You are here

Astrocytic Complex III ROS Amplifies Detrimental Neuroimmune Signaling and Dementia-related Pathogenesis

Who Should Attend: 
Event Flyer: 
PDF icon orr-12-19-23.pdf


Alterations in mitochondria are implicated in aging and disease and involve increases in superoxide and other reactive oxygen species (ROS). Mitochondrial complex III (CIII-ROS) is a key driver of oxidative changes, but its exact triggers and downstream molecular, functional, and pathogenic contributions are not clear. In our latest work, we used S3QELs (“sequels”), site-selective suppressors of CIII-ROS, together with live-cell imaging of subcompartmental ROS, stoichiometric redox proteomics, transcriptomics, and complementary models of dementiaassociated tauopathy and amyloid pathology to investigate the involvement of CIIIROS in diseaserelated processes. Our findings suggest that CIIIROS are induced in astrocytes in a context-dependent manner by select stimuli that dysregulate mitochondrial ion exchange. Increases in astrocytic CIII-ROS cause targeted protein oxidation and altered transcription that exacerbated pathogenic proceses. Therapeutic suppression of CIII-ROS reduced neuropathology in mouse models of dementia and extended lifespan. Therefore, CIII-ROS amplifies pathogenic processes in the brain and represents a new target for neurological disorders.


Adam L Orr, Leonardo Vargas, Carolina N Turk, Janine E Baaten, Jason T Matzen, Victoria J Dardov, Stephen J Attle, Jing Li, Douglas C Quackenbush, Renata L S Goncalves, Irina V Perevoshchikova, H Michael Petrassi, Shelly L Meeusen, Edward K Ainscow, Martin D Brand
Suppressors of superoxide production from mitochondrial complex III
Nat Chem Biol . 2015 Nov;11(11):834-6. doi: 10.1038/nchembio.1910. Epub 2015 Sep 14.
Martin D Brand, Renata L S Goncalves, Adam L Orr, Leonardo Vargas, Akos A Gerencser, Martin Borch Jensen, Yves T Wang, Simon Melov, Carolina N Turk, Jason T Matzen, Victoria J Dardov, H Michael Petrassi, Shelly L Meeusen, Irina V Perevoshchikova, Heinrich Jasper, Paul S Brookes, Edward K Ainscow
Suppressors of Superoxide-H2O2 Production at Site IQ of Mitochondrial Complex I Protect against Stem Cell Hyperplasia and Ischemia-Reperfusion Injury
Cell Metab . 2016 Oct 11;24(4):582-592. doi: 10.1016/j.cmet.2016.08.012. Epub 2016 Sep 22.
Avital Licht-Murava, Samantha M Meadows, Fernando Palaguachi, Soomin C Song, Stephanie Jackvony, Yaron Bram, Constance Zhou, Robert E Schwartz, Robert C Froemke, Adam L Orr, Anna G Orr
Astrocytic TDP-43 dysregulation impairs memory by modulating antiviral pathways and interferon-inducible chemokines
Sci Adv . 2023 Apr 21;9(16):eade1282. doi: 10.1126/sciadv.ade1282. Epub 2023 Apr 19.


Tuesday, December 19, 2023 - 12:30pm


Conference Room: 
Billings Building – Rosedale

More Information

Darlene White