crucial roles in energy stress.
  1. Trends Cell Biol. 2023 Oct 30. pii: S0962-8924(23)00208-8. [Epub ahead of print]
    Mitochondrial complexome and import network.
    Fabian den Brave, Uwe Schulte, Bernd Fakler, Nikolaus Pfanner, Thomas Becker.
      Mitochondria perform crucial functions in cellular metabolism, protein and lipid biogenesis, quality control, and signaling. The systematic analysis of protein complexes and interaction networks provided exciting insights into the structural and functional organization of mitochondria. Most mitochondrial proteins do not act as independent units, but are interconnected by stable or dynamic protein-protein interactions. Protein translocases are responsible for importing precursor proteins into mitochondria and form central elements of several protein interaction networks. These networks include molecular chaperones and quality control factors, metabolite channels and respiratory chain complexes, and membrane and organellar contact sites. Protein translocases link the distinct networks into an overarching network, the mitochondrial import network (MitimNet), to coordinate biogenesis, membrane organization and function of mitochondria.
    Keywords:  cell organelles; energetics; metabolism; mitochondria; morphology; protein assembly; protein networks; protein sorting
    DOI:  https://doi.org/10.1016/j.tcb.2023.10.004
  2. Nat Commun. 2023 Oct 30. 14(1): 6900
    DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress.
    Gautham Yepuri, Lisa M Ramirez, Gregory G Theophall, Sergei V Reverdatto, Nosirudeen Quadri, Syed Nurul Hasan, Lei Bu, Devi Thiagarajan, Robin Wilson, Raquel López Díez, Paul F Gugger, Kaamashri Mangar, Navneet Narula, Stuart D Katz, Boyan Zhou, Huilin Li, Aleksandr B Stotland, Roberta A Gottlieb, Ann Marie Schmidt, Alexander Shekhtman, Ravichandran Ramasamy.
      Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.
    DOI:  https://doi.org/10.1038/s41467-023-42521-x
  3. bioRxiv. 2023 Oct 19. pii: 2023.10.16.562128. [Epub ahead of print]
    Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma.
    C Galvan, A Flores, V Cerrillos, I Avila, C Murphy, W Zheng, T T To, H R Christofk, W E Lowry.
      Among the numerous changes associated with the transformation to cancer, cellular metabolism is one of the first discovered and most prominent[1, 2]. However, despite the knowledge that nearly every cancer is associated with the strong upregulation of various metabolic pathways, there has yet to be much clinical progress on the treatment of cancer by targeting a single metabolic enzyme directly[3-6]. We previously showed that inhibition of glycolysis through lactate dehydrogenase (LDHA) deletion in cancer cells of origin had no effect on the initiation or progression of cutaneous squamous cell carcinoma[7], suggesting that these cancers are metabolically flexible enough to produce the necessary metabolites required for sustained growth in the absence of glycolysis. Here we focused on glutaminolysis, another metabolic pathway frequently implicated as important for tumorigenesis in correlative studies. We genetically blocked glutaminolysis through glutaminase (GLS) deletion in cancer cells of origin, and found that this had little effect on tumorigenesis, similar to what we previously showed for blocking glycolysis. Tumors with genetic deletion of glutaminolysis instead upregulated lactate consumption and utilization for the TCA cycle, providing further evidence of metabolic flexibility. We also found that the metabolic flexibility observed upon inhibition of glycolysis or glutaminolysis is due to post-transcriptional changes in the levels of plasma membrane lactate and glutamine transporters. To define the limits of metabolic flexibility in cancer initiating hair follicle stem cells, we genetically blocked both glycolysis and glutaminolysis simultaneously and found that frank carcinoma was not compatible with abrogation of both of these carbon utilization pathways. These data point towards metabolic flexibility mediated by regulation of nutrient consumption, and suggest that treatment of cancer through metabolic manipulation will require multiple interventions on distinct pathways.
