Review
Biochemistry & Molecular Biology
Linlin Zhang, Jingyi Qi, Xu Zhang, Xiya Zhao, Peng An, Yongting Luo, Junjie Luo
Summary: Mitochondria are essential for cellular energy metabolism and the generation of oxygen free radicals, and also play a crucial role in cell death. Ca2+ acts as a messenger for cell proliferation and death, and is involved in the energy metabolism, physiology, and pathology of mitochondria.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Analytical
Helisa H. Wippel, Juan D. Chavez, Andrew D. Keller, James E. Bruce
Summary: The XL-MS technique provides insight into protein conformations and interactions within their cellular environment, while the iqPIR strategy allows for comparative interactome studies using isotope encoded chemical cross-linkers. Multiplexed iqPIR enables quantitative interactome analysis of up to six biological samples in a single LC-MS acquisition, revealing specific protein conformational and interaction changes in response to different inhibitors.
ANALYTICAL CHEMISTRY
(2022)
Article
Cell Biology
Yun-Zhi Zhao, Jun Wei, Ke-Xin Song, Chen Zhou, Zhen Chai
Summary: The present study found that non-hibernating Daurian ground squirrel (GS) neurons were more resistant to oxygen-glucose deprivation (OGD) compared to rat neurons. Glutamate-aspartate transporter 1 (GLAST) was identified as a cytoprotective factor that contributed to the tolerance against OGD injury in GS neurons. Overexpression of GLAST rescued viability in rat neurons, while knockdown of GLAST led to decreased viability in GS neurons. This study revealed a molecular mechanism underlying the survival of hibernating mammals and suggested GLAST as a potential target for ischemic stroke therapy.
JOURNAL OF CELLULAR PHYSIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Daisuke Takahashi, Kento Yonezawa, Yuki Okizaki, Jose M. M. Caaveiro, Tadashi Ueda, Atsushi Shimada, Fumio Sakane, Nobutaka Shimizu
Summary: Diacylglycerol kinases (DGKs) are multi-domain lipid kinases that regulate the levels of lipid messengers. This study investigated the structural properties of DGK alpha N-terminal (RVH and EF) domains, revealing that Ca2+ binding induces conformational changes mainly in the EF domain and identified the RVH domain as a novel Ca2+-binding domain.
Review
Oncology
Ruggiero Gorgoglione, Valeria Impedovo, Christopher L. Riley, Deborah Fratantonio, Stefano Tiziani, Luigi Palmieri, Vincenza Dolce, Giuseppe Fiermonte
Summary: In recent years, the role of aspartate in cancer cell metabolism has been increasingly recognized. Aspartate plays a crucial role in nucleotide and protein synthesis as well as redox homeostasis. Mitochondrial transporters are involved in the metabolism of aspartate and their involvement is cancer type-specific and dependent on the availability of glutamine. Targeting these transporters may be a promising strategy for cancer treatment.
Review
Cell Biology
Galina D. Mironova, Evgeny V. Pavlov
Summary: Mitochondrial permeability transition (mPT) is a sharp increase in the permeability of the mitochondrial inner membrane under Ca2+ and ROS stress, and can occur through opening protein channels or lipid pores. The formation of palmitate/Ca2+ induced pores may play a protective role against calcium and ROS toxicity.
