Article
Biochemistry & Molecular Biology
Emily Wachoski-Dark, Tian Zhao, Aneal Khan, Timothy E. Shutt, Steven C. Greenway
Summary: There is a unclear mechanistic link between human mitochondrial disorders and the development of cardiomyopathy. Defects in mitochondrial proteostasis, which involves the maintenance of mitochondrial protein homeostasis, can lead to mitochondrial cardiomyopathies. Disruptions in proteostasis can result in mitochondrial dysfunction and impact cardiac function.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Yi-Hsuan Wu, Hsi-Lung Hsieh
Summary: Bioenergetic mitochondrial dysfunction is a common feature of various diseases, including Alzheimer's disease. Redox imbalance and mitochondrial dysfunction play important roles in the development of Alzheimer's disease. This review summarizes the evidence for redox imbalance and mitochondrial dysfunction in Alzheimer's disease, and discusses current therapeutic strategies related to mitochondrial maintenance.
Article
Geriatrics & Gerontology
Prasanth S. Ariyannur, Guoqiang Xing, Erin S. Barry, Brandi Benford, Neil E. Grunberg, Pushpa Sharma
Summary: The study investigated the impact of TBI on rat brain regions and the effect of pyruvate on mild TBI outcomes. The results showed that pyruvate treatment improved the expression of some neurodegenerative proteins but had a negative effect on the acute phase of mTBI.
Article
Pharmacology & Pharmacy
Mohamed Touaibia, Patrick-Denis St-Coeur, Patrick Duff, Diene Codou Faye, Nicolas Pichaud
Summary: A series of thiazolidinediones were synthesized and studied for their effects on Drosophila melanogaster mitochondrial respiration. Compounds like 5-benzylidenethiazolidine-2,4-diones exhibited strong inhibitory capacity compared to other analogs, showing potential as potent mitochondrial pyruvate carrier inhibitors similar to UK5099. An analog, 5-benzylidenethiazolidine-2,4-dione 3, demonstrated positive effects on fruit fly survival and longevity, reversing the effects of a high fat diet and suggesting in vivo inhibition of MPC at the mitochondrial level.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Tianyang Lan, Kang Zhang, Feifei Lin, Qifu He, Shenghui Wu, Zhiming Xu, Yong Zhang, Fusheng Quan
Summary: MICU1 modulators enhance mitochondrial activity, pyruvate metabolism, and developmental competence of thawed oocytes after vitrification. Vitrification leads to adverse effects on mitochondrial function, but these effects can be mitigated by MICU1 activation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Baoyi Chen, Wenting Zhang, Chuyuan Lin, Lingyun Zhang
Summary: Mitochondria are crucial sites for oxidative phosphorylation in cells, and secondary mitochondrial diseases refer to any abnormal mitochondrial function beyond primary mitochondrial diseases. The catechins in tea can protect mitochondria from oxidative damage, playing a role in maintaining cell homeostasis and mitochondrial function.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Physiology
David F. Wilson, Franz M. Matschinsky
Summary: Living organisms rely on continuous extraction of energy from the environment, with metabolic processes regulated by thermodynamics. Key reactions in glycolysis are controlled by ATP consumption rate, adjusting substrate concentrations to maintain metabolic balance. Thermodynamic control emerged early in life forms and evolved with the addition of new metabolic functions.
FRONTIERS IN PHYSIOLOGY
(2021)
Article
Oncology
Kun-Chi Chen, I-Hsin Hsiao, Yu-Nan Huang, Yu-Tung Chou, Yi-Chun Lin, Ju-Yi Hsieh, Yung-Lung Chang, Kang-Hsi Wu, Guang-Yaw Liu, Hui-Chih Hung
Summary: Acute myeloid leukemia (AML) is a fast-growing and fatal blood cancer, and targeting the human mitochondrial NAD(P)(+)-dependent malic enzyme (ME2) shows promise in AML treatment. ME2 inhibition through silencing or using its allosteric inhibitor Na(2)EA decreases pyruvate, NADH, and NADPH levels, leading to reduced ATP production, increased reactive oxygen species (ROS), and cellular apoptosis. ME2 inhibition also impairs pyruvate metabolism and the biosynthetic pathway, inhibiting the growth of AML cells. Overall, ME2 plays a crucial role in AML energy metabolism, and its inhibition provides a potential approach for AML treatment.
Article
Medicine, Research & Experimental
Stephen T. Decker, Alexs A. Matias, Sean T. Bannon, Jack P. Madden, Nadia Alexandrou-Majaj, Gwenael Layec
Summary: Epidemiological and clinical evidence shows that exposure to cigarette smoke affects glucose and fatty acid metabolism, increasing the risk of metabolic disorders. This study aimed to examine the effects of cigarette smoke on mitochondrial respiratory capacity and sensitivity in muscle fibers. The results revealed that cigarette smoke reduced mitochondrial respiratory capacity and sensitivity to pyruvate in the gastrocnemius muscle. Only the sensitivity to pyruvate-stimulated respiration showed a trend towards decrease in the soleus muscle. The findings highlight that cigarette smoke impairs mitochondrial respiration and plays a key role in smoke-induced muscle dysfunction and metabolic disturbances.
