Arun John Peter

Lipids are the main building blocks of membrane-bound compartments called organelles, which underlie the function of cells in every organism. For lipids to execute their function in building and expanding organelle membranes, they need to be transported from their site of synthesis to their respective destination. Despite the fundamental importance of this process, we understand very little about how lipids are trafficked between organelles. Unlike the polymerase chain reaction (PCR) for DNA and green fluorescent protein (GFP) tagging for proteins, which accelerated our understanding of these key biomolecules, lipid biology has lagged behind due to the dearth of similar tools.

To address this challenge, we developed a novel method called METALIC (Mass tagging Enabled TrAcking of Lipids In Cells) to monitor lipid trafficking between organelles inside living cells. In this approach, distinct mass tagging agents are targeted to two chosen organelles of interest. Lipids that are mass-tagged in the first organelle receive another mass tag upon transport to the second one. By measuring doubly mass-tagged lipids with a mass spectrometer, we can track lipid transport between organelles.

The development of METALIC marks a significant advance in lipid cell biology. This tool builds a new framework to map the pipelines of lipid transport and understand how they impact organelle physiology. We can now investigate how the interorganelle lipid distribution network is re-purposed to aid the rapid proliferation of cancer cells, or to decipher how defects in it contribute to organelle dysfunction in neurodegenerative diseases.

1. Mapping the pipelines of lipid transport: Lipid synthesis in eukaryotic cells is mostly confined to the endoplasmic reticulum (ER), making interorganelle lipid transport an essential process.  How cells orchestrate and coordinate lipid transport from the ER to other organelles is an exciting question in lipid cell biology. Recent studies have implicated lipid transfer proteins (LTPs) which act at sites of close contact (10-30 nm) between organelles in lipid transport. Importantly, mutations in LTPs have been associated with distinct neurodegenerative disorders in humans. Our aim is to understand the molecular principles underlying lipid distribution between ER and other organelles by studying the activity, substrate specificity and regulation of specific LTPs in different physiological contexts.
2. Probing lipid function in organelle physiology: Organelle function is thought to be tightly coupled to its distinct lipid composition. Given the remarkable chemical and structural diversity of lipids, the functional significance of the different lipid species in organelle physiology remains unclear. Our goal here is to develop synthetic biology-based tools to alter the composition of specific lipid classes in an organelle-specific manner and investigate the consequences on its architecture and function.