Article
Multidisciplinary Sciences
Macarena Rodriguez-Prados, Elena Berezhnaya, Maria Teresa Castromonte, Sergio L. Menezes-Filho, Melanie Paillard, Gyorgy Hajnoczky
Summary: Mitochondrial Ca2+ uptake is regulated by the mtCU complex, which consists of MCU, EMRE, and MICU1/2/3 subunits. MICU1 has been proposed to physically block the mtCU pore and regulate Ca2+ flux at different cytoplasmic [Ca2+]. We studied the mtCU in divalent-free conditions and found that MICU1 restricts Na+ influx, but some mtCU channels appear to lack MICU1-dependent gating in cells with high endogenous MICU1 expression. The rearrangement of mtCU and loss of MICU1 during mitoplast preparation might have affected previous studies in divalent-free conditions.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Biochemistry & Molecular Biology
Cheng Huang, Kun Deng, Minghua Wu
Summary: Mitochondria are vital for energy metabolism and their structure is influenced by mitochondrial dynamics and cristae remodeling. This review focuses on key regulators of cristae structure, including the mitochondrial contact site and cristae organizing system, optic atrophy-1, mitochondrial calcium uniporter, and ATP synthase. Dysfunction or deletion of these regulators can lead to abnormal cristae morphology, impacting cellular respiration and contributing to diseases such as Parkinson's disease, Leigh syndrome, and dominant optic atrophy.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Review
Multidisciplinary Sciences
Wenping Wu, Jimin Zheng, Zongchao Jia
Summary: The mitochondrial uniporter is a Ca2+-selective ion-conducting channel in the inner mitochondrial membrane composed of MCU, MCUb, EMRE, MICU1, and MICU2. Recent structural studies have provided insights into the component structures and their spatial relationship, contributing to a better understanding of mitochondrial Ca2+ uptake and regulation. Further research in this area could lead to advancements in studying mitochondrial Ca2+ permeation and related diseases.
Editorial Material
Cell Biology
Benjamin Gottschalk, Roland Malli, Wolfgang F. Graier
Summary: Changes in mitochondrial ultrastructure and dynamics, including cytochrome c release, membrane potential rearrangement, and mitochondrial Ca2+ uptake dynamics, are observed in MICU1(-/-) cells due to its sensitivity to Ca2+ and its binding to Mic60 and CHCHD2. MICU1 is not only an interaction partner and regulator of the MCU complex, but also plays a crucial role in determining mitochondrial ultrastructure and initiating apoptosis.
Review
Physiology
Omar Lozano, Patricio Marcos, Felipe de Jesus Salazar-Ramirez, Anay F. Lazaro-Alfaro, Luis Sobrevia, Gerardo Garcia-Rivas
Summary: Cardiovascular diseases (CVDs) are the leading cause of death worldwide and are associated with mitochondrial dysfunction, specifically in the regulation of Ca2+ uptake. Modulating the activity of the mitochondrial Ca2+ uniporter (MCU) complex has been suggested as a potential therapeutic approach for CVDs.
Article
Critical Care Medicine
Xuexin Li, Bowen Sun, Jie Li, Wanlin Ye, Mingjuan Li, Fasheng Guan, Songlin Wu, Xuerong Luo, Jianguo Feng, Jing Jia, Xueru Liu, Tao Li, Li Liu
Summary: This study found that ICUAW is associated with impaired mitochondrial calcium uptake caused by a decreased MICU1:MCU protein ratio. Overexpression of MICU1 can improve this dysfunction and alleviate sepsis-induced skeletal muscle weakness and atrophy.
Article
Biochemistry & Molecular Biology
Macarena Rodriguez-Prados, Kai-Ting Huang, Katalin Marta, Melanie Paillard, Gyorgy Csordas, Suresh K. Joseph, Gyorgy Hajnoczky
Summary: Mitochondrial Ca2+ homeostasis is dysregulated in many diseases and can be targeted therapeutically. The uniporter channel (mtCU), comprised of MCU and regulated by MICU1, plays a crucial role in mitochondrial Ca2+ uptake. Understanding the molecular mechanisms of mtCU activators and inhibitors is essential for developing effective therapies.
CELL CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Toshitaka Nakamura, Motoyuki Ogawa, Kazuki Kojima, Saki Takayanagi, Shunya Ishihara, Kazuki Hattori, Isao Naguro, Hidenori Ichijo
Summary: The study revealed that mitochondrial Ca2+ regulation and hyperpolarization play a key role in lipid peroxidation and ferroptosis under cold stress.