    DOI:  https://doi.org/10.1101/2023.10.16.562128
  4. bioRxiv. 2023 Oct 18. pii: 2023.10.14.562276. [Epub ahead of print]
    Systems-level analyses dissociate genetic regulators of reactive oxygen species and energy production.
    Neal K Bennett, Megan Lee, Adam L Orr, Ken Nakamura.
      Respiratory chain dysfunction can decrease ATP and increase reactive oxygen species (ROS) levels. Despite the importance of these metabolic parameters to a wide range of cellular functions and disease, we lack an integrated understanding of how they are differentially regulated. To address this question, we adapted a CRISPRi- and FACS-based platform to compare the effects of respiratory gene knockdown on ROS to their effects on ATP. Focusing on genes whose knockdown is known to decrease mitochondria-derived ATP, we showed that knockdown of genes in specific respiratory chain complexes (I, III and CoQ10 biosynthesis) increased ROS, whereas knockdown of other low ATP hits either had no impact (mitochondrial ribosomal proteins) or actually decreased ROS (complex IV). Moreover, although shifting metabolic conditions profoundly altered mitochondria-derived ATP levels, it had little impact on mitochondrial or cytosolic ROS. In addition, knockdown of a subset of complex I subunits-including NDUFA8, NDUFB4, and NDUFS8-decreased complex I activity, mitochondria-derived ATP and supercomplex level, but knockdown of these genes had differential effects on ROS. Conversely, we found an essential role for ether lipids in the dynamic regulation of mitochondrial ROS levels independent of ATP. Thus, our results identify specific metabolic regulators of cellular ATP and ROS balance that may help dissect the roles of these processes in disease and identify therapeutic strategies to independently target energy failure and oxidative stress.
    Significance: Mitochondrial respiration generates both energy (ATP) and reactive oxygen species (ROS). Insufficient energy and increased ROS from respiratory chain dysfunction may be central to the pathophysiology of neurodegenerative diseases and aging. We established a screening platform using CRISPR and fluorescent-cell sorting to compare the impact of decreasing respiratory chain proteins on ROS and ATP levels. The results provide the first systems-level analysis of how ROS and ATP are differentially regulated, and identify genes and respiratory chain complexes that can manipulate each independently. These findings advance our understanding of the relative contributions of ATP and ROS to disease pathophysiology, and guide the development of therapies to preserve energy while minimizing ROS.
    DOI:  https://doi.org/10.1101/2023.10.14.562276
  5. PLoS One. 2023 ;18(11): e0286660
    Real-time resolution studies of the regulation of pyruvate-dependent lactate metabolism by hexokinases in single cells.
    Scott John, Guillaume Calmettes, Shili Xu, Bernard Ribalet.
      Lactate is a mitochondrial substrate for many tissues including neuron, muscle, skeletal and cardiac, as well as many cancer cells, however little is known about the processes that regulate its utilization in mitochondria. Based on the close association of Hexokinases (HK) with mitochondria, and the known cardio-protective role of HK in cardiac muscle, we have investigated the regulation of lactate and pyruvate metabolism by hexokinases (HKs), utilizing wild-type HEK293 cells and HEK293 cells in which the endogenous HKI and/or HKII have been knocked down to enable overexpression of wild type and mutant HKs. To assess the real-time changes in intracellular lactate levels the cells were transfected with a lactate specific FRET probe. In the HKI/HKII double knockdown cells, addition of extracellular pyruvate caused a large and sustained decrease in lactate. This decrease was rapidly reversed upon inhibition of the malate aspartate shuttle by aminooxyacetate, or inhibition of mitochondrial oxidative respiration by NaCN. These results suggest that in the absence of HKs, pyruvate-dependent activation of the TCA cycle together with the malate aspartate shuttle facilitates lactate transformation into pyruvate and its utilization by mitochondria. With replacement by overexpression of HKI or HKII the cellular response to pyruvate and NaCN was modified. With either hexokinase present, both the decrease in lactate due to the addition of pyruvate and the increase following addition of NaCN were either transient or suppressed altogether. Blockage of the pentose phosphate pathway with the inhibitor 6-aminonicotinamide (6-AN), abolished the effects of HK replacement. These results suggest that blocking of the malate aspartate shuttle by HK may involve activation of the pentose phosphate pathway and increased NADPH production.
