scholarly journals A Calcium Guard in the Outer Membrane: Is VDAC a Regulated Gatekeeper of Mitochondrial Calcium Uptake?

2021 ◽  
Vol 22 (2) ◽  
pp. 946
Author(s):  
Paulina Sander ◽  
Thomas Gudermann ◽  
Johann Schredelseker
Keyword(s):  
Mitochondrial Membrane ◽  
Calcium Release ◽  
Physiological Role ◽  
Mitochondrial Calcium ◽  
Inner Mitochondrial Membrane ◽  
New Era ◽  
Voltage Dependent ◽  
Common Opinion ◽  
Long Time ◽  
The Individual

Already in the early 1960s, researchers noted the potential of mitochondria to take up large amounts of Ca2+. However, the physiological role and the molecular identity of the mitochondrial Ca2+ uptake mechanisms remained elusive for a long time. The identification of the individual components of the mitochondrial calcium uniporter complex (MCUC) in the inner mitochondrial membrane in 2011 started a new era of research on mitochondrial Ca2+ uptake. Today, many studies investigate mitochondrial Ca2+ uptake with a strong focus on function, regulation, and localization of the MCUC. However, on its way into mitochondria Ca2+ has to pass two membranes, and the first barrier before even reaching the MCUC is the outer mitochondrial membrane (OMM). The common opinion is that the OMM is freely permeable to Ca2+. This idea is supported by the presence of a high density of voltage-dependent anion channels (VDACs) in the OMM, forming large Ca2+ permeable pores. However, several reports challenge this idea and describe VDAC as a regulated Ca2+ channel. In line with this idea is the notion that its Ca2+ selectivity depends on the open state of the channel, and its gating behavior can be modified by interaction with partner proteins, metabolites, or small synthetic molecules. Furthermore, mitochondrial Ca2+ uptake is controlled by the localization of VDAC through scaffolding proteins, which anchor VDAC to ER/SR calcium release channels. This review will discuss the possibility that VDAC serves as a physiological regulator of mitochondrial Ca2+ uptake in the OMM.

scholarly journals Discovery of EMRE in fungi resolves the true evolutionary history of the mitochondrial calcium uniporter

2020 ◽  
Author(s):  
Alexandros A. Pittis ◽  
Valerie Goh ◽  
Alberto Cebrian-Serrano ◽  
Jennifer Wettmarshausen ◽  
Fabiana Perocchi ◽  
...  
Keyword(s):  
Physiological Role ◽  
Fungal Species ◽  
Mitochondrial Calcium ◽  
Phylogenomic Analysis ◽  
Uptake System ◽  
Inner Mitochondrial Membrane ◽  
Regulatory Subunits ◽  
Functional Studies ◽  
Eukaryotic Origin

AbstractMitochondrial calcium (mt-Ca2+) uptake is central for the regulation of numerous cellular processes in eukaryotes1. This occurs through a highly selective Ca2+ uniporter located at the inner mitochondrial membrane and driven by the membrane potential2–4. While the physiological role of the uniporter was extensively studied for decades, its genetic identity was only recently determined, with MCU5,6, MICU17 and EMRE8 constituting pore-forming and regulatory subunits. Preliminary evolutionary analyses suggested an ancient eukaryotic origin of mt-Ca2+ uptake, but also pinpointed inconsistent phylogenetic distributions of MCU, MICU1, and EMRE within fungi, where homologs of MCU were present in the absence of the supposedly essential regulators, MICU1 and EMRE9,10. Here, we perform the most comprehensive phylogenomic analysis of the mt-Ca2+ uptake system and trace its evolution across 1,156 fully-sequenced eukaryotes. In contrast to earlier assumptions9–11 we find compelling evidence that previously identified animal and fungal MCUs, the targets of several structural and functional efforts11–16, represent two distinct paralogous subfamilies originating from an ancestral duplication. We further uncover a complete “animal-like” uniporter complex within chytrid fungi, including bona-fide orthologs of MCU, MICU1, and EMRE. This first identification of EMRE outside Holozoa (animals and their unicellular relatives) and its strong coevolution with “animal-like” MICU1 and MCU indicates that these three components formed the core of the ancestral opisthokont uniporter. We confirm this finding experimentally, by showing that chytrid EMRE orthologs in combination with either human or “animal-like” MCUs, but not with “fungal-specific” MCUs, can reconstitute mt-Ca2+ uptake in vivo in the yeast Saccharomyces cerevisiae. Hence, we here solve a purported evolutionary paradox: the presence of MCU homologs in fungal species devoid of other uniporter components and with no detectable mt-Ca2+ uptake. Altogether, our study clarifies the evolution of the mt-Ca2+ uniporter and identifies new important targets for comparative structural and functional studies.

Patch-clamping of the inner mitochondrial membrane reveals a voltage-dependent ion channel

Nature ◽  
1987 ◽  
Vol 330 (6147) ◽  
pp. 498-500 ◽  
Author(s):  
M. Catia Sorgato ◽  
Bernhard U. Keller ◽  
Walter Stühmer
Keyword(s):  
Ion Channel ◽  
Mitochondrial Membrane ◽  
Patch Clamping ◽  
Inner Mitochondrial Membrane ◽  
Voltage Dependent

scholarly journals ROMO1 is essential for glucose coupling in the pancreatic β cell of male mice

2021 ◽  
Author(s):  
Lisa Wells ◽  
Caterina Iorio ◽  
Andy Cheuk-Him Ng ◽  
Courtney Reeks ◽  
Siu-Pok Yee ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Mitochondrial Dynamics ◽  
Critical Role ◽  
Physiological Role ◽  
Glucose Sensing ◽  
Mitochondrial Fusion ◽  
Male Mice ◽  
Inner Mitochondrial Membrane ◽  
Β Cell ◽  
Respiratory Capacity

AbstractReactive oxygen species modulator 1 (ROMO1) is a highly conserved inner mitochondrial membrane protein that senses ROS and regulates mitochondrial dynamics 1. ROMO1 is required for mitochondrial fusion in vitro, and silencing ROMO1 increases sensitivity to cell death stimuli. How ROMO1 promotes mitochondrial fusion and its physiological role remain unclear. Here we show that ROMO1 is essential for embryonic development, as ROMO1-null mice die before embryonic day 8.5, earlier than GTPases OPA1 or MFN1/2 that catalyze mitochondrial membrane fusion. Knockout of ROMO1 in adult pancreatic β cells results in impaired glucose homeostasis in male mice due to an insulin secretion defect resulting from impaired glucose sensing. Mitochondria in ROMO1 β cell KO cells were swollen and fragmented, consistent with a role for ROMO1 in mitochondrial fusion in vivo. While basal respiration was normal in ROMO1β cell KO islets, spare respiratory capacity was lost. Taken together, our data indicate that ROMO1 is required for nutrient coupling in the β cell and point to a critical role for spare respiratory capacity in the maintenance of euglycemia in males.

scholarly journals MICU1 regulates mitochondrial cristae structure and function independent of the mitochondrial calcium uniporter channel

2019 ◽  
Author(s):  
Dhanendra Tomar ◽  
Manfred Thomas ◽  
Joanne F. Garbincius ◽  
Devin W. Kolmetzky ◽  
Oniel Salik ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Mitochondrial Protein ◽  
Coiled Coil ◽  
Membrane Dynamics ◽  
Size Exclusion ◽  
Mitochondrial Calcium ◽  
Cellular Functions ◽  
Inner Mitochondrial Membrane ◽  
Cytochrome C Release ◽  
And Function

AbstractMICU1 is an EF-hand-containing mitochondrial protein that is essential for gating of the mitochondrial Ca2+ uniporter channel (mtCU) and is reported to interact directly with the pore-forming subunit, MCU and scaffold EMRE. However, using size-exclusion proteomics, we found that MICU1 exists in mitochondrial complexes lacking MCU. This suggests that MICU1 may have additional cellular functions independent of regulating mitochondrial Ca2+ uptake. To discern mtCU-independent MICU1 functions, we employed a proteomic discovery approach using BioID2-mediated proximity-based (<10nm) biotinylation and subsequent LC-MS detection. The expression of a MICU1-BioID2 fusion protein in MICU1-/- and MCU-/- cells allowed the identification of total vs. mtCU-independent MICU1 interactors. Bioinformatics identified the Mitochondrial Contact Site and Cristae Organizing System (MICOS) components MIC60 (encoded by the IMMT gene) and Coiled-coil-helix-coiled-coil helix domain containing 2 (CHCHD2) as novel MICU1 interactors, independent of the mtCU. We demonstrate that MICU1 is essential for proper proteomic organization of the MICOS complex and that MICU1 ablation results in altered cristae organization and mitochondrial ultrastructure. We hypothesize that MICU1 serves as a MICOS calcium sensor, since perturbing MICU1 is sufficient to modulate cytochrome c release independent of mitochondrial Ca2+ uptake across the inner mitochondrial membrane (IMM). Here, we provide the first experimental evidence suggesting that MICU1 regulates cellular functions independent of mitochondrial calcium uptake and may serve as a critical mediator of Ca2+-dependent signaling to modulate mitochondrial membrane dynamics and cristae organization.

scholarly journals Schwann cell demyelination is triggered by a transient mitochondrial calcium release through Voltage Dependent Anion Channel 1

2019 ◽  
Author(s):  
Nicolas Tricaud ◽  
Benoit Gautier ◽  
Gerben Van Hameren ◽  
Jade Berthelot ◽  
Sergio Gonzalez ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Nerve Injury ◽  
Myelin Sheath ◽  
Calcium Release ◽  
Anion Channel ◽  
Mitochondrial Calcium ◽  
Voltage Dependent Anion Channel ◽  
Cellular Mechanisms ◽  
Voltage Dependent

