Drug delivery to mitochondria: the key to mitochondrial medicine
Introduction
The effectiveness of any drug or gene therapy depends on delivering a bioactive molecule to the correct organ and cell type, and also on targeting it to the appropriate location within the cell [1]. Delivering biologically-active molecules to the appropriate intracellular compartment should not only increase their effectiveness and minimise side effects, but also enable cellular metabolism to be manipulated in increasingly specific ways. Mitochondria are a promising intracellular target for drug delivery [2], because damage to this organelle contributes to a range of human disorders and because mitochondrial function is important in apoptosis, oxidative damage, calcium metabolism, diabetes and obesity [3]. Furthermore, biologically active molecules can be delivered selectively to the organelle [2]. In this review we outline why mitochondria are a promising target for drug delivery and discuss how to deliver molecules selectively to the organelle.
Section snippets
Properties of mitochondria relevant to drug targeting and gene therapy
Most human cells contain substantial numbers of mitochondria in their cytoplasm whose principal function is ATP synthesis by oxidative phosphorylation [4], [5]. Mitochondria make ATP by passing electrons derived from the oxidation of food down the respiratory chain to react with oxygen, using the redox energy to translocate protons across the mitochondrial inner membrane [4], [5]. This establishes a proton electrochemical potential gradient across the inner membrane comprising a membrane
Why target drugs to mitochondria?
Here we outline how mitochondria contribute to human diseases to illustrate why delivery of drugs or bioactive molecules to mitochondria may be therapeutically useful.
How can molecules be targeted to mitochondria?
If the goals outlined above for mitochondrial medicine are to be achieved, it is essential to be able to selectively target drugs and biologically active molecules to mitochondria within cells in living organisms. Two properties of mitochondria may facilitate this: the large membrane potential across the inner membrane and the organelle’s protein import machinery. In this section we outline how these can be used to deliver molecules to mitochondria.
Problems and possibilities
Lipophilic cations have been used to deliver antioxidants or toxins to mitochondria within cells and this approach can be extended in many ways, for example to deliver other protective molecules such as iron or calcium chelators. Furthermore, by attaching molecules of known biological or pharmacological function to lipophilic cations it should be possible to manipulate mitochondrial function rationally. While there are many possible uses for such an approach, the repair or prevention of
Conclusion
Mitochondrial dysfunction is central to a range of important human disorders. If these diseases area to be treated and mitochondrial medicine is to develop, we need to be able to manipulate mitochondrial function and protect against mitochondrial damage in rational ways. This requires the selective delivery of bioactive compounds to mitochondria. Strategies utilising the mitochondrial membrane potential through lipophilic cations, or exploiting the mitochondrial protein import machinery may be
Acknowledgements
Work in the authors’ laboratories is supported by grants from the Marsden Fund, administered by the Royal Society of NZ, the Health Research Council of NZ, the Neurological Foundation of NZ and the Lottery Health Grants Committee.
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