Naturally driven? — How ions get into mitochondria

PhD applicant to the EDCH program

ABSTRACT
Mitochondria are regarded as the “power stations” of the cell and their dysfunction can
lead to numerous aging and neurodegenerative diseases such as Alzheimer’s and
Parkinson’s.However, due to the dense, lipophilic inner mitochondrial membrane it is
difficult to target the organelle for treatment. Lipophilic delocalized cations are often used
to target mitochondria due to the Nernstian accumulation, which occurs because of the
negative potential over the membrane. Ion-pair model is used to predict whether a
molecule favours the Nernstian accumulation (crossing the membrane as a cation) or
prefers to cross as an ion-pair. We tested the model with density-functional theory
calculations on 13 molecules that are well known in biological literature and in all cases
the prediction agreed with the experimental observations.However, the model does not
predict if a molecule will accumulate inside the mitochondrial matrix. Therefore, we also
discussed the main physical parameters that increase the likelihood of accumulation –
increase in solvent-excluded surface area and partition coefficient and decrease in average
electric potential.Our findings can be used to make better predictions or even be useful in
designing new mitochondrial targeting molecules.