Implications of mitochondrial phosphatidylethanolamine in neuronal health and neurodegeneration

Phosphatidylethanolamine is a major phospholipid class abundant in the brain, particularly in the inner leaflet of the plasma and mitochondrial membranes. Although it is primarily synthesized from phosphatidylserine via decarboxylation in mitochondria or from ethanolamine via the cytidine diphosphate-ethanolamine pathway in the endoplasmic reticulum, phosphatidylethanolamine that resides in mitochondria is preferentially produced locally and is distinct and separate from the pool of phosphatidylethanolamine made in the endoplasmic reticulum. Mitochondria-derived phosphatidylethanolamine is not only essential for mitochondrial integrity but also is exported to other organelles to fulfill diverse cellular functions. Neurons are highly enriched with phosphatidylethanolamine, and the importance of phosphatidylethanolamine metabolism in neuronal health has recently been recognized following its reported links to Alzheimer's disease, Parkinson's disease, and hereditary spastic paraplegia, among other neurological disorders. Indeed, disturbances in mitochondrial function and phosphatidylethanolamine metabolism and the resulting neuronal dysfunction are the common features of individuals suffering from these diseases, highlighting the great importance of maintaining proper phosphatidylethanolamine homeostasis in neurons. In this review, we summarize the current knowledge of phosphatidylethanolamine metabolism and its role in neuronal function with a special emphasis on the phosphatidylethanolamine biosynthetic pathway in mitochondria. We then review findings on how phosphatidylethanolamine biosynthesis is affected in major neurodegenerative diseases. Finally, we highlight promising future research areas that will help advance the understanding of neuronal phosphatidylethanolamine mechanisms and identify phosphatidylethanolamine-targeted therapeutic strategies for combating such brain diseases.