Article
Cell Biology
Courtney E. Petersen, Junhui Sun, Kavisha Silva, Anna Kosmach, Robert S. Balaban, Elizabeth Murphy
Summary: The regulation of cell death by mitochondrial calcium overload and the potential role of mitochondrial calcium uniporter (MCU) in preventing cell death during ischemia/reperfusion are investigated using ex-vivo-perfused mouse hearts. It is found that inhibition of MCU reduces mitochondrial calcium accumulation during ischemia, but there is still an increase in mitochondrial calcium, suggesting that mitochondrial calcium overload is not solely dependent on MCU.
Review
Biochemistry & Molecular Biology
Jiho Yoo
Summary: Mitochondria, organelles responsible for various cellular functions, uptake Ca2+ ions through the MCU holo-complex. The protein structure of the MCU holo-complex has recently been identified, providing insights into the uptake and regulation mechanisms.
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
Chemistry, Medicinal
Jesus M. Aizpurua, Jose Miranda, Aitziber Irastorza, Endika Torres, Maite Eceiza, Maialen Sagartzazu-Aizpurua, Pablo Ferron, Garazi Aldanondo, Haizpea Lasa-Fernandez, Pablo Marco-Moreno, Naroa Dadie, Adolfo Lopez de Munain, Ainara Vallejo-Illarramendi
Summary: The study investigated the hypothesis of rescuing FKBP12/RyR1 interaction and intracellular calcium homeostasis through molecular reshaping of FKBP12. Novel triazoles were designed and synthesized, showing potential as therapeutic candidates for muscle disorders with nitro-oxidative stress, FKBP12/RyR1 dysfunction, and calcium dysregulation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Sang Youn Hwang, Hongqun Liu, Samuel S. Lee
Summary: Cirrhotic cardiomyopathy is a syndrome characterized by weakened cardiac systolic and diastolic function in patients with cirrhosis. The calcium handling system, including calcium channels, intracellular calcium-regulatory apparatus, and pertinent proteins, plays a crucial role in the cardiac function in cirrhotic cardiomyopathy. Multiple defects in calcium handling contribute to the pathogenesis of cirrhotic cardiomyopathy, including the reduction of L-type calcium channels and calcium leakage in cirrhotic cardiomyocytes. The decreased calcium storage in the sarcoplasmic reticulum leads to decreased cardiac contractility.
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
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
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
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
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.
Review
Physiology
Satvik Mareedu, Emily D. Million, Dongsheng Duan, Gopal J. Babu
Summary: Duchenne muscular dystrophy is a muscle-wasting disease caused by the loss of dystrophin, leading to muscle degeneration, necrosis, inflammation, and eventual weakness and premature death. Abnormal elevation of intracellular calcium in the dystrophin-deficient muscle is a major contributing factor to disease progression. Targeting calcium-handling proteins and mechanisms could be a promising therapeutic strategy for DMD.
FRONTIERS IN PHYSIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Laura R. Rodriguez, Tamara Lapena-Luzon, Noelia Beneto, Vicent Beltran-Beltran, Federico Pallardo, Pilar Gonzalez-Cabo, Juan Antonio Navarro
Summary: Calcium plays a crucial role in regulating various signaling pathways for cell maintenance. The communication between endoplasmic reticulum and mitochondria through MAMs is essential for maintaining mitochondrial function and cell homeostasis. Dysregulation of these pathways is associated with the development of neurological disorders.
Article
Pharmacology & Pharmacy
Yejin Kim, Chulhwan Kwak, Jong Bae Park, Do-Hyun Nam, Hyun-Woo Rhee, Sung Soo Kim
Summary: Adapted oxidative phosphorylation and tricarboxylic acid cycle activations play crucial roles in tumor microenvironments for abnormal energy consumption in cancer development and drug resistance. A longitudinal GBM mouse model with acquired resistance to bevacizumab was established to investigate the molecular mechanism related to mitochondrial metabolic dynamics and drug resistance in GBM. Proteomic analysis revealed enrichment of OXPHOS, TCA, and calcium signaling gene sets in the bevacizumab pre-resistance phase. Additionally, targeting the MCU protein, a pore-forming subunit of the mitochondrial calcium uniporter, showed promising therapeutic potential in combination with bevacizumab in recurrent GBM.
ADVANCED THERAPEUTICS
(2023)
Article
Anesthesiology
Dale George, Sandra Hackelberg, Nirupa Jayaraj, Dongjun Ren, Seby Edaserry, Craig Rathwell, Rachel Miller, Jeffery Savas, Richard Miller, Daniela Maria Menichella, Anne-Marie Malfait
Summary: This research identified elevated mitochondrial fission proteins and increased calcium signaling in dorsal root ganglion (DRG) neurons in a mouse model of painful diabetic neuropathy (PDN). By selectively deleting the mitochondrial calcium uniporter, the study demonstrated the restoration of normal mitochondrial morphology, prevention of axonal degeneration, and reversal of mechanical allodynia in the PDN mouse model. These findings indicate the potential of targeting calcium entry into nociceptor mitochondria as an effective therapeutic approach for PDN.
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.
