scholarly journals Structure and function of the N‐terminal domain of the human mitochondrial calcium uniporter

EMBO Reports ◽  
2015 ◽  
Vol 16 (10) ◽  
pp. 1318-1333 ◽  
Author(s):  
Youngjin Lee ◽  
Choon Kee Min ◽  
Tae Gyun Kim ◽  
Hong Ki Song ◽  
Yunki Lim ◽  
...  
Keyword(s):  
Structure And Function ◽  
Mitochondrial Calcium ◽  
Mitochondrial Calcium Uniporter ◽  
Terminal Domain ◽  
Calcium Uniporter ◽  
And Function

scholarly journals Mitochondrial Calcium Uniporter Deficiency in Zebrafish Causes Cardiomyopathy With Arrhythmia

2020 ◽  
Vol 11 ◽  
Author(s):  
Adam D. Langenbacher ◽  
Hirohito Shimizu ◽  
Welkin Hsu ◽  
Yali Zhao ◽  
Alexandria Borges ◽  
...  
Keyword(s):  
Energy Production ◽  
Mitochondrial Calcium ◽  
Sinus Arrest ◽  
Compact Layer ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter ◽  
Trabecular Density ◽  
And Function ◽  
Production Cell

Mitochondrial Ca2 + uptake influences energy production, cell survival, and Ca2 + signaling. The mitochondrial calcium uniporter, MCU, is the primary route for uptake of Ca2 + into the mitochondrial matrix. We have generated a zebrafish MCU mutant that survives to adulthood and exhibits dramatic cardiac phenotypes resembling cardiomyopathy and sinus arrest. MCU hearts contract weakly and have a smaller ventricle with a thin compact layer and reduced trabecular density. Damaged myofibrils and swollen mitochondria were present in the ventricles of MCU mutants, along with gene expression changes indicative of cell stress and altered cardiac structure and function. Using electrocardiography, we found that MCU hearts display conduction system defects and abnormal rhythm, with extended pauses resembling episodes of sinus arrest. Together, our findings suggest that proper mitochondrial Ca2 + homeostasis is crucial for maintaining a healthy adult heart, and establish the MCU mutant as a useful model for understanding the role of mitochondrial Ca2 + handling in adult cardiac biology.

scholarly journals Structural characterization of the N-terminal domain of the Dictyostelium discoideum mitochondrial calcium uniporter

2019 ◽  
Author(s):  
Yuan Yuan ◽  
Chan Cao ◽  
Maorong Wen ◽  
Min Li ◽  
Ying Dong ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Dictyostelium Discoideum ◽  
Self Assembly ◽  
Calcium Influx ◽  
Transmembrane Protein ◽  
Critical Role ◽  
Mitochondrial Calcium ◽  
Mitochondrial Calcium Uniporter ◽  
Terminal Domain ◽  
Calcium Uniporter

AbstractThe mitochondrial calcium uniporter (MCU) plays a critical role in the mitochondrial calcium uptake into the matrix. In metazoans, the uniporter is a tightly regulated multi-component system including the pore-forming subunit MCU and several regulators (MICU1, MICU2, EMRE). The calcium-conducting activity of metazoan MCU requires the single-transmembrane protein EMRE. Dictyostelium discoideum (Dd), however, developed a simplified uniporter for which the pore-forming MCU (DdMCU) alone is necessary and sufficient for calcium influx. Here, we report a crystal structure of the N-terminal domain (NTD) of DdMCU at 1.7 Å resolution. The DdMCU-NTD contains four helices and two strands arranged in a fold that is completely different from the known structures of other MCU-NTD homologs. Biochemical and biophysical analyses of DdMCU-NTD in solution indicated that the domain exists as oligomers, most probably as a pentamer or hexamer. Mutagenesis showed that the acidic residues Asp60, Glu72 and Glu74, which appeared to mediate the parallel interface as observed in the crystal structure, participated in the self-assembly of DdMCU-NTD. Intriguingly, the oligomeric complex readily dissociated to lower-order oligomers in the presence of calcium. We propose that the calcium-triggered dissociation of NTD regulates the channel activity of DdMCU by a yet unknown mechanism.

scholarly journals An essential role for cardiolipin in the stability and function of the mitochondrial calcium uniporter

2020 ◽  
Vol 117 (28) ◽  
pp. 16383-16390 ◽  
Author(s):  
Sagnika Ghosh ◽  
Writoban Basu Ball ◽  
Travis R. Madaris ◽  
Subramanya Srikantan ◽  
Muniswamy Madesh ◽  
...  
Keyword(s):  
Calcium Transport ◽  
Cardiac Tissue ◽  
Barth Syndrome ◽  
Mitochondrial Calcium ◽  
Mitochondrial Calcium Uniporter ◽  
Cellular Models ◽  
Calcium Uniporter ◽  
Protein Components ◽  
And Function

