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

Autor:	Mesa-Ciller C; Unidad de Investigación, Hospital de Santa Cristina, Instituto de Investigación del Hospital Universitario La Princesa, Departamento de Medicina, Universidad Autónoma de Madrid, Madrid, Spain., Turiel G; Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland., Guajardo-Grence A; Unidad de Investigación, Hospital de Santa Cristina, Instituto de Investigación del Hospital Universitario La Princesa, Departamento de Medicina, Universidad Autónoma de Madrid, Madrid, Spain., Lopez-Rodriguez AB; Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain.; Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, UAM, Madrid, Spain., Egea J; Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain.; Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, UAM, Madrid, Spain., De Bock K; Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland., Aragonés J; Unidad de Investigación, Hospital de Santa Cristina, Instituto de Investigación del Hospital Universitario La Princesa, Departamento de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.; CIBER de Enfermedades Cardiovasculares, Carlos III Health Institute, Madrid, Spain., Urrutia AA; Unidad de Investigación, Hospital de Santa Cristina, Instituto de Investigación del Hospital Universitario La Princesa, Departamento de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
Jazyk:	angličtina
Zdroj:	Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism [J Cereb Blood Flow Metab] 2023 Jan; Vol. 43 (1), pp. 44-58. Date of Electronic Publication: 2022 Aug 04.
DOI:	10.1177/0271678X221118236
Abstrakt:	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.
Databáze:	MEDLINE
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