Journal
REDOX BIOLOGY
Volume 51, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.redox.2022.102264
Keywords
VDAC3; Cysteine; ROS; Mitochondria; Complex I; High-resolution respirometry
Categories
Funding
- Italian Ministry of University and Research [PEPSLA POC 01_00054]
- University of Catania-linea PIACERI [ARVEST]
- AIM Linea 1-Salute [AIM1833071]
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Unraveling the role of VDAC3 within living cells is challenging but it is certain that this protein plays an important role in mitochondrial ROS homeostasis. Experimental evidence shows that VDAC3 cysteines are indispensable for the protein's ability to counteract ROS-induced oxidative stress.
Unraveling the role of VDAC3 within living cells is challenging and still requires a definitive answer. Unlike VDAC1 and VDAC2, the outer mitochondrial membrane porin 3 exhibits unique biophysical features that suggest unknown cellular functions. Electrophysiological studies on VDAC3 carrying selective cysteine mutations and mass spectrometry data about the redox state of such sulfur containing amino acids are consistent with a putative involvement of isoform 3 in mitochondrial ROS homeostasis. Here, we thoroughly examined this issue and provided for the first time direct evidence of the role of VDAC3 in cellular response to oxidative stress. Depletion of isoform 3 but not isoform 1 significantly exacerbated the cytotoxicity of redox cyclers such as menadione and paraquat, and respiratory complex I inhibitors like rotenone, promoting uncontrolled accumulation of mito-chondrial free radicals. High-resolution respirometry of transiently transfected HAP1-delta VDAC3 cells expressing the wild type or the cysteine-null mutant VDAC3 protein, unequivocally confirmed that VDAC3 cysteines are indispensable for protein ability to counteract ROS-induced oxidative stress.
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