Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca(2+) homeostasis with adipose tissue lipolysis.
Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca(2+) homeostasis with adipose tissue lipolysis.
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DOI：
10.1016/j.cmet.2021.07.008
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发表时间：
2021-09-07
期刊：
影响因子：
29
通讯作者：
Claret M
中科院分区：
文献类型：
--
作者：
Gómez-Valadés AG;Pozo M;Varela L;Boudjadja MB;Ramírez S;Chivite I;Eyre E;Haddad-Tóvolli R;Obri A;Milà-Guasch M;Altirriba J;Schneeberger M;Imbernón M;Garcia-Rendueles AR;Gama-Perez P;Rojo-Ruiz J;Rácz B;Alonso MT;Gomis R;Zorzano A;D'Agostino G;Alvarez CV;Nogueiras R;Garcia-Roves PM;Horvath TL;Claret M
适当的眉骨重塑是线粒体功能和生物能量学的决定因素，因此是细胞代谢适应的关键过程。在这里，我们发现，在原阿片黑素皮质素(POMC)神经元中的线粒体脊结构和主脊重塑蛋白OPA1的表达，是参与能量平衡控制的关键代谢感受器，受到营养供应波动的影响。OPA1基因失活可导致前庭神经元脊突拓扑、线粒体Ca~(2+)处理、靶区α-黑素细胞刺激素(α-MSH)水平降低、吞噬功能亢进、白色脂肪组织(WAT)脂肪分解减弱，从而导致肥胖。药物阻断线粒体钙离子内流可以恢复α-msh和脂解程序，同时改善突变小鼠的代谢缺陷。POMC神经元的化学发生操作证实了其在脂解控制中的作用。我们的结果揭示了一个新的轴，它将POMC神经元中的OPA1与线粒体脊、钙稳态和Wat脂解联系起来，以调节能量平衡。营养状态影响POMC神经元线粒体脊和OPA1的表达POMC神经元OPA1缺失改变线粒体钙的处理和α-MSH释放POMC OPA1缺陷小鼠表现出脂肪分解和代谢健康受损的药理恢复钙恢复的分子和代谢改变Gómez-ValadéS等人。报道称POMC神经元中的线粒体脊在营养状态下发生动态重塑。通过基因打靶，他们揭示了脊骨重塑蛋白OPA1对于维持前额叶神经元的脊骨结构和线粒体钙稳态是必不可少的，确保适当地调节α-msh的释放，脂肪组织中的脂肪分解程序和代谢健康。
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 Ca2+ 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 Ca2+ 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, Ca2+ homeostasis, and WAT lipolysis in the regulation of energy balance. Nutritional state shapes mitochondrial cristae and OPA1 expression in POMC neurons OPA1 deletion in POMC neurons alters mitochondrial Ca2+ handling and α-MSH release POMC OPA1-deficient mice show impaired fat lipolysis and metabolic health Pharmacological restoration of Ca2+ recovered molecular and metabolic alterations Gómez-Valadés et al. report that mitochondrial cristae dynamically reshape in POMC neurons in response to nutritional state. With genetic targeting, they reveal that the cristae-remodeling protein OPA1 is essential to sustain cristae structure and mitochondrial Ca2+ homeostasis in POMC neurons, ensuring appropriate modulation of α-MSH release, the lipolytic program in adipose tissue and metabolic health.
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影响因子：
21.3
作者：
通讯作者：
--
影响因子：
29
作者：
Civiletto G;Varanita T;Cerutti R;Gorletta T;Barbaro S;Marchet S;Lamperti C;Viscomi C;Scorrano L;Zeviani M
通讯作者：
Zeviani M
影响因子：
11.1
作者：
Gao, Arwen W.;Canto, Carles;Houtkooper, Riekelt H.
通讯作者：
Houtkooper, Riekelt H.
DOI：
10.1073/pnas.1106862108
发表时间：
2011-09-13
影响因子：
11.1
作者：
Chang, Karen T.;Niescier, Robert F.;Min, Kyung-Tai
通讯作者：
Min, Kyung-Tai
影响因子：
4.8
作者：
Brito, Marcia N.;Brito, Nilton A.;Bartness, Timothy J.
通讯作者：
Bartness, Timothy J.