# Transformation of mitochondrial VDAC1 between protective and lethal states

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $697,666

## Abstract

ABSTRACT
 The aim of this proposal is to investigate the mechanisms underlying transformation of the mitochondrial
voltage-dependent anion channel (VDAC1) from protective to lethal states. We postulate that site-specific
phosphorylation of VDAC1 is a key determinant of this transformation. In particular, we will test the hypothesis
that phosphorylation of specific sites differentially regulates the gating properties of the channel, and also its
ability to associate with pro- and anti-apoptotic proteins. We propose a novel paradigm that this
phosphorylation-dependent differential modulation of VDAC1 can shift the balance between cell death and
survival. Our studies will establish a mechanistic link between site-specific phosphorylation of VDAC1 and the
impact on mitochondrial and cellular functions. In preliminary experiments, we have obtained novel proteomics
results that identified candidate sites that impact VDAC1 gating properties and those that regulate its ability to
bind anti- and pro-apoptotic proteins. Based on these results, we will systematically target residues that 1)
regulate VDAC1 binding with pro- and anti-apoptotic proteins, and 2) alter the channel’s gating characteristics.
We will employ a highly orchestrated experimental-computational approach. In Aim 1, we will identify and
determine the impact of site-specific phosphorylation on the functional and binding properties of VDAC1. The
multifaceted experimental approach will include electrophysiology at the single channel level, mitochondrial
bioenergetic measurements, and biochemical and molecular biology approaches. In Aim 2, we will determine
the structural impact of site-specific phosphorylation of VDAC1. Molecular dynamics (MD) simulations will be
utilized to simulate VDAC1 to characterize the structural changes triggered by site-specific phosphorylation.
Free energy calculations of substrate permeation will determine the molecular mechanism that underlies
changes in gating due to phosphorylation of specific sites. Comparative MD simulations will be also used to
investigate how phosphorylation at more peripheral sites alters the structure, the electrostatics properties
affecting membrane/lipid interaction, and dynamics of the putative binding region for hexokinase, a major anti-
apoptotic protein that targets VDAC1. In Aim 3, we will test the cardioprotective capacity of VDAC1 mutants in
ex vivo and in vivo models. Using ex vivo hearts and in vivo animal models, we will test the transgenic
expression of mutant VDAC1 that harbors a specific phosphorylation-resistant site that regulates hexokinase
binding or a specific phosphorylated site(s) (phosphomimetic) that promotes cell survival. The proposed
research, ranging from the single channel to the in vivo model, will fill a significant void in our understanding of
how functional and structural changes in VDAC1 tip the balance between cell survival and cell death. Our long
term goal is to delineate how post-translational modifica...

## Key facts

- **NIH application ID:** 9857064
- **Project number:** 5R01HL131673-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** AMADOU K. CAMARA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $697,666
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857064

## Citation

> US National Institutes of Health, RePORTER application 9857064, Transformation of mitochondrial VDAC1 between protective and lethal states (5R01HL131673-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9857064. Licensed CC0.

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