Introduction

Phospholipids are the primary lipids that make up biological membranes and play essential roles in the construction and function of cellular and organelle membranes. Each phospholipid consists of a hydrophilic head and hydrophobic tails, and variations in their chemical structures result in a wide diversity of phospholipid species.

Among these, phosphoinositides are a representative class of phospholipids characterized by an inositol ring as their hydrophilic head group. There are eight major phosphoinositide species, defined by phosphorylation at the 3-, 4-, and 5-positions of the inositol ring (Figure 2a, b). These phosphoinositides are distributed throughout different intracellular compartments through precise spatial and temporal regulation by metabolic enzymes and transport proteins (Figure 2c). This asymmetric distribution imparts unique characteristics to each membrane, enabling the regulation of diverse cellular events such as signal transduction, membrane dynamics, cytoskeletal organization, and lipid transport.

Research Overview

Despite the tremendous diversity of lipids within biological membranes, the fundamental principles governing their spatial organization and contribution to membrane function—the “code of biological membranes”—remain largely unexplored. Our laboratory aims to address this challenge by focusing on lipid metabolism and lipid transport.

1. Mechanisms of Spatiotemporal Regulation of Membrane Lipids

Regulation by Metabolism 

Enzymes responsible for lipid synthesis and degradation are tightly controlled in both their activity and localization. This ensures the appropriate distribution and quantity of lipids in the cell. However, the detailed mechanisms behind this regulation remain poorly understood. We focus on phosphoinositides, a functionally important group of lipids, to uncover how their metabolic regulation occurs at specific subcellular locations.

Regulation by Transport 

Regions where cellular and organelle membranes are closely apposed, known as membrane contact sites (MCSs), have emerged as critical hubs for lipid transport. Recent research indicates that various lipid transport protein families mediate inter-organelle lipid exchange via these contact sites. Furthermore, our studies suggest that lipid transport across MCSs plays a pivotal role in temporally and spatially regulating lipid metabolic pathways. By investigating these transport proteins, the specific lipid species they shuttle, and their associated metabolic and regulatory pathways, we aim to unveil a new membrane regulation mechanism mediated by inter-organelle lipid transport systems.

Understanding Disease Mechanisms and Drug Discovery Related to Membrane Lipid Dysregulation

Lipid transport systems at membrane contact sites are increasingly recognized as key regulators of physiological processes such as signal response, neuronal development, and pathogen life cycles. Dysfunction of these systems is associated with a range of diseases and infections. We seek to elucidate these mechanisms at the molecular, cellular, and organismal levels to better understand how lipid transport between organelles affects physiological functions and contributes to disease pathogenesis. Our ultimate goal is to leverage this knowledge for therapeutic development.

Development of Analytical Tools for Lipid Dynamics

Lipids are not directly encoded by genes and are inherently difficult to manipulate, which has delayed the development of research tools in this field. In particular, imaging tools capable of visualizing and quantifying the intracellular localization and dynamics of lipids are crucial for understanding lipid function but remain underdeveloped. We are working to create such tools, enabling the real-time, high-resolution analysis of lipid behavior in living cells. These tools will also contribute to identifying and understanding the lipid-related abnormalities involved in various diseases.