    DOI:  https://doi.org/10.1371/journal.pone.0286660
  6. Nat Rev Cancer. 2023 Oct 31.
    Metabolic pathway analysis using stable isotopes in patients with cancer.
    Caroline R Bartman, Brandon Faubert, Joshua D Rabinowitz, Ralph J DeBerardinis.
      Metabolic reprogramming is central to malignant transformation and cancer cell growth. How tumours use nutrients and the relative rates of reprogrammed pathways are areas of intense investigation. Tumour metabolism is determined by a complex and incompletely defined combination of factors intrinsic and extrinsic to cancer cells. This complexity increases the value of assessing cancer metabolism in disease-relevant microenvironments, including in patients with cancer. Stable-isotope tracing is an informative, versatile method for probing tumour metabolism in vivo. It has been used extensively in preclinical models of cancer and, with increasing frequency, in patients with cancer. In this Review, we describe approaches for using in vivo isotope tracing to define fuel preferences and pathway engagement in tumours, along with some of the principles that have emerged from this work. Stable-isotope infusions reported so far have revealed that in humans, tumours use a diverse set of nutrients to supply central metabolic pathways, including the tricarboxylic acid cycle and amino acid synthesis. Emerging data suggest that some activities detected by stable-isotope tracing correlate with poor clinical outcomes and may drive cancer progression. We also discuss current challenges in isotope tracing, including comparisons of in vivo and in vitro models, and opportunities for future discovery in tumour metabolism.
    DOI:  https://doi.org/10.1038/s41568-023-00632-z
  7. J Biol Chem. 2023 Oct 26. pii: S0021-9258(23)02427-4. [Epub ahead of print] 105399
    Mitochondrial hydrogen peroxide production by pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGDH) in oxidative eustress and oxidative distress.
    Olivia Chalifoux, Ben Faerman, Ryan J Mailloux.
      Pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGDH) are vital entry points for monosaccharides and amino acids into the Krebs cycle and thus integral for mitochondrial bioenergetics. Both complexes produce mitochondrial hydrogen peroxide (mH2O2) and are deactivated by electrophiles. Here, we provide an update on the role of PDH and KGDH in mitochondrial redox balance and their function in facilitating metabolic reprogramming for the propagation of oxidative eustress signals in hepatocytes and how defects in these pathways can cause liver diseases. PDH and KGDH are known to account for ∼45% of the total mH2O2 formed by mitochondria and display rates of production several-fold higher than the canonical source complex I. This mH2O2 can also be formed by reverse electron transfer (RET) in vivo, which has been linked to metabolic dysfunctions that occur in pathogenesis. However, the controlled emission of mH2O2 from PDH and KGDH has been proposed to be fundamental for oxidative eustress signal propagation in several cellular contexts. Modification of PDH and KGDH with protein S-glutathionylation (PSSG) and S-nitrosylation (PSNO) adducts serves as a feedback inhibitor for mH2O2 production in response to glutathione (GSH) pool oxidation. PSSG and PSNO adduct formation also reprogram the Krebs cycle to generate metabolites vital for interorganelle and intercellular signaling. Defects in the redox modification of PDH and KGDH cause the over generation of mH2O2, resulting in oxidative distress and metabolic dysfunction-associated fatty liver disease (MAFLD). In aggregate, PDH and KGDH are essential platforms for emitting and receiving oxidative eustress signals.
    DOI:  https://doi.org/10.1016/j.jbc.2023.105399
  8. Sci Transl Med. 2023 Nov;15(720): eadg3049
    Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer.
