Distinct Molecular Signaling Pathways Governing Mitochondrial Fission and Their Roles in Mitochondrial Biogenesis and Mitophagy

Abstract

MTP18 (also known as MTFP1), a nuclear-encoded inner mitochondrial membrane protein, is crucial for mitochondrial integrity. MTP18 is found to promote mitochondrial fission. However, there are limited studies on the mechanistic role of MTP18 in contributing to mitochondrial fission. The current study found that MTP18 regulates the DRP1-MFF-FIS1 signaling axis to regulate mitochondrial fission. In this connection, MTP18 overexpression elevated mitochondrial biogenesis, DNA content, and ATP level and upregulated the symmetric mitochondrial fission by phosphorylating MFF, a DRP1 receptor. MTP18 also increased the recruitment of cytosolic DRP1 to mitochondria by phosphorylating DRP1 at Ser616 to initiate fission. In addition, MTP18 was also found to stabilize MFF by inhibiting its priming with ubiquitin and further proteasomal degradation. In addition, MTP18 induced FIS1-mediated asymmetric mitochondrial fission and mitophagy to clear mitochondrial damage induced by CCCP-mediated mitochondrial uncoupling. Moreover, we found that MTP18 functions as a mitophagy receptor that targets CCCP-induced dysfunctional mitochondria for elimination via autophagosomes. Interestingly, MTP18 interacts with members of the LC3 (also known as MAP1LC3) family through its LC3-interacting region (LIR) to induce mitochondrial autophagy. A mutation in the LIR motif (mLIR) inhibited that interaction, thus suppressing mitophagy. The study establishes that MTP18 signals distinct fission events for mitochondrial biogenesis or elimination, thereby maintaining mitochondrial homeostasis.