A Novel Role of Fragile-X Mental Retardation Protein in Mitochondrial Calcium Homeostasis

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Fragile X syndrome (FXS) is the most prevalent form of inherited intellectual disability and the primary genetic cause of autism. FXS is caused by loss of expression of the Fmr1 gene encoding Fragile X Mental Retardation Protein (FMRP), a protein with RNA-binding activity thought to act primarily as a translational regulator. In addition to intellectual disability, FXS patients present behavioral and cognitive symptoms, irregular physical features, and metabolic symptoms. The prevailing hypothesis of FXS pathogenesis posits FMRP as a promiscuous RNA-binding protein targeting hundreds of brain RNAs, with altered translation of these mRNA targets as the underlying cause of the synaptic and neural circuit defects and behavioral phenotypes seen in FXS. However, the recent clinical failures of treatment strategies targeting some of the key translational substrates of FMRP, and the current lack of effective treatment option for FXS, argue that investigations of new biological function of FMPR and new pathogenic mechanisms of FXS are warranted. Mitochondria are dynamic and complex organelles with essential roles in many aspects of biology, from energy production and intermediary metabolism to intracellular signaling and apoptosis. These broad functions position mitochondrion as a central player in human health. In neurons, mitochondria and synapses are intimately linked. In addition to their central role in bioenergetics, mitochondria are also critically important for maintaining cellular Ca2+ homeostasis. Ca2+ uptake by mitochondria helps buffer cytosolic Ca2+ transients arising from neuronal activation, protecting against the detrimental effects of Ca2+ influx. The ER-mitochondria contact site (ERMCS) are increasingly appreciated as key structures regulating mito-Ca2+ homeostasis, and there is an emerging role of altered ERMCS and mito-Ca2+ in the pathogenesis of neurodegenerative diseases. Whether ERMCS and its role in mito-Ca2+ homeostasis is affected in major neuropsychiatric diseases such as FXS is not known. The goal of this proposal is to test the central hypothesis that FMRP acts physically at ERMCS to direct Ca2+ signaling between organelles, and that defects in this process contribute to the etiology of FXS. To test this hypothesis, we propose to achieve the following Specific Aims in this exploratory project: Aim 1. Examine defects in ERMCS formation in the Drosophila dFmr1 model and FXS patient-derived models. Aim 2. Test the physiological roles of ERMCS proteins that direct mito-Ca2+ homeostasis in mediating FMRP function. By providing evidence for the involvement of ERMCS and mito-Ca2+ in mediating FMRP function at the organellar, synaptic, and organismal levels, these studies will lay the foundation for future mechanistic studies on the regulation and function of FMRP in normal synaptic and neuronal processes underlying brain function, cognition, emotion, and social behavior. Results from this study promise to significantly advance our understanding of the fundamental roles of mitochondria and Ca2+ signaling in FXS and various related mental disorders and offer novel and rational strategies to deliver health care for patients suffering from these devastating mental illnesses.