Article
Biology
Benjamin Gottschalk, Zhanat Koshenov, Markus Waldeck-Weiermair, Snjezana Radulovic, Furkan E. Oflaz, Martin Hirtl, Olaf A. Bachkoenig, Gerd Leitinger, Roland Malli, Wolfgang F. Graier
Summary: This study reveals the role of MICU1 in controlling the spatial membrane potential gradients in mitochondria, with changes in SMPGs and spatial cristae depolarization occurring when Ca2+ binds to MICU1.
COMMUNICATIONS BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Akshar Patel, Matthew Simkulet, Soumya Maity, Manigandan Venkatesan, Anastasios Matzavinos, Muniswamy Madesh, B. Rita Alevriadou
Summary: This study found that under shear stress, the increase in mitochondrial Ca2+ levels is associated with the function and energy metabolism of endothelial cells. Activation of the mechanosensitive channel Piezo1 and the endothelial nitric oxide synthase eNOS are involved in this process.
SCIENTIFIC REPORTS
(2022)
Review
Biochemistry & Molecular Biology
Giorgia Pallafacchina, Sofia Zanin, Rosario Rizzuto
Summary: Advances in scientific research have led to increasing interest in the regulation and physiological role of mitochondrial Ca2+ signaling, with the discovery and characterization of genes and pathways involved in recent years. The identification of the mitochondrial channel components and their function over the past decade has provided a clearer understanding of the role of mitochondrial Ca2+ signals in cellular processes. Recent studies have highlighted the importance of the MCU complex in controlling muscle nutrition and metabolism.
Article
Biology
Vivek Garg, Junji Suzuki, Ishan Paranjpe, Tiffany Unsulangi, Liron Boyman, Lorin S. Milescu, W. Jonathan Lederer, Yuriy Kirichok
Summary: The study reveals that the MICU subunits do not block the MCUcx pore in the absence or presence of extramitochondrial Ca2+, but instead potentiate MCUcx activity by modifying its gating properties to spend more time in the open state when extramitochondrial Ca2+ is elevated.
Article
Cell Biology
Melanie Paillard, Kai-Ting Huang, David Weaver, Jonathan P. Lambert, John W. Elrod, Gyorgy Hajnoczky
Summary: Heart failure is a significant cause of hospitalization and mortality worldwide. The regulation of mitochondrial calcium handling appears to play a crucial role in the progression of heart failure. This study investigated the protein composition of mitochondrial calcium uniporter (mtCU) in human hearts and observed alterations in the regulators MICU1 and MICU2, suggesting a possible role for adaptive/maladaptive changes in mtCU composition in the initiation/progression of human heart failure.
Article
Cell Biology
Claire Angebault, Mathieu Panel, Mathilde Lacote, Jennifer Rieusset, Alain Lacampagne, Jeremy Fauconnier
Summary: In the early stages of Duchenne muscular dystrophy (DMD), the heart exhibits impaired sarco-endoplasmic reticulum (SR/ER)-mitochondria interactions and mitochondrial dysfunction, resulting in disrupted mitochondrial Ca2+ homeostasis and complex I dysfunction. Treatment with metformin could reverse these abnormalities, offering a potential therapeutic perspective in DMD.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Cardiac & Cardiovascular Systems
Celio Damacena de Angelis, Benney T. Endoni, Daniel Nuno, Kathryn Lamping, Johannes Ledolter, Olha M. Koval, Isabella M. Grumbach
Summary: This study investigated sex differences in vasoreactivity and the role of mitochondrial Ca2+ entry via the MCU in resistance arteries. Female mice exhibited reduced vasodilation compared to male mice in genetic models of endothelial MCU ablation. These differences were attributed to higher cytosolic Ca2+ transients and enhanced mitochondrial Ca2+ entry in female mice. Estradiol treatment in human aortic endothelial cells also increased cytosolic Ca2+ transients and mitochondrial Ca2+ entry. These findings suggest that differences in mitochondrial function, rather than MCU complex composition, contribute to the sex-specific differences in vasodilation.
JOURNAL OF THE AMERICAN HEART ASSOCIATION
(2022)
Article
Cardiac & Cardiovascular Systems
Fotios Spyropoulos, Andrea Sorrentino, Jiska van der Reest, Peiran Yang, Markus Waldeck-Weiermair, Benjamin Steinhorn, Emrah Eroglu, Seyed Soheil Saeedi Saravi, Paul Yu, Marcia Haigis, Helen Christou, Thomas Michel
Summary: In this study, we developed a chemogenetic animal model of heart failure that mimics a central feature of human heart failure: increased cardiac redox stress. By using recombinant DAAO enzyme to generate H2O2 in cardiomyocytes, we induced cardiomyopathy. We observed significant changes in cardiac metabolome and transcriptome following chemogenetic heart failure, similar to those observed in human heart failure. Our findings help validate chemogenetic approaches for discovering novel therapeutic targets in heart failure.
