The most prominent side effect of FQ treatment, the specific down-regulation of the ETC complexes I and IV, could be linked to an interaction of FQs with AIFM1 and its functional impairment comparable to a cellular KO. However, insights on how FQ binding to AIFM1 induces the dysregulation is subject to future investigations, i.e. requiring insights from structural biology. As a consequence of this interaction, the corresponding damage in the respiratory chain causes a reduction in NAD+ levels, i. e. an accumulation of NADH, leading to metabolic rewiring and a switch in the catalysis of IDH2 from a-KG to isocitrate production. As simultaneous inhibition of IDH2 by FQs also inactivates this alternative reductive carboxylation route, mitochondria are incapable of compensating the shortage of crucial metabolites of the TCA cycle likely triggering a pronounced dysfunction (Figure ). Of note, mitochondrial NADH/NAD+ and NADPH/NADP+ pools are linked by the Nicotinamide nucleotide transhydrogenase (NNT), thus an accumulation of NADH due to mitochondrial dysfunction could also result in increased NADPH levels. Additionally, non-mitochondrial protein interactions with NUDT1, reported divalent ion chelation and other modes of action likely contribute to the side-effects. Besides the better understanding of molecular off-targets of FQs, it is important to study why only some patients are so severely affected by adverse reactions. While risk factors like concomitant drug prescriptions, additionally straining the organism and changed pharmacokinetics, e.g. due to renal impairment or age, leading to drug accumulation can partially explain the sensibility of some patients towards FQs, further studies are needed. To the best of our knowledge no studies into genetic predispositions of effected patients have been published, although insinuations about pending patent applications in this field have been made. The overlay of genomic data with the off-targets identified and validated in this study could potentially support and direct the development of safe FQ prescription practices and newer FQ generations.