Mitochondrial phospholipid transport: Role of contact sites and lipid transport proteins.

One of the major constituents of mitochondrial membranes is the phospholipids, which play a key role in maintaining the structure and the functions of the mitochondria. However, mitochondria do not synthesize most of the phospholipids in situ, necessitating the presence of phospholipid import pathways. Even for the phospholipids, which are synthesized within the inner mitochondrial membrane (IMM), the phospholipid precursors must be imported from outside the mitochondria. Therefore, the mitochondria heavily rely on the phospholipid transport pathways for its proper functioning. Since, mitochondria are not part of a vesicular trafficking network, the molecular mechanisms of how mitochondria receive its phospholipids remain a relevant question. One of the major ways that hydrophobic phospholipids can cross the aqueous barrier of inter or intraorganellar spaces is by apposing membranes, thereby decreasing the distance of transport, or by being sequestered by lipid transport proteins (LTPs). Therefore, with the discovery of LTPs and membrane contact sites (MCSs), we are beginning to understand the molecular mechanisms of phospholipid transport pathways in the mitochondria. In this review, we will present a brief overview of the recent findings on the molecular architecture and the importance of the MCSs, both the intraorganellar and interorganellar contact sites, in facilitating the mitochondrial phospholipid transport. In addition, we will also discuss the role of LTPs for trafficking phospholipids through the intermembrane space (IMS) of the mitochondria. Mechanistic insights into different phospholipid transport pathways of mitochondria could be exploited to vary the composition of membrane phospholipids and gain a better understanding of their precise role in membrane homeostasis and mitochondrial bioenergetics.

PHLPP1 promotes neutral lipid accumulation through AMPK/ChREBP-dependent lipid uptake and fatty acid synthesis pathways.

Infiltration of arterial intima by foamy macrophages is a hallmark of early atherosclerotic lesions. Here, we investigated the potential role of Ser/Thr phosphatase PHLPP1 in foam cell development. PHLPP1 levels were elevated in OxLDL-exposed macrophages and high-fat diet (HFD)-fed zebrafish larvae. Using overexpression and knockdown approaches, we show that PHLPP1 promotes the accumulation of neutral lipids, and augments cellular total cholesterol and free fatty acid (FFA) levels. RNA-Seq analysis uncovered PHLPP1 role in lipid metabolism pathways. PHLPP1 interacted with and modestly increased ChREBP recruitment to Fasn promoter. PHLPP1-mediated lipid accumulation was attenuated by AMPK activation. Pharmacological inhibition or CRISPR/Cas9-mediated disruption of PHLPP1 resulted in lower lipid accumulation in the intersegmental vessels of HFD-fed zebrafish larvae along with a reduction in total cholesterol and triglyceride levels. Deficiency of phlp-2, C. elegans PHLPP1/2 ortholog, abolished lipid accumulation in high cholesterol-fed worms. We conclude that PHLPP1 exerts a significant effect on lipid buildup.