Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.
Cell Metab
; 36(10): 2329-2340.e4, 2024 Oct 01.
Article
em En
| MEDLINE
| ID: mdl-39153480
ABSTRACT
To examine the roles of mitochondrial calcium Ca2+ ([Ca2+]mt) and cytosolic Ca2+ ([Ca2+]cyt) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium uniporter knockout (MCU KO) mouse model with reduced [Ca2+]mt and increased [Ca2+]cyt content. Despite decreased [Ca2+]mt, deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of [14C16]palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that [Ca2+]cyt activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from [Ca2+]mt and reveal a key role for [Ca2+]cyt in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.
Palavras-chave
CAMKII; Q-Flux; calcium; fat oxidation; glucose oxidation; isocitrate dehydrogenase flux; metabolic dysfunction-associated steatotic liver disease; mitochondria; mitochondrial calcium uniporter; succinate dehydrogenase flux; tricarboxylic acid cycle; type 2 diabetes; α-ketoglutarate dehydrogenase flux
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Citosol
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina
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Gluconeogênese
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Lipólise
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Fígado
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article