Bottom-up proteomics suggests an association between differential expression of mitochondrial proteins and chronic fatigue syndrome

Abstract

Chronic fatigue syndrome (CFS) is a debilitating and complex disorder characterized by unexplained fatigue not improved by rest. An area of investigation is the likely connection of CFS with defective mitochondrial function. In a previous work, we investigated the proteomic salivary profile in a couple of monozygotic twins discordant for CFS. Following this work, we analyzed mitochondrial proteins in the same couple of twins. Nano-liquid chromatography electrospray ionization mass spectrometry (nano-LC-MS) was used to study the mitochondria extracted from platelets of the twins. Subsequently, we selected three proteins that were validated using western blot analysis in a big cohort of subjects (n=45 CFS; n=45 healthy), using whole saliva (WS). The selected proteins were as follows: aconitate hydratase (ACON), ATP synthase subunit beta (ATPB) and malate dehydrogenase (MDHM). Results for ATPB and ACON confirmed their upregulation in CFS. However, the MDHM alteration was not confirmed. Thereafter, seeing the great variability of clinical features of CFS patients, we decided to analyze the expression of our proteins after splitting patients according to clinical parameters. For each marker, the values were actually higher in the group of patients who had clinical features similar to the ill twin. In conclusion, these results suggest that our potential markers could be one of the criteria to be taken into account for helping in diagnosis. Furthermore, the identification of biomarkers present in particular subgroups of CFS patients may help in shedding light upon the complex entity of CFS. Moreover, it could help in developing tailored treatments.

Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…Elevated TORC1 activity was recently observed in ME/CFS cells (lymphoblasts) and this was accompanied by inefficient mitochondrial ATP synthesis and abnormally high, presumably compensatory expression of mitochondrial proteins [41]. Elevated expression of mitochondrial proteins has also been found in other studies of patient saliva, lymphocytes and platelets [41,[49][50][51]. Furthermore, reduced creatine kinase (CK) levels in the serum of people with ME/CFS may suggest reduced cellular CK presence [15], which could contribute to inefficient ATP synthesis given the enzyme's roles in ATP homeostasis [52].…”

Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?

“…There is also evidence that NAD + levels may be elevated in CFS patients (Ciregia et al 2016; Mikirova et al 2012; Naviaux et al 2016). Furthermore, the dysfunction of the TCA cycle in CFS patients reported by (Yamano et al 2016), inhibition of glycolysis and reduced levels of pyruvate reported by (Armstrong et al 2015) and inactivated AMPK together with subnormal levels of IL-6 in the striated muscles of CFS patients reported by (Brown et al 2015) are all abnormalities consistent with a pattern of metabolic downregulation associated with the cellular hibernation associated with endotoxin tolerance.…”

Chronic fatigue syndrome: progress and possibilities

“…These data reinforce the low probability of finding any meaningful abnormality in the blood. A series of interesting but preliminary studies have used proteomics, metabolomics and microbiome analyses in cross‐sectional case–control studies of patients with CFS. As these approaches measure hundreds to thousands of variables, the studies have uniformly included tens of subjects only, and the technologies are relatively new and evolving, any preliminary findings require independent replication in larger cohorts.…”