PGAM5 is a mitochondrial phosphatase that is cleaved into two forms and regulates mitochondrial dynamics, respiration, and cell survival 15, 16, 17, 18. Moreover, PARL processes phosphoglycerate mutase family member 5 (PGAM5) under stress conditions 14. The rhomboid protease PARL cleaves the PTEN‐induced kinase PINK1 in the IM, which regulates the activity of respiratory complex I and the clearance of damaged mitochondria by mitophagy 10, 11, 12, 13.
OMA1 is a stress‐activated peptidase, which ensures protein quality control, fine‐tunes mitochondrial bioenergetic function, and controls cellular apoptotic resistance 5, 6, 7, 8, 9. YME1L also catalyzes the regulatory turnover of PRELID1, required at an early stage in the synthesis of the mitochondrial phospholipid cardiolipin (CL) 4. The IM proteases YME1L and OMA1 mediate the processing of the dynamin‐like GTPase OPA1, balancing fusion and fission of mitochondrial membranes, and regulating cristae morphogenesis 1, 2, 3. Proteolytic events at the inner membrane (IM) represent central regulatory steps in these processes, emphasizing the importance of mitochondrial IM proteases beyond their roles as gatekeepers of protein quality. Mitochondria are emerging as cellular signaling platforms deeply integrated into various cell survival and cell death cascades. Together, our results reveal an important role of SLP2 membrane scaffolds for the spatial organization of IM proteases regulating mitochondrial dynamics, quality control, and cell survival. SLP2 restricts OMA1‐mediated processing of the dynamin‐like GTPase OPA1 allowing stress‐induced mitochondrial hyperfusion under starvation conditions. Moreover, SLP2 inhibits the stress‐activated peptidase OMA1, which can bind to SLP2 and cleaves PGAM5 in depolarized mitochondria. Association with SLP2 in the SPY complex regulates PARL‐mediated processing of PTEN‐induced kinase PINK1 and the phosphatase PGAM5 in mitochondria. Here, we report that SLP2 anchors a large protease complex composed of the rhomboid protease PARL and the i‐ AAA protease YME1L, which we term the SPY complex (for SLP2–PARL–YME1L). Stomatin‐like protein 2 ( SLP2) is a member of this superfamily that localizes to the mitochondrial inner membrane (IM) where it acts as a membrane organizer.
The SPFH (stomatin, prohibitin, flotillin, HflC/K) superfamily is composed of scaffold proteins that form ring‐like structures and locally specify the protein–lipid composition in a variety of cellular membranes.
0 kommentar(er)