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
(2022)
Article
Biology
Zhanat Koshenov, Furkan E. Oflaz, Martin Hirtl, Benjamin Gottschalk, Rene Rost, Roland Malli, Wolfgang F. Graier
Summary: The study investigates the regulation of basal mitochondrial bioenergetics and reveals that Ca2+ fluxes from ER-mitochondria contact sites control basal mitochondrial metabolism and energetics. The researchers identify citrin as a primary regulator of this process and show that manipulation of Ca2+ dynamics can reprogram cellular and mitochondrial metabolism.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Ines Tawfik, Benjamin Gottschalk, Angelo Jarc, Doruntina Bresilla, Rene Rost, Barbara Obermayer-Pietsch, Wolfgang F. Graier, Corina T. Madreiter-Sokolowski
Summary: Thyroid hormones regulate mitochondrial Ca2+ uptake, leading to increased energy metabolism and reactive oxygen species production.
FREE RADICAL BIOLOGY AND MEDICINE
(2022)
Article
Cell Biology
Madeleine Goeritzer, Stefanie Schlager, Katharina B. Kuentzel, Nemanja Vujic, Melanie Korbelius, Silvia Rainer, Dagmar Kolb, Marion Mussbacher, Manuel Salzmann, Waltraud C. Schrottmaier, Alice Assinger, Axel Schlagenhauf, Corina T. Madreiter-Sokolowski, Sandra Blass, Thomas O. Eichmann, Wolfgang F. Graier, Dagmar Kratky
Summary: Loss of ATGL in platelets is associated with an anti-thrombogenic phenotype without pathological bleeding and platelet activation.
Article
Transplantation
Andras T. Deak, Katarina Belic, Anna-Maria Meissl, Katharina Artinger, Kathrin Eller, Bernd Rechberger, Tobias Niedrist, Wolfgang F. Graier, Roland Malli, Helmut Bischof, Sandra Burgstaller, Sandra Blass, Alexander Avian, Alexander R. Rosenkranz, Alexander H. Kirsch
Summary: This study assessed the performance of genetically encoded potassium-ion indicators (GEPIIs) in measuring salivary potassium concentration and found that salivary potassium levels exhibited similar kinetics to plasma potassium levels. However, further research is needed to determine if saliva could be a suitable sample type for monitoring plasma potassium levels.
NEPHROLOGY DIALYSIS TRANSPLANTATION
(2023)
Article
Biochemistry & Molecular Biology
Gulsah Sevimli, Matthew J. Smith, Tuba Akgul Caglar, Sukriye Bilir, Melike Secilmis, Hamza Y. Altun, Esra N. Yigit, Fan Yang, Thomas P. Keeley, Roland Malli, Gurkan Ozturk, Giovanni E. Mann, Emrah Eroglu
Summary: This study demonstrates the iron-dependency of the metalloprotein geNOps in cells and uncovers the different iron requirements between cells adapted to different oxygen levels.
Article
Biology
Benjamin Gottschalk, Zhanat Koshenov, Markus Waldeck-Weiermair, Snjezana Radulovic, Furkan E. Oflaz, Martin Hirtl, Olaf A. Bachkoenig, Gerd Leitinger, Roland Malli, Wolfgang F. Graier
Summary: This study reveals the role of MICU1 in controlling the spatial membrane potential gradients in mitochondria, with changes in SMPGs and spatial cristae depolarization occurring when Ca2+ binds to MICU1.
COMMUNICATIONS BIOLOGY
(2022)
Article
Chemistry, Analytical
Gulsah Sevimli, Amy E. Alston, Felix Funk, Beat Fluhmann, Roland Malli, Wolfgang F. Graier, Emrah Eroglu
Summary: The study used geNOps, a genetically encoded fluorescent biosensor, to measure available iron in cellular locales. The researchers found that in addition to ferrous iron salts, the complex of iron (III) with HBED can activate the biosensor. Furthermore, treatment with iron sucrose for only 20 minutes was sufficient to significantly activate the biosensor in the cytosol and mitochondria, while ferric carboxymaltose failed to functionalize the biosensor.
