The integrity of ER-mitochondria appositions ensures transfer of ions and phospholipids (PLs) between these organelles and exerts crucial effects on mitochondrial bioenergetics. Malfunctions within the ER-mitochondria contacts altering lipid trafficking homeostasis manifest in diverse pathologies, but the molecular effectors governing this process remain ill-defined. Here, we report that PERK promotes lipid trafficking at the ER-mitochondria contact sites (EMCS) through a non-conventional, unfolded protein response-independent, mechanism. PERK operates as an adaptor for the recruitment of the ER-plasma membrane tether and lipid transfer protein (LTP) Extended-Synaptotagmin 1 (E-Syt1), within the EMCS. In resting cells, the heterotypic E-Syt1-PERK interaction endorses transfer of PLs between the ER and mitochondria. Weakening the E-Syt1-PERK interaction or removing the lipid transfer SMP-domain of E-Syt1, compromises mitochondrial respiration. Our findings unravel E-Syt1 as a PERK interacting LTP and molecular component of the lipid trafficking machinery of the EMCS, which critically maintains mitochondrial homeostasis and fitness.ER-mitochondria contact sites (EMCS) regulate non-vesicular phospholipid transport between these organelles, but the molecular entities involved in lipid translocation remain undefined. Sassano et al. reveal that EMCS-associated PERK recruits the lipid transfer protein E-Syt1 at EMCS facilitating lipid transport to sustain mitochondrial homeostasis and respiration.

PERK recruits E-Syt1 at ER-mitochondria contacts for mitochondrial lipid transport and respiration / Sassano, Maria Livia; van Vliet, Alexander R; Vervoort, Ellen; Van Eygen, Sofie; Van den Haute, Chris; Pavie, Benjamin; Roels, Joris; Swinnen, Johannes V; Spinazzi, Marco; Moens, Leen; Casteels, Kristina; Meyts, Isabelle; Pinton, Paolo; Marchi, Saverio; Rochin, Leila; Giordano, Francesca; Felipe-Abrio, Blanca; Agostinis, Patrizia. - In: THE JOURNAL OF CELL BIOLOGY. - ISSN 0021-9525. - 222:3(2023). [10.1083/jcb.202206008]

PERK recruits E-Syt1 at ER-mitochondria contacts for mitochondrial lipid transport and respiration

Marchi, Saverio;
2023-01-01

Abstract

The integrity of ER-mitochondria appositions ensures transfer of ions and phospholipids (PLs) between these organelles and exerts crucial effects on mitochondrial bioenergetics. Malfunctions within the ER-mitochondria contacts altering lipid trafficking homeostasis manifest in diverse pathologies, but the molecular effectors governing this process remain ill-defined. Here, we report that PERK promotes lipid trafficking at the ER-mitochondria contact sites (EMCS) through a non-conventional, unfolded protein response-independent, mechanism. PERK operates as an adaptor for the recruitment of the ER-plasma membrane tether and lipid transfer protein (LTP) Extended-Synaptotagmin 1 (E-Syt1), within the EMCS. In resting cells, the heterotypic E-Syt1-PERK interaction endorses transfer of PLs between the ER and mitochondria. Weakening the E-Syt1-PERK interaction or removing the lipid transfer SMP-domain of E-Syt1, compromises mitochondrial respiration. Our findings unravel E-Syt1 as a PERK interacting LTP and molecular component of the lipid trafficking machinery of the EMCS, which critically maintains mitochondrial homeostasis and fitness.ER-mitochondria contact sites (EMCS) regulate non-vesicular phospholipid transport between these organelles, but the molecular entities involved in lipid translocation remain undefined. Sassano et al. reveal that EMCS-associated PERK recruits the lipid transfer protein E-Syt1 at EMCS facilitating lipid transport to sustain mitochondrial homeostasis and respiration.
2023
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11566/316711
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