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VPS13D bridges the ER to mitochondria and peroxisomes via Miro.

ABSTRACT: Mitochondria, which are excluded from the secretory pathway, depend on lipid transport proteins for their lipid supply from the ER, where most lipids are synthesized. In yeast, the outer mitochondrial membrane GTPase Gem1 is an accessory factor of ERMES, an ER-mitochondria tethering complex that contains lipid transport domains and that functions, partially redundantly with Vps13, in lipid transfer between the two organelles. In metazoa, where VPS13, but not ERMES, is present, the Gem1 orthologue Miro was linked to mitochondrial dynamics but not to lipid transport. Here we show that Miro, including its peroxisome-enriched splice variant, recruits the lipid transport protein VPS13D, which in turn binds the ER in a VAP-dependent way and thus could provide a lipid conduit between the ER and mitochondria. These findings reveal a so far missing link between function(s) of Gem1/Miro in yeast and higher eukaryotes, where Miro is a Parkin substrate, with potential implications for Parkinson's disease pathogenesis.

SUBMITTER: Guillen-Samander A

PROVIDER: S-EPMC8077184 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Glucocorticoid, a major risk factor of Alzheimer's disease (AD), is widely known to promote microtubule dysfunction recognized as the early pathological feature that culminates in memory deficits. However, the exact glucocorticoid receptor (GR)-mediated mechanism of how glucocorticoid triggers microtubule destabilization and following intracellular transport deficits remains elusive. Therefore, we investigated the effect of glucocorticoid on microtubule instability and cognitive impairment using male ICR mice and human neuroblastoma SH-SY5Y cells. The mice group that was exposed to corticosteroid, the major glucocorticoid form of rodents, showed reduced trafficking of ?-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) 1/2 and mitochondria, which are necessary for memory establishment, into the synapse due to microtubule destabilization. In SH-SY5Y cells, cortisol, the major glucocorticoid form of humans, also decreased microtubule stability represented by reduced acetylated ?-tubulin to tyrosinated ?-tubulin ratio (A/T ratio), depending on the mitochondria GR-mediated pathway. Cortisol translocated the Hsp70-bound GR into mitochondria which thereafter promoted GR-Bcl-2 interaction. Increased ER-mitochondria connectivity via GR-Bcl-2 coupling led to mitochondrial Ca2+ influx, which triggered mTOR activation. Subsequent autophagy inhibition by mTOR phosphorylation increased SCG10 protein levels via reducing ubiquitination of SCG10, eventually inducing microtubule destabilization. Thus, failure of trafficking AMPAR1/2 and mitochondria into the cell terminus occurred by kinesin-1 detachment from microtubules, which is responsible for transporting organelles towards periphery. However, the mice exposed to pretreatment of microtubule stabilizer paclitaxel showed the restored translocation of AMPAR1/2 or mitochondria into synapses and improved memory function compared to corticosterone-treated mice. In conclusion, glucocorticoid enhances ER-mitochondria coupling which evokes elevated SCG10 and microtubule destabilization dependent on mitochondrial GR. This eventually leads to memory impairment through failure of AMPAR1/2 or mitochondria transport into cell periphery.

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VPS13D bridges the ER to mitochondria and peroxisomes via Miro.

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