Decreased Mitochondrial Function, Biogenesis, and Degradation in Peripheral Blood Mononuclear Cells from Amyotrophic Lateral Sclerosis Patients as a Potential Tool for Biomarker Research

Autor(es)

Araujo, Beatriz Grisolia ; Souza e Silva, Luiz Felipe ; Torresi, Jorge Luiz de Barros ; Siena, Amanda ; Valerio, Berenice Cataldo Oliveira ; Brito, Mariana Dutra ; Rosenstock, Tatiana Rosado

• Tipo de documento: Artigo Científico
• Fonte: Molecular Neurobiology; v. 57, n. 12, p. 19-pg., 2020-08-25.

Resumo

Amyotrophic lateral sclerosis (ALS) is a multifactorial and progressive neurodegenerative disease of unknown etiology. Due to ALS's unpredictable onset and progression rate, the search for biomarkers that allow the detection and tracking of its development and therapeutic efficacy would be of significant medical value. Considering that alterations of energy supply are one of ALS's main hallmarks and that a correlation has been established between gene expression in human brain tissue and peripheral blood mononuclear cells (PBMCs), the present work investigates whether changes in mitochondrial function could be used to monitor ALS. To achieve this goal, PBMCs from ALS patients and control subjects were used; blood sampling is a quite non-invasive method and is cost-effective. Different parameters were evaluated, namely cytosolic calcium levels, mitochondrial membrane potential, oxidative stress, and metabolic compounds levels, as well as mitochondrial dynamics and degradation. Altogether, we observed lower mitochondrial calcium uptake/retention, mitochondria depolarization, and redox homeostasis deregulation, in addition to a decrease in critical metabolic genes, a diminishment in mitochondrial biogenesis, and an augmentation in mitochondrial fission and autophagy-related gene expression. All of these changes can contribute to the decreased ATP and pyruvate levels observed in ALS PBMCs. Our data indicate that PBMCs from ALS patients show a significant mitochondrial dysfunction, resembling several findings from ALS' neural cells/models, which could be exploited as a powerful tool in ALS research. Our findings can also guide future studies on new pharmacological interventions for ALS since assessments of brain samples are challenging and represent a relevant limited strategy. (AU)

• Processo FAPESP: 15/02041-1 - O papel das lisinas(K)-deacetilases para a neuroproteção de desordens mitocondriais: perspectivas de terapia epigenética para a esclerose lateral amiotrófica e esquizofrenia
• Beneficiário: Tatiana Rosado Rosenstock
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 16/12039-7 - A modulação de lisinas(K)-deacetilases e o seu papel no metabolismo, dinâmica e degradação mitocondrial: possível neuroproteção para a esclerose lateral amiotrófica
• Beneficiário: Mariana Dutra Brito
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 15/25595-2 - Sirtuínas na neuropatologia da esquizofrenia: implicação contra a disfunção mitocondrial na hipóxia
• Beneficiário: Luiz Felipe Souza e Silva
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 18/09084-6 - Estudo funcional em linfócitos de pacientes com Esclerose Lateral Amiotrófica: relevância para a determinação de biomarcadores
• Beneficiário: Beatriz Grisolia Araujo
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica