VDAC regulation of mitochondrial calcium flux: From channel biophysics to disease

Rosencrans, William M.; Rajendran, Megha; Bezrukov, Sergey M.; Rostovtseva, Tatiana K.

doi:10.1016/j.ceca.2021.102356

Cited by 63 publications

(38 citation statements)

References 124 publications

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“…At the MAMs, inositol-trisphosphate receptor (IP3R) channels interact through Glucose-regulated protein 75 (a member of the HSP70 family, HSP9A) [ 55 ] and DJ-1 (a.k.a. the Parkinsonism-associated deglycase, PARK-7) [ 56 ] with VDAC in the OMM, resulting in a high [Ca 2+ ] microdomain in the particular region of the IMS [ 57 ] ( Figure 3 ). Mitochondria-ER tethering through the ER protein PDZD8 is also required for proper Ca 2+ uptake in the mitochondria [ 58 ].…”

Section: Interdependent Ion Fluxes Drive Mitochondrial Functionmentioning

confidence: 99%

The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer

Pedersen

Flinck

Pardo

2021

IJMS

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Transport of ions and nutrients is a core mitochondrial function, without which there would be no mitochondrial metabolism and ATP production. Both ion homeostasis and mitochondrial phenotype undergo pervasive changes during cancer development, and both play key roles in driving the malignancy. However, the link between these events has been largely ignored. This review comprehensively summarizes and critically discusses the role of the reciprocal relationship between ion transport and mitochondria in crucial cellular functions, including metabolism, signaling, and cell fate decisions. We focus on Ca2+, H+, and K+, which play essential and highly interconnected roles in mitochondrial function and are profoundly dysregulated in cancer. We describe the transport and roles of these ions in normal mitochondria, summarize the changes occurring during cancer development, and discuss how they might impact tumorigenesis.

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Section: Interdependent Ion Fluxes Drive Mitochondrial Functionmentioning

confidence: 99%

The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer

Pedersen

Flinck

Pardo

2021

IJMS

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“…In cardiomyocytes, VDAC2 serves as a gatekeeper for transferring Ca 2+ into mitochondria under both normal physiological and stressed conditions (Rosencrans et al, 2021;Sander et al, 2021). For example, knockdown of VDAC2 significantly extended Ca 2+ sparks, supporting a physiological role for VDAC2 in Ca 2+ cycling (Subedi et al, 2011;Min et al, 2012).…”

Section: Introductionmentioning

confidence: 88%

Glutamate 73 Promotes Anti-arrhythmic Effects of Voltage-Dependent Anion Channel Through Regulation of Mitochondrial Ca2+ Uptake

Shimizu

Huber²,

Langenbacher

et al. 2021

Front. Physiol.

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Mitochondria critically regulate a range of cellular processes including bioenergetics, cellular metabolism, apoptosis, and cellular Ca2+ signaling. The voltage-dependent anion channel (VDAC) functions as a passageway for the exchange of ions, including Ca2+, across the outer mitochondrial membrane. In cardiomyocytes, genetic or pharmacological activation of isoform 2 of VDAC (VDAC2) effectively potentiates mitochondrial Ca2+ uptake and suppresses Ca2+ overload-induced arrhythmogenic events. However, molecular mechanisms by which VDAC2 controls mitochondrial Ca2+ transport and thereby influences cardiac rhythmicity remain elusive. Vertebrates express three highly homologous VDAC isoforms. Here, we used the zebrafish tremblor/ncx1h mutant to dissect the isoform-specific roles of VDAC proteins in Ca2+ handling. We found that overexpression of VDAC1 or VDAC2, but not VDAC3, suppresses the fibrillation-like phenotype in zebrafish tremblor/ncx1h mutants. A chimeric approach showed that moieties in the N-terminal half of VDAC are responsible for their divergent functions in cardiac biology. Phylogenetic analysis further revealed that a glutamate at position 73, which was previously described to be an important regulator of VDAC function, is sevolutionarily conserved in VDAC1 and VDAC2, whereas a glutamine occupies position 73 (Q73) of VDAC3. To investigate whether E73/Q73 determines VDAC isoform-specific anti-arrhythmic effect, we mutated E73 to Q in VDAC2 (VDAC2E73Q) and Q73 to E in VDAC3 (VDAC3Q73E). Interestingly, VDAC2E73Q failed to restore rhythmic cardiac contractions in ncx1 deficient hearts, while the Q73E conversion induced a gain of function in VDAC3. In HL-1 cardiomyocytes, VDAC2 knockdown diminished the transfer of Ca2+ from the SR into mitochondria and overexpression of VDAC2 or VDAC3Q73E restored SR-mitochondrial Ca2+ transfer in VDAC2 deficient HL-1 cells, whereas this rescue effect was absent for VDAC3 and drastically compromised for VDAC2E73Q. Collectively, our findings demonstrate a critical role for the evolutionary conserved E73 in determining the anti-arrhythmic effect of VDAC isoforms through modulating Ca2+ cross-talk between the SR and mitochondria in cardiomyocytes.

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“…Mitochondrial outer membranes contain large amounts of the mitochondrial porin termed the voltage-dependent anion channel (VDAC) [92,93]. When reconstituted into the artificial lipid bilayers, it forms ion channels that are phenotypically reminiscent of the maxi-anion channels: they have large conductance of app.…”

Section: Molecular Identity Of Maxi-cl: Rejected Candidatesmentioning

confidence: 99%

The ATP-Releasing Maxi-Cl Channel: Its Identity, Molecular Partners, and Physiological/Pathophysiological Implications

Sabirov

Islam

Okada

et al. 2021

Life

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The Maxi-Cl phenotype accounts for the majority (app. 60%) of reports on the large-conductance maxi-anion channels (MACs) and has been detected in almost every type of cell, including placenta, endothelium, lymphocyte, cardiac myocyte, neuron, and glial cells, and in cells originating from humans to frogs. A unitary conductance of 300–400 pS, linear current-to-voltage relationship, relatively high anion-to-cation selectivity, bell-shaped voltage dependency, and sensitivity to extracellular gadolinium are biophysical and pharmacological hallmarks of the Maxi-Cl channel. Its identification as a complex with SLCO2A1 as a core pore-forming component and two auxiliary regulatory proteins, annexin A2 and S100A10 (p11), explains the activation mechanism as Tyr23 dephosphorylation at ANXA2 in parallel with calcium binding at S100A10. In the resting state, SLCO2A1 functions as a prostaglandin transporter whereas upon activation it turns to an anion channel. As an efficient pathway for chloride, Maxi-Cl is implicated in a number of physiologically and pathophysiologically important processes, such as cell volume regulation, fluid secretion, apoptosis, and charge transfer. Maxi-Cl is permeable for ATP and other small signaling molecules serving as an electrogenic pathway in cell-to-cell signal transduction. Mutations at the SLCO2A1 gene cause inherited bone and gut pathologies and malignancies, signifying the Maxi-Cl channel as a perspective pharmacological target.

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VDAC regulation of mitochondrial calcium flux: From channel biophysics to disease

Cited by 63 publications

References 124 publications

The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer

The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer

Glutamate 73 Promotes Anti-arrhythmic Effects of Voltage-Dependent Anion Channel Through Regulation of Mitochondrial Ca2+ Uptake

The ATP-Releasing Maxi-Cl Channel: Its Identity, Molecular Partners, and Physiological/Pathophysiological Implications

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