Review
Physiology
Joanne F. Garbincius, John W. Elrod
Summary: The uptake and extrusion of calcium into and from the mitochondrial matrix have significant effects on cellular metabolism, signaling, and survival. Disruption of mitochondrial calcium cycling is associated with various diseases and inherited neuromuscular disorders. This review provides an overview of the molecular machinery involved in calcium flux across the inner mitochondrial membrane and discusses the physiological implications and potential therapeutic interventions for diseases characterized by aberrant calcium handling. Critical unanswered questions regarding the biology of calcium flux are also highlighted.
PHYSIOLOGICAL REVIEWS
(2022)
Article
Biochemistry & Molecular Biology
Elianne P. Bulthuis, Merel J. W. Adjobo-Hermans, Bastiaan de Potter, Saskia Hoogstraten, Lisanne H. T. Wezendonk, Omar A. Z. Tutakhel, Liesbeth T. Wintjes, Bert van den Heuvel, Peter H. G. M. Willems, Erik-Jan Kamsteeg, M. Estela Rubio Gozalbo, Suzanne C. E. H. Sallevelt, Suzanne M. Koudijs, Joost Nicolai, Charlotte I. de Bie, Jessica E. Hoogendijk, Werner J. H. Koopman, Richard J. Rodenburg
Summary: In this study, the genetic, clinical, and cellular characteristics of two patients with SMDT1 variants and muscle problems were investigated. The variants were found to result in the absence of EMRE protein, formation of MCU subcomplex, and impaired mitochondrial Ca2+ uptake, potentially contributing to the muscle-related symptoms observed in the patients.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2023)
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
Biochemistry & Molecular Biology
Chen-Wei Tsai, Madison X. Rodriguez, Anna M. Van Keuren, Charles B. Phillips, Hannah M. Shushunov, Jessica E. Lee, Anastacia M. Garcia, Amrut Ambardekar, Joseph C. Cleveland, Julie A. Reisz, Catherine Proenza, Kathryn C. Chatfield, Ming-Feng Tsai
Summary: Mitochondrial Ca2+ uptake is regulated by the mitochondrial Ca2+ uniporter and plays important roles in various physiological functions. Skeletal-muscle and kidney uniporters also interact with a MICU1-MICU1 homodimer, while cardiac uniporters mostly lack MICUs. Cells use protein-import machinery to regulate the abundance of MICU1 homo- and heterodimers and protect properly assembled dimers from proteolysis. However, enhancing Ca2+ uptake can lead to increased ATP production, but also elevated ROS levels, impaired basal metabolism, and higher susceptibility to death.
Review
Cell Biology
Sayantan Datta, Manish Jaiswal
Summary: Mitochondria play crucial roles in neurons by increasing ATP production, buffering and regulating calcium influx to maintain normal synaptic activity.
Article
Multidisciplinary Sciences
Pooja Jadiya, Henry M. Cohen, Devin W. Kolmetzky, Ashlesha A. Kadam, Dhanendra Tomar, John W. Elrod
Summary: Mitochondrial calcium overload contributes to neurodegenerative disease development and progression. Loss of the mitochondrial sodium/calcium exchanger (NCLX) promotes calcium overload, metabolic derangement, redox stress, and cognitive decline in Alzheimer's disease models. Neuronal deletion of NCLX induces an Alzheimer's disease-like pathology, including memory decline, amyloid deposition, tau pathology, synaptic remodeling, and cell death.
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
Agriculture, Multidisciplinary
Xudong Sun, Shuang Gao, Shengbin Luo, Renxu Chang, Hongdou Jia, Qiushi Xu, Qianming Jiang, Juan J. Loor, Chuang Xu
Summary: The metabolic stress after calving leads to mitochondrial damage in bovine mammary epithelial cells. The key protein-coding gene MCUR1 mediates mitochondrial calcium ion (Ca2+) uptake and plays a vital role in maintaining mitochondrial homeostasis. This study aimed to investigate how MCUR1-mediated Ca2+ homeostasis affects bovine mammary epithelial cell mitochondria during an inflammatory challenge with lipopolysaccharide (LPS). The results showed that LPS induced MCUR1 overexpression, increased mitochondrial Ca2+ content and reactive oxygen species, and led to mitochondrial damage and apoptosis. Overall, MCUR1-mediated Ca2+ homeostasis could be a potential target for treating mitochondrial damage in bovine mammary epithelial cells.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2023)
Article
Biology
Li Zhang, Felicia Dietsche, Bruno Seitaj, Liliana Rojas-Charry, Nadina Latchman, Dhanendra Tomar, Rob C. Wust, Alexander Nickel, Katrin B. M. Frauenknecht, Benedikt Schoser, Sven Schumann, Michael J. Schmeisser, Johannes vom Berg, Thorsten Buch, Stefanie Finger, Philip Wenzel, Christoph Maack, John W. Elrod, Jan B. Parys, Geert Bultynck, Axel Methner
Summary: Ion fluxes across the inner mitochondrial membrane play crucial roles in controlling mitochondrial volume, energy production, and apoptosis. TMBIM5, a highly conserved protein, is involved in maintaining mitochondrial cristae architecture, ATP production, and apoptosis. Overexpression of TMBIM5 can mediate mitochondrial calcium uptake, while loss of TMBIM5 results in increased potassium and reduced proton levels in the mitochondrial matrix.
