A Perspective on the Link between Mitochondria-Associated Membranes (MAMs) and Lipid Droplets Metabolism in Neurodegenerative Diseases

SIMPLE SUMMARY: Neurodegenerative diseases affect millions of people worldwide, and their prevalence rises dramatically with age. Although a few therapeutic options help to relieve symptoms associated with these disorders, slowing their progression is not presently possible and no cure exists. Therefore, the scientific community continues to improve our understanding regarding alterations in cellular function and develop new approaches for prevention and treatment. In recent years, the endoplasmic reticulum–mitochondria interaction, called mitochondria-associated membranes, has gained special attention in neurodegenerative diseases since this region is involved in regulation of several cellular processes, including lipid synthesis and transport, and is affected by defective communication between both organelles. Here, we provide an overview of the structure and function of mitochondria-associated membranes and how these structures are involved in metabolism of lipids, especially in biogenesis and degradation of lipid droplets in neurodegenerative disorders. These lipid storage organelles prevent lipotoxicity and maintain energy homeostasis, and changes in their metabolism can accelerate cellular stress, contributing to development of neurodegenerative diseases. This review supports the growing research interest in lipid (dys)metabolism as a key player in neurodegeneration. ABSTRACT: Mitochondria interact with the endoplasmic reticulum (ER) through contacts called mitochondria-associated membranes (MAMs), which control several processes, such as the ER stress response, mitochondrial and ER dynamics, inflammation, apoptosis, and autophagy. MAMs represent an important platform for transport of non-vesicular phospholipids and cholesterol. Therefore, this region is highly enriched in proteins involved in lipid metabolism, including the enzymes that catalyze esterification of cholesterol into cholesteryl esters (CE) and synthesis of triacylglycerols (TAG) from fatty acids (FAs), which are then stored in lipid droplets (LDs). LDs, through contact with other organelles, prevent the toxic consequences of accumulation of unesterified (free) lipids, including lipotoxicity and oxidative stress, and serve as lipid reservoirs that can be used under multiple metabolic and physiological conditions. The LDs break down by autophagy releases of stored lipids for energy production and synthesis of membrane components and other macromolecules. Pathological lipid deposition and autophagy disruption have both been reported to occur in several neurodegenerative diseases, supporting that lipid metabolism alterations are major players in neurodegeneration. In this review, we discuss the current understanding of MAMs structure and function, focusing on their roles in lipid metabolism and the importance of autophagy in LDs metabolism, as well as the changes that occur in neurogenerative diseases.