    Jingbo Li, Jiao Liu, Zhuan Zhou, Runliu Wu, Xin Chen, Chunhua Yu, Brent Stockwell, Guido Kroemer, Rui Kang, Daolin Tang.
      Lipid peroxidation-dependent ferroptosis has become an emerging strategy for tumor therapy. However, current strategies not only selectively induce ferroptosis in malignant cells but also trigger ferroptosis in immune cells simultaneously, which can compromise anti-tumor immunity. Here, we used In-Cell Western assays combined with an unbiased drug screening to identify the compound N6F11 as a ferroptosis inducer that triggered the degradation of glutathione peroxidase 4 (GPX4), a key ferroptosis repressor, specifically in cancer cells. N6F11 did not cause the degradation of GPX4 in immune cells, including dendritic, T, natural killer, and neutrophil cells. Mechanistically, N6F11 bound to the RING domain of E3 ubiquitin ligase tripartite motif containing 25 (TRIM25) in cancer cells to trigger TRIM25-mediated K48-linked ubiquitination of GPX4, resulting in its proteasomal degradation. Functionally, N6F11 treatment caused ferroptotic cancer cell death that initiated HMGB1-dependent antitumor immunity mediated by CD8+ T cells. N6F11 also sensitized immune checkpoint blockade that targeted CD274/PD-L1 in advanced cancer models, including genetically engineered mouse models of pancreatic cancer driven by KRAS and TP53 mutations. These findings may establish a safe and efficient strategy to boost ferroptosis-driven antitumor immunity.
    DOI:  https://doi.org/10.1126/scitranslmed.adg3049
  9. Science. 2023 Nov 02. eadf4154
    Autoregulatory control of mitochondrial glutathione homeostasis.
    Yuyang Liu, Shanshan Liu, Anju Tomar, Frederick S Yen, Gokhan Unlu, Nathalie Ropek, Ross A Weber, Ying Wang, Artem Khan, Mark Gad, Junhui Peng, Erdem Terzi, Hanan Alwaseem, Alexandra E Pagano, Søren Heissel, Henrik Molina, Benjamin Allwein, Timothy C Kenny, Richard L Possemato, Li Zhao, Richard K Hite, Ekaterina V Vinogradova, Sheref S Mansy, Kıvanç Birsoy.
      Mitochondria must maintain adequate amounts of metabolites for protective and biosynthetic functions. However, how mitochondria sense the abundance of metabolites and regulate metabolic homeostasis is not well understood. We focused on glutathione (GSH), a critical redox metabolite in mitochondria and identified a feedback mechanism that controls its abundance through the mitochondrial GSH transporter, SLC25A39. Under physiological conditions, SLC25A39 is rapidly degraded by a mitochondrial protease, AFG3L2. Depletion of GSH dissociates AFG3L2 from SLC25A39, causing a compensatory increase in mitochondrial GSH uptake. Genetic and proteomic analysis identified a putative iron-sulfur cluster in the matrix-facing loop of SLC25A39 to be essential for this regulation, coupling mitochondrial iron homeostasis to GSH import. Altogether, our work revealed a paradigm for the autoregulatory control of metabolic homeostasis in organelles.
    DOI:  https://doi.org/10.1126/science.adf4154
  10. Nat Metab. 2023 Oct 30.
    PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy.
    Xuefeng Dou, Qiang Fu, Qilai Long, Shuning Liu, Yejun Zou, Da Fu, Qixia Xu, Zhirui Jiang, Xiaohui Ren, Guilong Zhang, Xiaoling Wei, Qingfeng Li, Judith Campisi, Yuzheng Zhao, Yu Sun.
      Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here, we report upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon senescence, particularly in some stromal cell lines. Senescent cells display a PDK4-dependent increase in aerobic glycolysis and enhanced lactate production but maintain mitochondrial respiration and redox activity, thus adopting a special form of metabolic reprogramming. Medium from PDK4+ stromal cells promotes the malignancy of recipient cancer cells in vitro, whereas inhibition of PDK4 causes tumor regression in vivo. We find that lactate promotes reactive oxygen species production via NOX1 to drive the senescence-associated secretory phenotype, whereas PDK4 suppression reduces DNA damage severity and restrains the senescence-associated secretory phenotype. In preclinical trials, PDK4 inhibition alleviates physical dysfunction and prevents age-associated frailty. Together, our study confirms the hypercatabolic nature of senescent cells and reveals a metabolic link between cellular senescence, lactate production, and possibly, age-related pathologies, including but not limited to cancer.
    DOI:  https://doi.org/10.1038/s42255-023-00912-w
  11. Trends Cell Biol. 2023 Oct 31. pii: S0962-8924(23)00207-6. [Epub ahead of print]
    Mitochondrial regulation in stem cells.
    Yifei Wang, Marine Barthez, Danica Chen.
      Stem cells persist throughout the lifespan to repair and regenerate tissues due to their unique ability to self-renew and differentiate. Here we reflect on the recent discoveries in stem cells that highlight a mitochondrial metabolic checkpoint at the restriction point of the stem cell cycle. Mitochondrial activation supports stem cell proliferation and differentiation by providing energy supply and metabolites as signaling molecules. Concomitant mitochondrial stress can lead to loss of stem cell self-renewal and requires the surveillance of various mitochondrial quality control mechanisms. During aging, a mitochondrial protective program mediated by several sirtuins becomes dysregulated and can be targeted to reverse stem cell aging and tissue degeneration, giving hope for targeting the mitochondrial metabolic checkpoint for treating tissue degenerative diseases.
    Keywords:  NAD; NLRP3; SIRT2; SIRT3; SIRT7; aging
    DOI:  https://doi.org/10.1016/j.tcb.2023.10.003
  12. J Fluoresc. 2023 Oct 28.
    Biodistribution of Intravenously Transplanted Mitochondria Conjugated with Graphene Quantum Dots in Diabetic Rats.
    Pallavi Mudgal, Jyotsna Pareek, Swati Paliwal.
      Mitochondria transplantation has emerged as a successful therapeutic modality to treat several degenerative diseases. However, the biodistribution of transplanted mitochondria has not been well studied. We investigated the ex-vivo systemic biodistribution and therapeutic efficacy of intravenously transplanted graphene quantum dots (GQDs) conjugated to isolated mitochondria (Mt-GQDs) in diabetic rat tissues. The results revealed that Mt-GQDs facilitate the tracking of transplanted mitochondria without affecting their therapeutic efficacy. It is compelling to note that Mt-GQDs and isolated mitochondria show comparable therapeutic efficacies in decreasing blood glucose levels, oxidative stress, inflammatory gene expressions, and restoration of different mitochondrial functions in pancreatic tissues of diabetic rats. In addition, histological section examination under a fluorescence microscope demonstrated the localization of Mt-GQDs in multiple tissues of diabetic rats. In conclusion, this study indicates that Mt-GQDs provide an effective mitochondrial transplantation tracking modality.
    Keywords:  And Bioimaging; Diabetic rats; GQDs; Mitochondrial Transplantation; Mt-GQDs
    DOI:  https://doi.org/10.1007/s10895-023-03480-0
  13. Proc Natl Acad Sci U S A. 2023 Nov 07. 120(45): e2301398120
    Minorities drive growth resumption in cross-feeding microbial communities.
    Gabriele Micali, Alyson M Hockenberry, Alma Dal Co, Martin Ackermann.
