Effects of local pH on the formation and regulation of cristae morphologies.

Cristae, folded subcompartments of the inner mitochondrial membrane (IMM), have complex and dynamic morphologies. Since cristae are the major site of adenosine triphosphate synthesis, morphological changes of cristae have been studied in relation to functional states of mitochondria. In this sense, investigating the functional and structural significance of cristae may be critical for understanding progressive mitochondrial dysfunction. However, the detailed mechanisms of the formation and regulation of these cristae structures have not been fully elucidated. Among the hypotheses concerning the regulation of cristae morphologies, we exclusively investigate the effects of the local pH gradient on the cristae morphologies by using a numerical model. An area-difference induced curvature of the membrane is modeled as a function of local pH. This curvature is then applied to the finite element model of a closed lipid bilayer in order to find the energetically favorable membrane configuration. From this study, we substantiate the hypothesis that a tubular crista structure can be formed and regulated by the local pH gradient. Through the simulations with various initial conditions, we further demonstrate that the diameter of a crista is mainly determined by the local pH gradient, and the energetically favorable direction of crista growth is perpendicular to the longitudinal axis of a mitochondrion. Finally, the simulation results at the mitochondrial scale suggest that the cristae membrane may have a lower local pH value and/or a higher cardiolipin composition than the other parts of the IMM.