细胞膜钙通过 CAMKII 激活调节肝线粒体氧化、肝内脂肪分解和葡萄糖生成。

Cell metabolism Pub Date : 2024-10-01 Epub Date: 2024-08-16 DOI:10.1016/j.cmet.2024.07.016
Traci E LaMoia, Brandon T Hubbard, Mateus T Guerra, Ali Nasiri, Ikki Sakuma, Mario Kahn, Dongyan Zhang, Russell P Goodman, Michael H Nathanson, Yasemin Sancak, Mark Perelis, Vamsi K Mootha, Gerald I Shulman
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引用次数: 0

摘要

为了研究线粒体钙 Ca2+ ([Ca2+]mt)和细胞膜 Ca2+ ([Ca2+]cyt)在调节肝线粒体脂肪氧化中的作用,我们研究了一种肝特异性线粒体钙单运体基因敲除(MCU KO)小鼠模型,该模型的[Ca2+]mt含量降低,而[Ca2+]cyt含量增加。尽管[Ca2+]mt 减少了,但肝脏 MCU 的缺失增加了体内异柠檬酸脱氢酶通量、α-酮戊二酸脱氢酶通量和琥珀酸脱氢酶通量的速率。MCU KO肝脏切片中[14C16]棕榈酸酯氧化速率和肝内脂肪分解速率增加,导致肝脏三酰甘油含量降低。激活 CAMKII 可再现这些效应,而敲除 CAMKII 则可消除这些效应,这表明 CAMKII 的[Ca2+]cyt 激活可能是 MCU 缺失促进肝线粒体氧化增加的主要机制。总之,这些数据证明肝线粒体氧化可与[Ca2+]mt分离,并揭示了[Ca2+]cyt在调节肝脂肪线粒体氧化、肝内脂肪分解、葡萄糖生成和脂质积累中的关键作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.

Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.

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.

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