Focusing on the mitochondrial expression of TSPO as a marker and promoter of neuroinflammation

Accumulation of damaged mitochondria is a hallmark of ageing cells and it is particularly debilitating in post-mitotic cells, making the brain particularly vulnerable. Senescent mitochondria undergo structural and functional alterations that reduce their capacity to generate ATP by oxidative phosphorylation, but increase their production of damaging reactive oxygen species (ROS). Such damaged and dangerous mitochondria are normally removed by mitophagy, but ROS inhibits this defence mechanism (1). The opportunity therefore exists for a positive feedback in which damaged mitochondria accumulate and perpetuate their existence. This deleterious outcome may be especially problematic in microglia, because ROS accumulation promotes their activation, and such activation is widely held to underscore neurodegenerative mechanisms (2). Interestingly, microglial activation involves markedly increased expression of the mitochondrial translocator protein (TSPO) receptor (3-5), and changes in this expression can be monitored in animals and patients using radio-labelled ligands detectable by positron emission tomography (PET), such as ligand [18F]GE-180 developed by our collaborators (6).

Consistent with this background, our most recent data highlight that TSPO overexpression increases cellular oxidative stress and an impairment of the Parkin-mediated selection of mitophagy (7). However, it remains unclear whether the TSPO-mediated inhibition of mitophagy contributes to the activation of the microglia and hence if the impaired clearance of defective mitochondria has a role in sustaining their immune response.
Another uncertainty is whether the redox state of the cell influences the affinity of the radio-ligand to the TSPO. If it does, the interpretation of PET images becomes problematic, not least because the redox state can change with age.
We will explore these problems by adopting in vitro and in vivo protocols to modulate TSPO expression and monitor its contribution to cell mitophagy in microglia, correlating the findings with ROS and anti-ROS signalling mechanisms to examine the binding affinity of TSPO ligands and how this may change with age.
This work will outline a fundamental and regulatory pathway, TSPO-dependent, for the activation of the brain's immune cells by impacting the ontology of mitophagy in microglial adaptation via selection of mitochondria during stress conditions. Proof of concept to improve TSPO targeting for advanced PET imaging of neuroinflammation will be also obtained.