A1 Refereed original research article in a scientific journal
The RAB27A effector SYTL5 regulates mitophagy and mitochondrial metabolism
Authors: Lapão, Ana; Johnson, Lauren Sophie; Trachsel-Moncho, Laura; Rodgers, Samuel J; Singh, Sakshi; Ng, Matthew YW; Nakken, Sigve; Eskelinen, Eeva-Liisa; Simonsen, Anne
Publisher: eLife Sciences Publications, Ltd
Publication year: 2025
Journal: eLife
Article number: RP105541
Volume: 14
ISSN: 2050-084X
eISSN: 2050-084X
DOI: https://doi.org/10.7554/eLife.105541
Publication's open availability at the time of reporting: Open Access
Publication channel's open availability : Open Access publication channel
Web address : https://doi.org/10.7554/elife.105541
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/505621462
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 under hypoxia mimicking conditions, indicating a role for these proteins in mitophagy. Indeed, we find that SYTL5 interacts with proteins involved in vesicle-mediated transport and cellular response to stress and that its depletion compromises mitochondrial respiration and increases glucose uptake. Intriguingly, SYTL5 expression is significantly reduced in tumours of the adrenal gland and correlates positively with survival for patients with adrenocortical carcinoma.
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Funding information in the publication:
Kreftforeningen (190251)
Laura Trachsel-Moncho
Samuel J Rodgers
Anne Simonsen
Norges Forskningsråd (262652)
Sigve Nakken
Anne Simonsen
Norges Forskningsråd (249753)
Lauren Sophie Johnson
Matthew YW Ng
Anne Simonsen
HORIZON EUROPE Marie Sklodowska-Curie Actions
https://doi.org/10.3030/765912
Ana Lapão
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
