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A Targeted Mutation Disrupting Mitochondrial Complex IV Function in Primary Afferent Neurons Leads to Pain Hypersensitivity Through P2Y1 Receptor Activation

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Abstract

As mitochondrial dysfunction is evident in neurodegenerative disorders that are accompanied by pain, we generated inducible mutant mice with disruption of mitochondrial respiratory chain complex IV, by COX10 deletion limited to sensory afferent neurons through the use of an Advillin Cre-reporter. COX10 deletion results in a selective energy-deficiency phenotype with minimal production of reactive oxygen species. Mutant mice showed reduced activity of mitochondrial respiratory chain complex IV in many sensory neurons, increased ADP/ATP ratios in dorsal root ganglia and dorsal spinal cord synaptoneurosomes, as well as impaired mitochondrial membrane potential, in these synaptoneurosome preparations. These changes were accompanied by marked pain hypersensitivity in mechanical and thermal (hot and cold) tests without altered motor function. To address the underlying basis, we measured Ca2+ fluorescence responses of dorsal spinal cord synaptoneurosomes to activation of the GluK1 (kainate) receptor, which we showed to be widely expressed in small but not large nociceptive afferents, and is minimally expressed elsewhere in the spinal cord. Synaptoneurosomes from mutant mice showed greatly increased responses to GluK1 agonist. To explore whether altered nucleotide levels may play a part in this hypersensitivity, we pharmacologically interrogated potential roles of AMP-kinase and ADP-sensitive purinergic receptors. The ADP-sensitive P2Y1 receptor was clearly implicated. Its expression in small nociceptive afferents was increased in mutants, whose in vivo pain hypersensitivity, in mechanical, thermal and cold tests, was reversed by a selective P2Y1 antagonist. Energy depletion and ADP elevation in sensory afferents, due to mitochondrial respiratory chain complex IV deficiency, appear sufficient to induce pain hypersensitivity, by ADP activation of P2Y1 receptors.

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Acknowledgments

We are grateful to Professors Carlos Moraes and John Wood FRS, for generously providing COX10flox/flox and Adv-CreERT2−/− mutants, respectively. Thanks to Anisha Kubasik-Thayil from the IMPACT Confocal Imaging facility at the University of Edinburgh for expert imaging assistance.

Funding

This work was supported by a Progressive Multiple Sclerosis Alliance Challenge Award to DJM (PA0051).

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Authors and Affiliations

  1. Centre for Discovery Brain Sciences, Edinburgh Medical School: Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK

    Rory Mitchell, Marta Mikolajczak & Sue M. Fleetwood-Walker

  2. Centre for Clinical Brain Sciences, Edinburgh Medical School, College of Medicine and Veterinary Medicine, University of Edinburgh, Chancellor’s Building, Little France, Edinburgh, Edinburgh, EH16 4SB, UK

    Graham Campbell, Katie McGill & Don Mahad

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  1. Rory Mitchell
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Mitchell, R., Campbell, G., Mikolajczak, M. et al. A Targeted Mutation Disrupting Mitochondrial Complex IV Function in Primary Afferent Neurons Leads to Pain Hypersensitivity Through P2Y1 Receptor Activation. Mol Neurobiol 56, 5917–5933 (2019). https://doi.org/10.1007/s12035-018-1455-4

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