Article
Endocrinology & Metabolism
N. Vishnu, A. Hamilton, A. Bagge, A. Wernersson, E. Cowan, H. Barnard, Y. Sancak, K. J. Kamer, P. Spegel, M. Fex, A. Tengholm, V. K. Mootha, D. G. Nicholls, H. Mulder
Summary: This study demonstrated that deficiency of the accessory protein MICU2 leads to decreased mitochondrial Ca2+ uptake in insulin-secreting cells, resulting in disrupted insulin secretion and impaired mitochondrial function.
MOLECULAR METABOLISM
(2021)
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)
Article
Pharmacology & Pharmacy
Ju Tang, Weixia Duan, Ping Deng, Huijuan Li, Cong Liu, Yu Duan, Min Feng, Shangcheng Xu
Summary: Cadmium exposure slows down the rapid movement of mitochondria in neurons, leading to abnormal distribution and excessive fragmentation of mitochondria, ultimately causing mitochondrial membrane potential loss and neuronal damage. Chelating overloaded cytosolic calcium is a promising strategy to prevent cadmium-induced neurotoxicity.
Editorial Material
Cell Biology
Janane F. Rahbani, Lawrence Kazak
Summary: The study suggests that the mitochondrial calcium uniporter binds uncoupling protein 1 via the MCU regulator to form a protein complex called the thermoporter. Through this complex, calcium influx into the mitochondrial matrix is enhanced, leading to increased NADH production and thermogenesis in brown adipose tissue.
Article
Chemistry, Multidisciplinary
Zhouyang Huang, Samantha N. N. MacMillan, Justin J. J. Wilson
Summary: In this study, a new fluorogenic mitochondrial calcium uniporter (MCU) inhibitor, RuOCou, is introduced. This compound exhibits both increased MCU-inhibitory activity and fluorescence intensity after aquation. By monitoring its fluorescence response, the aquation of RuOCou can be observed in HeLa cell lysates and live HeLa cells. This fluorogenic prodrug shows potential as a theranostic MCU inhibitor for the treatment of human diseases associated with MCU activity.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Review
Physiology
Deng Pan, Lin Xu, Dazhuo Shi, Ming Guo
Summary: In the past decade, research on mitochondrial calcium uniporter (MCU) has steadily grown. Current studies focus on the structure of the mitochondrial calcium uniporter complex and its regulatory effect on mitochondrial calcium homeostasis. Additionally, the potential role of mitochondrial calcium uniporter in different diseases has been explored. Current investigations mainly involve cancer and neurodegenerative diseases. Our analysis provides guidance and new insights for further mitochondrial calcium uniporter research.
FRONTIERS IN PHYSIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Roberto Docampo, Anibal Eugenio Vercesi
Summary: This review discusses the mechanisms of mitochondrial oxidant generation and removal, and the involvement of Ca2+ in trypanosome cell death, highlighting the need for further studies on ROS generation, defense mechanisms, and mitochondrial permeability transition pore in trypanosomatids.
ANTIOXIDANTS & REDOX SIGNALING
(2022)
Article
Cell Biology
Swagatika Panda, Suchismita Behera, Mohd Faraz Alam, Gulam Hussain Syed
Summary: Calcium ions serve as secondary messengers in cellular processes, with ER and mitochondria relying on Ca2+ for their function. Viruses exploit Ca2+ signaling to establish infection and evade host immune defenses, highlighting the significance of this interplay on viral life cycles and disease pathogenesis.
Article
Cell Biology
Emily Fernandez Garcia, Usha Paudel, Michael C. Noji, Caitlyn E. Bowman, Anil K. Rustgi, Jason R. Pitarresi, Kathryn E. Wellen, Zolt Arany, Jillian S. Weissenrieder, J. Kevin Foskett
Summary: Inhibition of MCU in oncogenic cell lines leads to an energetic crisis and reduced cell proliferation unless media is supplemented with nucleosides, pyruvate or a-KG.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Hadyn M. M. Rose, Beatriz Ferran, Rojina Ranjit, Anthony M. M. Masingale, Daniel B. B. Owen, Stacy Hussong, Michael T. T. Kinter, Veronica Galvan, Sreemathi Logan, Carlos Manlio Diaz-Garcia
Summary: Genetic down-regulation of the Mcu gene in dentate granule cells (DGCs) of the hippocampus leads to increased respiratory activity of mitochondrial complexes I and II, causing the generation of reactive oxygen species and impaired electron transport chain. The metabolic remodeling of MCU-deficient neurons involves changes in glycolysis, tricarboxylic acid cycle, and cellular antioxidant defenses. In middle-aged mice, MCU deficiency does not affect circadian rhythms, spontaneous exploratory behavior, or cognitive function, but significantly impairs reversal learning.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Cristina Ruberti, Elias Feitosa-Araujo, Zhaolong Xu, Stephan Wagner, Matteo Grenzi, Essam Darwish, Sophie Lichtenauer, Philippe Fuchs, Ambra Selene Parmagnani, Daria Balcerowicz, Sebastjen Schoenaers, Carolina de la Torre, Khansa Mekkaoui, Adriano Nunes-Nesi, Markus Wirtz, Kris Vissenberg, Olivier Van Aken, Bettina Hause, Alex Costa, Markus Schwarzlaender
Summary: The study demonstrates that MCU proteins mediate mitochondrial Ca2+ transport in plants, serving as the major route for fast Ca2+ uptake. Knockout of mcu genes limits mitochondrial Ca2+ uptake, leading to impaired subcellular Ca2+ transport and deregulated jasmonic acid-related signaling and thigmomorphogenesis.
