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.

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.

Mitochondrial calcium uniporter affects neutrophil bactericidal activity during Staphylococcus aureus infection

2021 ◽  
Author(s):  
Andrew J. Monteith ◽  
Jeanette M. Miller ◽  
William N. Beavers ◽  
K. Nichole Maloney ◽  
Erin L. Seifert ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Ion Flux ◽  
Mitochondrial Calcium ◽  
Dependent Manner ◽  
Mitochondrial Calcium Uniporter ◽  
Mitochondrial Homeostasis ◽  
Mitochondrial Superoxide ◽  
Calcium Uniporter ◽  
Mitochondrial Calcium Uptake

Neutrophils simultaneously restrict Staphylococcus aureus dissemination and facilitate bactericidal activity during infection through the formation of neutrophil extracellular traps (NETs). Neutrophils that produce higher levels of mitochondrial superoxide undergo enhanced terminal NET formation (suicidal NETosis) in response to S. aureus ; however, mechanisms regulating mitochondrial homeostasis upstream of neutrophil antibacterial processes are not fully resolved. Here, we demonstrate that mitochondrial calcium uptake 1 (MICU1)-deficient (MICU1 -/- ) neutrophils accumulate higher levels of calcium and iron within the mitochondria in a mitochondrial calcium uniporter (MCU)-dependent manner. Corresponding with increased ion flux through the MCU, mitochondrial superoxide production is elevated, thereby increasing the propensity for MICU1 -/- neutrophils to undergo suicidal NETosis rather than primary degranulation in response to S. aureus . Increased NET formation augments macrophage killing of bacterial pathogens. Similarly, MICU1 -/- neutrophils alone are not more antibacterial towards S. aureus , but rather enhanced suicidal NETosis by MICU1 -/- neutrophils facilitates increased bactericidal activity in the presence of macrophages. Similarly, mice with a deficiency in MICU1 restricted to cells expressing LysM exhibit lower bacterial burdens in the heart with increased survival during systemic S. aureus infection. Coinciding with the decrease in S. aureus burdens, MICU1 -/- neutrophils in the heart produced higher levels of mitochondrial superoxide and undergo enhanced suicidal NETosis. These results demonstrate that ion flux by the MCU affects the antibacterial function of neutrophils during S. aureus infection.

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 Insights into Mitochondrial Calcium Uniporter Regulation by Divalent Cations

2016 ◽  
Vol 23 (9) ◽  
pp. 1157-1169 ◽  
Author(s):  
Samuel K. Lee ◽  
Santhanam Shanmughapriya ◽  
Mac C.Y. Mok ◽  
Zhiwei Dong ◽  
Dhanendra Tomar ◽  
...  
Keyword(s):  
Divalent Cations ◽  
Mitochondrial Calcium ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter ◽  
Structural Insights

scholarly journals Decision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination

2020 ◽  
Vol 117 (8) ◽  
pp. 4281-4291 ◽  
Author(s):  
Su Jin Ham ◽  
Daewon Lee ◽  
Heesuk Yoo ◽  
Kyoungho Jun ◽  
Heejin Shin ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Missense Mutation ◽  
Dopaminergic Neurons ◽  
Calcium Uptake ◽  
Mitochondrial Calcium ◽  
Dependent Manner ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter ◽  
Mitochondrial Calcium Uptake ◽  
Transgenic Flies

VDAC1 is a critical substrate of Parkin responsible for the regulation of mitophagy and apoptosis. Here, we demonstrate that VDAC1 can be either mono- or polyubiquitinated by Parkin in a PINK1-dependent manner. VDAC1 deficient with polyubiquitination (VDAC1 Poly-KR) hampers mitophagy, but VDAC1 deficient with monoubiquitination (VDAC1 K274R) promotes apoptosis by augmenting the mitochondrial calcium uptake through the mitochondrial calcium uniporter (MCU) channel. The transgenic flies expressing Drosophila Porin K273R, corresponding to human VDAC1 K274R, show Parkinson disease (PD)-related phenotypes including locomotive dysfunction and degenerated dopaminergic neurons, which are relieved by suppressing MCU and mitochondrial calcium uptake. To further confirm the relevance of our findings in PD, we identify a missense mutation of Parkin discovered in PD patients, T415N, which lacks the ability to induce VDAC1 monoubiquitination but still maintains polyubiquitination. Interestingly, Drosophila Parkin T433N, corresponding to human Parkin T415N, fails to rescue the PD-related phenotypes of Parkin-null flies. Taken together, our results suggest that VDAC1 monoubiquitination plays important roles in the pathologies of PD by controlling apoptosis.

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
Sign in / Sign up

Export Citation Format

Share Document