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

Rosencrans, William M. and Aguilella, Vicente M. and Rostovtseva, Tatiana K. and Bezrukov, Sergey M. (2021) α-Synuclein emerges as a potent regulator of VDAC-facilitated calcium transport. Cell Calcium, 95 . Art. No. 102355. ISSN 0143-4160. doi:10.1016/j.ceca.2021.102355.

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Voltage-dependent anion channel (VDAC) is the most ubiquitous channel at the mitochondrial outer membrane, and is believed to be the pathway for calcium entering or leaving the mitochondria. Therefore, understanding the molecular mechanisms of how VDAC regulates calcium influx and efflux from the mitochondria is of particular interest for mitochondrial physiology. When the Parkinson’s disease (PD) related neuronal protein, alpha-synuclein (αSyn), is added to the reconstituted VDAC, it reversibly and partially blocks VDAC conductance by its acidic C-terminal tail. Using single-molecule VDAC electrophysiology of reconstituted VDAC we now demonstrate that, at CaCl2 concentrations below 150 mM, αSyn reverses the channel’s selectivity from anionic to cationic. Importantly, we find that the decrease in channel conductance upon its blockage by αSyn is hugely overcompensated by a favorable change in the electrostatic environment for calcium, making the blocked state orders-of-magnitude more selective for calcium and thus increasing its net flux. -Our findings with higher calcium concentrations also demonstrate that the phenomenon of “charge inversion” is taking place at the level of a single polypeptide chain. Measurements of ion selectivity of three VDAC isoforms in CaCl2 gradient show that VDAC3 exhibits the highest calcium permeability among them, followed by VDAC2 and VDAC1, thus pointing to isoform-dependent physiological function. Mutation of the E73 residue – VDAC1 purported calcium binding site – shows that there is no measurable effect of the mutation in either open or αSyn-blocked VDAC1 states. Our results confirm VDACs involvement in calcium signaling and reveal a new regulatory role of αSyn, with clear implications for both normal calcium signaling and PD-associated mitochondrial dysfunction.

Item Type:Article
Related URLs:
URLURL TypeDescription
Rosencrans, William M.0000-0003-1461-8891
Aguilella, Vicente M.0000-0002-2420-2649
Rostovtseva, Tatiana K.0000-0001-7299-7362
Additional Information:© 2021 Published by Elsevier Ltd. Received 16 December 2020, Accepted 4 January 2021, Available online 2 February 2021. W.M.R., T.K.R, and S.M.B were supported by the Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). V.M.A received support from the USA. Government of Spain (PID2019-108434GB-I00 AEI/FEDER, UE), Generalitat Valenciana (AICO/2020/066), and Universitat Jaume I (UJI-B2018-53), Spain. CRediT authorship contribution statement: William M. Rosencrans: Conceptualization, Formal analysis, Investigation, Writing - original draft, Writing - review & editing. Vicente M. Aguilella: Methodology, Formal analysis, Funding acquisition, Writing - original draft, Writing - review & editing. Tatiana K. Rostovtseva: Conceptualization, Methodology, Formal analysis, Supervision, Writing - original draft, Writing - review & editing. Sergey M. Bezrukov: Conceptualization, Methodology, Supervision, Funding acquisition, Writing - original draft, Writing - review & editing. The authors declare that they have no competing interests with the contents of this article.
Funding AgencyGrant Number
Ministerio de Ciencia e Innovación (MCINN)PID2019-108434GB-I00
Fondo Europeo de Desarrollo Regional (FEDER)UNSPECIFIED
Generalitat ValencianaAICO/2020/066
Universitat Jaume IUJI-B2018-53
Subject Keywords:Voltage-dependent anion channel; Intrinsically disordered proteins; Ion selectivity, beta-barrel channels; Single-molecule measurement; Calcium signaling; Charge inversion
Record Number:CaltechAUTHORS:20210503-110343631
Persistent URL:
Official Citation:William M. Rosencrans, Vicente M. Aguilella, Tatiana K. Rostovtseva, Sergey M. Bezrukov, α-Synuclein emerges as a potent regulator of VDAC-facilitated calcium transport, Cell Calcium, Volume 95, 2021, 102355, ISSN 0143-4160, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108924
Deposited By: Tony Diaz
Deposited On:03 May 2021 18:10
Last Modified:03 May 2021 18:10

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