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
Cell Biology
Simona Feno, Rosario Rizzuto, Anna Raffaello, Denis Vecellio Reane
Summary: The discovery of the Mitochondrial Calcium Uniporter (MCU) gene in 2011 led to an explosion of studies on the composition, regulation, and pathophysiological roles of the MCU complex. Recent research has provided new insights into the molecular structure and composition of the MCU complex, as well as the mechanisms that regulate MCU channel activity.
Article
Multidisciplinary Sciences
Chen-Wei Tsai, Tsung-Yun Liu, Fan-Yi Chao, Yung-Chi Tu, Madison X. Rodriguez, Anna M. Van Keuren, Zhiwei Ma, John Bankston, Ming-Feng Tsai
Summary: The mitochondrial calcium uniporter is a Ca2+ channel that imports cytoplasmic Ca2+ into the mitochondrial matrix to regulate cell bioenergetics, intracellular Ca2+ signaling, and apoptosis. The uniporter contains the pore-forming MCU subunit, an auxiliary EMRE protein, and the regulatory MICU1/MICU2 subunits. Structural and biochemical studies have suggested that MICU1 gates MCU by blocking/unblocking the pore. However, mitoplast patch-clamp experiments argue that MICU1 does not block, but instead potentiates MCU via allosteric mechanisms.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Rongjin Yang, Xiaomeng Zhang, Pingping Xing, Shun Zhang, Feiyu Zhang, Jianbang Wang, Jun Yu, Xiaoling Zhu, Pan Chang
Summary: This study demonstrated that Grpel2 expression is upregulated during myocardial ischemia/reperfusion (I/R) injury. Knockdown of Grpel2 exacerbates mitochondrial fission, cardiomyocyte death, and cardiac contractile dysfunction induced by I/R injury. The study also showed that Grpel2 knockdown increases the expression of MCU and mitochondrial calcium content.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Noelia Lander, Miguel A. Chiurillo, Roberto Docampo
Summary: Trypanosoma cruzi is a unicellular parasite responsible for Chagas disease, with a digenetic life cycle alternating between mammalian and insect hosts. This parasite must adapt to various environmental conditions such as temperature, nutrient availability, pH, and oxidative stress, which are regulated by signaling pathways. This review will focus on the signaling pathways and second messengers involved in the responses to these environmental changes.
MOLECULAR MICROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Brian S. Mantilla, Leticia D. Do Amaral, Henning J. Jessen, Roberto Docampo
Summary: The study highlights the importance of highly phosphorylated IPs in the life cycle of T. cruzi, identifying new highly phosphorylated IPs and the kinases involved in their synthesis.
ACS CHEMICAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Brian S. Mantilla, Karunakaran Kalesh, Nathaniel W. Brown, Dorothea Fiedler, Roberto Docampo
Summary: This study identified potential targets of 5-IP7 in Trypanosoma cruzi using pull-down experiments and mass spectrometry analysis, revealing new functional roles of 5-IP7 in this divergent eukaryote and providing potential new targets for chemotherapy.
MOLECULAR MICROBIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Roberto Docampo, Guozhong Huang
Summary: Trypanosoma cruzi and the T. brucei group of parasites are neglected diseases affecting millions of people globally. These microorganisms have complex life cycles involving insect vectors and mammalian hosts, and possess unique signaling pathways and receptor adaptations that differentiate them from their mammalian counterparts.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Andrew J. Stasic, Eric J. Dykes, Ciro D. Cordeiro, Stephen A. Vella, Mojtaba S. Fazli, Shannon Quinn, Roberto Docampo, Silvia N. J. Moreno
Summary: Proton transport plays a crucial role in maintaining cytosolic Ca2+ levels, Ca2+ influx, and Ca2+ storage by acidic compartments in Toxoplasma gondii. It impacts the concentration of polyphosphate, a key player in binding and storing Ca2+, further influencing Ca2+ signaling pathways and downstream cellular processes such as motility and egress.
