Mitochondrial targeting of deferoxamine triggers mitophagy and affects the activity of Fe-S cluster-containing enzymes
Sandoval-Acuña C.1, Torrealba N.1, Tomkova V.1, Repkova K.1, Stursa J.1, Neuzil J.1,2, Werner L.1, Truksa J.1
1Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic; 2School of Medical Science, Griffith University, Southport, Qld, Australia
Iron represents an indispensable micronutrient required for many enzymatic reactions, including mitochondrial respiration, due to its ability to accept and donate electrons. Within cells, iron is primarily stored in mitochondria, where it is essential for the synthesis of Fe-S clusters and heme. Since iron is a crucial nutrient especially for proliferating cells, iron chelation has been proposed as an alternative strategy to selectively target cancer cells.
Mitophagy is an adaptive mechanism, triggered upon mitochondrial damage, responsible for the recycling of dysfunctional mitochondria in an attempt to prevent cell death. However, upon severe and continuous mitochondrial insults, mitophagy eventually depletes the mitochondrial pool, leading to a decrease in cellular viability. Therefore, we have synthesized a mitochondrially targeted derivative of the iron chelator deferoxamine (mDFO) and evaluated its ability to eliminate cancer cells selectively. Moreover, we analyzed the effect of mDFO on the induction of mitophagy and the activity of Fe-S cluster-containing enzymes.
Our results show that mDFO is at least 100-fold more efficient than DFO in killing breast cancer cells. Interestingly, mDFO induced a strong anti-proliferative effect at low concentrations (2 µM) and a cytotoxic effect only at slightly higher concentrations (5-10 µM). Furthermore, mDFO triggered a reorganization of the mitochondrial network towards smaller and less perinuclear mitochondria. In addition, mDFO was shown to activate mitophagy, and severely diminish the activity of the Fe-S cluster-dependent enzyme aconitase and the formation of mitochondrial respiratory supercomplexes, evidencing that the disruption of Fe-S clusters assembly might underlie the cytotoxic effect of the compound. Taken together, our data strongly support the role of mDFO as a novel and efficient compound in the selective elimination of cancer cells.
Funding: This work has been supported by GACR grants 16-12816S and 18-13103S to J.T. and also by the MEYS of CR within the LQ1604 National Sustainability Program II (Project BIOCEV-FAR).