Article
Cell Biology
Furkan E. Oflaz, Zhanat Koshenov, Martin Hirtl, Olaf A. Bachkoenig, Wolfgang F. Graier, Benjamin Gottschalk
Summary: Mitochondrial uncoupling proteins UCP1 and UCP2 have different molecular mechanisms for executing their mitochondria uncoupling function, with UCP1 dissipating the proton motive force and UCP2 modulating the permeability of the cristae junction. This mini-review discusses the molecular mechanisms of UCP1 in brown adipose tissue and UCP2 in aged and cancer non-excitable cells, and the synergistic effects of both UCPs with the mitochondrial Ca2+ uptake machinery.
Article
Genetics & Heredity
Lukas Kaufmann, Johannes Pilic, Lisa Auinger, Anna-Lena Mayer, Jasmin Blatterer, Johann Semmler-Bruckner, Safdar Abbas, Khurram Rehman, Muhammad Ayaz, Wolfgang F. Graier, Roland Malli, Erwin Petek, Klaus Wagner, Ali Al Kaissi, Muzammil Ahmad Khan, Christian Windpassinger
Summary: Restrictive dermopathy (RD) is a lethal condition caused by loss-of-function mutations in ZMPSTE24, while mutations preserving residual enzymatic activity lead to mandibuloacral dysplasia with type B lipodystrophy (MADB) phenotype. A new homozygous loss-of-function mutation in ZMPSTE24 was identified in two consanguineous Pakistani families with MADB. Functional analysis revealed that alternative translation initiation sites were utilized, preventing complete loss of protein function and explaining the relatively mild phenotype in affected patients. Our findings suggest considering the creation of new potential start codons in other disease-associated genes with N-terminal mutations.
Article
Biochemistry & Molecular Biology
Madeleine Goeritzer, Katharina B. Kuentzel, Sarah Beck, Melanie Korbelius, Silvia Rainer, Ivan Bradic, Dagmar Kolb, Marion Mussbacher, Waltraud C. Schrottmaier, Alice Assinger, Axel Schlagenhauf, Rene Rost, Benjamin Gottschalk, Thomas O. Eichmann, Thomas Zuellig, Wolfgang F. Graier, Nemanja Vujic, Dagmar Kratky
Summary: Monoglyceride lipase (MGL) hydrolyzes monoacylglycerols (MG) and plays a role in platelet function. MGL deficiency leads to decreased platelet aggregation and impaired response to collagen activation, resulting in reduced thrombus formation and prolonged bleeding time. Genetic deletion of MGL is associated with altered thrombogenesis in mice.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Asal Ghaffari Zaki, Seyed Mohammad Miri, Seyma Cimen, Tuba Akgul Caglar, Esra N. Yigit, Mehmet S. Aydin, Gurkan Ozturk, Emrah Eroglu
Summary: pH-Control is a novel enzymatic method that allows precise control of ultralocal acidification in living cells. The genetically encoded biosensor SypHer3s demonstrated that pH-Control effectively acidifies cytosolic, mitochondrial, and nuclear pH in a concentration-dependent manner. This approach shows promise in investigating the ultralocal pH imbalance associated with various diseases.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Atida Selmani, Ramona Jeitler, Michael Auinger, Carolin Tetyczka, Peter Banzer, Brian Kantor, Gerd Leitinger, Eva Roblegg
Summary: Biocompatible gold nanoparticles have been utilized in wound healing due to their radical scavenging activity. An acidic microenvironment is also found to promote wound healing through cell proliferation and inhibit bacterial growth. Combining these two approaches shows promising results for wound healing.
Editorial Material
Cell Biology
Benjamin Gottschalk, Roland Malli, Wolfgang F. Graier
Summary: Changes in mitochondrial ultrastructure and dynamics, including cytochrome c release, membrane potential rearrangement, and mitochondrial Ca2+ uptake dynamics, are observed in MICU1(-/-) cells due to its sensitivity to Ca2+ and its binding to Mic60 and CHCHD2. MICU1 is not only an interaction partner and regulator of the MCU complex, but also plays a crucial role in determining mitochondrial ultrastructure and initiating apoptosis.
Article
Chemistry, Multidisciplinary
Zuzana Klepcova, Ivana Spakova, Corina T. T. Madreiter-Sokolowski, Wolfgang Graier, Katarina Kalinova, Erika Samolova, Romana Smolkova, Lukas Smolko, Miroslava Rabajdova
Summary: Two novel Mn(II) complexes with fenamic acid and flufenamic acid as ligands and neocuproine as a supporting ligand were synthesized and characterized. The complexes exhibit moderate radical scavenging activity and cytotoxic effects on selected cell lines, with the flufenamic acid complex being able to induce apoptosis. Both complexes target inflammatory processes on a cellular level.
NEW JOURNAL OF CHEMISTRY
(2023)
