Altered ER–mitochondria contact sites in neurons: Mechanisms and functional implications

Mitochondria and the endoplasmic reticulum (ER) are distributed throughout all neuronal compartments, where they control diverse biochemical processes. Recent studies have shown that these organelles do not function independently but instead form specialized physical interfaces known as mitochondria–ER contact sites (MERCS), which enable coordinated biochemical regulation. Although MERCS were first identified in neurons more than 50 years ago, and alterations in MERCS have been implicated in various neurological disorders, their physiological roles and regulatory mechanisms have only recently begun to emerge. In this review, we highlight recent advances in understanding neuronal MERCS, focusing on insights gained from volume electron microscopy (volume EM or vEM), genetically encoded imaging tools, and genetic manipulation of mitochondria–ER tethering proteins. Elucidating the spatiotemporal regulation and physiological functions of MERCS will provide insight into how subcellular compartmentalization expands the functional complexity of neurons, thereby supporting the brain’s remarkable information-processing capacity within a limited volume.