Model proposed for the mechanism of mitochondrial generation of ROS dependent on free Fe²⁺ release from Fe–S-containing proteins in <i>S. cerevisiae</i>.

<p>The [2Fe–2S] commonly carried by the multi-protein complex (Ssq1-Jac1-Mge1-Grx5) can also be assembled into recipient apoproteins, such as the Rieske protein of cytochrome <i>bc1</i> from respiratory complex III. The Isa1 and Iba57 proteins may function as iron reservoirs, from which the metal can subsequently be transferred to [Fe–S] centers or heme prosthetic groups from cytochrome <i>bc₁</i>. When superoxide (O₂^•−) is generated by electron leaking in the ETC, and other ROS are produced by oxidative metabolism or by oxidant agents, the [4Fe–4S], [3Fe–4S], or [2Fe–2S] clusters contained in the ETC complexes are disrupted. This event provokes a generalized uncoupling/denaturation of Fe–S proteins, causing a release and thus an increment in the iron labile pool (Fe²⁺), which increases mitochondrial ROS levels via the Fenton and Haber–Weiss reactions. If the ISC assembly system is dysfunctional, supercomplex (III₂IV₂) formation is affected, as is [Fe–S] recycling, provoking ETC dysfunction. Hence, the levels of ROS generation increase in an additive manner by a vicious circle of disruption of iron-containing or iron storage proteins, causing an imbalanced ROS content (increment of species such as H₂O₂ and superoxide species), that provokes mitochondrial dysfunction and may ultimately lead to apoptotic events.