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

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2023-08, Vol.1869 (6), p.166716-166716, Article 166716
• Main Authors: Bernal, Anna Fernàndez, Mota, Natàlia, Pamplona, Reinald, Area-Gomez, Estela, Portero-Otin, Manuel
• Format: Article
• Language: English
• Subjects: Amyotrophic Lateral Sclerosis - metabolism; Calcium metabolism; Endoplasmic Reticulum - metabolism; Humans; Lipid synthesis; Mitochondria; Mitochondria - metabolism; Mitochondrial Membranes - metabolism; Neurodegeneration; Neurodegenerative Diseases - pathology; TDP-43
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2023.166716

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease leading to selective and progressive 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 glycerophospholipids, 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. Morphological abnormalities, alterations in calcium homeostasis, bioenergetic abnormalities and excessive ROS production in mitochondria and ER stress, all of them alterations of mitochondria and ER, contribute to neurodegeneration in ALS. Some studies show that TDP-43 can disrupt ER-mitochondria crosstalk and lead to calcium homeostasis disruption and others of the mentioned ER-mito alterations observed in ALS. Therefore, ER-mito alterations observed in ALS can be secondary to TDP-43 pathology- related MAMs dysfunction? [Display omitted]