The membrane scaffold SLP2 anchors a proteolytic hub in mitochondria containing PARL and the i ‐AAA protease YME1L

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.

PINK1 and Parkin: emerging themes in mitochondrial homeostasis

“…Under steady state conditions, PINK1 is constitutively imported into mitochondria, cleaved and degraded via the N-end rule pathway. The proteolysis of PINK1 is mediated by the inner mitochondrial membrane associated PARL protease, and regulated by the recently described SPY complex [3]. Upon the loss of mitochondrial membrane potential that can be induced artificially by mitochondrial uncouplers (e.g.…”

Targeted OMA1 therapies for cancer

“…OMA1 and YME1L1 are organized in the mitochondrial inner membrane by the prohibitins PHB and PHB2 and other scaffolding proteins, such as SLP2 (synaptotagmin‐like protein 2) . Prohibitins will be discussed in more details below.…”

“…116,117 OMA1 and YME1L1 are organized in the mitochondrial inner membrane by the prohibitins PHB and PHB2 and other scaffolding proteins, such as SLP2 (synaptotagmin-like protein 2). 113,118,119 Prohibitins will be discussed in more details below. The important point here is that prohibitins can inhibit OMA1 and constrain its proteolytic activity.…”

Metalloproteases of the Inner Mitochondrial Membrane

“…Instead, the recent study described a novel supramolecular complex consisting of the YME1L, membrane scaffold stomatin-like protein SLP2, and the rhomboid protease PARL. 85 This ∼2 MDa complex, named SPY, appears to facilitate the proteolytic activity of i-AAA under conditions of high substrate load; in this role, it resembles the PHB−m-AAA supercomplex and may exert a modulatory effect on i-AAA actvity toward specific substrates. 85 …”