A Mitochondrial Transport Protein Protects Cancer Cells from Toxic Nanoparticles

A recent paper stressed the importance of linking the use of anticancer nanoparticle drugs and drug carriers to a basic understanding of the role of the mitochondria in the apoptotic process.

Cancer cells are surprisingly resistant to toxic effects of positively charged gold nanoparticles (+AuNPs). Investigators at the Mayo Clinic (Rochester, MN, USA) examined the interaction of +AuNPs with ovarian cancer cells growing in culture in order to determine the molecular mechanism protecting the cancer cells from the nanoparticles.

They reported in the April 24, 2013, online edition of the Journal of Biological Chemistry that the protein MICU1, a mitochondrial calcium uniporter, as a key molecule conferring cancer cells with resistance to +AuNPs. A uniporter is an integral membrane protein, either a channel or a carrier protein that is involved in facilitated diffusion. Uniporter carrier proteins work by binding to one molecule of solute at a time and transporting it with the solute gradient.

The MICU1 (mitochondrial calcium uptake 1) gene encodes an essential regulator of mitochondrial Ca2+ uptake under basal conditions. The encoded protein interacts with the mitochondrial calcium uniporter, a mitochondrial inner membrane Ca2+ channel, and is essential in preventing mitochondrial Ca2+ overload, which can cause excessive production of reactive oxygen species and cell stress.

The investigators found that in the ovarian cancer cells the increase in cytosolic Ca2+ induced by +AuNPs was balanced by MICU1, which prevented cell death. Silencing MICU1 decreased Bcl-2 (B-cell lymphoma 2), expression and increased caspase-3 activity and cytosolic cytochrome C levels—effects further enhanced in the presence of +AuNPs—thus initiating the mitochondrial pathway for apoptosis.

"This study identifies a novel mechanism that protects ovarian cancer cells by preventing the cell death, or apoptosis, which should occur when they encounter positively charged nanoparticles," said senior author Dr. Priyabrata Mukherjee, associate professor of biomedical engineering at the Mayo Clinic. "Furthermore, this work establishes MICU1 as a novel regulator of the apoptotic machinery in cancer cells and emphasizes the need to synergize nanoparticle design with understanding of mitochondrial machinery for enhancing targeted cellular toxicity."


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