This ex vivo study used live-cell calcium (Ca²⁺) imaging to examine the downstream impact of TRPM3 ion channel dysfunction on cytosolic and mitochondrial Ca²⁺ mobilization in NK cells from 8 post-COVID-19 condition (PCC) patients versus 8 age- and sex-matched healthy controls (HC), using pregnenolone sulfate (PregS) to stimulate TRPM3 and ononetin to inhibit it.
Passive cytosolic Ca²⁺ influx amplitude was significantly reduced in PCC vs. HC (p < 0.0001), while passive mitochondrial Ca²⁺ mobilization was significantly increased (p < 0.0001). TRPM3-dependent cytosolic Ca²⁺ mobilization (PCC median 1.06 vs. HC median 1.11, p < 0.001) and mitochondrial Ca²⁺ mobilization (p < 0.0005) were both significantly reduced in PCC; cytoplasmic and mitochondrial response rates (slope) to PregS stimulation were also significantly lower in PCC (p < 0.001).
- Very small sample size (N=8 per group) with strict exclusion criteria limits generalizability. - Ex vivo primary NK cells had limited yield per participant, constraining the number of experimental conditions testable. - All experiments performed at room temperature (20–25°C), which may not reflect physiological conditions.
TRPM3 dysfunction in NK cells appears to impair both cytosolic and mitochondrial Ca²⁺ signalling in PCC, potentially underpinning reduced NK cell cytotoxicity. Clinicians should be aware that PCC may involve measurable ion channel and mitochondrial dysfunction, supporting the case for further mechanistic and therapeutic research targeting Ca²⁺ signalling pathways in this condition.
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