Endoplasmic reticulum–mitochondria junction is required for iron homeostasis

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 () 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.

Yeast and other lower eukaryotic organisms for studies of Vps13 proteins in health and disease

“…68,73 Also, dominant mutations in VPS13 suppress known ERMES complex-deficient phenotypes, probably by increasing the formation or function of vCLAMPs. 73,75 This role in MCS is in agreement with the current reports that purified Vps13 exhibits ATP-stimulated binding to yeast membranes 54 and interacts with various membrane lipids, as described above. Moreover, association of Vps13 with lipids is important for its localization, as microscopy studies showed that Vps13-GFP is abnormally accumulated in large perivacuolar membrane compartments of endocytic origin 57 and I2749R (see Table 2 for a list of human missense mutations investigated in yeast).…”

“…Deletion of VPS13 is synthetically lethal in combination with mutations of MMM1 , encoding an integral ER membrane protein that is a subunit of the ER mitochondria encounter structure (ERMES) complex, tethering the ER and mitochondria . Also, dominant mutations in VPS13 suppress known ERMES complex‐deficient phenotypes, probably by increasing the formation or function of vCLAMPs . This role in MCS is in agreement with the current reports that purified Vps13 exhibits ATP‐stimulated binding to yeast membranes and interacts with various membrane lipids, as described above.…”

MCHM acts as a hydrotrope, altering the balance of metals in yeast

“…This includes higher levels of iron from increased expression of iron transporters and lower endogenous zinc levels. These petite yeast were induced by loss of the mitochondrial genome and petite yeast caused by other types of mutations also had differences in internal metals and regulation in the iron regulome (39). There is an interplay between metal levels, as zinc transporters are also important for responding to high levels of copper (24).…”

The heme biosynthetic enzyme, 5-aminolevulinic acid synthase (ALAS), and GTPases in control of mitochondrial dynamics and ER contact sites, regulate heme mobilization to the nucleus

“…An alternative, but far less studied potential mechanism for heme distribution is through mitochondrial membrane contact sites (Hanna et al, 2017; Piel et al, 2019; Reddi and Hamza, 2016). Endoplasmic reticulum (ER)-mitochondrial encounter structures (ERMES), one type of mitochondrial-ER contact site (Elbaz-Alon et al, 2014), are highly dynamic tethers that physically link the mitochondrial and ER networks and have been proposed to play a role in the transfer of lipids and regulate iron homeostasis (Lackner, 2019; Murley and Nunnari, 2016a; Xue et al, 2017). The frequency of ERMES is in part dependent on mitochondrial division (Elbaz-Alon et al, 2014).…”