Implications of Mitochondrial ATP-Sensitive Potassium Channel Activity on Brown Adipocyte

• Ano de defesa: 2024
• Autor(a) principal: Pereira Junior, Osvaldo Rodrigues
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: eng
• Instituição de defesa: Biblioteca Digitais de Teses e Dissertações da USP
• Palavras-chave em Português: Brown adipose tissue; Mitochondria; Mitochondrial volume; Mitocôndrias; Potássio; Potassium; Tecido Adiposo Marrom; Termogênese; Thermogenesis; Volume mitocondrial
• Link de acesso: https://www.teses.usp.br/teses/disponiveis/46/46131/tde-11042025-113406/

Brown Adipose Tissue (BAT) plays a central role in non-shivering thermogenesis for mammals by dissipating mitochondrial membrane potentials in the form of heat through UCP1. Mitochondria from every tissue are known to be permeable to potassium ions (K+), even in the absence of a specific protein pathway for that, mostly due to their high membrane potentials. K+ influx to the mitochondrial matrix is associated with increased osmotic pressure, directly impacting on matrix volume. Although this can happen in the absence of a protein pathway, a specific transporter protein for K+ entry to the mitochondrial matrix, MitoKATP, was previously described through its activity, and had its genes recently identified. Given that mitochondria from BAT have lower membrane potentials due to UCP1 activity, we hypothesized that K+ influx could be more reliant on MitoKATP as non-protein mediated K+ influx is highly dependent of potential energy as its driving force. We determined that cold exposure in mice increases MitoK levels in total BAT lysates, relative to thermoneutrality. Additionally, we observed that MitoK mRNA levels were upregulated both in mouse and human brown adipocyte differentiation. Surprisingly, hormonal stimulation of differentiated mouse adipocytes led to MitoK protein degradation after 24h. Mitochondria from CL316-stimulated BAT displayed decrease swelling rates, despite a lack of changes in their MitoK ad MitoSUR levels and oxidant production. UCP1-linkedrespiration was increased in mitochondria from CL316-stimulated BAT only in the presence of a MitoK inhibitor, but not with a MitoK activator. Moreover, pharmacological inhibition of MitoKATP in mature adipocytes was able to boost adrenergic-recruited oxygen consumption, while inhibition of the channel was necessary to support pyruvate consumption by brown adipocyte mitochondria. In preadipocytes, genetic ablation of the gene that codes for the pore-forming subunit of MitoKATP led to decreased proliferation of human pre-adipocytes, therefore compromising differentiation of these cells. For mouse pre-adipocytes, although the cellular proliferation phenotype wasn’t reproduced, ablation of the MitoK gene through the same strategy significantly impaired oxygen consumption. Overall, our results suggest that this still unexplored pathway can be of utmost importance for brown adipocyte metabolism by controlling mitochondrial volume and oxidant production.