MOLECULAR MICROBIOLOGY
(2021)
Article
Microbiology
Raquel S. Negreiros, Noelia Lander, Miguel A. Chiurillo, Anibal E. Vercesi, Roberto Docampo
Summary: Pyruvate, the end product of glycolysis, is transported into the mitochondria through the mitochondrial pyruvate carriers MPC1 and MPC2. Knockout of MPC1 and MPC2 in Trypanosoma cruzi affects pyruvate-driven respiration, host cell invasion, and intracellular replication of amastigotes.
Article
Microbiology
Srinivasan Ramakrishnan, Linn M. Unger, Rodrigo P. Baptista, Teresa Cruz-Bustos, Roberto Docampo
Summary: This study demonstrates that ablation of a Golgi-localized cation transporter in Trypanosoma cruzi prevents normal protein glycosylation, host cell invasion, and intracellular replication, while glycosylation can be rescued by Mn2+ but not by other cations. These findings highlight the crucial role of Mn2+ in host-parasite interaction and protein glycosylation.
Article
Biochemistry & Molecular Biology
Roberto Docampo, Anibal Eugenio Vercesi
Summary: This review discusses the mechanisms of mitochondrial oxidant generation and removal, and the involvement of Ca2+ in trypanosome cell death, highlighting the need for further studies on ROS generation, defense mechanisms, and mitochondrial permeability transition pore in trypanosomatids.
ANTIOXIDANTS & REDOX SIGNALING
(2022)
Article
Microbiology
Fatma Gomaa, Zhu-Hong Li, David J. Beaudoin, Heba Alzan, Peter R. Girguis, Roberto Docampo, Virginia P. Edgcomb
Summary: Developing transfection protocols for marine protists is an emerging field. In this study, we successfully developed a CRISPR/Cas9 editing protocol for Bodo saltans and identified two mechanisms for repairing double-strand breaks in this organism.
ENVIRONMENTAL MICROBIOLOGY
(2022)
Review
Microbiology
Roberto Docampo, Guozhong Huang
Summary: Acidocalcisomes are organelles found in bacteria and eukaryotes. They play important roles in autophagy, ion and phosphorus storage, osmoregulation, pH homeostasis, and pathogenesis. Recent studies have also revealed their involvement in phosphate utilization, calcium ion signaling, and bioenergetics.
JOURNAL OF EUKARYOTIC MICROBIOLOGY
(2022)
Article
Chemistry, Medicinal
Alejandro Pezza, Luis E. Tavernelli, Victoria L. Alonso, Virginia Perdomo, Raquel Gabarro, Rab Prinjha, Elvio Rodriguez Araya, Inmaculada Rioja, Roberto Docampo, Felix Calderon, Julio Martin, Esteban Serra
Summary: TcBDF2 is an important bromodomain protein in T. cruzi, playing a crucial role in infection, replication, and differentiation of the parasite, as well as pathogenesis.
ACS INFECTIOUS DISEASES
(2022)
Article
Cell Biology
Mayara S. Bertolini, Roberto Docampo
Summary: In this study, we generated TcMICU1/TcMICU2 double knockout cell lines using CRISPR/Cas9 genome editing and found that these knockout cell lines were unable to uptake calcium at low extramitochondrial calcium concentrations. Further investigation revealed that Mg2+ negatively regulates the mitochondrial calcium uptake mediated by MCUC.
Editorial Material
Cell Biology
Roberto Docampo
Article
Microbiology
Nuria W. Negrao, Logan P. Crowe, Brian S. Mantilla, Rodrigo P. Baptista, Sharon King-Keller, Guozhong Huang, Roberto Docampo
Summary: Trypanosoma brucei is the causative agent of African trypanosomiasis, and there is a need for new drugs due to limited treatment options and evidence of resistance. A phosphoinositide phospholipase C (TbPI-PLC-like) with an X and PDZ domain was discovered, similar to TbPI-PLC1. Recombinant TbPI-PLC-like does not hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP2) and does not modulate TbPI-PLC1 activity, but its knockdown affects the proliferation of trypanosomes.
Review
Microbiology
Roberto Docampo, Corrella S. Detweiler
Summary: Acidocalcisomes are organelles with acidity and high content of polyphosphate and calcium, and they have various functions and interactions with other organelles.
MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS
(2023)
