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Organelles are separate yet interdependent units of eukaryotic cells. They provide an appropriate milieu for the catalysis of many biochemical reactions, and they must establish physical links to communicate and exchange metabolites throughout the cell. Interorganelle communication is an important, yet still poorly understood, aspect of cell biology. We recently identified a protein complex that we refer to as ERMES [endoplasmic reticulum (ER)-mitochondria encounter structure], the main function of which is to provide a tethering force between the ER and the mitochondria. This complex, composed of both ER and mitochondrial transmembrane proteins, is located at the interface of the two organelles and serves to zipper them together. Previous work had implicated several ERMES components in many different physiological processes. The identification of ERMES as an interorganelle tether allows us to re-examine the amply documented phenotypic consequences of the loss of this complex in the light of this new function, thus providing a unique opportunity to assess the physiological relevance of ER-mitochondria junctions. These phenotypes hint at a broad role for ER-mitochondria connections in regulating mitochondrial and cell physiology. In this Hypothesis, we speculate on the potential role of ER-mitochondria connections as hubs in regulating several aspects of mitochondrial biology, including the regulation of mitochondrial membrane biosynthesis, genome replication, Ca(2+) signaling and protein import. Finally, we discuss how cells might use ER-mitochondria communication to fine-tune these processes according to their metabolic needs.

ERMES-mediated ER-mitochondria contacts: molecular hubs for the regulation of mitochondrial biology