Post-Translationally Modified Cardiac Mitochondrial VDAC1 Gating Kinetics Analyzed Using Continuous-Time MCMC Model

Mitochondrial homeostasis, maintained via the outer mitochondrial membrane (OMM), is critical for maintaining mitochondrial function. The voltage-dependent anion channel (VDAC1 isoform) is the most abundant protein on the OMM, and it regulates the exchange of ions and molecules across the membrane. VDAC1 possesses a remarkable ability to conduct metabolites and anions in its high conductance state and cations in its low conductance state. Despite its significance, no integrated mitochondrial bioenergetics model incorporates for VDAC1. Our electrophysiological recordings of VDAC1 incorporated into lipid bilayers revealed that post-translational modification (PTM) by phosphorylation and nitration significantly impacted VDAC1 gating kinetics. Consequently, a thorough statistical treatment was applied by modeling VDAC1 activity using a generalized continuous-time Markov chain Monte Carlo (MCMC) method. The MCMC method returns probability distribution of identified model parameters from which important model information such as appropriateness and parameterization can be easily obtained. Our analyses suggest that phosphorylation and nitration of VDAC1 facilitate multiple conductance states wherein a simple kinetic model incorporating three open states (O1 ↔ O2 ↔ O3) describes the experimental data. The long-term goal is to link the changes in VDAC1 gating kinetics to mitochondrial function.