Lipid Droplet-Mitochondria Contacts in Health and Disease

Abstract

The orchestration of cellular metabolism and redox balance is a complex, multifaceted process crucial for maintaining cellular homeostasis. Lipid droplets (LDs), once considered inert storage depots for neutral lipids, are now recognized as dynamic organelles critical in lipid metabolism and energy regulation. Mitochondria, the powerhouses of the cell, play a central role in energy production, metabolic pathways, and redox signaling. The physical and functional contacts between LDs and mitochondria facilitate a direct transfer of lipids, primarily fatty acids, which are crucial for mitochondrial β-oxidation, thus influencing energy homeostasis and cellular health. This review highlights recent advances in understanding the mechanisms governing LD-mitochondria interactions and their regulation, drawing attention to proteins and pathways that mediate these contacts. We discuss the physiological relevance of these interactions, emphasizing their role in maintaining energy and redox balance within cells, and how these processes are critical in response to metabolic demands and stress conditions. Furthermore, we explore the pathological implications of dysregulated LD-mitochondria interactions, particularly in the context of metabolic diseases such as obesity, diabetes, and non-alcoholic fatty liver disease, and their potential links to cardiovascular and neurodegenerative diseases. Conclusively, this review provides a comprehensive overview of the current understanding of LD-mitochondria interactions, underscoring their significance in cellular metabolism and suggesting future research directions that could unveil novel therapeutic targets for metabolic and degenerative diseases.

Keywords: disease; lipid droplet; metabolism; mitochondria; redox.

Figure 1

Composition and metabolic process of lipid droplets: LDs are unique cellular organelles composed of a monolayer of phospholipids surrounding a core of neutral lipids (triglycerides, cholesterol, sterols). They originate from the endoplasmic reticulum, initially accumulating as lens-like structures in the ER membrane and ultimately released into the cytoplasm via budding. Free LDs grow through fusion or autonomous growth, leading to the formation of mature LDs. The surface of LDs contains lipolytic enzymes, activated during starvation, which hydrolyze neutral lipids into fatty acids. Additionally, LDs can be targeted and broken down by autophagolysosomes, releasing fatty acids that undergo beta-oxidation in mitochondria to provide energy. TAG: Triacylglycerol; DAG: Diacylglycerol; MAG: Monoacylglycerol; ATGL: Adipose triglyceride lipase; HSL: Hormone-sensitive lipase; MGL: Monoacylglycerol lipase.

Figure 2

Mechanisms of Mitochondria–LD Interaction. (1) PLIN5 and FATP4 interaction: The C-terminal structural domain of PLIN5 interacts with FATP4, enhancing the connections between LDs and mitochondria. Starvation triggers the phosphorylation of PLIN5, leading to lipolysis and the release of fatty acids from LDs into mitochondria. These fatty acids are then converted to fatty acyl-CoAs for oxidation. (2) ARFRP1 and SNAP23 recruitment: ARFRP1 recruits SNAP23 to a site near the LD, promoting LD–mitochondria interactions and facilitating LD amplification. (3) MIGA2 linkage: The mitochondrial outer membrane protein MIGA2 links mitochondria to LD proteins, enabling efficient lipid storage within the LD. (4) Mfn2 and Hsc70/PLIN1 complex formation: Mitochondria-localized Mfn2 and LD-localized Hsc70 or PLIN1 form a complex at the mitochondria–LD membrane contact site. This complex tethers mitochondria to the LD, facilitating the transfer of fatty acids from LDs to mitochondria for β-oxidation.

Figure 3

Role of LD–Mitochondria Interaction in Diverse Diseases. (1) Type 2 diabetes: Excessive storage of lipid droplets (LDs) in skeletal muscle is a hallmark of type 2 diabetes. High-intensity interval training (HIIT) exercise alters the size, subcellular distribution, and mitochondrial content of LDs, improving the deficiency of intramuscular LDs. (2) Viral replication: The ORF6 protein inserts into the LD lipid monolayer through its two amphipathic helices. It interacts with endoplasmic reticulum (ER) membrane proteins BAP31 and USE1 to mediate the formation of ER–LD contacts. Additionally, ORF6 connects mitochondria to LDs by interacting with the SAM complex in the mitochondrial outer membrane, promoting cellular lipolysis and LD biogenesis, reprogramming lipid fluxes, and facilitating viral replication. (3) Astrocyte reactivity: When fatty acid load exceeds the oxidative phosphorylation (OxPhos) capacity of astrocytes, elevated acetyl-CoA levels induce astrocyte reactivity by enhancing STAT3 acetylation and activation. (4) Fatty acid utilization in skeletal muscle: In rat skeletal muscle cells, the energy sensor AMPK increases the GTP-binding activity of Rab8a, facilitating LD–mitochondria interactions by binding to PLIN5 under starvation conditions. The assembly of the Rab8a-PLIN5 tethering complex recruits ATGL, mobilizing and transferring long-chain fatty acids (LCFAs) from LDs to mitochondria for β-oxidation. Rab8a deficiency in a mouse model impairs fatty acid utilization and reduces exercise endurance. The arrows mean decrease or increase.