Unidad de Investigación, Hospital de Santa Cristina, Instituto de Investigación del Hospital Universitario La Princesa, Departamento de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland.
J Cereb Blood Flow Metab. 2023 Jan;43(1):44-58. doi: 10.1177/0271678X221118236. Epub 2022 Aug 4.
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, conditional inactivation in pericyte targeting 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.
对脑氧供不足的中枢反应是代谢的深刻重编程，主要由缺氧诱导因子（HIF）调节。在其他反应中，HIF 诱导非典型线粒体亚基 NDUFA4L2 的表达。令人惊讶的是，在非缺氧条件下，NDUFA4L2 在脑中持续表达。对公开可用的单细胞转录组学 (scRNA-seq) 数据集进行分析，并结合高分辨率多重荧光 RNA 原位杂交 (RNA FISH)，结果表明在鼠和人脑中，NDUFA4L2 仅在壁细胞中表达，其中周细胞中的表达水平最高，沿动静脉平滑肌细胞轴逐渐降低。另一个非典型线粒体亚基 COX4I2 也呈现出这种模式。在体外培养的人脑周细胞中也观察到高 NDUFA4L2 表达，当周细胞肌化时表达降低，并通过 HIF 稳定以 PHD2/PHD3 依赖的方式进一步诱导。在体内，周细胞靶向的条件性缺失在转基因小鼠中显著诱导 NDUFA4L2 表达。最后，周细胞中的 NDUFA4L2 失活增加了耗氧量，从而增加了缺氧诱导 HIF 通路的程度。总之，我们的工作表明，NDUFA4L2 与 COX4I2 一起是一种关键的缺氧诱导代谢标志物，在周细胞中持续表达，将线粒体耗氧量与细胞缺氧反应偶联。
