The study investigates the communication between organelles, specifically the endoplasmic reticulum (ER) and mitochondria, in eukaryotic cells. The authors used a synthetic biology approach to identify components involved in these organelle junctions by screening for mutants that could be complemented by a synthetic protein designed to artificially tether the ER and mitochondria. They identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a key molecular tether between the ER and mitochondria. This complex, referred to as ERMES (ER-mitochondria encounter structure), consists of proteins resident in both organelles. Through genome-wide mapping of genetic interactions, the authors found that ERMES components are functionally connected to genes involved in phospholipid biosynthesis and calcium signaling. In mutant cells, phospholipid biosynthesis was impaired, and ERMES localized to discrete foci, suggesting that these sites facilitate interorganelle calcium and phospholipid exchange. The study also revealed that ERMES disruption impairs phospholipid exchange between the ER and mitochondria, leading to reduced cardiolipin levels and impaired mitochondrial function. These findings highlight the importance of ERMES in maintaining the integrity of ER-mitochondria connections and suggest that ERMES may serve as a platform for recruiting other molecules to carry out specific physiological roles, such as lipid transport and calcium exchange.The study investigates the communication between organelles, specifically the endoplasmic reticulum (ER) and mitochondria, in eukaryotic cells. The authors used a synthetic biology approach to identify components involved in these organelle junctions by screening for mutants that could be complemented by a synthetic protein designed to artificially tether the ER and mitochondria. They identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a key molecular tether between the ER and mitochondria. This complex, referred to as ERMES (ER-mitochondria encounter structure), consists of proteins resident in both organelles. Through genome-wide mapping of genetic interactions, the authors found that ERMES components are functionally connected to genes involved in phospholipid biosynthesis and calcium signaling. In mutant cells, phospholipid biosynthesis was impaired, and ERMES localized to discrete foci, suggesting that these sites facilitate interorganelle calcium and phospholipid exchange. The study also revealed that ERMES disruption impairs phospholipid exchange between the ER and mitochondria, leading to reduced cardiolipin levels and impaired mitochondrial function. These findings highlight the importance of ERMES in maintaining the integrity of ER-mitochondria connections and suggest that ERMES may serve as a platform for recruiting other molecules to carry out specific physiological roles, such as lipid transport and calcium exchange.