Dolphin
Senior Member (Voting Rights)
via Dr. Marc-Alexander Fluks
Source: La Trobe University
Date: March 29, 2021
URL:
https://opal.latrobe.edu.au/article...ood_Cell-Based_Biomarkers_of_Disease/15153465
'A Cellular Chronic Fatigue'-dysregulated mitochondrial respiratory
function, metabolic and signalling pathways in ME/CFS and the
identification of blood cell-based biomarkers of disease
-------------------------------------------------------------------
Daniel Missailidis
- La Trobe University
- School of Life Sciences, Department of Physiology, Anatomy and
Microbiology, Discipline of Microbiology, College of Science,
Health and Engineering, La Trobe University, Victoria, Australia
Abstract
The lack of objective, timely, and accurate diagnostic criteria or
biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
(ME/CFS) can leave patients for long periods without a clear diagnosis.
Treatment is often based on individual trial and error due to the lack
of mechanistic understanding of the disease. It is therefore paramount
that fundamental molecular explanations for the underlying
pathophysiology of ME/CFS are pursued, as these could contribute towards
the development of reliable, faster diagnostics and rational, effective
treatments.
To address these issues, this PhD project has focused on using stably
proliferative and metabolically active cell lines(lymphoblasts)created
from ME/CFS patient blood (for the first time) to investigate
mitochondrial function, related metabolic or signalling pathways, and
potential diagnostic biomarkers. The results show that in ME/CFS
lymphoblasts, there is an isolated Complex Vinefficiency in ATP
synthesis at the final step in mitochondrial oxidative phosphorylation.
This is accompanied by multiple homeostatic compensations including
increased respiratory capacity, elevated expression of a diverse array
of mitochondrial proteins, elevated Target of Rapamycin Complex I
(TORC1) activity, and evidence suggesting dysregulated substrate
provision towards the TCA cycle and oxidative phosphorylation.
Whole-cell proteomics and transcriptomics suggested that in ME/CFS
lymphoblasts there is an increased use of alternatives to glycolysis in
provisioning the mitochondria with oxidisable substrate. This may
represent a homeostatic compensation for the respiratory inefficiency by
Complex V.Together, these compensatory changes appear to be sufficient
to meet the normal needs of active metabolism despite the inefficiency
of ATP synthesis by Complex V. However, this may leave the cells less
able to respond to further acute increases in ATP demand despite the
elevated respiratory capacity, since the signalling and metabolic
pathways involved are already chronically upregulated.
If this 'cellular chronic fatigue' is present in other cell types, it
may contribute to the unexplained fatigue experienced by ME/CFS
patients. This is suggested bythe fact that all of the mitochondrial
abnormalities observed were correlated with the severity of patient
symptoms. It was also found that multiple observed abnormalities
constituted promising biomarkers, each of them able to distinguish
ME/CFS patient and control samples with high reliability, while 100%
discriminatory accuracy became possible when using the best combinations
of variables available. This project has therefore made significant
strides in the mechanistic understanding of ME/CFS and has highlighted
promising candidate diagnostic biomarkers.
Source: La Trobe University
Date: March 29, 2021
URL:
https://opal.latrobe.edu.au/article...ood_Cell-Based_Biomarkers_of_Disease/15153465
'A Cellular Chronic Fatigue'-dysregulated mitochondrial respiratory
function, metabolic and signalling pathways in ME/CFS and the
identification of blood cell-based biomarkers of disease
-------------------------------------------------------------------
Daniel Missailidis
- La Trobe University
- School of Life Sciences, Department of Physiology, Anatomy and
Microbiology, Discipline of Microbiology, College of Science,
Health and Engineering, La Trobe University, Victoria, Australia
Abstract
The lack of objective, timely, and accurate diagnostic criteria or
biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
(ME/CFS) can leave patients for long periods without a clear diagnosis.
Treatment is often based on individual trial and error due to the lack
of mechanistic understanding of the disease. It is therefore paramount
that fundamental molecular explanations for the underlying
pathophysiology of ME/CFS are pursued, as these could contribute towards
the development of reliable, faster diagnostics and rational, effective
treatments.
To address these issues, this PhD project has focused on using stably
proliferative and metabolically active cell lines(lymphoblasts)created
from ME/CFS patient blood (for the first time) to investigate
mitochondrial function, related metabolic or signalling pathways, and
potential diagnostic biomarkers. The results show that in ME/CFS
lymphoblasts, there is an isolated Complex Vinefficiency in ATP
synthesis at the final step in mitochondrial oxidative phosphorylation.
This is accompanied by multiple homeostatic compensations including
increased respiratory capacity, elevated expression of a diverse array
of mitochondrial proteins, elevated Target of Rapamycin Complex I
(TORC1) activity, and evidence suggesting dysregulated substrate
provision towards the TCA cycle and oxidative phosphorylation.
Whole-cell proteomics and transcriptomics suggested that in ME/CFS
lymphoblasts there is an increased use of alternatives to glycolysis in
provisioning the mitochondria with oxidisable substrate. This may
represent a homeostatic compensation for the respiratory inefficiency by
Complex V.Together, these compensatory changes appear to be sufficient
to meet the normal needs of active metabolism despite the inefficiency
of ATP synthesis by Complex V. However, this may leave the cells less
able to respond to further acute increases in ATP demand despite the
elevated respiratory capacity, since the signalling and metabolic
pathways involved are already chronically upregulated.
If this 'cellular chronic fatigue' is present in other cell types, it
may contribute to the unexplained fatigue experienced by ME/CFS
patients. This is suggested bythe fact that all of the mitochondrial
abnormalities observed were correlated with the severity of patient
symptoms. It was also found that multiple observed abnormalities
constituted promising biomarkers, each of them able to distinguish
ME/CFS patient and control samples with high reliability, while 100%
discriminatory accuracy became possible when using the best combinations
of variables available. This project has therefore made significant
strides in the mechanistic understanding of ME/CFS and has highlighted
promising candidate diagnostic biomarkers.
