Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients

Cabanas, Hélène; Muraki, Katsuhiko; Eaton, Natalie; Balinas, Cassandra; Staines, Donald; Marshall‐Gradisnik, Sonya

doi:10.1186/s10020-018-0046-1

Cited by 37 publications

(84 citation statements)

References 68 publications

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“…Therefore, a disturbance to calcium signalling could contribute to pathological outcomes involving immune system or bioenergetic dysfunction, both of which have been implicated in ME/CFS. In addition to the previous evidence of altered surface proteins on NK cells from ME/CFS patients, a reduction in the expression of transient receptor potential melastatin 3 (TRPM3) calcium ion channels [79] has been reported in a subpopulation of ME/CFS NK cells [80][81][82]. The reason for the reduced expression of TRPM3 in these cells is unknown but in other cell types, expression of TRPM3 is repressed by the activity of microRNA-204 (miR-204), encoded by intron 6 of the TRPM3 gene [83].…”

Section: Calcium Signallingmentioning

confidence: 90%

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Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Missailidis¹,

Annesley²,

Fisher³

2019

Preprint

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The underlying molecular basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion ("post-exertional malaise") and variably presenting, multi-system symptoms, ME/CFS is a complex disease which demands a concerted biomedical investigation from disparate fields of expertise. ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work. Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is mostly comprised of disturbances to immunological and inflammatory pathways, autonomic and neurological dysfunction, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiota disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a farreaching homeostatic shift. Due to the variability of non-overlapping symptom presentation or precipitating events such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition. Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.compounded by medical guidelines in some developed countries which are out of date regarding ME/CFS clinical practice and require urgent, overdue revision.Case definitions such as the commonly termed Oxford [1] or Fukuda [2] criteria are most often utilized throughout the UK and USA respectively, yet may fail to discriminate between generalized chronic fatigue and ME/CFS which specifically also involves PEM, which aids in characterizing this disorder as a discrete clinical entity. Also in usage are the Canadian Consensus Criteria [3] and International Consensus Criteria [4] which mandate PEM for a diagnosis of ME/CFS and therefore may be considered more specific definitions. While the presence of PEM is an optional component of the Fukuda criteria, PEM is, unfortunately, not required for research participation by all studies using this or other less strict definitions. Consequently, the discovery of a reliable diagnostic biomarker is perhaps the most common recurring theme in modern ME/CFS research. Despite myriad relevant study outcomes [5][6][7][8][9][10][11][12][13][14][15][16], no such discovery has yet been widely validated or implemented as a suitable diagnostic biomarker of ME/CFS. Not only does ME/CFS affect multiple body systems and organs, but it does so with different and time-varying levels of severity and different patterns of comorbidities in different individuals, thereby producing a highly heterogeneous patient population [7,[17][18][19][20][21][22][23]. This complexity represents a major challenge to the task of incrim...

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Section: Calcium Signallingmentioning

confidence: 90%

“…However, the opposite was observed when Ca 2+ levels were assayed by flow cytometry using Indo1, a Ca 2+ -sensitive fluorescent dye in the TRPM3-depleted NK cells [80]. Subsequent studies using whole cell patch clamping, however, have reported loss of PregS-stimulated Ca 2+ responses [81,82].…”

Section: Calcium Signallingmentioning

confidence: 99%

Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Missailidis¹,

Annesley²,

Fisher³

2019

Preprint

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“…The BOLD response is determined by neurovascular coupling (NVC) which consists of an initial feedforward mechanism of glutamate activation of a Ca 2+ dependent signalling pathway in both neurons and astrocytes to release vasoactive factors to increase local blood flow, and secondary feedback driven by metabolism [77]. Several recent studies have demonstrated that Ca 2+ mobilisation is impaired in ME/CFS from genetic [78,79], molecular biological [80], and electrophysiological aspects [81]. These observations would suggest, it is plausible that glutamate-Ca 2+ NVC pathways in patients with ME/CFS may be impaired because of reduced TRPM3 activity and Ca 2+ mobilisation.…”

Section: Discussionmentioning

confidence: 99%

Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review

et al. 2020

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Background: Since the 1990s, neuroimaging has been utilised to study Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating illness with unknown aetiology. While brain abnormalities in ME/CFS have been identified, relatively little is known regarding which specific abnormalities are consistently observed across research groups and to what extent the observed abnormalities are reproducible. Method: To identify consistent and inconsistent neuroimaging observations in ME/CFS, this retrospective and systematic review searched for studies in which neuroimaging was used to investigate brain abnormalities in ME/CFS in Ovid MEDLINE, PubMed (NCBI), and Scopus from January 1988 to July 2018. A qualitative synthesis of observations was performed to identify brain abnormalities that were consistently and inconsistently reported. Results: 63 full-text articles were included in the synthesis of results from 291 identified papers. Additional brain area recruitment for cognitive tasks and abnormalities in the brain stem are frequent observations in 11 and 9 studies using different modalities from different research teams respectively. Also, sluggish blood oxygenation level-dependent (BOLD) signal responses to tasks, reduced serotonin transporters, and regional hypometabolism are consistent observations by more than two research teams. Single observations include abnormal brain tissue properties, regional metabolic abnormalities, and association of brain measures with ME/CFS symptoms. Reduced resting cerebral blood flow and volumetric brain changes are inconsistent observations across different studies. Conclusion: Neuroimaging studies of ME/CFS have frequently observed additional brain area recruitment during cognitive tasks and abnormalities in the brain stem. The frequent observation of additional brain area recruitment and consistent observation of sluggish fMRI signal response suggest abnormal neurovascular coupling in ME/CFS.

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“…Mitochondrial processes including respiratory function are Ca 2+ -dependent, cytosolic Ca 2+ levels influence uptake by mitochondria through Ca 2+ -dependent channels [37,38]. Disruption of Ca 2+ channel function, specifically transient receptor potential melastatin 3, has been implicated in ME/CFS/SEID patient NK cell pathology resulting in decreased Ca 2+ mobilization [39,40]. As Ca 2+ is fundamental for many NK cell processes including cytotoxicity, NK cell function is consequently impaired [39,40].…”

Section: Discussionmentioning

confidence: 99%

A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease

et al. 2020

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Background Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) present with a constellation of symptoms including debilitating fatigue that is unrelieved by rest. The pathomechanisms underlying this illness are not fully understood and the search for a biomarker continues, mitochondrial aberrations have been suggested as a possible candidate. The aim of this systematic review is to collate and appraise current literature on mitochondrial changes in ME/CFS/SEID patients compared to healthy controls. Methods Embase, PubMed, Scopus and Medline (EBSCO host) were systematically searched for articles assessing mitochondrial changes in ME/CFS/SEID patients compared to healthy controls published between January 1995 and February 2020. The list of articles was further refined using specific inclusion and exclusion criteria. Quality and bias were measured using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies. Results Nineteen studies were included in this review. The included studies investigated mitochondrial structural and functional differences in ME/CFS/SEID patients compared with healthy controls. Outcomes addressed by the papers include changes in mitochondrial structure, deoxyribonucleic acid/ribonucleic acid, respiratory function, metabolites, and coenzymes. Conclusion Based on the included articles in the review it is difficult to establish the role of mitochondria in the pathomechanisms of ME/CFS/SEID due to inconsistencies across the studies. Future well-designed studies using the same ME/CFS/SEID diagnostic criteria and analysis methods are required to determine possible mitochondrial involvement in the pathomechanisms of ME/CFS/SEID.

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Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients

Cited by 37 publications

References 68 publications

Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review

A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease

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