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Brain and Mind Research Institute

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https://hdl.handle.net/1813/116811

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Recent Submissions

Now showing 1 - 4 of 4
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    Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology
    Barnett, D.; Zimmer, T.S.; Booraem, C.; Palaguachi, F.; Meadows, S.M.; Xiao, H.; Wong, M.Y.; Luo, W.; Gan, L.; Chouchani, E.T.; Orr, A.G.; Orr, A.L. (Nature Research, 2025-11-04)
    Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signalling, but its triggers, temporal dynamics, targets and disease relevance are not clear. Here, using site-selective suppressors and genetic manipulations together with live mitochondrial ROS imaging and multiomic profiling, we show that CIII is a dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII ROS production is dependent on nuclear factor-κB and the mitochondrial sodium-calcium exchanger (NCLX) and causes oxidation of select cysteines within immune- and metabolism-associated proteins linked to neurological disease. CIII ROS amplify metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitate neuronal toxicity. Therapeutic suppression of CIII ROS in mice decreases dementia-linked tauopathy and neuroimmune cascades and extends lifespan. Our findings establish CIII ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease.
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    Scientists on the spot: Costantino Iadecola.
    Adao, R.; Iadecola, C. (Oxford University Press, 4/8/25)
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    The pathobiology of neurovascular aging.
    Santisteban, M.M.; Iadecola, C. (Cell Press, 1/8/25)
    As global life expectancy increases, age-related brain diseases such as stroke and dementia have become leading causes of death and disability. The aging of the neurovasculature is a critical determinant of brain aging and disease risk. Neurovascular cells are particularly vulnerable to aging, which induces significant structural and functional changes in arterial, venous, and lymphatic vessels. Consequently, neurovascular aging impairs oxygen and glucose delivery to active brain regions, disrupts endothelial transport mechanisms essential for blood-brain exchange, compromises proteostasis by reducing the clearance of potentially toxic proteins, weakens immune surveillance and privilege, and deprives the brain of key growth factors required for repair and renewal. In this review, we examine the effects of neurovascular aging on brain function and its role in stroke, vascular cognitive impairment, and Alzheimer's disease. Finally, we discuss key unanswered questions that must be addressed to develop neurovascular strategies aimed at promoting healthy brain aging.