In vivo measurement of mitochondrial ROS production in mouse models of photoreceptor degeneration

Katja E Menger; Angela Logan; Ulrich F O Luhmann; Alexander J Smith; Alan F Wright; Robin R Ali; Michael P Murphy

doi:10.1016/j.rbc.2023.100007

In vivo measurement of mitochondrial ROS production in mouse models of photoreceptor degeneration

Redox Biochem Chem. 2023 Dec:5-6:None. doi: 10.1016/j.rbc.2023.100007.

Authors

Katja E Menger¹, Angela Logan², Ulrich F O Luhmann¹, Alexander J Smith¹, Alan F Wright³, Robin R Ali¹, Michael P Murphy²

Affiliations

¹ UCL Institute of Ophthalmology, Bath St, London, EC1V 9EL, UK.
² MRC-Mitochondrial Biology Unit, The Keith Peters Building, University of Cambridge, Cambridge, CB2 0XY, UK.
³ MRC Human Genetics Unit, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK.

Abstract

Retinitis pigmentosa (RP) is a disease characterised by photoreceptor cell death. It can be initiated by mutations in a number of different genes, primarily affecting rods, which will die first, resulting in loss of night vision. The secondary death of cones then leads to loss of visual acuity and blindness. We set out to investigate whether increased mitochondrial reactive oxygen species (ROS) formation, plays a role in this sequential photoreceptor degeneration. To do this we measured mitochondrial H₂O₂ production within mouse eyes in vivo using the mass spectrometric probe MitoB. We found higher levels of mitochondrial ROS that preceded photoreceptor loss in four mouse models of RP: Pde6b^rd1/rd1; Prhp2^rds/rds; RPGR^-/-; Cln6^nclf. In contrast, there was no increase in mitochondrial ROS in loss of function models of vision loss (GNAT^-/-, OGC), or where vision loss was not due to photoreceptor death (Cln3). Upregulation of Nrf2 transcriptional activity with dimethylfumarate (DMF) lowered mitochondrial ROS in RPGR^-/- mice. These findings have important implications for the mechanism and treatment of RP.

Keywords: Mitochondria: hydrogen peroxide; Photoreceptor; Retinitis pigmentosa: MitoB.