Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function.

The EMBO journal 2020 Sep 15

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Parvalbumin-positive (PV+ ) fast-spiking interneurons are essential to control the firing activity of principal neuron ensembles, thereby regulating cognitive processes. The high firing frequency activity of PV+ interneurons imposes high-energy demands on their metabolism that must be supplied by distinctive machinery for energy generation. Exploring single-cell transcriptomic data for the mouse cortex, we identified a metabolism-associated gene with highly restricted expression to PV+ interneurons: Cox6a2, which codes for an isoform of a cytochrome c oxidase subunit. Cox6a2 deletion in mice disrupts perineuronal nets and enhances oxidative stress in PV+ interneurons, which in turn impairs the maturation of their morphological and functional properties. Such dramatic effects were likely due to an essential role of COX6A2 in energy balance of PV+ interneurons, underscored by a decrease in the ATP-to-ADP ratio in Cox6a2-/- PV+ interneurons. Energy disbalance and aberrant maturation likely hinder the integration of PV+ interneurons into cortical neuronal circuits, leading to behavioral alterations in mice. Additionally, in a human patient bearing mutations in COX6A2, we found a potential association of the mutations with mental/neurological abnormalities. © 2020 The Authors.

Citation

Berta Sanz-Morello, Ulrich Pfisterer, Nikolaj Winther Hansen, Samuel Demharter, Ashish Thakur, Katsunori Fujii, Sergey A Levitskii, Alexia Montalant, Irina Korshunova, Pradeep Pa Mammen, Piotr Kamenski, Satoru Noguchi, Blanca Irene Aldana, Karin Sørig Hougaard, Jean-François Perrier, Konstantin Khodosevich. Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function. The EMBO journal. 2020 Sep 15;39(18):e105759