Article
Multidisciplinary Sciences
Chun-Shik Shin, Shuxia Meng, Spiros D. Garbis, Annie Moradian, Robert W. Taylor, Michael J. Sweredoski, Brett Lomenick, David C. Chan
Summary: This study reveals that the mitochondrial protease LONP1 is essential for the mtHSP70 chaperone system, regardless of its protease activity. LONP1 plays a critical role in maintaining the solubility of DNAJA3 and mtHSP70 in the mitochondria, showing intrinsic chaperone-like activity and collaborating with mtHSP70 to stabilize protein folding intermediates.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Marcel Morgenstern, Christian D. Peikert, Philipp Luebbert, Ida Suppanz, Cinzia Klemm, Oliver Alka, Conny Steiert, Nataliia Naumenko, Alexander Schendzielorz, Laura Melchionda, Wignand W. D. Muehlhaeuser, Bettina Knapp, Jakob D. Busch, Sebastian B. Stiller, Stefan Dannenmaier, Caroline Lindau, Mariya Licheva, Christopher Eickhorst, Riccardo Galbusera, Ralf M. Zerbes, Michael T. Ryan, Claudine Kraft, Vera Kozjak-Pavlovic, Friedel Drepper, Sven Dennerlein, Silke Oeljeklaus, Nikolaus Pfanner, Nils Wiedemann, Bettina Warscheid
Summary: Researchers have classified and identified human mitochondrial proteins, establishing a high-confidence mitochondrial proteome containing over 1,100 proteins, which account for 7% of cellular proteins and are linked to various diseases.
Article
Biochemistry & Molecular Biology
Iwona Zwolak, Ewa Wnuk
Summary: Vanadium, an important metal in the steel industry, is known to cause harm to the environment and human health. This study found that sodium pyruvate can protect cells from vanadium-induced toxicity by reducing reactive oxygen species (ROS) generation and preserving mitochondrial functions.
Article
Biochemistry & Molecular Biology
Jisoo Song, Gwonhwa Song, Sunwoo Park, Whasun Lim
Summary: The flavonoid compound 6,8-diprenylorobol extracted from Cudrania tricuspidata has been found to inhibit the growth of endometriosis cells by affecting cell cycle, mitochondrial function, oxidative stress, and calcium homeostasis. It does not affect normal cells. Moreover, 6,8-diprenylorobol acts on the AKT and P38 MAPK pathways and reduces mitochondrial respiration in endometriosis cells.
Review
Cell Biology
Kaya L. Persad, Gary D. Lopaschuk
Summary: Changes in energy metabolism have significant impacts on the fate of cardiomyocytes during development, particularly during the transition to a mature state. Mitochondrial biogenesis is regulated by fatty acid oxidation and PGC1-alpha, playing crucial roles in cardiac development and cell fate. Adult stem cells may secrete factors that protect cardiomyocytes, aiding in their differentiation and survival.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Naintara Jain, Ridhima Gomkale, Olaf Bernhard, Peter Rehling, Luis Daniel Cruz-Zaragoza
Summary: Mitochondria play a crucial role in cellular energy production and metabolism, and errors in mitochondrial protein import can lead to metabolic disorders. This study establishes a fluorescence-based import assay to analyze protein import into mitochondria, offering the advantage of quantifying import with high sensitivity. The assay can be adapted to a screening-compatible format and used to monitor the assembly of the F1F0 ATP synthase in purified mitochondria.
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)
Review
Biochemistry & Molecular Biology
Vanessa Joanne Xavier, Jean-Claude Martinou
Summary: The human mitochondrial genome regulates its transcription products in specialized ways through mtDNA, with RNA regulation organized within the Mitochondrial RNA Granules. Recent findings show that dsRNA species can form granules in the mitochondria matrix. Dysfunctions in mitochondria, such as RNA processing defects, may lead to loss or aberrant accumulation of these RNA granules, emphasizing the link between mitochondrial maintenance and proper gene expression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biophysics
Joel Jose Montalvo-Acosta, Edmund R. S. Kunji, Jonathan J. Ruprecht, Francois Dehez, Christophe Chipot
Summary: Research has shown that cardiolipins play a minor stabilizing role in the structure of the mitochondrial ADP/ATP carrier (AAC), particularly in the formation of interdomain salt bridges and hydrogen bonds. Additionally, cardiolipins contribute to preserving the pseudosymmetric structure of AAC, making it more compactly organized.
BIOPHYSICAL JOURNAL
(2021)
Article
Genetics & Heredity
Akira Ohkubo, Lindsey S. Van Haute, Danielle Rudler, Maike S. Stentenbach, Florian Steiner, Oliver S. Rackham, Michal Minczuk, Aleksandra S. Filipovska, Jean-Claude Martinou
Summary: Mitochondria have a unique gene expression system involving canonical and non-canonical RNA processing, with FASTK family proteins playing a crucial role in regulating RNA junctions. Disruption of the FASTKD5 gene results in defects in mitochondrial translation and oxidative phosphorylation, highlighting the importance of FASTK protein family members in non-canonical RNA processing in mitochondria.
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
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
Francesco Petrelli, Valentina Scandella, Sylvie Montessuit, Nicola Zamboni, Jean-Claude Martinou, Marlen Knobloch
Summary: Cellular metabolism plays a crucial role in the behavior of adult neural stem/progenitor cells (NSPCs). The mitochondrial pyruvate carrier (MPC) is identified as an important factor in controlling NSPC quiescence and activation.
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
Medicine, Research & Experimental
Stephany Jaiquel Baron, Martin S. King, Edmund R. S. Kunji, Tom J. J. Schirris
Summary: An increasing number of commonly prescribed drugs are known to interfere with mitochondrial function, causing cellular toxicity. However, the underlying mechanisms are largely unknown, and it has been found that only a subset of the 18 published AAC inhibitors can inhibit cellular respiratory capacity, raising questions about the effectiveness of all compounds in inhibiting this central metabolic process. Further research has provided new insights into the chemical compound features important for inhibition of mitochondrial transport proteins.
