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• Lapao, Ana Sofia Da Silva; Johnson, Lauren Sophie; Moncho, Laura Cristina Trachsel; Rodgers, Samuel J; Singh, Sakshi & Ng, Matthew [Show all 9 contributors for this article] (2025). The RAB27A effector SYTL5 regulates mitophagy and mitochondrial metabolism. eLIFE. 14. doi: 10.7554/elife.105541. Full text in Research Archive Show summary

  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.

• Moncho, Laura Cristina Trachsel; Veroni, Chiara; Mathai, Benan John; Lapao, Ana Sofia Da Silva; Singh, Sakshi & Asp, Nagham Theres [Show all 9 contributors for this article] (2025). SNX10 functions as a modulator of piecemeal mitophagy and mitochondrial bioenergetics. Journal of Cell Biology. ISSN 0021-9525. 224(5). doi: 10.1083/jcb.202404009. Full text in Research Archive Show summary

  We here identify the endosomal protein SNX10 as a negative regulator of piecemeal mitophagy of OXPHOS machinery components. In control conditions, SNX10 localizes to early endocytic compartments in a PtdIns3P-dependent manner and modulates endosomal trafficking but also shows dynamic connections with mitochondria. Upon hypoxia-mimicking conditions, SNX10 localizes to late endosomal structures containing selected mitochondrial proteins, including COX-IV and SAMM50, and the autophagy proteins SQSTM1/p62 and LC3B. The turnover of COX-IV was enhanced in SNX10-depleted cells, with a corresponding reduced mitochondrial respiration and citrate synthase activity. Importantly, zebrafish larvae lacking Snx10 show reduced levels of Cox-IV, as well as elevated ROS levels and ROS-mediated cell death in the brain, demonstrating the in vivo relevance of SNX10-mediated modulation of mitochondrial bioenergetics.

• Pankiv, Serhiy; Dahl, Anette Kathinka; Aas, Aleksander; Andersen, Rosa Linn; Brech, Andreas & Holland, Petter [Show all 9 contributors for this article] (2024). BEACH domain proteins function as cargo-sorting adaptors in secretory and endocytic pathways. Journal of Cell Biology. ISSN 0021-9525. 223(12). doi: 10.1083/jcb.202408173. Full text in Research Archive Show summary

  We identify BEACH domain–containing proteins (BDCPs) as novel membrane coat proteins involved in the sorting of transmembrane proteins (TMPs) on the trans-Golgi network and tubular sorting endosomes. The seven typical mammalian BDCPs share a predicted alpha-solenoid-beta propeller structure, suggesting they have a protocoatomer origin and function. We map the subcellular localization of seven BDCPs based on their dynamic colocalization with RAB and ARF small GTPases and identify five typical BDCPs on subdomains of dynamic tubular-vesicular compartments on the intersection of endocytic recycling and post-Golgi secretory pathways. We demonstrate that BDCPs interact directly with the cytosolic tails of selected TMPs and identify a subset of TMPs, whose trafficking to the plasma membrane is affected in cells lacking BDCP. We propose that the competitive binding of BDCPs and clathrin coat adaptors to the cytosolic tails of TMPs, followed by their clustering to distinct subdomains of secretory/recycling tubules function as a mechanism for sorting of TMPs in pleomorphic tubular-vesicular compartments that lack a clathrin coat.

• Huang, Chengqun; Sharma, Ankush; Thakur, Reetu; Rai, Deepika; Katiki, Madhusudhanarao & Germano, Juliana de Freitas [Show all 15 contributors for this article] (2022). Asporin, an extracellular matrix protein, is a beneficial regulator of cardiac remodeling. Matrix Biology. ISSN 0945-053X. 110, p. 40–59. doi: 10.1016/j.matbio.2022.04.005. Full text in Research Archive
• Ng, Matthew; Charsou, Chara; Lapao, Ana Sofia Da Silva; Singh, Sakshi; Moncho, Laura Cristina Trachsel & Schultz, Sebastian Wolfgang [Show all 9 contributors for this article] (2022). The cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics. Nature Communications. 13(1). doi: 10.1038/s41467-022-33933-2. Full text in Research Archive Show summary

  Abstract During autophagy, cytosolic cargo is sequestered into double-membrane vesicles called autophagosomes. The contributions of specific lipids, such as cholesterol, to the membranes that form the autophagosome, remain to be fully characterized. Here, we demonstrate that short term cholesterol depletion leads to a rapid induction of autophagy and a corresponding increase in autophagy initiation events. We further show that the ER-localized cholesterol transport protein GRAMD1C functions as a negative regulator of starvation-induced autophagy and that both its cholesterol transport VASt domain and membrane binding GRAM domain are required for GRAMD1C-mediated suppression of autophagy initiation. Similar to its yeast orthologue, GRAMD1C associates with mitochondria through its GRAM domain. Cells lacking GRAMD1C or its VASt domain show increased mitochondrial cholesterol levels and mitochondrial oxidative phosphorylation, suggesting that GRAMD1C may facilitate cholesterol transfer at ER-mitochondria contact sites. Finally, we demonstrate that expression of GRAMD family proteins is linked to clear cell renal carcinoma survival, highlighting the pathophysiological relevance of cholesterol transport proteins.

• Munson, Michael Joseph; Mathai, Benan J.; Ng, Matthew; Moncho, Laura Cristina Trachsel; Ballina, Laura R de la & Schultz, Sebastian W. [Show all 13 contributors for this article] (2021). GAK and PRKCD are positive regulators of PRKN-independent mitophagy. Nature Communications. 12(1). doi: 10.1038/s41467-021-26331-7. Full text in Research Archive Show summary

  The mechanisms involved in programmed or damage-induced removal of mitochondria by mitophagy remains elusive. Here, we have screened for regulators of PRKN-independent mitophagy using an siRNA library targeting 197 proteins containing lipid interacting domains. We identify Cyclin G-associated kinase (GAK) and Protein Kinase C Delta (PRKCD) as regulators of PRKN-independent mitophagy, with both being dispensable for PRKN- dependent mitophagy and starvation-induced autophagy. We demonstrate that the kinase activity of both GAK and PRKCD are required for efficient mitophagy in vitro, that PRKCD is present on mitochondria, and that PRKCD facilitates recruitment of ULK1/ATG13 to early autophagic structures. Importantly, we demonstrate in vivo relevance for both kinases in the regulation of basal mitophagy. Knockdown of GAK homologue (gakh-1) in C. elegans or knockout of PRKCD homologues in zebrafish led to significant inhibition of basal mitophagy, highlighting the evolutionary relevance of these kinases in mitophagy regulation.

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