Magic Bullet Targeting Subcellular Organelle: Mitochondria

Mitochondria, known as “cellular power plants,” are the membrane-bound organelles in the mammalian cells that play an essential role in generating adenosine triphosphate (ATP), the main fuel source for the work of the cells. Apart from that, mitochondria are also responsible for the maintenance of oxidation-reduction homeostasis, intracellular calcium level and apoptosis-survival signal. Impairment of mitochondria has been demonstrated to cause neurodegenerative disease, cancer, diabetes, aging and other disorders. Although scientists have been dedicated to conducting research for in-depth understanding of mitochondria dysfunctions and development of therapy to effectively treat them, no specific therapeutic regimes have been conceived for any kind of mitochondrial diseases. This is primarily because therapeutic molecules can barely be delivered to the site of action by virtue of two barriers: cytoplasm membrane and mitochondria membranes.

In the July 2011 issue of Molecular Therapy, Dr. Yuda Yamada and colleagues have devised a novel liposome-based nano carrier that could potentially deliver macromolecules to the mitochondrial matrix within the cells. The nano carrier was proposed to be a tetra-lamellar (four layers) structured nano particle, formed in a stepwise coating approach by electrostatic interaction. The outer bilayers were formulated for efficient cytoplasmic delivery with the aid of heavily coated octaarginine, a synthetic eight amino acid peptide shown to facilitate the cellular uptake and cytosolic release of nanoparticles. Peeling off the outer membrane intracellularly exposed the inner bilayers, which were formulated with optimized mitochondrial membrane fusion activity. The results showed a selective delivery of model cargo, DNase I, to the mitochondrial matrix, which was demonstrated by the exclusive degradation of mitochondrial DNA.

Although octaarginine coating compromises the targeting ability of nanoparticles to specific cell population, leading to adverse side effects if administered systemically, the mitochondria targeted delivery which is solely based on membrane fusion activity of liposome provides a novel approach to subcellular delivery. This delivery system holds much promise to be exploited in the treatment of mitochondrial disease, provided that the mechanism of action is explicitly understood.