Mitochondrial Ca²⁺Uptake Is Essential for Synaptic Plasticity in Pain

Abstract

The increase of cytosolic free Ca2+ ([Ca2+]C) due to NMDA receptor activation is a key step for spinal cord synaptic plasticity by altering cellular signal transduction pathways. We focus on this plasticity as a cause of persistent pain. To provide a mechanism for these classic findings, we report that [Ca2+]C does not trigger synaptic plasticity directly but must first enter into mitochondria. Interfering with mitochondrial Ca2+ uptake during a [Ca2+]C increase blocks induction of behavioral hyperalgesia and accompanying downstream cell signaling, with reduction of spinal long term potentiation (LTP). Furthermore, reducing the accompanying mitochondrial superoxide levels lessens hyperalgesia and LTP induction. These results indicate that [Ca2+]C requires downstream mitochondrial Ca2+ uptake with consequent production of reactive oxygen species (ROS) for synaptic plasticity underlying chronic pain. These results suggest modifying mitochondrial Ca2+ uptake and thus ROS as a type of chronic pain therapy that should also have broader biologic significance.

Miro1‐dependent mitochondrial positioning drives the rescaling of presynaptic Ca 2+ signals during homeostatic plasticity

“…This agrees with previous studies suggesting that mitochondria play a role after Ca 2+ has accumulated in the presynaptic terminal 20, 21 and is also supported by earlier less direct studies which demonstrate that either pharmacological inhibition of mitochondrial Ca 2+ buffering or genetic intervention to direct mitochondria out of terminals increases presynaptic Ca 2+ responses 6, 22, 23, 24, 25. The threshold of 20 stimuli could correspond to depletion of the entire readily releasable pool of neurotransmitter vesicles, because this is thought to be fully released within 2 s of 20 Hz stimulation 26.…”

The Contribution of Mitochondria to Sensory Processing and Pain

“…NMDA evoked a 2.5-fold increase in mitochondrial Ca 2+ levels (visualized with Rhod2/AM) in the superficial and deep dorsal horn which was markedly inhibited by pretreatment, but not posttreatment, with Ru360. 16 Ru360 also inhibited NMDA-evoked increases in mitochondrial superoxide levels in the superficial and deep dorsal horn. Using spinal cord slice preparations, Ru360 was shown to block spinal LTP despite large increases in cytosolic Ca 2+ levels (which were unaffected by Ru360).…”

“…16 Pretreatment with intrathecal Ru360 significantly inhibited the development of NMDA-evoked mechanical hypersensitivity in the hind paw. However, Ru360 had no effect on established NMDAevoked mechanical hypersensitivity.…”

“…Using spinal cord slice preparations, Ru360 was shown to block spinal LTP despite large increases in cytosolic Ca 2+ levels (which were unaffected by Ru360). 16 This indicates that high levels of Ca 2+ cannot directly trigger LTP unless Ca 2+ is first sequestered by mitochondria. Blockade of mitochondrial Ca 2+ uptake also prevented the phosphorylation of several protein kinases in the spinal cord that have been implicated in synaptic plasticity and pain processing, namely protein kinase C, protein kinase A (PKA), and extracellular signal-related kinase (ERK).…”

“…Blockade of mitochondrial Ca 2+ uptake also prevented the phosphorylation of several protein kinases in the spinal cord that have been implicated in synaptic plasticity and pain processing, namely protein kinase C, protein kinase A (PKA), and extracellular signal-related kinase (ERK). 16 In recent years, different components of mitochondrial Ca 2+ transport have been identified in major breakthroughs for the field of mitochondrial research. [17][18][19] Using RT-PCR of RNA extracted from neuron-enriched DRG cultures, transcripts of the MCU, mitochondrial calcium uptake 1, Na + /Ca 2+ /Li + exchanger, and leucine zipper EF hand-containing transmembrane protein (Letm1) were all observed, providing further evidence for mitochondrial calcium buffering in sensory neurons.…”