Reduced glycolytic reserve in isolated natural killer cells from Myalgic encephalomyelitis/chronic fatigue syndrome patients: A preliminary investigation

Nguyen, Thao; Staines, Donald; Johnston, Samantha; Marshall‐Gradisnik, Sonya

doi:10.12932/ap-011117-0188

Cited by 17 publications

(21 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results support the existence of a metabolic shift, but we found no deficiency in glycolysis rates, glycolytic reserve or glycolytic capacity. Although there have been reports of reduced rates of glycolysis in ME/CFS lymphocytes [26], this contrasts with reports by others [8]. Instead of impaired glycolytic capacity driving the shift in metabolism, our results suggest that the change may be driven by elevated usage of alternatives such as the β oxidation of fatty acids.…”

Section: Discussioncontrasting

confidence: 99%

“…Other work suggests that glycolysis itself is unimpaired and that reduced conversion of pyruvate to acetyl CoA by PDH is responsible for a similar downstream consequence [17]. However, Tomas et al (2017) found no difference in glycolysis between lymphocytes from ME/CFS and control individuals [8], while Nguyen et al (2018) reported a reduction in glycolytic capacity in a small sample of NK cells from ME/CFS patients [26]. Most recently, glycolytic rates were reported to be reduced in ME/CFS CD4 + and CD8 + T-cells [15].…”

Section: Glycolytic Rates Are Unaffected In Me/cfs Lymphoblasts But mentioning

confidence: 98%

See 1 more Smart Citation

An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients

Missailidis

Annesley

Allan

et al. 2020

IJMS

View full text Add to dashboard Cite

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or “PEM”), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular marker or known underlying pathological mechanism for the condition. Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolizing patient blood cells. We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays. As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and “proton leak” as a proportion of the basal OCR. This was accompanied by a reduction of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signaling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters, and enzymes of the β-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged. Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid β-oxidation. This homeostatically returns ATP synthesis and steady state levels to “normal” in the resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated.

show abstract

Section: Discussioncontrasting

confidence: 99%

Section: Glycolytic Rates Are Unaffected In Me/cfs Lymphoblasts But mentioning

confidence: 98%

An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients

Missailidis

Annesley

Allan

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…As noted above, glycolytic catabolism of glucose is a major supplier of acetyl CoA to the TCA cycle, and this can be assayed in intact cells by measuring the rate of acidification of the medium by cells provided with glucose as a substrate. This has been reported recently using Natural Killer (NK) cells from a small sample of six patients and six healthy controls [53]. Although the authors found no differences in aerobic respiration rates, they did observe a reduced glycolytic reserve in the ME/CFS cells.…”

Section: Inefficient Atp Synthesis and Abnormal Energy Stress Signallingsupporting

confidence: 55%

Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Missailidis¹,

Annesley²,

Fisher³

2019

Preprint

View full text Add to dashboard Cite

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...

show abstract

Section: One Of the Key Upstream Regulators Of Mitochondrial Protein contrasting

confidence: 63%

Section: Glycolytic Rates Are Unaffected In Me/cfs Lymphoblasts But mentioning

confidence: 98%

An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients

Missailidis¹,

Annesley²,

Allan³

et al. 2020

Preprint

View full text Add to dashboard Cite

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or “PEM”), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular marker or known underlying pathological mechanism for the condition. Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolising patient blood cells. We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays. As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and “proton leak” as a proportion of the basal OCR. This was accompanied by a reduction of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signalling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters and enzymes of the β-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged. Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid β-oxidation. This homeostatically returns ATP synthesis and steady state levels to “normal” in the resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated.

show abstract

Reduced glycolytic reserve in isolated natural killer cells from Myalgic encephalomyelitis/chronic fatigue syndrome patients: A preliminary investigation

Cited by 17 publications

References 25 publications

An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients

An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients

Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients

Contact Info

Product

Resources

About