Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function.
Berta Sanz-MorelloUlrich PfistererNikolaj Winther HansenSamuel DemharterAshish ThakurKatsunori FujiiSergey A LevitskiiAlexia MontalantIrina KorshunovaPradeep Pa MammenPiotr KamenskiSatoru NoguchiBlanca Irene AldanaKarin Sørig HougaardJean-François Marie PerrierKonstantin KhodosevichPublished in: The EMBO journal (2020)
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.
Keyphrases
- oxidative stress
- single cell
- dna damage
- poor prognosis
- rna seq
- mental health
- high fat diet induced
- case report
- ischemia reperfusion injury
- type diabetes
- genome wide
- risk assessment
- climate change
- transcription factor
- gene expression
- metabolic syndrome
- insulin resistance
- induced apoptosis
- human health
- sensitive detection