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

Abstract

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.

Mitochondrial origins of the pressure to sleep

“…4a). Consistent with the importance of PA for the fusion reaction 31,42 , and of mitochondrial fusion for the regulation of sleep, R23E10-GAL4 -driven interference with the expression of the mitoPLD zucchini or the outer membrane protein Mitoguardin (Miga), which stabilizes catalytically active mitoPLD 43 and/or transfers phospholipids (including PA) from other cellular membranes to mitochondria 44 , recapitulated the sleep losses seen when the protein-based fusion machinery of these neurons was targeted by RNAi or antagonized by the overexpression of Drp1 (Fig. 4b, Supplementary Fig.…”

Spartin-mediated lipid transfer facilitates lipid droplet turnover

“…In the assay, the candidate LTP is tethered between donor and acceptor liposomes, mimicking localization to sites of organellar apposition. Lipid transfer between membranes and the LTP is stochastic and rate determining in the transfer reaction (9), and tethering assures that the LTP associates with liposomes sufficiently for the transfer to occur (discussed in (3)). We tethered together donor and acceptor liposomes using a previously described linker construct (12).…”

“…The mechanisms by which lipids are transferred to or mobilized from LDs remain poorly understood but have been speculated to involve protein-mediated lipid transfer, presumably at sites of close apposition between LDs and other organelles (1, 2). Thus, the lipid transport ability of mitoguardin-2, between mitochondria and LDs, plays a role in LD biogenesis (3) ; and lipid transport proteins (LTPs) in the VPS13-family and the VPS13-like protein ATG2 localize to LDs (4, 5), although their function in LD biology is not well established. The protein spartin (SPG20) also localizes to LDs and participates in their turnover (6), and it is recently proposed as a receptor that delivers LDs to autophagosomes for degradation via macrolipophagy (7).…”

Unbiased MD simulations characterize lipid binding to lipid transfer proteins

“…S1), indicating that our protocol is unable to discriminate between lipids with different headgroups. This is also true when lipids with significantly different sterical hindrances were tested, as is the case for oleic acid in Miga2 and FABP1 (for both proteins fatty acids have been proposed to be a natural substrate) 36,37 . Finally, analysis of the polar heads placement in our simulations reveals a large variability in the binding poses between replicas (Fig.…”