Unexpected Modifications of Cysteines in VDAC3: Indication that VDAC3 may Signal the Mitochondrial Intermembrane Redox State

Abstract

The accumulation in mitochondria of oxidative agents must be signaled to the cell. Neverthless the organelle is the source of redox species. The accumulation in mitochondria of oxidative agents must be signaled to the cell and an organelle heavily loaded with ROS evidenced. We addressed specific structural questions related to the function of VoltageDependentAnion-selectiveChannel isoform 3 (VDAC3) cysteines. We show that VDAC3 (1–3) may be relevant for signaling the redox potential existing in the mitochondrial intermembrane space. We found that VDAC3 can be progressively modified by an accumulation of ROS, resulting in the oxidation at different extents of the exposed cysteine residues. We discovered that each single VDAC3 molecule in the membrane can contain a differently oxidated set of cysteine residues, thus giving rise to what we call “redox isomers” (4). A disulfide bridge was evidenced by mass spectrometry (5). A recent paper indicated a putative disulfide bridge that we did not find by MassSpec (6), neither the authirs detected intermediate oxidation states. Since this complex oxidation pattern is a consequence of the ROS level in the IMS, VDAC3 monitores the redox homeostasis. In our opinion this work represents a pathbreaking finding in the field of mitochondrial redox sensing.Acknowledgements MIUR-PRIN 2010-2011 n. 2010CSJX4F[1] Messina A. et al, 2012, BiochimBiophysActa 1818, 1466-1476[2] Checchetto V. et al, 2014, Cell Physiol. Biochem. 34, 842-53[3] Messina A. et al, 2014, Mol. Biosyst. 10, 2134-45[4] Reina S. et al 2015, SUBMITTED[5] Saletti R. et al, 2015, SUBMITTED[6] Okazaki M. et al, 2015, BiochimBiophysActa, in press