Porin 1 Modulates Autophagy in Yeast

Abstract

Autophagy is a cellular recycling program which efficiently reduces the cellular burden of ageing. Autophagy is characterised by nucleation of isolation membranes, which grow in size and further expand to form autophagosomes, engulfing cellular material to be degraded by fusion with lysosomes (vacuole in yeast). Autophagosomal membranes do not bud from a single cell organelle, but are generated de novo. Several lipid sources for autophagosomal membranes have been identified, but the whole process of their generation is complex and not entirely understood. In this study, we investigated how the mitochondrial outer membrane protein porin 1 (Por1), the yeast orthologue of mammalian voltage-dependent anion channel (VDAC), affects autophagy in yeast. We show that POR1 deficiency reduces the autophagic capacity and leads to changes in vacuole and lipid homeostasis. We further investigated whether limited phosphatidylethanolamine (PE) availability in por1∆ was causative for reduced autophagy by overexpression of the PE-generating phosphatidylserine decarboxylase 1 (Psd1). Altogether, our results show that POR1 deficiency is associated with reduced autophagy, which can be circumvented by additional PSD1 overexpression. This suggests a role for Por1 in Psd1-mediated autophagy regulation.

Loss of actin dynamics leads to VDAC dependent MAPK signalling and altered lipid homeostasis that promotes cell death in yeast cells

“…Loss of CL has also been shown to impair CWI signalling which led to defective mitophagy 36 . We also detected changes in the lipid profile of POR1deleted cells as such, which is in line with recently published findings 24,37,38 . This raises the possibility that actin triggers changes in lipid homeostasis through transcription factors with porin acting as a central point of flux control.…”

Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase

“…Purified Mcp1 was recently shown to have scramblase activity 66 and it remains to be seen whether this is also the case for Mdm10. In agreement with this concept, previous studies placed VDAC at ER-mitochondria contact sites and at hubs of lipid synthesis and distribution 3 , 54 , 55 . Thus, in yeast, the VDAC homolog Por1 is thought to interact with the ERMES complex, the Ups-Mdm35 lipid transfer complex as well as Mdm31/32, the latter two being important for phospholipid transport across the IMS 3 , 54 , 55 .…”

“…In agreement with this concept, previous studies placed VDAC at ER-mitochondria contact sites and at hubs of lipid synthesis and distribution 3 , 54 , 55 . Thus, in yeast, the VDAC homolog Por1 is thought to interact with the ERMES complex, the Ups-Mdm35 lipid transfer complex as well as Mdm31/32, the latter two being important for phospholipid transport across the IMS 3 , 54 , 55 . In this scenario, VDAC constitutes a nexus between the phospholipid transport machineries on both sides of the OMM, scrambling phospholipids to enable their entry(exit) into(from) these machineries.…”

Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase

“…Purified Mcp1 was recently shown to have scramblase activity and it remains to be seen whether this is also the case for Mdm10. In agreement with this concept, previous studies placed VDAC at ER-mitochondria contact sites and at hubs of lipid synthesis and distribution (Broeskamp et al , 2021; Miyata et al , 2018; Tamura et al ., 2020). Thus, in yeast, the VDAC homolog Por1 is thought to interact with the ERMES complex, the Ups-Mdm35 lipid transfer complex as well as Mdm31/32, the latter two being important for phospholipid transport across the IMS (Broeskamp et al ., 2021; Miyata et al ., 2018; Tamura et al ., 2020).…”

“…In agreement with this concept, previous studies placed VDAC at ER-mitochondria contact sites and at hubs of lipid synthesis and distribution (Broeskamp et al , 2021; Miyata et al , 2018; Tamura et al ., 2020). Thus, in yeast, the VDAC homolog Por1 is thought to interact with the ERMES complex, the Ups-Mdm35 lipid transfer complex as well as Mdm31/32, the latter two being important for phospholipid transport across the IMS (Broeskamp et al ., 2021; Miyata et al ., 2018; Tamura et al ., 2020). In this scenario, VDAC constitutes a nexus between the phospholipid transport machineries on both side of the OMM, scrambling phospholipids to enable their entry(exit) into(from) these machineries.…”