Hakuna MAM-Tata: Investigating the role of mitochondrial-associated membranes in ALS

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease leading to selective and pro-gressive motor neuron (MN) death. Despite significant heterogeneity in pathogenic and clinical terms, MN demise ultimately unifies patients. Across the many disturbances in neuronal biology present in the disease and its models, two common trends are loss of calcium homeostasis and dysregulations in lipid metabolism. Since both mitochondria and endoplasmic reticulum (ER) are essential in these functions, their intertwin through the so-called mitochondrial-associated membranes (MAMs) should be relevant in this disease. In this review, we present a short overview of MAMs functional aspects and how its dysfunction could explain a substantial part of the cellular disarrangements in ALS's natural history. MAMs are hubs for lipid synthesis, integrating glycer-ophospholipids, sphingolipids, and cholesteryl ester metabolism. These lipids are essential for membrane biology, so there should be a close coupling to cellular energy demands, a role that MAMs may partially fulfill. Not surprisingly, MAMs are also host part of calcium signaling to mitochondria, so their impairment could lead to mitochondrial dysfunction, affecting oxidative phosphorylation and enhancing the vulnerability of MNs. We present data supporting that MAMs' maladaptation could be essential to MNs' vulnerability in ALS.

Automated summary

Amyotrophic lateral sclerosis (ALS) is characterized by the death of motor neurons (MNs), and dysfunction in mitochondrial-associated membranes (MAMs) may play a crucial role in the cellular disarrangements in ALS, including dysregulations in lipid metabolism and calcium homeostasis.