Abstract
The endoplasmic reticulum (ER)-mitochondria encounter structure (ERMES) is a protein complex that physically tethers the two organelles to each other and creates the physical basis for communication between them. ERMES functions in lipid exchange between the ER and mitochondria, protein import into mitochondria, and maintenance of mitochondrial morphology and genome. Here, we report that ERMES is also required for iron homeostasis. Loss of ERMES components activates an Aft1-dependent iron deficiency response even in iron-replete conditions, leading to accumulation of excess iron inside the cell. This function is independent of known ERMES roles in calcium regulation, phospholipid biosynthesis, or effects on mitochondrial morphology. A mutation in the vacuolar protein sorting 13 (VPS13) gene that rescues the glycolytic phenotype of ERMES mutants suppresses the iron deficiency response and iron accumulation. Our findings reveal that proper communication between the ER and mitochondria is required for appropriate maintenance of cellular iron levels.
Highlights
The endoplasmic reticulum (ER)–mitochondria encounter structure (ERMES) is a protein complex that physically tethers the two organelles to each other and creates the physical basis for communication between them
The iron regulon genes are up-regulated in mmm1⌬ and mdm34⌬ strains compared with WT, which is similar to when WT cells are grown in iron-poor medium through treatment of cells with bathophenanthroline disulfonate (BPS), a strong iron chelator (Fig. 1B)
Analysis of all the iron homeostasis genes annotated in the Saccharomyces Genome Database (n ϭ 28 genes) revealed that the median expression level of iron homeostasis genes is significantly higher in mmm1⌬ and mdm34⌬ strains as well as in BPS-treated WT cell compared with WT cells grown in rich medium (Fig. 1, C and D)
Summary
The endoplasmic reticulum (ER)–mitochondria encounter structure (ERMES) is a protein complex that physically tethers the two organelles to each other and creates the physical basis for communication between them. Loss of ERMES components activates an Aft1-dependent iron deficiency response even in iron-replete conditions, leading to accumulation of excess iron inside the cell. This function is independent of known ERMES roles in calcium regulation, phospholipid biosynthesis, or effects on mitochondrial morphology. A mutation in the vacuolar protein sorting 13 (VPS13) gene that rescues the glycolytic phenotype of ERMES mutants suppresses the iron deficiency response and iron accumulation. Deletions of ERMES subunits cause slow growth, respiratory deficiency, and abnormal mitochondrial morphology (6 –9) These phenotypes can be suppressed by overexpression of vacuole and mitochondria patch (vCLAMP) components [5]; dominant mutations in vacuolar protein sorting 13 (Vps13p). Our findings indicate that ER–mitochondrial junctions are required for proper iron usage by the cell, expanding the functional repertoire of this important protein complex
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