An ER-Mitochondria Tethering Complex Revealed by a Synthetic Biology Screen

TLDR

Communication between organelles is a key feature of eukaryotic cells. The study screened for mutants that could be complemented by a synthetic tether designed to link mitochondria and the ER, aiming to uncover junction components. A genome‑wide genetic interaction map linked the tethering complex to phospholipid biosynthesis and calcium‑signaling pathways. The Mmm1/Mdm10/Mdm12/Mdm34 complex, composed of ER and mitochondrial proteins, forms discrete foci that tether the two organelles and is essential for phospholipid biosynthesis and calcium exchange.

Abstract

Communication between organelles is an important feature of all eukaryotic cells. To uncover components involved in mitochondria/endoplasmic reticulum (ER) junctions, we screened for mutants that could be complemented by a synthetic protein designed to artificially tether the two organelles. We identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between ER and mitochondria. The tethering complex was composed of proteins resident of both ER and mitochondria. With the use of genome-wide mapping of genetic interactions, we showed that the components of the tethering complex were functionally connected to phospholipid biosynthesis and calcium-signaling genes. In mutant cells, phospholipid biosynthesis was impaired. The tethering complex localized to discrete foci, suggesting that discrete sites of close apposition between ER and mitochondria facilitate interorganelle calcium and phospholipid exchange.