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The endoplasmic reticulum (ER) and mitochondria are fundamental organelles highly interconnected with a specialized set of proteins in cells. ER–mitochondrial interconnections form specific microdomains, called mitochondria‐associated ER membranes, that have been found to play important roles in calcium signaling and lipid homeostasis, and more recently in mitochondrial dynamics, inflammation, and autophagy. It is not surprising that perturbations in ER–mitochondria connections can result in the progression of disease, especially neurological disorders; hence, their architecture and regulation are crucial in determining the fate of cells and disease. The molecular identity of the specialized proteins regulating ER–mitochondrial crosstalk remains unclear. Our discussion here describes the physical and functional crosstalk between these two dynamic organelles and emphasizes the outcome of altered ER–mitochondrial interconnections in neurological disorders.

Mitophagy and inflammasomes have a pivotal role in the development of neuropathology. Molecular mechanisms behind mitophagy and inflammasomes are well-understood, but lacunae prevail in understanding the crosstalk between them in various neurological disorders. As mitochondrial dysfunction is the prime event in neurodegeneration, the clearance of impaired mitochondria is one of the main tasks for maintaining cell integrity in the majority of neuropathologies. Along with it, inflammasome activation also plays a major role, which is usually followed by mitochondrial dysfunction. The present review highlights basics of autophagy, mitophagy, and inflammasomes and the molecular mechanisms involved, and more importantly, it tries to elaborate the interplay between mitophagy and inflammasomes in various neurological disorders. This will help in upgrading the reader’s understanding in exploring the link between mitophagy and inflammasomes, which has dealt with limitations in past studies.

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Calreticulin (CALR), a lectin-like ER chaperone, was initially known only for its housekeeping function, but today it is recognized for many versatile roles in different compartments of a cell. Apart from canonical roles in protein folding and calcium homeostasis, it performs a variety of noncanonical roles, mostly in CNS development. In the past, studies have linked Calreticulin with various other biological components which are detrimental in deciding the fate of neurons. Many neurological disorders that differ in their etiology are commonly associated with aberrant levels of Calreticulin, that lead to modulation of apoptosis and phagocytosis, and impact on transcriptional pathways, impairment in proteostatis, and calcium imbalances. Such multifaceted properties of Calreticulin are the reason why it has been implicated in vital roles of the nervous system in recent years. Hence, understanding its role in the physiology of neurons would help to unearth its involvement in the spectrum of neurological disorders. This Review aims toward exploring the interplay of Calreticulin in neurological disorders which would aid in targeting Calreticulin for developing novel neurotherapeutics.