Abstract: Mitochondria and mitochondria-associated e n d o p l a s m i c r e t i c u l u m m e m b r a n e i n neurodegenerative diseases: Mitochondria generate most of the chemical energy needed to power the biochemical reactions of cells, and thus are often referred to as the “powerhouse” of the cell. Nevertheless, this organelle is also involved in a plethora of different cellular functions such as calcium (Ca2+) homeostasis, apoptosis, oxidative stress, and several metabolic pathways including oxidative phosphorylation, tricarboxylic acid cycle, and β-oxidation of fatty acids. Many of these functions require the contact between the mitochondria and the endoplasmic reticulum (ER), which is mediated by several tether proteins located on the respective organellar surfaces, enabling the formation of mitochondria-associated ER membrane (MAMs). Given that the brain is one of the high-energy-demanding organs in the body, neurons are uniquely vulnerable to reactive oxygen species, and that Ca2+ homeostasis is crucial for neuronal functionality, there has been a longstanding interest in mitochondrial functions and their communications with the ER within the fields of neurology and neuropathology. Alterations in mitochondrial physical and functional tethers along with their biochemical dysfunction are now recognized as common hallmarks of different neurodegenerative and neurodevelopmental conditions including Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and autistic spectrum disorders, as well as rare, early-onset neurodegenerative diseases such as Wolfram syndrome 1 (WS) (Johri and Beal, 2012; Paillusson et al., 2016; Delprat et al., 2018; Mishra et al., 2021). Thus, the identification of effective treatments acting on biochemical pathways involving the mitochondria is of great biomedical interest.