Cargando…

Unique expression of the atypical mitochondrial subunit NDUFA4L2 in cerebral pericytes fine tunes HIF activity in response to hypoxia

A central response to insufficient cerebral oxygen delivery is a profound reprograming of metabolism, which is mainly regulated by the Hypoxia Inducible Factor (HIF). Among other responses, HIF induces the expression of the atypical mitochondrial subunit NDUFA4L2. Surprisingly, NDUFA4L2 is constitut...

Descripción completa

Detalles Bibliográficos
Autores principales: Mesa-Ciller, Claudia, Turiel, Guillermo, Guajardo-Grence, Andrea, Lopez-Rodriguez, Ana Belen, Egea, Javier, De Bock, Katrien, Aragonés, Julián, Urrutia, Andrés A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9875353/
https://www.ncbi.nlm.nih.gov/pubmed/35929074
http://dx.doi.org/10.1177/0271678X221118236
_version_ 1784877942412673024
author Mesa-Ciller, Claudia
Turiel, Guillermo
Guajardo-Grence, Andrea
Lopez-Rodriguez, Ana Belen
Egea, Javier
De Bock, Katrien
Aragonés, Julián
Urrutia, Andrés A
author_facet Mesa-Ciller, Claudia
Turiel, Guillermo
Guajardo-Grence, Andrea
Lopez-Rodriguez, Ana Belen
Egea, Javier
De Bock, Katrien
Aragonés, Julián
Urrutia, Andrés A
author_sort Mesa-Ciller, Claudia
collection PubMed
description A central response to insufficient cerebral oxygen delivery is a profound reprograming of metabolism, which is mainly regulated by the Hypoxia Inducible Factor (HIF). Among other responses, HIF induces the expression of the atypical mitochondrial subunit NDUFA4L2. Surprisingly, NDUFA4L2 is constitutively expressed in the brain in non-hypoxic conditions. Analysis of publicly available single cell transcriptomic (scRNA-seq) data sets coupled with high-resolution multiplexed fluorescence RNA in situ hybridization (RNA F.I.S.H.) revealed that in the murine and human brain NDUFA4L2 is exclusively expressed in mural cells with the highest levels found in pericytes and declining along the arteriole-arterial smooth muscle cell axis. This pattern was mirrored by COX4I2, another atypical mitochondrial subunit. High NDUFA4L2 expression was also observed in human brain pericytes in vitro, decreasing when pericytes are muscularized and further induced by HIF stabilization in a PHD2/PHD3 dependent manner. In vivo, Vhl conditional inactivation in pericyte targeting Ng2-cre transgenic mice dramatically induced NDUFA4L2 expression. Finally NDUFA4L2 inactivation in pericytes increased oxygen consumption and therefore the degree of HIF pathway induction in hypoxia. In conclusion our work reveals that NDUFA4L2 together with COX4I2 is a key hypoxic-induced metabolic marker constitutively expressed in pericytes coupling mitochondrial oxygen consumption and cellular hypoxia response.
format Online
Article
Text
id pubmed-9875353
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher SAGE Publications
record_format MEDLINE/PubMed
spelling pubmed-98753532023-01-26 Unique expression of the atypical mitochondrial subunit NDUFA4L2 in cerebral pericytes fine tunes HIF activity in response to hypoxia Mesa-Ciller, Claudia Turiel, Guillermo Guajardo-Grence, Andrea Lopez-Rodriguez, Ana Belen Egea, Javier De Bock, Katrien Aragonés, Julián Urrutia, Andrés A J Cereb Blood Flow Metab Original Articles A central response to insufficient cerebral oxygen delivery is a profound reprograming of metabolism, which is mainly regulated by the Hypoxia Inducible Factor (HIF). Among other responses, HIF induces the expression of the atypical mitochondrial subunit NDUFA4L2. Surprisingly, NDUFA4L2 is constitutively expressed in the brain in non-hypoxic conditions. Analysis of publicly available single cell transcriptomic (scRNA-seq) data sets coupled with high-resolution multiplexed fluorescence RNA in situ hybridization (RNA F.I.S.H.) revealed that in the murine and human brain NDUFA4L2 is exclusively expressed in mural cells with the highest levels found in pericytes and declining along the arteriole-arterial smooth muscle cell axis. This pattern was mirrored by COX4I2, another atypical mitochondrial subunit. High NDUFA4L2 expression was also observed in human brain pericytes in vitro, decreasing when pericytes are muscularized and further induced by HIF stabilization in a PHD2/PHD3 dependent manner. In vivo, Vhl conditional inactivation in pericyte targeting Ng2-cre transgenic mice dramatically induced NDUFA4L2 expression. Finally NDUFA4L2 inactivation in pericytes increased oxygen consumption and therefore the degree of HIF pathway induction in hypoxia. In conclusion our work reveals that NDUFA4L2 together with COX4I2 is a key hypoxic-induced metabolic marker constitutively expressed in pericytes coupling mitochondrial oxygen consumption and cellular hypoxia response. SAGE Publications 2022-08-04 2023-01 /pmc/articles/PMC9875353/ /pubmed/35929074 http://dx.doi.org/10.1177/0271678X221118236 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Articles
Mesa-Ciller, Claudia
Turiel, Guillermo
Guajardo-Grence, Andrea
Lopez-Rodriguez, Ana Belen
Egea, Javier
De Bock, Katrien
Aragonés, Julián
Urrutia, Andrés A
Unique expression of the atypical mitochondrial subunit NDUFA4L2 in cerebral pericytes fine tunes HIF activity in response to hypoxia
title Unique expression of the atypical mitochondrial subunit NDUFA4L2 in cerebral pericytes fine tunes HIF activity in response to hypoxia
title_full Unique expression of the atypical mitochondrial subunit NDUFA4L2 in cerebral pericytes fine tunes HIF activity in response to hypoxia
title_fullStr Unique expression of the atypical mitochondrial subunit NDUFA4L2 in cerebral pericytes fine tunes HIF activity in response to hypoxia
title_full_unstemmed Unique expression of the atypical mitochondrial subunit NDUFA4L2 in cerebral pericytes fine tunes HIF activity in response to hypoxia
title_short Unique expression of the atypical mitochondrial subunit NDUFA4L2 in cerebral pericytes fine tunes HIF activity in response to hypoxia
title_sort unique expression of the atypical mitochondrial subunit ndufa4l2 in cerebral pericytes fine tunes hif activity in response to hypoxia
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9875353/
https://www.ncbi.nlm.nih.gov/pubmed/35929074
http://dx.doi.org/10.1177/0271678X221118236
work_keys_str_mv AT mesacillerclaudia uniqueexpressionoftheatypicalmitochondrialsubunitndufa4l2incerebralpericytesfinetuneshifactivityinresponsetohypoxia
AT turielguillermo uniqueexpressionoftheatypicalmitochondrialsubunitndufa4l2incerebralpericytesfinetuneshifactivityinresponsetohypoxia
AT guajardogrenceandrea uniqueexpressionoftheatypicalmitochondrialsubunitndufa4l2incerebralpericytesfinetuneshifactivityinresponsetohypoxia
AT lopezrodriguezanabelen uniqueexpressionoftheatypicalmitochondrialsubunitndufa4l2incerebralpericytesfinetuneshifactivityinresponsetohypoxia
AT egeajavier uniqueexpressionoftheatypicalmitochondrialsubunitndufa4l2incerebralpericytesfinetuneshifactivityinresponsetohypoxia
AT debockkatrien uniqueexpressionoftheatypicalmitochondrialsubunitndufa4l2incerebralpericytesfinetuneshifactivityinresponsetohypoxia
AT aragonesjulian uniqueexpressionoftheatypicalmitochondrialsubunitndufa4l2incerebralpericytesfinetuneshifactivityinresponsetohypoxia
AT urrutiaandresa uniqueexpressionoftheatypicalmitochondrialsubunitndufa4l2incerebralpericytesfinetuneshifactivityinresponsetohypoxia