New Players of the Mitochondria-ER Crosstalk

The Outer Mitochondrial Membrane (OMM) and Endoplasmic Reticulum are physically connected
at the Mitochondria-ER contact sites (MERCs). The two organelles are kept together by
proteinaceous bridges, whose nature is still largely unknown. In the last years, we established a
FRET based assay to monitor mitochondria-ER interaction (FEMP, Naon et al, 2016) and we scaled
up this approach to perform a genome wide short hairpin RNA (shRNA) screen coupled to high
content microscopy. Automated image and statistical analysis revealed gene candidates able to
change the proximity between the two organelles: we classified our hits as tethers if their
downregulation increased ER-mitochondria distance and as spacers if their ablation decreased ERmitochondria
proximity.
Pathway enrichment analysis revealed that these hits are mainly involved in lipid metabolism, cell
death and inflammatory responses. Interestingly, 4 proteins have already been retrieved at both the
ER and OMM, which makes them ideal candidates for the generation/modulation of mitochondria-
ER tethering complexes.
Overall, our screen provides an overview of the molecular anatomy of MERCs and unveils novel
functions for some disease-linked genes.