Mitoguardin-2-mediated lipid transfer preserves mitochondrial morphology and lipid droplet formation

Mitochondrial protein mitoguardin-2, at contacts with the ER or with lipid droplets (LDs), binds fatty acids and phospholipids, and non-specifically transfers phospholipids between membranes in vitro. Its lipid transfer ability is required for roles in mitochondrial and LD biology. Lipid transport proteins at membrane contacts, where organelles are closely apposed, are critical in redistributing lipids from the endoplasmic reticulum (ER), where they are made, to other cellular membranes. Such protein-mediated transfer is especially important for maintaining organelles disconnected from secretory pathways, like mitochondria. We identify mitoguardin-2, a mitochondrial protein at contacts with the ER and/or lipid droplets (LDs), as a lipid transporter. An x-ray structure shows that the C-terminal domain of mitoguardin-2 has a hydrophobic cavity that binds lipids. Mass spectrometry analysis reveals that both glycerophospholipids and free-fatty acids co-purify with mitoguardin-2 from cells, and that each mitoguardin-2 can accommodate up to two lipids. Mitoguardin-2 transfers glycerophospholipids between membranes in vitro, and this transport ability is required for roles both in mitochondrial and LD biology. While it is not established that protein-mediated transfer at contacts plays a role in LD metabolism, our findings raise the possibility that mitoguardin-2 functions in transporting fatty acids and glycerophospholipids at mitochondria-LD contacts.

Automated summary

Mitoguardin-2 is a mitochondrial protein that binds fatty acids and phospholipids at contacts with the ER or lipid droplets, and can transfer phospholipids between membranes. It plays crucial roles in mitochondrial and lipid droplet biology.