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

Tidsskriftartikel - 2020

Resume

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.

Reference

Sanz-Morello B, Pfisterer U, Winther Hansen N, Demharter S, Thakur A, Fujii K, Levitskii SA, Montalant A, Korshunova I, Mammen PP, Kamenski P, Noguchi S, Aldana BI, Hougaard KS, Perrier J, Khodosevich K. Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function. EMBO Journal 2020;e105759.
doi: 10.15252/embj.2020105759

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