Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology.

Autor:	Barnett D; Helen and Robert Appel Alzheimer's Disease Research Institute, Weill Cornell Medicine, New York, NY.; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY.; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY., Zimmer TS; Helen and Robert Appel Alzheimer's Disease Research Institute, Weill Cornell Medicine, New York, NY.; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY., Booraem C; Helen and Robert Appel Alzheimer's Disease Research Institute, Weill Cornell Medicine, New York, NY.; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY.; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY., Palaguachi F; Helen and Robert Appel Alzheimer's Disease Research Institute, Weill Cornell Medicine, New York, NY.; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY., Meadows SM; Helen and Robert Appel Alzheimer's Disease Research Institute, Weill Cornell Medicine, New York, NY.; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY.; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY., Xiao H; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.; Department of Cell Biology, Harvard Medical School, Boston, MA., Chouchani ET; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.; Department of Cell Biology, Harvard Medical School, Boston, MA., Orr AG; Helen and Robert Appel Alzheimer's Disease Research Institute, Weill Cornell Medicine, New York, NY.; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY.; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY., Orr AL; Helen and Robert Appel Alzheimer's Disease Research Institute, Weill Cornell Medicine, New York, NY.; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY.; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Aug 20. Date of Electronic Publication: 2024 Aug 20.
DOI:	10.1101/2024.08.19.608708
Abstrakt:	Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signaling, but its triggers, targets, and disease relevance are not clear. Using site-selective suppressors and genetic manipulations together with mitochondrial ROS imaging and multiomic profiling, we found that CIII is the dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII-ROS production was dependent on nuclear factor-κB (NF-κB) and the mitochondrial sodium-calcium exchanger (NCLX) and caused oxidation of select cysteines within immune and metabolism-associated proteins linked to neurological disease. CIII-ROS amplified metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitated neuronal toxicity in a non-cell-autonomous manner. As proof-of-concept, suppression of CIII-ROS in mice decreased dementia-linked tauopathy and neuroimmune cascades and extended lifespan. Our findings establish CIII-ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease. Competing Interests: Competing Interests A.L.O. and A.G.O. have a patent application WO20221333237A2 for the use of SELs in treating neurodegenerative disorders and STAT3-linked cancers. E.T.C is co-founder of Matchpoint Therapeutics and co-founder of Aevum Therapeutics.
Databáze:	MEDLINE
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