Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation

Abstract

Calcium dynamics control synaptic transmission. Calcium triggers synaptic vesicle fusion, determines release probability, modulates vesicle recycling, participates in long-term plasticity and regulates cellular metabolism. Mitochondria, the main source of cellular energy, serve as calcium signaling hubs. Mitochondrial calcium transients are primarily determined by the balance between calcium influx, mediated by the mitochondrial calcium uniporter (MCU), and calcium efflux through the sodium/lithium/calcium exchanger (NCLX). We identified a human recessive missense SLC8B1 variant that impairs NCLX activity and is associated with severe mental retardation. On this basis, we examined the effect of deleting NCLX in mice on mitochondrial and synaptic calcium homeostasis, synaptic activity, and plasticity. Neuronal mitochondria exhibited basal calcium overload, membrane depolarization, and a reduction in the amplitude and rate of calcium influx and efflux. We observed smaller cytoplasmic calcium transients in the presynaptic terminals of NCLX-KO neurons, leading to a lower probability of release and weaker transmission. In agreement, synaptic facilitation in NCLX-KO hippocampal slices was enhanced. Importantly, deletion of NCLX abolished long term potentiation of Schaffer collateral synapses. Our results show that NCLX controls presynaptic calcium transients that are crucial for defining synaptic strength as well as short- and long-term plasticity, key elements of learning and memory processes.

Abnormal levels of mitochondrial Ca 2+ channel proteins in plasma neuron‐derived extracellular vesicles of early schizophrenia

“…The identification of diverse mitochondrial and ion channel proteins as susceptibility biomarkers for the development of schizophrenia in both genome‐wide association study (GWAS) and whole exome protein‐coding sequence studies 9,15,17,18 is in agreement with our findings of abnormal NDEV levels of NCLX, LETM1, and CACNA‐1C, in FP (Figure 2). CACNA‐1C is a voltage‐regulated calcium channel that regulates mitochondrial bioenergetics at several levels.…”

Disrupted expression of mitochondrial NCLX sensitizes neuroglial networks to excitotoxic stimuli and renders synaptic activity toxic

“…As attempts to validate NCLX knockdown on the protein level using several commercially available antibodies yielded variable results—consistent with a number of recent studies citing the inadequacy of most anti-NCLX antibodies to detect native NCLX protein ( 28 , 29 , 30 )—we verified the effectiveness of our shRNAs for reducing NCLX protein expression by cotransfecting human embryonic kidney 293 (HEK293) cells with a plasmid driving the coexpression of enhanced GFP (EGFP) and murine NCLX (pAAV-EGFP.T2A.NCLX; Fig. S2 A ) and plasmids driving the expression of shCTRL, shNCLX, shNCLX-2, or none of these ( Fig.…”

Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients

“…The difference in excitability might reflect altered synaptic activity in KO neurons. A recent study showed that the deletion of NCLX caused decreased synaptic activity and plasticity in neuronal mitochondria ( 58 ). When we included in our analysis only those neurons that were responsive to Bicu + 4AP, we found that Δ[Ca 2+ ] c rise was not significantly attenuated in KO as compared with WT neurons ( Fig.…”