Journal Article

Carbon Monoxide Stimulates Both Mitophagy And Mitochondrial Biogenesis to Mediate Protection Against Oxidative Stress in Astrocytes

Ramírez-Pardo, Ignacio, Boya, Patricia, Vieira, Helena L. A., Figueiredo-Pereira, Cláudia, Tavares, Diana, Villarejo-Zori, Beatriz, Cipriano, Pedro C.

2023

Overview

Astrocytes are key glial cells for the metabolic and functional support of the brain. Mitochondrial quality control (MQC), in particular the balance between mitophagy and mitochondrial biogenesis, is a major event for the maintenance of cellular homeostasis. Carbon monoxide (CO) is an endogenous gasotransmitter that inhibits cell death and inflammation by targeting mitochondria. It is well established that CO promotes cytoprotection by increasing mitochondrial population and metabolism (oxidative phosphorylation). Thus, it is hypothesized that CO-induced cytoprotection may also be mediated by the balance between mitophagy and mitochondrial biogenesis. Herein, the carbon monoxide releasing molecule-A1 (CORM-A1) was used in primary cultures of astrocytes to assess CO role on mitochondrial turnover. PINK1/Parkin-dependent mitophagy was stimulated by CORM-A1 following 1 h of treatment. While at 24 h after treatment, CORM-A1 increased mitochondrial population, which may indicate mitochondrial biogenesis. In fact, mitochondrial biogenesis was confirmed by the enhancement of PGC-1α expression that upregulates several mitochondrial transcription factors. Furthermore, inhibition of mitophagy by knocking down PINK1 expression reverted CO-induced mitochondrial biogenesis, indicating that mitochondrial turnover is dependent on modulation of mitophagy. Finally, CORM-A1 prevented astrocytic cell death induced by oxidative stress in a mitophagy-dependent manner. In fact, whenever PINK1 was knocked down, CORM-A1-induced cytoprotection was lost. In summary, CORM-A1 stimulates mitochondrial turnover, which in turn prevents astrocytic cell death. CO cytoprotection depends on increasing mitochondrial population and on eliminating dysfunctional mitochondria.

• Publisher: Springer US,Springer Nature B.V
• Subject: Apoptosis / Astrocytes / Astrocytes - metabolism / Biomedical and Life Sciences / Biomedicine / Biosynthesis / Carbon monoxide / Carbon Monoxide - metabolism / Carbon Monoxide - pharmacology / Cell Biology / Cell death / Glial cells / Homeostasis / Mitochondria / Mitophagy / Neurobiology / Neurology / Neurosciences / Organelle Biogenesis / Oxidative metabolism / Oxidative phosphorylation / Oxidative Stress / Phosphorylation / Protein Kinases - metabolism / PTEN-induced putative kinase / Quality control / Transcription factors / Ubiquitin-Protein Ligases - metabolism