      Microbial communities are fundamental to life on Earth. Different strains within these communities are often connected by a highly connected metabolic network, where the growth of one strain depends on the metabolic activities of other community members. While distributed metabolic functions allow microbes to reduce costs and optimize metabolic pathways, they make them metabolically dependent. Here, we hypothesize that such dependencies can be detrimental in situations where the external conditions change rapidly, as they often do in natural environments. After a shift in external conditions, microbes need to remodel their metabolism, but they can only resume growth once partners on which they depend have also adapted to the new conditions. It is currently not well understood how microbial communities resolve this dilemma and how metabolic interactions are reestablished after an environmental shift. To address this question, we investigated the dynamical responses to environmental perturbation by microbial consortia with distributed anabolic functions. By measuring the regrowth times at the single-cell level in spatially structured communities, we found that metabolic dependencies lead to a growth delay after an environmental shift. However, a minority of cells-those in the immediate neighborhood of their metabolic partners-can regrow quickly and come to numerically dominate the community after the shift. The spatial arrangement of a microbial community is thus a key factor in determining the communities' ability to maintain metabolic interactions and growth in fluctuating conditions. Our results suggest that environmental fluctuations can limit the emergence of metabolic dependencies between microorganisms.
    Keywords:  cross-feeding microbial communities; distributed metabolic functions; minorities-driven dynamics; single-cell dynamics; spatiotemporal scales in ecology
    DOI:  https://doi.org/10.1073/pnas.2301398120
  14. FASEB J. 2023 Dec;37(12): e23280
    A practical perspective on how to develop, implement, execute, and reproduce high-resolution respirometry experiments: The physiologist's guide to an Oroboros O2k.
    Maureen A Walsh, Robert V Musci, Robert A Jacobs, Karyn L Hamilton.
      The development of high-resolution respirometry (HRR) has greatly expanded the analytical scope to study mitochondrial respiratory control relative to specific tissue/cell types across various metabolic states. Specifically, the Oroboros Oxygraph 2000 (O2k) is a common tool for measuring rates of mitochondrial respiration and is the focus of this perspective. The O2k platform is amenable for answering numerous bioenergetic questions. However, inherent variability with HRR-derived data, both within and amongst users, can impede progress in bioenergetics research. Therefore, we advocate for several vital considerations when planning and conducting O2k experiments to ultimately enhance transparency and reproducibility across laboratories. In this perspective, we offer guidance for best practices of mitochondrial preparation, protocol selection, and measures to increase reproducibility. The goal of this perspective is to propagate the use of the O2k, enhance reliability and validity for both new and experienced O2k users, and provide a reference for peer reviewers.
    Keywords:  Oroboros O2k; bioenergetics; isolated mitochondria; mitochondria; permeabilized fibers; protocol development
    DOI:  https://doi.org/10.1096/fj.202301644RR
  15. Nat Commun. 2023 Nov 01. 14(1): 6949
    A carbon-nitrogen negative feedback loop underlies the repeated evolution of cnidarian-Symbiodiniaceae symbioses.
    Guoxin Cui, Jianing Mi, Alessandro Moret, Jessica Menzies, Huawen Zhong, Angus Li, Shiou-Han Hung, Salim Al-Babili, Manuel Aranda.
      Symbiotic associations with Symbiodiniaceae have evolved independently across a diverse range of cnidarian taxa including reef-building corals, sea anemones, and jellyfish, yet the molecular mechanisms underlying their regulation and repeated evolution are still elusive. Here, we show that despite their independent evolution, cnidarian hosts use the same carbon-nitrogen negative feedback loop to control symbiont proliferation. Symbiont-derived photosynthates are used to assimilate nitrogenous waste via glutamine synthetase-glutamate synthase-mediated amino acid biosynthesis in a carbon-dependent manner, which regulates the availability of nitrogen to the symbionts. Using nutrient supplementation experiments, we show that the provision of additional carbohydrates significantly reduces symbiont density while ammonium promotes symbiont proliferation. High-resolution metabolic analysis confirmed that all hosts co-incorporated glucose-derived 13C and ammonium-derived 15N via glutamine synthetase-glutamate synthase-mediated amino acid biosynthesis. Our results reveal a general carbon-nitrogen negative feedback loop underlying these symbioses and provide a parsimonious explanation for their repeated evolution.
