Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Alicia G. Gómez-valadés
  • Macarena Pozo
  • Luis Varela
  • Mehdi Boutagouga Boudjadja
  • Sara Ramírez
  • Iñigo Chivite
  • Elena Eyre
  • Roberta Haddad-tóvolli
  • Arnaud Obri
  • Maria Milà-guasch
  • Jordi Altirriba
  • Marc Schneeberger
  • Mónica Imbernón
  • Angela R. Garcia-rendueles
  • Pau Gama-perez
  • Jonathan Rojo-ruiz
  • Bence Rácz
  • Maria Teresa Alonso
  • Ramon Gomis
  • Antonio Zorzano
  • Clara V. Alvarez
  • Rubén Nogueiras
  • Pablo M. Garcia-roves
  • Tamas L. Horvath
  • Marc Claret

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 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.

Bibliographical metadata

Original languageEnglish
Pages (from-to)1820-1835.e9
JournalCell Metabolism
Volume33
Issue number9
Early online date2 Aug 2021
DOIs
Publication statusPublished - 2 Aug 2021