• Laura Giusti, Angelo Molinaro, Maria Grazia Alessandrì, Claudia Boldrini, Federica Ciregia, Serena Lacerenza, Maurizio Ronci, Andrea Urbani, Giovanni Cioni, Maria Rosa Mazzoni, Tommaso Pizzorusso, Antonio Lucacchini, and Laura Baroncelli.
• Department of Clinical and Experimental Medicine, University of Pisa, I-56126, Pisa, Italy; School of Pharmacy, University of Camerino, I-62032 Camerino, Italy.
• Neuroscience. 2019 Jun 15; 409: 276-289.

AbstractCreatine (Cr) is a small metabolite with a central role in energy metabolism and mitochondrial function. Creatine deficiency syndromes are inborn errors of Cr metabolism causing Cr depletion in all body tissues and particularly in the nervous system. Patient symptoms involve intellectual disability, language and behavioral disturbances, seizures and movement disorders suggesting that brain cells are particularly sensitive to Cr depletion. Cr deficiency was found to affect metabolic activity and structural abnormalities of mitochondrial organelles; however a detailed analysis of molecular mechanisms linking Cr deficit, energy metabolism alterations and brain dysfunction is still missing. Using a proteomic approach we evaluated the proteome changes of the brain mitochondrial fraction induced by the deletion of the Cr transporter (CrT) in developing mutant mice. We found a marked alteration of the mitochondrial proteomic landscape in the brain of CrT deficient mice, with the overexpression of many proteins involved in energy metabolism and response to oxidative stress. Moreover, our data suggest possible abnormalities of dendritic spines, synaptic function and plasticity, network excitability and neuroinflammatory response. Intriguingly, the alterations occurred in coincidence with the developmental onset of neurological symptoms. Thus, cerebral mitochondrial alterations could represent an early response to Cr deficiency that could be targeted for therapeutic intervention.Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.

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