biostudies-literatureLapao ANorges ForskningsrådKreftforeningenHORIZON EUROPE Marie Sklodowska-Curie ActionsRP105541https://www.ebi.ac.uk/biostudies/studies/S-EPMC12656530biostudies-literatureUnknown14SYTL5 is a member of the Synaptotagmin-Like (SYTL) protein family that differs from the Synaptotagmin family by having a unique N-terminal Synaptotagmin homology domain that directly interacts with the small GTPase RAB27A. Several SYTL protein family members have been implicated in plasma membrane transport and exocytosis, but the specific function of SYTL5 remains unknown. We here show that SYTL5 is a RAB27A effector and that both proteins localise to mitochondria and vesicles containing mitochondrial material. Mitochondrial recruitment of SYTL5 depends on its interaction with functional RAB27A. We demonstrate that SYTL5-RAB27A positive vesicles containing mitochondrial material, autophagy proteins and LAMP1 form during hypoxia and that depletion of SYTL5 and RAB27A reduces mitophagy undeeLifeThe RAB27A effector SYTL5 regulates mitophagy and mitochondrial metabolism.PMC1265653019025124975326265210.3030/765912Ng MYWEskelinen ELTrachsel-Moncho LSimonsen AJohnson LSSingh SLapao ANakken SRodgers SJfalseThe RAB27A effector SYTL5 regulates mitophagy and mitochondrial metabolism.SYTL5 is a member of the Synaptotagmin-Like (SYTL) protein family that differs from the Synaptotagmin family by having a unique N-terminal Synaptotagmin homology domain that directly interacts with the small GTPase RAB27A. Several SYTL protein family members have been implicated in plasma membrane transport and exocytosis, but the specific function of SYTL5 remains unknown. We here show that SYTL5 is a RAB27A effector and that both proteins localise to mitochondria and vesicles containing mitochondrial material. Mitochondrial recruitment of SYTL5 depends on its interaction with functional RAB27A. We demonstrate that SYTL5-RAB27A positive vesicles containing mitochondrial material, autophagy proteins and LAMP1 form during hypoxia and that depletion of SYTL5 and RAB27A reduces mitophagy unde2025-01-01T00:00:00Z2025 Nov2026-06-05T16:57:29.891Z2026-06-05T03:07:09.137ZS-EPMC126565304129400910.7554/eLife.105541