Figure 3.

Impact of ISG15 on mitochondrial activities. Mitochondria are targets of ISG15 and ISGylation in murine bone marrow-derived macrophages (BMDMs). ISGylated proteins can be found in all mitochondrial localizations, mainly in the mitochondrial intermembrane space (IMS) and inner mitochondrial membrane (IMM), where free ISG15 is also present. ISG15 and ISGylation are involved in the regulation of mitochondrial metabolism. Absence of ISG15 leads to alterations in OXPHOS, with lower oxygen consumption rates and ATP production levels, in addition to aberrant ETC supercomplexes assembly. Such disruption of OXPHOS mechanisms decreases ROS production, with repercussions for macrophage polarization. Mitophagy is also altered in cells lacking ISG15. Finally, ISG15-/- BMDM accumulate defective mitochondria and Parkin cannot be found in mitochondrial extracts, suggesting that ISG15 is important during the translocation of Parkin from the cytoplasm to mitochondria.