Adaptation of the late ISC pathway in the anaerobic mitochondrial organelles of Giardia intestinalis

Author summary Anaerobic parasitic protists, such as Giardia intestinalis, have dramatically reduced their mitochondrial metabolism. Large mitochondrial networks known from aerobic eukaryotes have evolved into minimalist vesicles that are still enclosed by a double membrane but have lost the mitochondrial genome, respiratory chain, and most mitochondrial enzymes. However, these small mitochondria still contain the so-called ISC pathway, which synthesizes iron-sulfur clusters, essential cofactors for the function of respiratory chain complexes, and other mitochondrial enzymes. In this work, we have begun to characterize the ISC pathway in G. intestinalis to understand whether and why iron-sulfur clusters are formed in these small mitochondrial organelles known as mitosomes. We found that while the ‘early’ part of the ISC pathway responsible for the formation of the simplest [2Fe-2S] clusters is functional in mitosomes, the function of the ‘late’ components involved in [4Fe-4S] cluster formation remains unclear due to unknown substrates that require these clusters. Identifying the role of the "late" ISC pathway is crucial to understanding why mitosomes remain present in anaerobic eukaryotes at all.