LIFE SCIENCE ALLIANCE
(2022)
Article
Pharmacology & Pharmacy
Zhiwang Zhang, Zupeng Luo, Lin Yu, Yang Xiao, Siqi Liu, Zhier ALuo, Zeqiang Ma, Liang Huang, Lianggui Xiao, Mengting Jia, Ziyi Song, Haojie Zhang, Yixing Li, Lei Zhou
Summary: This study investigates the role of mitochondrial calcium uniporter (MCU) in hepatic steatosis induced by high-fat diet (HFD). The results show that inhibition of liver MCU can prevent HFD-induced liver steatosis. The study also reveals that HFD enlarges the mitochondria-associated membranes (MAM) and disrupts mitochondrial calcium homeostasis, leading to liver fat deposition. Inhibition of MAM and MCU can alleviate HFD-induced hepatic steatosis. MCU inhibitors can block MCU channels and reduce mitochondrial calcium levels, providing a potential drug target for the treatment of hepatic steatosis.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Review
Cell Biology
Grant C. C. Walters, Yuriy M. M. Usachev
Summary: Mitochondria play essential roles in cellular function, including ATP synthesis, reactive oxygen species production, calcium buffering, and apoptotic signaling. In neurons, calcium buffering is particularly important for regulating various calcium-dependent functions. Recent discoveries of molecular components involved in mitochondrial calcium transport have shed light on the roles of mitochondrial calcium regulation in neuronal function and its implications in neurological diseases. This review discusses the multiple roles of mitochondrial calcium uptake and release mechanisms in normal neuronal function and provides insight into the calcium-dependent mechanisms underlying mitochondrial dysfunction in neurological diseases. The targeting of calcium uptake and release mechanisms could potentially lead to novel therapeutic strategies for these diseases.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Cell Biology
Paloma Garcia-Casas, Michela Rossini, Riccardo Filadi, Paola Pizzo
Summary: Alzheimer's disease is a neurodegenerative disease without an effective cure, and dysfunctional mitochondrial Ca2+ pathways have been proposed as a causal event for the neurodegeneration that characterizes this disease. Evidence suggests that important neurophysiological processes are altered before the onset of clinical symptoms, offering a possibility for identifying biological targets useful for new therapies.
Review
Biochemistry & Molecular Biology
Paulina Sander, Thomas Gudermann, Johann Schredelseker
Summary: Research on mitochondrial Ca2+ uptake mainly focuses on the function, regulation, and localization of the mitochondrial calcium uniporter complex (MCUC), while also investigating the role of the outer mitochondrial membrane channels in regulating this process.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Cell Biology
Jack G. Allen, Jeffery S. Tessem
Summary: The MCU Complex plays a crucial role in beta-cell function and insulin secretion by regulating mitochondrial calcium influx. Dysfunction in this complex can result in impaired insulin secretion.
Article
Biochemistry & Molecular Biology
Akira Watanabe, Kousuke Maeda, Atsushi Nara, Mei Hashida, Mizune Ozono, Ayaka Nakao, Akiko Yamada, Yasuo Shinohara, Takenori Yamamoto
Summary: Mitochondrial calcium homeostasis is crucial in cell survival and aerobic metabolism. This study provides insights into the stoichiometry of the mitochondrial calcium uniporter (MCU) and essential MCU regulator (EMRE), revealing tissue-specific differences and proposing a novel stoichiometric model.
