In Silico Evidence for Enterobactin-Facilitated Ferric Iron Import into Mitochondria via ATP Synthase Alpha Subunit Binding
1Indian Institute of Science Education and Research Kolkata (IISER Kolkata), Mohanpur, Nadia 741246, West Bengal, India
2School of Chemistry and Biosciences, University of Bradford, Bradford BD7 1DP, United Kingdom
3Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Yoshida-Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan
Article History
ReceivedApril 24, 2026
AcceptedOctober 25, 2026
Available OnlineOctober 27, 2026
Abstract
Research on mitochondrial iron metabolism has largely focused on Fe(II), as it is relatively soluble
and readily available under physiological conditions. By contrast, the role of Fe(III) remains less well
understood. Its poor solubility and tendency to form potentially harmful ferric hydroxides mean that
it must remain bound to suitable ligands or chaperones during transport. Canonically, iron is delivered
to cells via transferrin (Tf), which binds the transferrin receptor (TfR1) for receptor-mediated
endocytosis. Acidification of endosomes releases Fe(III), which is then reduced to Fe(II) by STEAP3
and transported into the cytosol by DMT1, forming a labile iron pool for mitochondrial use. However,
the direct trafficking of Fe(III) into mitochondria has remained unexplored. Here, we propose a
potential model for Fe(III) uptake into mitochondria through enterobactin, a bacterial siderophore
known to influence host iron metabolism. Using in silico docking with AutoDock Vina and
AlphaFold2-derived mitochondrial F-type ATP synthase structures, we observe that Fe(III)-
enterobactin complexes yield docking scores comparable to Fe(II)-enterobactin complexes at the ATP
synthase alpha subunit. In addition, enterobactin itself adopts compatible binding poses at the protein
surface. These observations are consistent with a possible interaction framework but do not establish
a dissociative mechanism for iron delivery within the mitochondrial matrix. These docking analyses
support the structural plausibility of an enterobactin-associated ferric iron interaction with the
mitochondrial ATP synthase alpha subunit. Although these findings do not establish a specific
transport mechanism, they raise the possibility of an alternative route for mitochondrial iron
trafficking. Further experimental work is needed to determine whether this pathway operates in cells
and how it contributes to iron homeostasis. More broadly, the proposed model suggests a possible
connection between microbial siderophores and mitochondrial iron handling, with potential
physiological and pathological relevance