Calcium uptake by the mitochondrial calcium uniporter coordinates cytosolic signaling events with mitochondrial bioenergetics. During the past decade all protein components of the mitochondrial calcium uniporter have been identified, including MCU, the pore-forming subunit. However, the specific lipid requirements, if any, for the function and formation of this channel complex are currently not known. Here we utilize yeast, which lacks the mitochondrial calcium uniporter, as a model system to address this problem. We use heterologous expression to functionally reconstitute human uniporter machinery both in wild-type yeast as well as in mutants defective in the biosynthesis of phosphatidylethanolamine, phosphatidylcholine, or cardiolipin (CL). We uncover a specific requirement of CL for in vivo reconstituted MCU stability and activity. The CL requirement of MCU is evolutionarily conserved with loss of CL triggering rapid turnover of MCU homologs and impaired calcium transport. Furthermore, we observe reduced abundance and activity of endogenous MCU in mammalian cellular models of Barth syndrome, which is characterized by a partial loss of CL. MCU abundance is also decreased in the cardiac tissue of Barth syndrome patients. Our work raises the hypothesis that impaired mitochondrial calcium transport contributes to the pathogenesis of Barth syndrome, and more generally, showcases the utility of yeast phospholipid mutants in dissecting the phospholipid requirements of ion channel complexes.

Abstract 366: The Role of Mitochondrial Calcium Uniporter Complex in Cardiac Contractility and Function

2018 ◽  
Vol 123 (Suppl_1) ◽  
Author(s):  
Dhanendra Tomar ◽  
Santhanam Shanmughapriya ◽  
Rajika Roy ◽  
Xueqian Zhang ◽  
Jianliang Song ◽  
...  
Keyword(s):  
Cardiac Contractility ◽  
Mitochondrial Calcium ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter ◽  
And Function

scholarly journals Mitochondrial Calcium Uniporter Structure and Function in Different Types of Muscle Tissues in Health and Disease

2019 ◽  
Vol 20 (19) ◽  
pp. 4823 ◽  
Author(s):  
Nadezhda Tarasova ◽  
Polina Vishnyakova ◽  
Yulia Logashina ◽  
Andrey Elchaninov
Keyword(s):  
Mitochondrial Calcium ◽  
Inner Mitochondrial Membrane ◽  
Regulatory Subunits ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter ◽  
Muscle Tissues ◽  
Different Types ◽  
Health And Disease ◽  
The Moment ◽  
And Function

Calcium ions (Ca2+) influx to mitochondrial matrix is crucial for the life of a cell. Mitochondrial calcium uniporter (mtCU) is a protein complex which consists of the pore-forming subunit (MCU) and several regulatory subunits. MtCU is the main contributor to inward Ca2+ currents through the inner mitochondrial membrane. Extensive investigations of mtCU involvement into normal and pathological molecular pathways started from the moment of discovery of its molecular components. A crucial role of mtCU in the control of these pathways is now recognized in both health and disease. In particular, impairments of mtCU function have been demonstrated for cardiovascular and skeletal muscle-associated pathologies. This review summarizes the current state of knowledge on mtCU structure, regulation, and function in different types of muscle tissues in health and disease.

scholarly journals Restoring mitochondrial calcium uniporter expression in diabetic mouse heart improves mitochondrial calcium handling and cardiac function

2018 ◽  
Vol 293 (21) ◽  
pp. 8182-8195 ◽  
Author(s):  
Jorge Suarez ◽  
Federico Cividini ◽  
Brian T. Scott ◽  
Kim Lehmann ◽  
Julieta Diaz-Juarez ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Glucose Oxidation ◽  
Cardiac Myocyte ◽  
Diabetic Mouse ◽  
Metabolic Reprogramming ◽  
Mitochondrial Calcium ◽  
Adeno Associated Virus ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter ◽  
And Function