Article
Biology
Tatsuya Kubota, Erika Kurihara, Kazuya Watanabe, Kohei Ogata, Ryosuke Kaneko, Masaru Goto, Toshihisa Ohshima, Kazuaki Yoshimune
Summary: Overexpression of the enzyme StHSD in the bacterium E. coli led to the activation of the immature enzyme when exposed to heat. Two crystal structures of the immature enzyme were determined, revealing that a flexible part of the enzyme showed smaller conformational changes compared to mature enzymes. The immature enzyme formed a complex with NADP(+), indicating that the substrate-binding pocket of the immature enzyme was not sufficient for substrate binding, efficient catalysis, or release of NADP(+). Specific conformational changes within the catalytic region are responsible for the heat-induced activation of this hyperthermophilic enzyme.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Silvia Garcia-Catalan, Luis Gonzalez-Moreno, Araceli del Arco
Summary: Research has found two variants of ATP-Mg2+/Pi carriers in unicellular eukaryotes, with a common origin unrelated to ADP/ATP translocases, suggesting recurrent losses of the regulatory module in different phyla. These truncated variants of SCaMC are predominantly found in parasitic protists and green algae, indicating a potential relationship with specific lifestyles. Additionally, these variants exhibit intricate structural diversity that may be associated with their pathogenicity.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2021)
Article
Neurosciences
Kiran Sapkota, Erica S. Burnell, Mark W. Irvine, Guangyu Fang, Dinesh Y. Gawande, Shashank M. Dravid, David E. Jane, Daniel T. Monaghan
Summary: The study characterizes a novel NMDAR antagonist, UBP792, which displays partial subtype-selectivity and inhibits NMDAR responses by reducing the potency and efficacy of L-glutamate and glycine. It acts non-competitively, with activity independent of voltage and affected by pH, and potentially stabilizes different channel conformations to inhibit NMDAR function. This expands the possibilities for developing NMDAR modulators with appropriate selectivity for therapeutic indications.
Article
Thermodynamics
Shuai Guo, Guoliang Qi, Jialiang Gao, Deng Zhao, Kaixin Chen, Chenchen Zhao, Xingcan Li, Guangyu Li
Summary: This study investigated the effect of CaO on NOx precursor formation during glutamate pyrolysis. The findings suggest that CaO can promote the formation of NOx precursors and alter the nitrogen content in the tar. These results provide important insights into the regulation of amino acid pyrolysis and NOx precursor production by CaO.
THERMAL SCIENCE AND ENGINEERING PROGRESS
(2023)
Article
Cell Biology
Amit S. Korde, William F. Maragos
Summary: The research findings indicate that NMDA(m) activation modulates mitochondrial bioenergetics through both Ca2+-dependent and Ca2+-independent mechanisms.
Article
Chemistry, Physical
Catherine Ghosh, Biman Jana
Summary: Metal ions, especially calcium, play crucial roles in cellular functions. This study investigates how calcium affects the conformation dynamics of calmodulin and its interaction with the target protein smMLCK. The findings suggest that while calcium-independent, calcium can regulate the binding site of smMLCK peptide on calmodulin.
JOURNAL OF PHYSICAL CHEMISTRY B
(2021)
Article
Multidisciplinary Sciences
Glaucio Monteiro Ferreira, Thanigaimalai Pillaiyar, Mario Hiroyuki Hirata, Antti Poso, Thales Kronenberger
Summary: This study used molecular dynamics simulations to investigate the interaction between SARS-CoV-2's PLpro and various ligands, revealing the conformational changes and interactions of inhibitors. The study found that the BL2 loop of PLpro plays a critical role in the accessibility of inhibitors, and bulkier substituents near Tyr268 and Gln269 can enhance the inhibition.
SCIENTIFIC REPORTS
(2022)
Article
Biochemistry & Molecular Biology
Paola Lunetti, Rene Massimiliano Marsano, Rosita Curcio, Vincenza Dolce, Giuseppe Fiermonte, Anna Rita Cappello, Federica Marra, Roberta Moschetti, Yuan Li, Donatella Aiello, Araceli del Arco Martinez, Graziantonio Lauria, Francesco De Leonardis, Alessandra Ferramosca, Vincenzo Zara, Loredana Capobianco
Summary: The study identified six isoforms of the aralar1 gene in Drosophila melanogaster, with variations in expression during development or in different tissues. Recombinant Aralar1-PA and Aralar1-PE proteins showed similar efficiency in exchanging glutamate and aspartate, and exhibited substrate affinities comparable to human isoforms.
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
(2021)
Article
Immunology
Neetu Saini, Sowmya Lakshminarayanan, Priyanka Kundu, Apurva Sarin
Summary: This study reveals that calcium uptake and mitochondrial metabolism play a crucial role in regulating the survival of regulatory T cells (Tregs) and Notch1 activity is a key factor in modulating these processes. By modulating cellular calcium dynamics, Notch1 regulates mitochondrial homeostasis and anti-apoptotic activity, thus impacting the survival of Tregs.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Biochemistry & Molecular Biology
J. J. Ruprecht, E. R. S. Kunji
Summary: Members of the mitochondrial carrier family transport a variety of molecules across the mitochondrial inner membrane, playing crucial roles in cellular processes. The transport mechanism involves a central substrate-binding site, gates with salt-bridge networks, and conformational changes triggered by substrate binding during import and export.
