α-Synuclein emerges as a potent regulator of VDAC-facilitated calcium transport

Rosencrans, William M.; Aguilella, Vicente M.; Rostovtseva, Tatiana K.; Bezrukov, Sergey M.

doi:10.1016/j.ceca.2021.102355

Cited by 36 publications

(39 citation statements)

References 67 publications

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“…The increased levels of cytosolic Ca 2+ in SNc dopaminergic neurons have been further linked to the expression of α-Syn, suggesting a converging pathway for these two pathogenic factors in PD (Lieberman et al, 2017). In support of this, a recent study showed that a-Syn dynamically binds to VDACs and modifies their Ca 2+ permeability (Figure 3; Rosencrans et al, 2021). It is therefore likely that pathological aggregations of α-Syn might affect VDAC binding and thus mitochondrial Ca 2+ buffering.…”

Section: Calcium Handlingmentioning

confidence: 85%

Selective Neuron Vulnerability in Common and Rare Diseases—Mitochondria in the Focus

Paß

Wiesner

Pla‐Martín

2021

Front. Mol. Biosci.

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Mitochondrial dysfunction is a central feature of neurodegeneration within the central and peripheral nervous system, highlighting a strong dependence on proper mitochondrial function of neurons with especially high energy consumptions. The fitness of mitochondria critically depends on preservation of distinct processes, including the maintenance of their own genome, mitochondrial dynamics, quality control, and Ca2+ handling. These processes appear to be differently affected in common neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, as well as in rare neurological disorders, including Huntington’s disease, Amyotrophic Lateral Sclerosis and peripheral neuropathies. Strikingly, particular neuron populations of different morphology and function perish in these diseases, suggesting that cell-type specific factors contribute to the vulnerability to distinct mitochondrial defects. Here we review the disruption of mitochondrial processes in common as well as in rare neurological disorders and its impact on selective neurodegeneration. Understanding discrepancies and commonalities regarding mitochondrial dysfunction as well as individual neuronal demands will help to design new targets and to make use of already established treatments in order to improve treatment of these diseases.

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Section: Calcium Handlingmentioning

confidence: 85%

Selective Neuron Vulnerability in Common and Rare Diseases—Mitochondria in the Focus

Paß

Wiesner

Pla‐Martín

2021

Front. Mol. Biosci.

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“…Recently, αSyn has been shown to modulate the VDAC permeability to Ca 2+ . In fact, as a result of αSyn binding, VDAC1 selectivity for calcium increases, which leads to a higher Ca 2+ flux through the channel [ 163 ].…”

Section: Vdac As αSyn Binding Partner For Better or For Worsementioning

confidence: 99%

Alpha-Synuclein and Mitochondrial Dysfunction in Parkinson’s Disease: The Emerging Role of VDAC

et al. 2021

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Alpha-Synuclein (αSyn) is a protein whose function is still debated, as well as its role in modulation of mitochondrial function in both physiological and pathological conditions. Mitochondrial porins or Voltage-Dependent Anion Channel (VDAC) proteins are the main gates for ADP/ATP and various substrates towards the organelle. Furthermore, they act as a mitochondrial hub for many cytosolic proteins, including αSyn. This review analyzes the main aspects of αSyn-mitochondria interaction, focusing on the role of VDAC and its emerging involvement in the pathological processes.

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“…Using VDAC reconstitution experiments, it was initially shown by Colombini’s group that VDAC might regulate calcium fluxes to and from mitochondria by voltage gating [ 15 ]. More recently, our group has demonstrated that calcium flux through VDAC is greatly facilitated by αSyn [ 122 ]. These experiments were performed on VDAC reconstituted in a membrane subjected to a CaCl 2 salt gradient that allows measurement of VDACs ionic selectivity in the open and αSyn-blocked states.…”

Section: Physiological Implications Of α-Synuclein and Tubulin Interaction With Vdac: Similarities And Differencesmentioning

confidence: 99%

“…These experiments were performed on VDAC reconstituted in a membrane subjected to a CaCl 2 salt gradient that allows measurement of VDACs ionic selectivity in the open and αSyn-blocked states. From these measurements, the calcium currents through both states were calculated, showing that the calcium permeability of the blocked state is >10 times higher than that of the open state [ 122 ]. The high permeability to calcium in the presence of αSyn is due to the favorable electrostatic environment created by the anionic CTT inside the pore, which overcompensates the physical obstruction of the pore by an order of magnitude.…”

Section: Physiological Implications Of α-Synuclein and Tubulin Interaction With Vdac: Similarities And Differencesmentioning

confidence: 99%

Regulation of Mitochondrial Respiration by VDAC Is Enhanced by Membrane-Bound Inhibitors with Disordered Polyanionic C-Terminal Domains

Rostovtseva

Bezrukov

Hoogerheide

2021

IJMS

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The voltage-dependent anion channel (VDAC) is the primary regulating pathway of water-soluble metabolites and ions across the mitochondrial outer membrane. When reconstituted into lipid membranes, VDAC responds to sufficiently large transmembrane potentials by transitioning to gated states in which ATP/ADP flux is reduced and calcium flux is increased. Two otherwise unrelated cytosolic proteins, tubulin, and α-synuclein (αSyn), dock with VDAC by a novel mechanism in which the transmembrane potential draws their disordered, polyanionic C-terminal domains into and through the VDAC channel, thus physically blocking the pore. For both tubulin and αSyn, the blocked state is observed at much lower transmembrane potentials than VDAC gated states, such that in the presence of these cytosolic docking proteins, VDAC’s sensitivity to transmembrane potential is dramatically increased. Remarkably, the features of the VDAC gated states relevant for bioenergetics—reduced metabolite flux and increased calcium flux—are preserved in the blocked state induced by either docking protein. The ability of tubulin and αSyn to modulate mitochondrial potential and ATP production in vivo is now supported by many studies. The common physical origin of the interactions of both tubulin and αSyn with VDAC leads to a general model of a VDAC inhibitor, facilitates predictions of the effect of post-translational modifications of known inhibitors, and points the way toward the development of novel therapeutics targeting VDAC.

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α-Synuclein emerges as a potent regulator of VDAC-facilitated calcium transport

Cited by 36 publications

References 67 publications

Selective Neuron Vulnerability in Common and Rare Diseases—Mitochondria in the Focus

Selective Neuron Vulnerability in Common and Rare Diseases—Mitochondria in the Focus

Alpha-Synuclein and Mitochondrial Dysfunction in Parkinson’s Disease: The Emerging Role of VDAC

Regulation of Mitochondrial Respiration by VDAC Is Enhanced by Membrane-Bound Inhibitors with Disordered Polyanionic C-Terminal Domains

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