Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca 2+ homeostasis with adipose tissue lipolysis

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 proopiomelanocor...

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Published inCell metabolism Vol. 33; no. 9; p. 1820
Main Authors Gómez-Valadés, Alicia G, Pozo, Macarena, Varela, Luis, Boudjadja, Mehdi Boutagouga, Ramírez, Sara, Chivite, Iñigo, Eyre, Elena, Haddad-Tóvolli, Roberta, Obri, Arnaud, Milà-Guasch, Maria, Altirriba, Jordi, Schneeberger, Marc, Imbernón, Mónica, Garcia-Rendueles, Angela R, Gama-Perez, Pau, Rojo-Ruiz, Jonathan, Rácz, Bence, Alonso, Maria Teresa, Gomis, Ramon, Zorzano, Antonio, D'Agostino, Giuseppe, Alvarez, Clara V, Nogueiras, Rubén, Garcia-Roves, Pablo M, Horvath, Tamas L, Claret, Marc
Format Journal Article
LanguageEnglish
Published United States 07.09.2021
Subjects
Adipose Tissue - metabolism
Animals
GTP Phosphohydrolases
Homeostasis
Lipolysis
Mice
Neurons - metabolism
Pro-Opiomelanocortin - metabolism
cristae
mitochondria
OPA-1
POMC neurons
lipolysis
hypothalamus
obesity
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Summary: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.
ISSN:1932-7420