Altered TRPM3-Dependent Cytosolic and Mitochondrial Calcium Influx in Natural Killer Cells of Post-COVID-19 Condition Patients.
Source: PubMed, NCBI / U.S. National Library of Medicine
According to the World Health Organization (WHO), approximately 6% of COVID-19 cases develop serious long-term sequelae referred to as post-COVID-19 condition (PCC). Immunological disturbances such as persistent activation of immune cells and reduced cytotoxicity by natural killer (NK) cells are reported as key aspects in PCC. Recently, electrophysiological studies by our group demonstrated impairment of transient receptor potential melastatin 3 (TRPM3) ion channels in NK cells from PCC patients. The significant reduction in TRPM3 channel function and reduced functional activity by NK cells warrants further investigation. Hence, using live cell calcium (Ca) imaging ex vivo, we examined the downstream impact of TRPM3 ion channel dysfunction on intracellular and mitochondrial Camobilization in NK cells from N = 8 PCC patients, age and sex matched to N = 8 PCC healthy controls (HC). Our findings provide new evidence of altered passive and TRPM3-mediated Cainflux, significantly impacting cytoplasmic and mitochondrial Camobilization in PCC. Passive cytosolic Cainflux amplitude (p < 0.0001) was significantly reduced in PCC; however, passive mitochondrial Camobilization (p < 0.0001) was significantly increased. Importantly, cytoplasmic and mitochondrial response rates (slope, p < 0.001) to pregnenolone sulphate stimulation were significantly reduced in PCC. Consequently, TRPM3-dependent cytosolic (p < 0.001) and mitochondrial (p < 0.0005) Camobilization were significantly reduced in
Abstract
According to the World Health Organization (WHO), approximately 6% of COVID-19 cases develop serious long-term sequelae referred to as post-COVID-19 condition (PCC). Immunological disturbances such as persistent activation of immune cells and reduced cytotoxicity by natural killer (NK) cells are reported as key aspects in PCC. Recently, electrophysiological studies by our group demonstrated impairment of transient receptor potential melastatin 3 (TRPM3) ion channels in NK cells from PCC patients. The significant reduction in TRPM3 channel function and reduced functional activity by NK cells warrants further investigation. Hence, using live cell calcium (Ca) imaging ex vivo, we examined the downstream impact of TRPM3 ion channel dysfunction on intracellular and mitochondrial Camobilization in NK cells from N = 8 PCC patients, age and sex matched to N = 8 PCC healthy controls (HC). Our findings provide new evidence of altered passive and TRPM3-mediated Cainflux, significantly impacting cytoplasmic and mitochondrial Camobilization in PCC. Passive cytosolic Cainflux amplitude (p < 0.0001) was significantly reduced in PCC; however, passive mitochondrial Camobilization (p < 0.0001) was significantly increased. Importantly, cytoplasmic and mitochondrial response rates (slope, p < 0.001) to pregnenolone sulphate stimulation were significantly reduced in PCC. Consequently, TRPM3-dependent cytosolic (p < 0.001) and mitochondrial (p < 0.0005) Camobilization were significantly reduced in PCC compared with HC. Altered ion channel Casignalling can severely impact both the immune system and bioenergetic processes, potentially leading to broader systemic dysregulations underpinning the pathomechanism of the PCC condition, and warrants further investigations.