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WWOX inhibition by Zfra1-31 restores mitochondrial homeostasis and viability of neuronal cells exposed to high glucose

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Abstract

Diabetes has been associated with an increased risk of cognitive decline and dementia. However, the mechanisms underlying this association remain unclear and no effective therapeutic interventions exist. Accumulating evidence demonstrates that mitochondrial defects are a key feature of diabetes contributing to neurodegenerative events. It has also been demonstrated that the putative tumor suppressor WW domain-containing oxidoreductase 1 (WWOX) can interact with mitochondria in several pathological conditions. However, its role in diabetes-associated neurodegeneration remains unknown. So, this study aimed to evaluate the role of WWOX activation in high glucose-induced neuronal damage and death. Our experiments were mainly performed in differentiated SH-SY5Y neuroblastoma cells exposed to high glucose and treated (or not) with Zfra1-31, the specific inhibitor of WWOX. Several parameters were analyzed namely cell viability, WWOX activation (tyrosine 33 residue phosphorylation), mitochondrial function, reactive oxygen species (ROS) production, biogenesis, and dynamics, autophagy and oxidative stress/damage. The levels of the neurotoxic proteins amyloid β (Aβ) and phosphorylated Tau (pTau) and of synaptic integrity markers were also evaluated. We observed that high glucose increased the levels of activated WWOX. Interestingly, brain cortical and hippocampal homogenates from young (6-month old) diabetic GK rats showed increased levels of activated WWOX compared to older GK rats (12-month old) suggesting that WWOX plays an early role in the diabetic brain. In neuronal cells, high glucose impaired mitochondrial respiration, dynamics and biogenesis, increased mitochondrial ROS production and decreased mitochondrial membrane potential and ATP production. More, high glucose augmented oxidative stress/damage and the levels of Aβ and pTau proteins and affected autophagy, contributing to the loss of synaptic integrity and cell death. Of note, the activation of WWOX preceded mitochondrial dysfunction and cell death. Importantly, the inhibition of WWOX with Zfra1-31 reversed, totally or partially, the alterations promoted by high glucose. Altogether our observations demonstrate that under high glucose conditions WWOX activation contributes to mitochondrial anomalies and neuronal damage and death, which suggests that WWOX is a potential therapeutic target for early interventions. Our findings also support the efficacy of Zfra1-31 in treating hyperglycemia/diabetes-associated neurodegeneration.

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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

The authors’ work is supported by the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme, the COMPETE 2020—Operational Programme for Competitiveness and Healthy Aging 2020 (CENTRO-01-0145-FEDER-000012) and national funds from FCT—Foundation for Science and Technology under the project PEst-C/SAU/LA0001/2013-2014; EXPL/MED-FSL/0033/2021 and strategic projects UIDB/04539/2020; UIDP/04539/2020 and LA/P/0058/2020". Cristina Carvalho has a work contract under the Individual Call to Scientific Employment Stimulus—1st Edition (CEECIND/02201/2017).

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Authors and Affiliations

  1. Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal

    Cristina Carvalho, Sónia C. Correia & Paula I. Moreira

  2. Center for Innovation in Biomedicine and Biotechnology (CIBB), Coimbra, Portugal

    Cristina Carvalho, Sónia C. Correia & Paula I. Moreira

  3. Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal

    Cristina Carvalho & Sónia C. Correia

  4. Institute of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    Raquel Seiça & Paula I. Moreira

  5. Laboratory of Physiology, Faculty of Medicine, University of Coimbra, 3000-354, Coimbra, Portugal

    Paula I. Moreira

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All authors contributed to the study conception and design and results interpretation. Material preparation, data collection and analysis were performed by CC. Cells acquisition and preparation were made by SC. RS was responsible for GK and Wistar control rats colonies maintenance and breeding. The first draft of the manuscript was written by CC. PM helped in the experimental design, results discussion and revised the manuscript.

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Correspondence to Cristina Carvalho or Paula I. Moreira.

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Carvalho, C., Correia, S.C., Seiça, R. et al. WWOX inhibition by Zfra1-31 restores mitochondrial homeostasis and viability of neuronal cells exposed to high glucose. Cell. Mol. Life Sci. 79, 487 (2022). https://doi.org/10.1007/s00018-022-04508-7

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