    DOI:  https://doi.org/10.1038/s41467-023-42582-y
  16. ACS Cent Sci. 2023 Oct 25. 9(10): 1864-1893
    Tumor Metabolism-Rewriting Nanomedicines for Cancer Immunotherapy.
    Xiao Dong, Shu Xia, Shubo Du, Mao-Hua Zhu, Xing Lai, Shao Q Yao, Hong-Zhuan Chen, Chao Fang.
      Cancer immunotherapy has become an established therapeutic paradigm in oncologic therapy, but its therapeutic efficacy remains unsatisfactory in the majority of cancer patients. Accumulating evidence demonstrates that the metabolically hostile tumor microenvironment (TME), characterized by acidity, deprivation of oxygen and nutrients, and accumulation of immunosuppressive metabolites, promotes the dysfunction of tumor-infiltrating immune cells (TIICs) and thereby compromises the effectiveness of immunotherapy. This indicates the potential role of tumor metabolic intervention in the reinvigoration of antitumor immunity. With the merits of multiple drug codelivery, cell and organelle-specific targeting, controlled drug release, and multimodal therapy, tumor metabolism-rewriting nanomedicines have recently emerged as an attractive strategy to strengthen antitumor immune responses. This review summarizes the current progress in the development of multifunctional tumor metabolism-rewriting nanomedicines for evoking antitumor immunity. A special focus is placed on how these nanomedicines reinvigorate innate or adaptive antitumor immunity by regulating glucose metabolism, amino acid metabolism, lipid metabolism, and nucleotide metabolism at the tumor site. Finally, the prospects and challenges in this emerging field are discussed.
    DOI:  https://doi.org/10.1021/acscentsci.3c00702
  17. J Cell Biol. 2023 Dec 04. pii: e202305032. [Epub ahead of print]222(12):
    Super-resolution microscopy: Insights into mitochondria-lysosome crosstalk in health and disease.
    Eric D Leisten, Abby C Woods, Yvette C Wong.
      Live super-resolution microscopy has allowed for new insights into recently identified mitochondria-lysosome contact sites, which mediate crosstalk between mitochondria and lysosomes, including co-regulation of Rab7 GTP hydrolysis and Drp1 GTP hydrolysis. Here, we highlight recent findings and future perspectives on this dynamic pathway and its roles in health and disease.
    DOI:  https://doi.org/10.1083/jcb.202305032
  18. Elife. 2023 Oct 30. pii: RP87419. [Epub ahead of print]12
    Hepatic conversion of acetyl-CoA to acetate plays crucial roles in energy stress.
    Jinyang Wang, Yaxin Wen, Wentao Zhao, Yan Zhang, Furong Lin, Cong Ouyang, Huihui Wang, Lizheng Yao, Huanhuan Ma, Yue Zhuo, Huiying Huang, Xiulin Shi, Liubin Feng, Donghai Lin, Bin Jiang, Qinxi Li.
      Accumulating evidence indicates that acetate is increased under energy stress conditions such as those that occur in diabetes mellitus and prolonged starvation. However, how and where acetate is produced and the nature of its biological significance are largely unknown. We observed overproduction of acetate to concentrations comparable to those of ketone bodies in patients and mice with diabetes or starvation. Mechanistically, ACOT12 and ACOT8 are dramatically upregulated in the liver to convert free fatty acid-derived acetyl-CoA to acetate and CoA. This conversion not only provides a large amount of acetate, which preferentially fuels the brain rather than muscle, but also recycles CoA, which is required for sustained fatty acid oxidation and ketogenesis. We suggest that acetate is an emerging novel 'ketone body' that may be used as a parameter to evaluate the progression of energy stress.
    Keywords:  ACOT12; ACOT8; acetate; biochemistry; cell biology; chemical biology; diabetes mellitus; human; mouse
    DOI:  https://doi.org/10.7554/eLife.87419
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