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POMC 神经元中线粒体嵴重塑蛋白 OPA1 将钙稳态与脂肪组织脂解相偶联。

Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca homeostasis with adipose tissue lipolysis.

机构信息

Neuronal Control of Metabolism (NeuCoMe) Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.

Neuronal Control of Metabolism (NeuCoMe) Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.

出版信息

Cell Metab. 2021 Sep 7;33(9):1820-1835.e9. doi: 10.1016/j.cmet.2021.07.008. Epub 2021 Aug 2.

DOI:10.1016/j.cmet.2021.07.008
PMID:34343501
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8432968/
Abstract

Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca homeostasis, and WAT lipolysis in the regulation of energy balance.

摘要

适当的嵴重塑是线粒体功能和生物能量的决定因素，因此代表了细胞代谢适应的关键过程。在这里，我们表明，在参与能量平衡控制的关键代谢传感器促肾上腺皮质激素释放素原（POMC）神经元中，线粒体嵴结构和主嵴重塑蛋白 OPA1 的表达受营养物质可用性波动的影响。POMC 神经元中 OPA1 的基因失活导致嵴拓扑结构、线粒体 Ca 处理、靶向区域 α-黑色素细胞刺激素（α-MSH）减少、进食过度和白色脂肪组织（WAT）脂肪分解减少，从而导致肥胖。线粒体 Ca 内流的药理学阻断恢复了 α-MSH 和脂肪分解程序，同时改善了突变小鼠的代谢缺陷。POMC 神经元的化学遗传操作证实了其在脂肪分解控制中的作用。我们的研究结果揭示了一条新的轴，将 POMC 神经元中的 OPA1 与线粒体嵴、Ca 动态平衡和 WAT 脂肪分解联系起来，调节能量平衡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/d068578ba1bb/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/b943fd913d6d/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/3d3022d18388/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/21d2b307ebdd/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/e1e051c6348f/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/d333ea0463d3/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/03622dfc5a15/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/c086df0760b0/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/d068578ba1bb/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/b943fd913d6d/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/3d3022d18388/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/21d2b307ebdd/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/e1e051c6348f/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/d333ea0463d3/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/03622dfc5a15/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/c086df0760b0/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8414/8432968/d068578ba1bb/gr7.jpg

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