Integrative Profiling of Amyotrophic Lateral Sclerosis Lymphoblasts Identifies Unique Metabolic and Mitochondrial Disease Fingerprints

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with a rapid progression and no effective treatment. Metabolic and mitochondrial alterations in peripheral tissues of ALS patients may present diagnostic and therapeutic interest. We aimed to identify mitochondrial ngerprints in lymphoblast from ALS patients harboring SOD1 mutations (mutSOD1) or with unidenti ed mutations (undSOD1), compared with age/sex matched controls.Three groups of lymphoblasts, from mutSOD1 or undSOD1 ALS patients and age/sex-matched controls, were obtained from Coriell Biobank and divided into 3 age/sex-matched cohorts. Mitochondria-associated metabolic pathways were analyzed using Seahorse MitoStress and ATP Rate assays, complemented with metabolic phenotype microarrays, metabolite levels, gene expression, and protein expression and activity. Pooled (all cohorts) and paired (intra-cohort) analyses were performed by using bioinformatic tools, and the features with higher information gain values were selected and used for principal component analysis and Naïve Bayes classi cation.Pooled analysis revealed that undSOD1 patients had statistically higher glycolytic ATP production rate and lower Tfam protein content compared to controls, which were also the experimental features highlighted by multidimensional analysis. Metabolic phenotypic pro les in lymphoblasts from ALS patients with mutSOD1 and undSOD1 revealed unique age-dependent different substrate oxidation pro les. For most parameters, different patterns of variation were found between cohorts, which may be due to age or sex.In the present work, we investigated several metabolic and mitochondrial hallmarks in lymphoblasts from each donor and, although a high heterogeneity of results was found, we identi ed speci c metabolic and mitochondrial ngerprints that may have a diagnostic and therapeutic interest. Age 46 46 46 46 46 46 26 27

Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis

“…This shift in metabolic strategy is probably driven by the heightened energy demands of large MNs, which are particularly susceptible to changes in metabolism [163]. Interestingly, the glycolytic ATP production rate showed potential diagnostic and therapeutic interest in lymphoblasts from ALS patients [174].…”

“…Taken together, these observations of varying protein and mRNA levels of mitochondrial markers in both animal models and patients, particularly in the spinal cord and skeletal muscle of individuals with SOD1 mutations, indicate a potential disruption in the mitochondrial biogenesis process affecting the cellular capacity to maintain a healthy network of functional mitochondria, which further underscoring mitochondrial relevance in ALS pathogenesis. Interestingly, Tfam protein levels in the lymphoblasts of ALS patients are of potential diagnostic and therapeutic interest [174].…”

Metabolic Priming as a Tool in Redox and Mitochondrial Theragnostics

“…Impaired mitochondrial biogenesis and mitochondrial dynamics [55][56][57] Excess ROS production [58] Decreased intracellular Ca 2+ buffering [58] Decreased respiratory capacity and/or loss of mitochondrial transmembrane potential [59] Disruption of intracellular trafficking-associated neurotoxicity [52,[60][61][62][63] mtDNA-mitochondrial DNA; OXPHOS-oxidative phosphorylation; TCA-tricarboxylic acid cycle; ROS-reactive oxygen species; AD-Alzheimer's disease, PD-Parkinson's disease; HD-Huntington's disease; ALS-amyotrophic lateral sclerosis.…”

“…Neurodegenerative diseases also have an important component of mitochondrial dysfunction and loss of redox homeostasis, as described in Table 1 [55][56][57][58][59][60]64]. Thus, mitochondria are important drug targets for neurodegenerative diseases, and some small molecules or peptide sequences targeting mitochondria are being developed (see Section 4.4.2) for different mitochondrial targets, since several mitochondrial structures/functions are affected in these diseases [65].…”