ANNUAL REVIEW OF BIOCHEMISTRY, VOL 90, 2021
(2021)
Article
Multidisciplinary Sciences
Chancievan Thangaratnarajah, Jan Rheinberger, Cristina Paulino, Dirk J. Slotboom
Summary: Energy-coupling factor (ECF)-type transporters are small, asymmetric membrane protein complexes that import micronutrients into bacterial cells. Recent research suggests that during the transport process, protein-induced membrane deformations facilitate the toppling of the S component.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Endocrinology & Metabolism
Sotiria Tavoulari, Tom J. J. Schirris, Vasiliki Mavridou, Chancievan Thangaratnarajah, Martin S. King, Daniel T. D. Jones, Shujing Ding, Ian M. Fearnley, Edmund R. S. Kunji
Summary: This study characterized the human mitochondrial pyruvate carrier (MPC) protein and identified the chemical features necessary for high-affinity inhibition. It found that three hydrogen bond acceptors followed by an aromatic ring are shared characteristics of all inhibitors and represent the minimal requirement for high potency. The study also discovered 14 new MPC inhibitors, with one compound outperforming a known inhibitor by tenfold.
MOLECULAR METABOLISM
(2022)
Article
Clinical Neurology
Luis Carlos Tabara, Fatema Al-Salmi, Reza Maroofian, Amna Mohammed Al-Futaisi, Fathiya Al-Murshedi, Joanna Kennedy, Jacob O. Day, Thomas Courtin, Aisha Al-Khayat, Hamid Galedari, Neda Mazaheri, Margherita Protasoni, Mark Johnson, Joseph S. Leslie, Claire G. Salter, Lettie E. Rawlins, James Fasham, Almundher Al-Maawali, Nikol Voutsina, Perrine Charles, Laura Harrold, Boris Keren, Edmund R. S. Kunji, Barbara Vona, Gholamreza Jelodar, Alireza Sedaghat, Gholamreza Shariati, Henry Houlden, Andrew H. Crosby, Julien Prudent, Emma L. Baple
Summary: Hereditary spastic paraplegia (HSP), a genetically diverse neurodegenerative disease, can be classified as pure or complex forms. Biallelic variants in the TMEM63C gene were identified in individuals with HSP and mild intellectual disability. Further analysis showed that TMEM63C plays a role in regulating both endoplasmic reticulum and mitochondrial morphologies.
Review
Endocrinology & Metabolism
Sotiria Tavoulari, Denis Lacabanne, Chancievan Thangaratnarajah, Edmund R. S. Kunji
Summary: Citrin deficiency is a globally prevalent mitochondrial disease with three stages: neonatal intrahepatic cholestasis, a mild adaptation stage, and adult citrullinemia. It is caused by the absence or dysfunction of the calcium-regulated mitochondrial aspartate/glutamate carrier 2 (AGC2/SLC25A13), also known as citrin. This deficiency affects the malate-aspartate shuttle, gluconeogenesis, amino acid homeostasis, and the urea cycle.
TRENDS IN ENDOCRINOLOGY AND METABOLISM
(2022)
Article
Multidisciplinary Sciences
Vasiliki Mavridou, Martin S. King, Sotiria Tavoulari, Jonathan J. Ruprecht, Shane M. Palmer, Edmund R. S. Kunji
Summary: The authors investigate the molecular details of substrate binding in the mitochondrial ADP/ATP carrier, revealing the binding site and key residues involved in the transport process. This finding contributes to a better understanding of the mechanism and properties of adenine nucleotide transport.
NATURE COMMUNICATIONS
(2022)
Article
Endocrinology & Metabolism
Riccardo Cavalieri, Marlou Klein Hazebroek, Camila A. Cotrim, Yang Lee, Edmund R. S. Kunji, Martin Jastroch, Susanne Keipert, Paul G. Crichton
Summary: This study elucidates the interaction between activators and UCP1, and demonstrates the potential of targeting UCP1 in cells as a therapeutic avenue using approved drugs, but requires variants with more effective delivery in brown adipocytes.
