16p11.2 haploinsufficiency reduces mitochondrial biogenesis in brain endothelial cells and alters brain metabolism in adult mice

Alexandria Béland-Millar; Alexia Kirby; Yen Truong; Julie Ouellette; Sozerko Yandiev; Khalil Bouyakdan; Chantal Pileggi; Shama Naz; Melissa Yin; Micaël Carrier; Pavel Kotchetkov; Marie-Kim St-Pierre; Marie-Ève Tremblay; Julien Courchet; Mary-Ellen Harper; Thierry Alquier; Claude Messier; Adam J Shuhendler; Baptiste Lacoste

doi:10.1016/j.celrep.2023.112485

16p11.2 haploinsufficiency reduces mitochondrial biogenesis in brain endothelial cells and alters brain metabolism in adult mice

Cell Rep. 2023 May 30;42(5):112485. doi: 10.1016/j.celrep.2023.112485. Epub 2023 May 6.

Authors

Alexandria Béland-Millar¹, Alexia Kirby², Yen Truong³, Julie Ouellette⁴, Sozerko Yandiev⁵, Khalil Bouyakdan⁶, Chantal Pileggi⁷, Shama Naz⁸, Melissa Yin⁹, Micaël Carrier¹⁰, Pavel Kotchetkov⁴, Marie-Kim St-Pierre¹⁰, Marie-Ève Tremblay¹¹, Julien Courchet⁵, Mary-Ellen Harper⁷, Thierry Alquier⁶, Claude Messier¹², Adam J Shuhendler¹³, Baptiste Lacoste¹⁴

Affiliations

¹ Neuroscience Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada; School of Psychology, University of Ottawa, Ottawa, ON, Canada.
² Faculty of Science, Department of Biology, University of Ottawa, Ottawa, ON, Canada.
³ Faculty of Science, Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON, Canada.
⁴ Neuroscience Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada; Faculty of Medicine, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
⁵ University Lyon 1, CNRS, INSERM, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène, 69008 Lyon, France.
⁶ Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Department of Medicine Université de Montréal, Montreal, QC, Canada.
⁷ Faculty of Medicine, Department of Biochemistry Microbiology and Immunology, Ottawa, ON, Canada.
⁸ University of Ottawa Metabolomics Core Facility, Faculty of Medicine, Ottawa, ON, Canada.
⁹ FUJIFILM VisualSonics, Inc, Toronto, ON, Canada.
¹⁰ Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
¹¹ Division of Medical Sciences, University of Victoria, Victoria, BC, Canada; Neurology and Neurosurgery Department, McGill University, Montreal, QC, Canada; Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada.
¹² School of Psychology, University of Ottawa, Ottawa, ON, Canada.
¹³ Faculty of Science, Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada.
¹⁴ Neuroscience Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada; Faculty of Medicine, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada. Electronic address: blacoste@uottawa.ca.

PMID: 37149866
DOI: 10.1016/j.celrep.2023.112485

Abstract

Neurovascular abnormalities in mouse models of 16p11.2 deletion autism syndrome are reminiscent of alterations reported in murine models of glucose transporter deficiency, including reduced brain angiogenesis and behavioral alterations. Yet, whether cerebrovascular alterations in 16p11.2^df/+ mice affect brain metabolism is unknown. Here, we report that anesthetized 16p11.2^df/+ mice display elevated brain glucose uptake, a phenomenon recapitulated in mice with endothelial-specific 16p11.2 haplodeficiency. Awake 16p11.2^df/+ mice display attenuated relative fluctuations of extracellular brain glucose following systemic glucose administration. Targeted metabolomics on cerebral cortex extracts reveals enhanced metabolic responses to systemic glucose in 16p11.2^df/+ mice that also display reduced mitochondria number in brain endothelial cells. This is not associated with changes in mitochondria fusion or fission proteins, but 16p11.2^df/+ brain endothelial cells lack the splice variant NT-PGC-1α, suggesting defective mitochondrial biogenesis. We propose that altered brain metabolism in 16p11.2^df/+ mice is compensatory to endothelial dysfunction, shedding light on previously unknown adaptative responses.

Keywords: 16p11.2 deletion; CP: Metabolism; CP: Neuroscience; autism; brain; endothelium; glucose; lactate; metabolism; mitochondrion; mouse.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Brain
Chromosome Deletion
Endothelial Cells* / metabolism
Haploinsufficiency*
Mice
Organelle Biogenesis

Supplementary concepts

16p11.2 Deletion Syndrome