TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control

Gatliff, J; East, D A; Crosby, J; Abeti, R; Harvey, R; Craigen, W; Parker, P; Campanella, M

Abstract

The 18-kDa TSPO (translocator protein) localizes on the outer mitochondrial membrane (OMM) and participates in cholesterol transport. Here, we report that TSPO inhibits mitochondrial autophagy downstream of the PINK1-PARK2 pathway, preventing essential ubiquitination of proteins. TSPO abolishes mitochondrial relocation of SQSTM1/p62 (sequestosome 1), and consequently that of the autophagic marker LC3 (microtubule-associated protein 1 light chain 3), thus leading to an accumulation of dysfunctional mitochondria, altering the appearance of the network. Independent of cholesterol regulation, the modulation of mitophagy by TSPO is instead dependent on VDAC1 (voltage-dependent anion channel 1), to which TSPO binds, reducing mitochondrial coupling and promoting an overproduction of reactive oxygen species (ROS) that counteracts PARK2-mediated ubiquitination of proteins. These data identify TSPO as a novel element in the regulation of mitochondrial quality control by autophagy, and demonstrate the importance for cell homeostasis of its expression ratio with VDAC1.

Citation

Gatliff, J., East, D. A., Crosby, J., Abeti, R., Harvey, R., Craigen, W., Parker, P., & Campanella, M. (2014). TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control. Autophagy, 10(12), 2279-96. https://doi.org/10.4161/15548627.2014.991665

• Journal Article Type: Article
• Acceptance Date: Sep 22, 2014
• Publication Date: Dec 3, 2014
• Deposit Date: Feb 18, 2015
• Publicly Available Date: Feb 18, 2015
• Journal: Autophagy
• Print ISSN: 1554-8627
• Electronic ISSN: 1554-8635
• Publisher: Taylor and Francis
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 12
• Pages: 2279-96
• DOI: https://doi.org/10.4161/15548627.2014.991665
• Public URL: https://rvc-repository.worktribe.com/output/1404635