FIGURE 3.

Mitochondrial perturbations induced by TIA1 and TIAR. TIA1 and TIAR mediate exon 4b inclusion in the pre-mRNA of OPA1 generating the OPA1 variant 5, which is associated with a smaller mitochondria, mitochondrial clustering, and remodeling around the perinuclear region. Further, cytosolic TIA1 enhances the translation of MFF mRNA and promotes DRP1 translocation to mitochondria leading to mitochondrial fragmentation. In parallel, TIA1 and TIAR induce modest downregulation of the pro-fusion proteases OMA1, YMEL1, and MFN2, further contributing to the pro-fission phenotype and mitophagy. TIA1 also has pro-apoptotic properties inhibited by FAST. FAST is released from its mitochondrial tether during stress, a process mediated by tBID and BAX. Following its release, FAST binds to TIA1 and prevents TIA1-mediated silencing of mRNAs encoding inhibitors of apoptosis, such cIAP-1 and XIAP. When TIA1 is in excess, it binds FAST and obstruct its anti-apoptotic events. Finally, TIA1 and TIAR increase LC3-II levels, yet the mechanism is unknown, leading to increased mitophagic events.