MOLECULAR METABOLISM
(2022)
Article
Biochemistry & Molecular Biology
Chancievan Thangaratnarajah, Jan Rheinberger, Cristina Paulino
Summary: Single-particle cryo-EM is a powerful technique for structural characterization of membrane proteins. Recent advancements in hardware and software have made high-resolution 3D reconstructions routine. The use of 200kV cryo-TEMs is gaining prominence, offering improved resolutions for soluble and membrane proteins.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Camila Cimadamore-Werthein, Stephany Jaiquel Baron, Martin S. King, Roger Springett, Edmund R. S. Kunji
Summary: The mitochondrial ADP/ATP carrier plays a crucial role in oxidative phosphorylation by importing ADP into the mitochondrial matrix and exporting ATP. Recent studies have revealed that the carrier functions as a monomer with a single substrate binding site and operates with a ping-pong kinetic mechanism. These findings reconcile the discrepancy between the previous assumptions and provide insights into the alternating access mechanism of the carrier.
Article
Multidisciplinary Sciences
Scott A. Jones, Prerana Gogoi, Jonathan J. Ruprecht, Martin S. King, Yang Lee, Thomas Zogg, Els Pardon, Deepak Chand, Stefan Steimle, Danielle M. Copeman, Camila A. Cotrim, Jan Steyaert, Paul G. Crichton, Vera Moiseenkova-Bell, Edmund R. S. Kunji
Summary: Mitochondrial uncoupling protein 1 (UCP1) is responsible for the ability of brown adipose tissue in mammals to burn calories as heat for thermoregulation. UCP1 can be activated by fatty acids to generate heat by catalyzing the leakage of protons across the mitochondrial inner membrane. However, purine nucleotides can bind and inhibit UCP1, regulating proton leak through an unknown molecular mechanism. The cryo-electron microscopy structure of the GTP-inhibited state of UCP1 provides insights into the specific interactions and pH dependency of the regulatory mechanism, indicating that inhibitor binding prevents the conformational changes necessary for proton leak.
Review
Physiology
Sotiria Tavoulari, Maximilian Sichrovsky, Edmund R. S. Kunji
Summary: Mitochondrial pyruvate carrier (MPC) plays a crucial role in connecting cytosolic and mitochondrial metabolism by transporting pyruvate into the mitochondrial matrix. Due to its importance, MPC has been proposed as a potential target for various diseases. However, the knowledge about its structure and mechanism is limited. This article provides critical insights into the composition, structure, and function of MPC, and summarizes the different classes of small molecule inhibitors and their potential in therapeutics.
Article
Biochemistry & Molecular Biology
Justyna Zitek, Martin S. King, Priscila Pen, Eva Pyrihov, Alannah C. King, Edmund R. S. Kunji, Vladimir Hampl
Summary: Paratrimastix pyriformis is a free-living flagellate belonging to the group Metamonada and it has a mitochondrion-related organelle involved in one-carbon folate metabolism. The organelle contains solute carrier family 25 (SLC25) members responsible for metabolite exchange across the mitochondrial inner membrane. PpMC1, the adenine nucleotide carrier, was shown to transport ATP, ADP, and to a lesser extent, AMP, but not phosphate. It represents a distinct class of adenine nucleotide carriers different from ADP/ATP carriers and ATP-Mg/phosphate carriers.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2023)
Article
Multidisciplinary Sciences
Chancievan Thangaratnarajah, Mark Nijland, Luis Borges-Araujo, Aike Jeucken, Jan Rheinberger, Siewert J. J. Marrink, Paulo C. T. Souza, Cristina Paulino, Dirk J. J. Slotboom
Summary: The final step in the transport cycle of ECF transporters involves the expulsion of the substrate binding protein from the motor. The motor uses ATP binding to induce a shape change, allowing for the dissociation of the binding protein. This study provides insights into the chemo-mechanical coupling in the transport cycle of ECF transporters.
NATURE COMMUNICATIONS
(2023)
