A synthetic biology screen identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between the endoplasmic reticulum (ER) and mitochondria. This complex, composed of proteins resident in both organelles, was shown to be functionally connected to phospholipid biosynthesis and calcium signaling. Mutant cells with impaired tethering exhibited defects in phospholipid biosynthesis, suggesting that discrete ER-mitochondria contacts facilitate interorganelle exchange of calcium and phospholipids. The study used a synthetic protein, ChiMERA, to artificially tether ER and mitochondria, which rescued growth defects in mutants lacking components of the tethering complex. ChiMERA localized to ER membranes and mitochondria, forming discrete foci that suggested sites of close apposition between the two organelles. A second version of ChiMERA, ChiMERA-ra, localized to discrete foci and colocalized with both ER and mitochondria, but did not distort mitochondrial shape. Genetic interaction analysis confirmed that ERMES components are functionally related. ERMES was shown to be necessary for efficient interorganelle phospholipid exchange, and its disruption impaired phospholipid exchange between ER and mitochondria. This defect was partially reversed by ChiMERA expression in some mutants. ERMES mutants also exhibited reduced cardiolipin (CL) levels, a mitochondrial-specific phospholipid essential for respiration. Deletion of any ERMES component was synthetically lethal with deletion of CRD1, which encodes CL synthase. The study also identified GEM1 and PSD1 as genes strongly correlated with ERMES components. PSD1 is the only aminoglycerophospholipid biosynthetic enzyme in mitochondria, and its deletion led to reduced CL levels. ERMES mutants showed impaired CL synthesis, consistent with the role of ERMES in mediating ER-mitochondria junctions. The results suggest that ERMES functions as a molecular zipper connecting ER and mitochondria, facilitating interorganelle communication. The complex is composed of ER-resident Mmm1 and OMM-resident Mdm10, with Mdm12 and Mdm34 promoting their association. ERMES is essential for maintaining mitochondrial structure and function, and its disruption leads to defects in phospholipid biosynthesis and mitochondrial membrane maintenance. The study highlights the importance of ER-mitochondria contacts in cellular function and provides insights into the molecular mechanisms underlying interorganelle communication.A synthetic biology screen identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between the endoplasmic reticulum (ER) and mitochondria. This complex, composed of proteins resident in both organelles, was shown to be functionally connected to phospholipid biosynthesis and calcium signaling. Mutant cells with impaired tethering exhibited defects in phospholipid biosynthesis, suggesting that discrete ER-mitochondria contacts facilitate interorganelle exchange of calcium and phospholipids. The study used a synthetic protein, ChiMERA, to artificially tether ER and mitochondria, which rescued growth defects in mutants lacking components of the tethering complex. ChiMERA localized to ER membranes and mitochondria, forming discrete foci that suggested sites of close apposition between the two organelles. A second version of ChiMERA, ChiMERA-ra, localized to discrete foci and colocalized with both ER and mitochondria, but did not distort mitochondrial shape. Genetic interaction analysis confirmed that ERMES components are functionally related. ERMES was shown to be necessary for efficient interorganelle phospholipid exchange, and its disruption impaired phospholipid exchange between ER and mitochondria. This defect was partially reversed by ChiMERA expression in some mutants. ERMES mutants also exhibited reduced cardiolipin (CL) levels, a mitochondrial-specific phospholipid essential for respiration. Deletion of any ERMES component was synthetically lethal with deletion of CRD1, which encodes CL synthase. The study also identified GEM1 and PSD1 as genes strongly correlated with ERMES components. PSD1 is the only aminoglycerophospholipid biosynthetic enzyme in mitochondria, and its deletion led to reduced CL levels. ERMES mutants showed impaired CL synthesis, consistent with the role of ERMES in mediating ER-mitochondria junctions. The results suggest that ERMES functions as a molecular zipper connecting ER and mitochondria, facilitating interorganelle communication. The complex is composed of ER-resident Mmm1 and OMM-resident Mdm10, with Mdm12 and Mdm34 promoting their association. ERMES is essential for maintaining mitochondrial structure and function, and its disruption leads to defects in phospholipid biosynthesis and mitochondrial membrane maintenance. The study highlights the importance of ER-mitochondria contacts in cellular function and provides insights into the molecular mechanisms underlying interorganelle communication.