AbstractThe maintenance of the myelin sheath by Schwann cells around peripheral nerve axons is essential for the rapid propagation of action potentials. A large number of peripheral neuropathies results for the loss of this myelin sheath, a process called demyelination. Demyelination is a program of cell dedifferentiation characterized by reprograming and several catabolic and anabolic events. This process was best characterized in Wallerian demyelination that occurs following nerve injury. In this model, the earliest well characterized steps are MAPK pathways activation and cJun phosphorylation and nuclear localization starting around 4hrs after nerve injury. Here we show, using in vivo imaging of virally-delivered fluorescent probes to mitochondria, that Schwann cell mitochondria pH, motility and calcium are altered as soon as 1hr after nerve injury. Mitochondrial calcium release through VDAC1 mitochondrial channel and mPTP directly induced Schwann cell demyelination via MAPK and c-Jun activation. Decreasing mitochondrial calcium release through VDAC1 silencing or TRO19622 blocking prevented MAPK and cJun activation and demyelination. VDAC1 opening with Methyl Jasmonate induced these cellular mechanisms in absence of nerve injury. Taken together, these data indicate that mitochondria calcium homeostasis through VDAC1 is instrumental in the Schwann cell demyelination process and therefore provide a molecular basis for an anti-demyelinating drug approach.

scholarly journals The Mitochondrial Permeability Transition in Mitochondrial Disorders

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Justina Šileikytė ◽  
Michael Forte
Keyword(s):  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Physiological Role ◽  
Mitochondrial Diseases ◽  
Atp Synthesis ◽  
Permeability Transition ◽  
Mitochondrial Disorders ◽  
Molecular Entity ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Permeability

Mitochondrial permeability transition pore (PTP), a (patho)physiological phenomenon discovered over 40 years ago, is still not completely understood. PTP activation results in a formation of a nonspecific channel within the inner mitochondrial membrane with an exclusion size of 1.5 kDa. PTP openings can be transient and are thought to serve a physiological role to allow quick Ca2+ release and/or metabolite exchange between mitochondrial matrix and cytosol or long-lasting openings that are associated with pathological conditions. While matrix Ca2+ and oxidative stress are crucial in its activation, the consequence of prolonged PTP opening is dissipation of the inner mitochondrial membrane potential, cessation of ATP synthesis, bioenergetic crisis, and cell death—a primary characteristic of mitochondrial disorders. PTP involvement in mitochondrial and cellular demise in a variety of disease paradigms has been long appreciated, yet the exact molecular entity of the PTP and the development of potent and specific PTP inhibitors remain areas of active investigation. In this review, we will (i) summarize recent advances made in elucidating the molecular nature of the PTP focusing on evidence pointing to mitochondrial FoF1-ATP synthase, (ii) summarize studies aimed at discovering novel PTP inhibitors, and (iii) review data supporting compromised PTP activity in specific mitochondrial diseases.

scholarly journals Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria

2002 ◽  
Vol 159 (4) ◽  
pp. 613-624 ◽  
Author(s):  
Elena Rapizzi ◽  
Paolo Pinton ◽  
György Szabadkai ◽  
Mariusz R. Wieckowski ◽  
Grégoire Vandecasteele ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
High Speed ◽  
Recombinant Expression ◽  
Anion Channel ◽  
Fast Diffusion ◽  
Inner Mitochondrial Membrane ◽  
Voltage Dependent Anion Channel ◽  
High Speed Imaging ◽  
Physiological Relevance ◽  
Voltage Dependent

Although the physiological relevance of mitochondrial Ca2+ homeostasis is widely accepted, no information is yet available on the molecular identity of the proteins involved in this process. Here we analyzed the role of the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane in the transmission of Ca2+ signals between the ER and mitochondria by measuring cytosolic and organelle [Ca2+] with targeted aequorins and Ca2+-sensitive GFPs. In HeLa cells and skeletal myotubes, the transient expression of VDAC enhanced the amplitude of the agonist-dependent increases in mitochondrial matrix Ca2+ concentration by allowing the fast diffusion of Ca2+ from ER release sites to the inner mitochondrial membrane. Indeed, high speed imaging of mitochondrial and cytosolic [Ca2+] changes showed that the delay between the rises occurring in the two compartments is significantly shorter in VDAC-overexpressing cells. As to the functional consequences, VDAC-overexpressing cells are more susceptible to ceramide-induced cell death, thus confirming that mitochondrial Ca2+ uptake plays a key role in the process of apoptosis. These results reveal a novel function for the widely expressed VDAC channel, identifying it as a molecular component of the routes for Ca2+ transport across the mitochondrial membranes.

Modulation of the calcium-activated BK-channel of the inner mitochondrial membrane by hypoxia

2007 ◽  
Vol 34 (S 2) ◽  
Author(s):  
D Siemen ◽  
Y Cheng ◽  
X Gu ◽  
P Bednarczyk ◽  
GG Haddad ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Bk Channel ◽  
Inner Mitochondrial Membrane
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