Mitochondrial Chemical Biology

Mitochondria are very interesting compartments within the eukaryotic cell with a unique evolutionary history.  The bacterial origin of mitochondria and retention of a genome differentiate this organelle from others within the cell.  Because of the impermeable nature of the mitochondrial membranes, genetic manipulation of the mitochondrial is difficult and as a result little is know about the processes within the organelle that involve nucleic acids.

We recently developed a peptide-based delivery vector that can carry reactive cargo into the mitochondria of live mammalian cells.  By attaching agents that generate reactive oxygen species or alkylation damage, we can site-specifically probe the cellular response to these insults and deconvolute this response from that resulting from nuclear damage.  This approach is revealing new insights into how mitochondrial DNA damage is responded to, and has also indicated that the makeup of mitochondria make them susceptible to other types of biomolecular damage.

Featured publications:

"Re-directing an Alkylating Agent to Mitochondria Alters Drug Target and Cell Death Mechanism." R. Mourtada, S. B. Fonseca, S.P. Wisnovsky, M.P. Pereira, X. Wang, R. Hurren, J. Parfitt, L. Larsen, R.A.J. Smith, M.P. Murphy, A.D. Schimmer, S.O. Kelley, PLOS One, 2013, 8, e60253. link

"Re-routing Chlorambucil to Mitochondria Enhances Potency and Combats Drug Resistance in Cancer Cells " S.B. Fonseca, M.P. Pereira, R. Mourtada, M. Gronda, R. Hurren, M.D. Minden, A.D. Schimmer, S.O. Kelley, Chemistry and Biology, 2011, 18, 445. link

“Mitochondria-Penetrating Peptides.”  K.L. Horton, K.M. Stewart, S.B. Fonseca, Q. Guo, S.O. Kelley, Chemistry & Biology, 2008, 15, 375. link

"Deconvolution of the Oxidative Stress Response using Organelle-Specific Peptides" K.P. Mahon, T.B. Potocky, D. Blair, M.D. Roy, T.C. Chiles, S.O. Kelley, Chemistry and Biology, 2007, 14, 923.

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