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

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dc.contributor.authorBéland-Millar, Alexandria
dc.contributor.authorKirby, Alexia
dc.contributor.authorTruong, Yen
dc.contributor.authorOuellette, Julie
dc.contributor.authorYandiev, Sozerko
dc.contributor.authorBouyakdan, Khalil
dc.contributor.authorPileggi, Chantal
dc.contributor.authorNaz, Shama
dc.contributor.authorYin, Melissa
dc.contributor.authorCarrier, Micaël
dc.contributor.authorKotchetkov, Pavel
dc.contributor.authorSt-Pierre, Marie-Kim
dc.contributor.authorTremblay, Marie-Ève
dc.contributor.authorCourchet, Julien
dc.contributor.authorHarper, Mary-Ellen
dc.contributor.authorAlquier, Thierry
dc.contributor.authorMessier, Claude
dc.contributor.authorShuhendler, Adam J.
dc.contributor.authorLacoste, Baptiste
dc.date.accessioned2023-11-07T22:01:46Z
dc.date.available2023-11-07T22:01:46Z
dc.date.copyright2023en_US
dc.date.issued2023
dc.descriptionWe thank Carlie Boisvert (Lacoste lab) for technical assistance and Andrew Heinmiller (Fujifilm VisualSonics) for guidance on photoacoustic imaging. We thank the CRCHUM rodent metabolic phenotyping core facility for their help with tolerance tests.en_US
dc.description.abstractSummary 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 16p11.2df/+ mice affect brain metabolism is unknown. Here, we report that anesthetized 16p11.2df/+ mice display elevated brain glucose uptake, a phenomenon recapitulated in mice with endothelial-specific 16p11.2 haplodeficiency. Awake 16p11.2df/+ 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 16p11.2df/+ mice that also display reduced mitochondria number in brain endothelial cells. This is not associated with changes in mitochondria fusion or fission proteins, but 16p11.2df/+ brain endothelial cells lack the splice variant NT-PGC-1α, suggesting defective mitochondrial biogenesis. We propose that altered brain metabolism in 16p11.2df/+ mice is compensatory to endothelial dysfunction, shedding light on previously unknown adaptative responses.en_US
dc.description.reviewstatusRevieweden_US
dc.description.scholarlevelFacultyen_US
dc.description.sponsorshipMetabolites were analyzed at the University of Ottawa Metabolomics Core Facility; this facility is supported by the Terry Fox Foundation and Ottawa University. B.L. was supported by start-up funds from the Ottawa Hospital Research Institute, a Canadian Institutes of Health Research (grant #388805), an award from The Scottish Rite Charitable Foundation of Canada (grant #17112), and a J.P. Bickell Foundation medical research grant. Part of this work is also funded by an Autism Research Program Idea Development Award from the US Department of Defense office of the Congressionally Directed Medical Research Programs (grant #AR210134). C.M. was supported by the Natural Sciences and Engineering Council of Canada (grant #RGPIN 2019-03945) and by an equipment grant from the Canadian Foundation for Innovation and the Ontario Research Fund. T.A. was supported by a salary award from Fonds de Recherche du Québec – Santé (FRQS). M.C. is supported by a doctoral training award from the FRQS. J.O. is supported by a doctoral training award from CIHR. P.K. is supported by a doctoral training award from uOBMRI. A.J.S. thanks the Canada Research Chairs program (950-230754), the Canadian Foundation for Innovation - John Evans Leadership Fund, and NSERC (grant RGPIN 2015-05796).en_US
dc.identifier.citationBéland-Millar, A., Kirby, A., Truong, Y., Ouellette, J., Yandiev, S., Bouyakdan, K., ... Lacoste, B. (2023). 16p11.2 haploinsufficiency reduces mitochondrial biogenesis in brain endothelial cells and alters brain metabolism in adult mice. Cell Reports, 42(5), 112485. https://doi.org/10.1016/j.celrep.2023.112485en_US
dc.identifier.urihttps://doi.org/10.1016/j.celrep.2023.112485
dc.identifier.urihttp://hdl.handle.net/1828/15598
dc.language.isoenen_US
dc.publisherCell Reportsen_US
dc.subjectautismen_US
dc.subjectendotheliumen_US
dc.subject16p11.2 deletionen_US
dc.subjectmetabolismen_US
dc.subjectbrainen_US
dc.subjectglucoseen_US
dc.subjectlactateen_US
dc.subjectmouseen_US
dc.subjectmitochondrionen_US
dc.title16p11.2 haploinsufficiency reduces mitochondrial biogenesis in brain endothelial cells and alters brain metabolism in adult miceen_US
dc.typeArticleen_US

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