TY - JOUR
T1 - Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis
AU - Gómez-valadés, Alicia G.
AU - Pozo, Macarena
AU - Varela, Luis
AU - Boudjadja, Mehdi Boutagouga
AU - Ramírez, Sara
AU - Chivite, Iñigo
AU - Eyre, Elena
AU - Haddad-tóvolli, Roberta
AU - Obri, Arnaud
AU - Milà-guasch, Maria
AU - Altirriba, Jordi
AU - Schneeberger, Marc
AU - Imbernón, Mónica
AU - Garcia-rendueles, Angela R.
AU - Gama-perez, Pau
AU - Rojo-ruiz, Jonathan
AU - Rácz, Bence
AU - Alonso, Maria Teresa
AU - Gomis, Ramon
AU - Zorzano, Antonio
AU - D’agostino, Giuseppe
AU - Alvarez, Clara V.
AU - Nogueiras, Rubén
AU - Garcia-roves, Pablo M.
AU - Horvath, Tamas L.
AU - Claret, Marc
N1 - Funding Information:
We thank Servier Medical Art for illustrations. We are grateful to Justin J. Wilson and Nick Bigham (Cornell University) for providing Ru265 and Elisenda Sanz (Universitat Auton?noma de Barcelona) for assistance with RiboTag protocols. This work was supported by Agencia Estatal de Investigaci?n y Fondo Social Europeo, Proyecto BFU2016-76973-R FEDER (C.V.A.); AG052005, AG052986, AG051459, DK111178 from NIH and NKFI-KKP-126998 from Hungarian National Research, Development and Innovation Office (T.L.H.); MR/P009824/2 from Medical Research Council UK (G.D.); and Ayudas Fundaci?n BBVA a Investigadores y Creadores Culturales (2015), European Research Council (ERC) under the European Union's Horizon 2020 Research And Innovation Program (grant agreement 725004) and CERCA Programme/Generalitat de Catalunya (M.C.). A.O. is supported by a Miguel Servet contract (CP19/00083) from Instituto de Salud Carlos III and co-financed by FEDER. This work was carried out in part at the Esther Koplowitz Centre. Conceptualization, A.G.G.-V. and M.C.; methodology, A.G.G.-V. and M.C.; formal analysis, A.G.G.-V. M.P. L.V. M.B.B. E.E. J.A. J.R.-R. and M.C.; investigation, A.G.G.-V. M.P. L.V. S.R. I.C. R.H.-T. A.O. M.M.-G. M.S. M.I. A.R.G.-R. P.G.-P. P.M.G.-R. J.R.-R. and B.R.; resources, M.T.A. C.V.A. A.Z. R.N. R.G. G.D. T.L.H. and M.C.; writing ? original draft, A.G.G.-V. and M.C.; writing ? review & editing, all authors; supervision, A.G.G.-V. G.D. C.V.A. R.N. P.M.G.-R. T.L.H. and M.C.; project administration, A.G.G.-V. and M.C.; funding acquisition, C.V.A. G.D. T.L.H. and M.C. The authors declare no competing interests.
Funding Information:
We thank Servier Medical Art for illustrations. We are grateful to Justin J. Wilson and Nick Bigham (Cornell University) for providing Ru265 and Elisenda Sanz (Universitat Autonònoma de Barcelona) for assistance with RiboTag protocols. This work was supported by Agencia Estatal de Investigación y Fondo Social Europeo , Proyecto BFU2016-76973-R FEDER (C.V.A.); AG052005 , AG052986 , AG051459 , DK111178 from NIH and NKFI-KKP-126998 from Hungarian National Research, Development and Innovation Office (T.L.H.); MR/P009824/2 from Medical Research Council UK (G.D.); and Ayudas Fundación BBVA a Investigadores y Creadores Culturales (2015), European Research Council (ERC) under the European Union’s Horizon 2020 Research And Innovation Program (grant agreement 725004 ) and CERCA Programme/Generalitat de Catalunya (M.C.). A.O. is supported by a Miguel Servet contract ( CP19/00083 ) from Instituto de Salud Carlos III and co-financed by FEDER . This work was carried out in part at the Esther Koplowitz Centre .
Publisher Copyright:
© 2021 The Authors
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2021/8/2
Y1 - 2021/8/2
N2 - 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.
AB - 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.
KW - OPA-1
KW - POMC neurons
KW - cristae
KW - hypothalamus
KW - lipolysis
KW - mitochondria
KW - obesity
U2 - 10.1016/j.cmet.2021.07.008
DO - 10.1016/j.cmet.2021.07.008
M3 - Article
C2 - 34343501
VL - 33
SP - 1820-1835.e9
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 9
ER -