Review
Cell Biology
Jyoti Tanwar, Rajender K. Motiani
Article
Biochemistry & Molecular Biology
Rajender K. Motiani, Jyoti Tanwar, Desingu Ayyappa Raja, Ayushi Vashisht, Shivangi Khanna, Sachin Sharma, Sonali Srivastava, Sridhar Sivasubbu, Vivek T. Natarajan, Rajesh S. Gokhale
Article
Cell Biology
Ayushi Vashisht, Jyoti Tanwar, Rajender K. Motiani
Article
Developmental Biology
Desingu Ayyappa Raja, Yogaspoorthi Subramaniam, Ayush Aggarwal, Vishvabandhu Gotherwal, Aswini Babu, Jyoti Tanwar, Rajender K. Motiani, Sridhar Sivasubbu, Rajesh S. Gokhale, Vivek T. Natarajan
Review
Cell Biology
Jyoti Tanwar, Samriddhi Arora, Rajender K. Motiani
Article
Biochemistry & Molecular Biology
Paras Sehgal, Samatha Mathew, Ambily Sivadas, Arjun Ray, Jyoti Tanwar, Sushma Vishwakarma, Gyan Ranjan, K. Shamsudheen, Rahul C. Bhoyar, Abhishek Pateria, Elvin Leonard, Mukesh Lalwani, Archana Vats, Rajeev R. Pappuru, Mudit Tyagi, Saumya Jakati, Shantanu Sengupta, B. K. Binukumar, Subhabrata Chakrabarti, Inderjeet Kaur, Rajender K. Motiani, Vinod Scaria, Sridhar Sivasubbu
Summary: The study identified a novel vascular endothelial-associated lncRNA named VEAL2, which regulates endothelial permeability and function through interaction with PRKCB2, and is implicated in diabetic retinopathy.
Review
Biochemistry & Molecular Biology
Suman Saurav, Jyoti Tanwar, Kriti Ahuja, Rajender K. Motiani
Summary: Calcium (Ca2+) plays a critical role in viral infections by modulating virus entry, replication, and severity. Many viruses, including SARS-CoV-2, manipulate cellular Ca2+ dynamics for host cell entry and replication. Targeting intracellular Ca2+ signaling with FDA-approved drugs shows promise in inhibiting viral infections, potentially aiding in better management and treatment of diseases like COVID-19.
MOLECULAR ASPECTS OF MEDICINE
(2021)
Article
Oncology
Samriddhi Arora, Jyoti Tanwar, Nutan Sharma, Suman Saurav, Rajender K. Motiani
Summary: Orai3, a highly Ca2+ selective plasma membrane channel, is overexpressed in pancreatic cancer and is associated with poor prognosis. It modulates cell proliferation, apoptosis, and migration, playing a critical role in PC metastasis. This study suggests Orai3 as a potential therapeutic target for managing PC metastasis.
Article
Cell Biology
Jyoti Tanwar, Suman Saurav, Reelina Basu, Jaya Bharti Singh, Anshu Priya, Maitreyee Dutta, Uma Santhanam, Manoj Joshi, Stephen Madison, Archana Singh, Nirmala Nair, Rajesh S. Gokhale, Rajender K. Motiani
Summary: Inter-organellar communication plays a crucial role in regulating cellular physiology, and MFN2 is a key regulator involved in this process. Our study reveals that MFN2 negatively regulates melanogenesis, and its knockout leads to enhanced melanin synthesis, possibly through the modulation of mitochondrial ROS levels.
Article
Biochemistry & Molecular Biology
Farina Sultan, Reelina Basu, Divya Murthy, Manisha Kochar, Kuldeep S. Attri, Ayush Aggarwal, Pooja Kumari, Pooja Dnyane, Jyoti Tanwar, Rajender K. Motiani, Archana Singh, Chetan Gadgil, Neel Sarovar Bhavesh, Pankaj K. Singh, Vivek T. Natarajan, Rajesh S. Gokhale
Summary: This study investigates the temporal dynamics of melanogenesis and identifies three dominant phases of metabolic and transcriptional reprogramming. The findings suggest that fatty acid metabolism could be a potential therapeutic target for the treatment of various hyperpigmentary cutaneous diseases.
Article
Biochemistry & Molecular Biology
Jyoti Tanwar, Akshay Sharma, Suman Saurav, Shyamveer, Nidhi Jatana, Rajender K. Motiani
Summary: Research showed that physiological melanogenic stimuli alpha-melanocyte stimulating hormone (alpha MSH) can increase STIM1 expression by driving MITF, providing new insights into the molecular mechanisms regulating STIM1 expression.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Shruti Gupta, Gaurav Bartwal, Ashima Singh, Jyoti Tanwar, J. M. Khurana
Summary: This study developed an efficient catalyst-free synthesis method to combine the Quinoline and Pyrimidine pharmacophores into a single molecule for improved biological applications. Among the synthesized compounds, three compounds with methyl and dioxyl ring substitutions showed potent anticancer activity, with IVi being the most effective compound against breast cancer cells.
RESULTS IN CHEMISTRY
(2022)