Diabetes mellitus is a growing health care problem, resulting in significant cardiovascular morbidity and mortality. Diabetes also increases the risk for heart failure (HF) and decreased cardiac myocyte function, which are linked to changes in cardiac mitochondrial energy metabolism. The free mitochondrial calcium level ([Ca2+]m) is fundamental in activating the mitochondrial respiratory chain complexes and ATP production and is also known to regulate pyruvate dehydrogenase complex (PDC) activity. The mitochondrial calcium uniporter (MCU) complex (MCUC) plays a major role in mediating mitochondrial Ca2+ import, and its expression and function therefore have a marked impact on cardiac myocyte metabolism and function. Here, we investigated MCU's role in mitochondrial Ca2+ handling, mitochondrial function, glucose oxidation, and cardiac function in the heart of diabetic mice. We found that diabetic mouse hearts exhibit altered expression of MCU and MCUC members and a resulting decrease in [Ca2+]m, mitochondrial Ca2+ uptake, mitochondrial energetic function, and cardiac function. Adeno-associated virus-based normalization of MCU levels in these hearts restored mitochondrial Ca2+ handling, reduced PDC phosphorylation levels, and increased PDC activity. These changes were associated with cardiac metabolic reprogramming toward normal physiological glucose oxidation. This reprogramming likely contributed to the restoration of both cardiac myocyte and heart function to nondiabetic levels without any observed detrimental effects. These findings support the hypothesis that abnormal mitochondrial Ca2+ handling and its negative consequences can be ameliorated in diabetes by restoring MCU levels via adeno-associated virus–based MCU transgene expression.

scholarly journals Structural insights into the Ca2+-dependent gating of the human mitochondrial calcium uniporter

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Yan Wang ◽  
Yan Han ◽  
Ji She ◽  
Nam X Nguyen ◽  
Vamsi K Mootha ◽  
...  
Keyword(s):  
Mitochondrial Calcium ◽  
Dependent Manner ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter ◽  
Ef Hand ◽  
Conductive Channel ◽  
And Function ◽  
Structural Insights ◽  
Mitochondrial Membrane Protein

Mitochondrial Ca2+ uptake is mediated by an inner mitochondrial membrane protein called the mitochondrial calcium uniporter. In humans, the uniporter functions as a holocomplex consisting of MCU, EMRE, MICU1 and MICU2, among which MCU and EMRE form a subcomplex and function as the conductive channel while MICU1 and MICU2 are EF-hand proteins that regulate the channel activity in a Ca2+-dependent manner. Here, we present the EM structures of the human mitochondrial calcium uniporter holocomplex (uniplex) in the presence and absence of Ca2+, revealing distinct Ca2+ dependent assembly of the uniplex. Our structural observations suggest that Ca2+ changes the dimerization interaction between MICU1 and MICU2, which in turn determines how the MICU1-MICU2 subcomplex interacts with the MCU-EMRE channel and, consequently, changes the distribution of the uniplex assemblies between the blocked and unblocked states.

scholarly journals Structural insights into the Ca2+-dependent gating of the human mitochondrial calcium uniporter

2020 ◽  
Author(s):  
Yan Wang ◽  
Yan Han ◽  
Ji She ◽  
Nam X. Nguyen ◽  
Vamsi K. Mootha ◽  
...  
Keyword(s):  
Electrostatic Interactions ◽  
Mitochondrial Calcium ◽  
Dependent Manner ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Calcium Uniporter ◽  
Channel Pore ◽  
Atp Production ◽  
Calcium Uniporter ◽  
Ef Hand ◽  
And Function

AbstractMitochondrial Ca2+ uptake plays an important role in cellular physiology such as modulating ATP production, regulating cytoplasmic Ca2+ dynamics, and triggering cell death, and is mediated by the mitochondrial calcium uniporter, a highly selective calcium channel localized to the inner mitochondrial membrane. In humans, the uniporter functions as a holocomplex consisting of MCU, EMRE, MICU1 and MICU2, among which MCU and EMRE form a subcomplex and function as the conductive channel while MICU1 and MICU2 are EF-hand proteins that regulate the channel activity in a Ca2+ dependent manner. Here we present the EM structures of the human mitochondrial calcium uniporter holocomplex (uniplex) in the presence and absence of Ca2+, revealing distinct Ca2+ dependent assembly of the uniplex. In the presence of Ca2+, MICU1 and MICU2 form a heterotetramer of MICU1-(MICU2)2-MICU1 and bridge the dimeric form of the MCU-EMRE subcomplex through electrostatic interactions between MICU1 and EMRE, leaving the MCU channel pore unblocked. In the absence of Ca2+, multiple uniplex assemblies are observed but is predominantly occupied by the MICU1 subunit from a MICU1-MICU2 heterodimer blocking the MCU channel pore. Our structural observations suggest that Ca2+ changes the dimerization interaction between MICU1 and MICU2, which in turn determines how the MICU1-MICU2 subcomplex interacts with the MCU-EMRE channel and, consequently, changes the distribution of the uniplex assemblies between the blocked and unblocked states.

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