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Characterization of VDAC3 isoform channel activity and its putative role in mitochondria homeostasis and neurodegeneration

Thursday, September 13, 2018 — Poster Session IV

3:30 p.m. – 5:00 p.m.
FAES Terrace
NICHD
BIOENG-11

Authors

  • M Queralt-Martin
  • L Bergdoll
  • J Abramson
  • TK Rostovtseva
  • SM Bezrukov

Abstract

The voltage-dependent anion channels (VDACs) are the most abundant channel-forming proteins in the mitochondrial outer membrane (MOM), controlling MOM permeability and function. Among the three known isoforms in mammals, VDAC1 is the most abundant and best characterized, while in contrast, VDAC3 is the least abundant and poorly characterized isoform which role in the control of MOM function remains mostly elusive. Despite sequence similarity with VDAC1 pointing to a similar pore-forming ability of the two isoforms, VDAC3 has been reported to form low-conducting, unstable channels when reconstituted in planar lipid membranes (PLM). In this work, using PLM, we for the first time successfully reconstitute recombinant human VDAC3 channel in a high-conducting or “open” state similar to that of mammalian VDAC1. A set of cysteine residues in VDAC3 has been hypothesized to account for protein inability to form typical open channels. To test this hypothesis, we study an engineered cysteine-less hVDAC3 mutant (Dcys). We show that hVDAC3-Dcys forms functional channels with higher open probability compared to wt, but otherwise similar properties. VDAC1 is known to interact with high efficiency (nM) with alpha-synuclein (aS), a disordered neuronal protein, a hallmark of Parkinson’s disease, mediating aS-induced mitochondrial dysfunction in neurodegeneration. A comparative analysis of aS interaction with VDAC3 wt and Dcys and with VDAC1 wt and Dcys provides new clues about putative physiological role of VDAC3. This work is the first step towards an in-depth functional characterization of VDAC3 channel and its involvement in mitochondrial metabolism in health and in neurodegeneration.

Category: Biomedical Engineering and Biophysics