Acidification asymmetrically affects voltage-dependent anion channel implicating the involvement of salt bridges.

摘要: The voltage-dependent anion channel (VDAC) is the major pathway for ATP, ADP, and other respiratory substrates through mitochondrial outer membrane, constituting a crucial point of metabolism regulation. VDAC characterized by its ability to “gate” between an open several “closed” states under applied voltage. In early stages tumorigenesis or during ischemia, partial total absence oxygen supply cells results in cytosolic acidification. Motivated these facts, we investigated effects pH variations on gating properties. We reconstituted into planar lipid membranes found that acidification reversibly increases gating. Furthermore, both selectivity single conductance increased with acidification, agreement titration negatively charged residues at low values. Analysis dependences parameters yielded similar pKa values close 4.0. also response was highly asymmetric. presumably (cis) side most sensitive whereas intermembrane space (trans) barely responded changes. Molecular dynamic simulations suggested stable salt bridges cis side, which are susceptible disruption upon contribute this asymmetry. pronounced sensitivity here vitro might provide helpful insights regulatory role protective effect ischemia vivo.