Journal of Bioenergetics and Biomembranes

, Volume 45, Issue 1, pp 165–173

Mitochondrial accumulation of a lipophilic cation conjugated to an ionisable group depends on membrane potential, pH gradient and pK a: implications for the design of mitochondrial probes and therapies

Authors

  • Peter G. Finichiu
    • MRC Mitochondrial Biology Unit
  • Andrew M. James
    • MRC Mitochondrial Biology Unit
  • Lesley Larsen
    • Department of ChemistryUniversity of Otago
  • Robin A. J. Smith
    • Department of ChemistryUniversity of Otago
    • MRC Mitochondrial Biology Unit
Open AccessArticle

DOI: 10.1007/s10863-012-9493-5

Cite this article as:
Finichiu, P.G., James, A.M., Larsen, L. et al. J Bioenerg Biomembr (2013) 45: 165. doi:10.1007/s10863-012-9493-5

Abstract

Mitochondria play key roles in a broad range of biomedical situations, consequently there is a need to direct bioactive compounds to mitochondria as both therapies and probes. A successful approach has been to target compounds to mitochondria by conjugation to lipophilic cations, such as triphenylphosphonium (TPP), which utilize the large mitochondrial membrane potential (Δψm, negative inside) to drive accumulation. This has proven effective both in vitro and in vivo for a range of bioactive compounds and probes. However so far only neutral appendages have been targeted to mitochondria in this way. Many bioactive functional moieties that we would like to send to mitochondria contain ionisable groups with pK a in the range that creates an assortment of charged species under physiological conditions. To see if such ionisable compounds can also be taken up by mitochondria, we determined the general requirements for the accumulation within mitochondria of a TPP cation conjugated to a carboxylic acid or an amine. Both were taken up by energised mitochondria in response to the protonmotive force. A lipophilic TPP cation attached to a carboxylic acid was accumulated to a greater extent than a simple TPP cation due to the interaction of the weakly acidic group with the pH gradient (ΔpH). In contrast, a lipophilic TPP cation attached to an amine was accumulated less than the simple cation due to exclusion of the weakly basic group by the ΔpH. From these data we derived a simple equation that describes the uptake of lipophilic cations containing ionisable groups as a function of Δψm, ΔpH and pK a. These findings may facilitate the rational design of additional mitochondrial targeted probes and therapies.

Keywords

Mitochondria Mitochondria-targeting Triphenylphosphonium cation Lipophilic cation Mitochondrial pH gradient

Supplementary material

10863_2012_9493_MOESM1_ESM.docx (119 kb)
ESM 1 (DOCX 118 kb)

Copyright information

© The Author(s) 2012