Figure 3.

Regulatory circuit of FUNDC1-mediated mitophagy. FUNDC1 is phosphorylated by CSNK2, ULK1 and SRC kinases at Ser13, Ser17 and Tyr18, respectively. The Ser13 is dephosphorylated by mitochondrial phosphatase PGAM5, which is finely tuned by BCL2L1. The phosphorylation at Ser17 while dephosphorylation at Ser13 and Tyr18 under mitochondrial stresses (especially hypoxia) enhances the FUNDC1-MAP1LC3 interaction and stimulates mitophagy induction. The mitochondrial E3 ligase MARCHF5 could ubiquitinate FUNDC1 at Lys118 for its proteasomal degradation and thus desensitize hypoxia induced mitophagy. FUNDC1 is also tuned by transcriptional factor NRF1-PPARGC1A and MIR137 at transcriptional and post-transcriptional level, respectively. FUNDC1 is enriched in MAM structure by interacting with ER resident CANX and ITPR2, where it promotes the release of ER Ca²⁺ to mitochondria and cytosol. Under mitochondrial stresses, FUNDC1 disassociates with OPA1 and CANX, while associates with DNM1L at MAMs to facilitate mitochondrial fission and mitophagy.