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Free keywords:
ATPases Associated with Diverse Cellular Activities
Blood Proteins/genetics/*metabolism
GTP Phosphohydrolases/genetics/metabolism
HEK293 Cells
HeLa Cells
Humans
Membrane Potential, Mitochondrial/physiology
Membrane Proteins/genetics/*metabolism
Metalloendopeptidases/genetics/*metabolism
Metalloproteases/genetics/*metabolism
Mitochondria/*metabolism
*Mitochondrial Dynamics
Mitochondrial Membranes/metabolism
Mitochondrial Proteins/genetics/*metabolism
Peptide Hydrolases/metabolism
Phosphoprotein Phosphatases/genetics/metabolism
Protein Binding
Protein Kinases/genetics/metabolism
Proteolysis
*oma1
*slp2
*yme1l
*membrane scaffold
*mitochondria
*rhomboid
Abstract:
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. 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. 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). Association with SLP2 in the SPY complex regulates PARL-mediated processing of PTEN-induced kinase PINK1 and the phosphatase PGAM5 in mitochondria. Moreover, SLP2 inhibits the stress-activated peptidase OMA1, which can bind to SLP2 and cleaves PGAM5 in depolarized mitochondria. SLP2 restricts OMA1-mediated processing of the dynamin-like GTPase OPA1 allowing stress-induced mitochondrial hyperfusion under starvation conditions. 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.
