Regulation of PRUNE and the ATP synthase is involved in Myalgic encephalomyelitis

In 2011 an analysis identified eleven genes which may play important roles in Myalgic encephalomyelitis (ME) (1):

WASF3 = WAVE3

NUP98

PRUNE = PRUNE1

KIRREL = KIRREL3  

TNK2 = ACK1

EIF3S8 = EIF3C

HOXA1

PMS2L5 = PMS2P5

HDAC7A =  HDAC7

GRP41 = FFAR3

MAP3K2

In 2023 it was shown that WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in Myalgic encephalomyelitis (2).

What about the ten other genes on the list?

PRUNE is interesting! Data indicate that the protein Prune regulates the activity of the mitochondrial ATP synthase (complex V). The loss of Prune inhibits the activity of the ATP synthase, and it decreases the prodution af ATP (3). 

And research suggest that ME patients may have a defect in the ATP synthase and dysregulated mitochondrial function (4).

Prune regulates the metabolism of inorganic polyphosphate (polyP). We need to look into what role polyP may have in ME. Start reading:  

Human Prune Regulates the Metabolism of Mammalian Inorganic Polyphosphate and Bioenergetics

Enzymatic Depletion of Mitochondrial Inorganic Polyphosphate (polyP) Increases the Generation of Reactive Oxygen Species (ROS) and the Activity of the Pentose Phosphate Pathway (PPP) in Mammalian Cells

Inorganic polyphosphate and energy metabolism in mammalian cells

Depletion of mitochondrial inorganic polyphosphate (polyP) in mammalian cells causes metabolic shift from oxidative phosphorylation to glycolysis

Inorganic polyphosphate is produced and hydrolyzed in F0F1-ATP synthase of mammalian mitochondria

Is there a link between inorganic polyphosphate (polyP), mitochondria, and neurodegeneration?

Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation

Excessive release of inorganic polyphosphate by ALS/FTD astrocytes causes non-cell-autonomous toxicity to motoneurons

References

1) Pihur V, Datta S, Datta S. Meta analysis of Chronic Fatigue Syndrome through integration of clinical, gene expression, SNP and proteomic data. Bioinformation. 2011 Apr 22;6(3):120-4. doi: 10.6026/97320630006120. PMID: 21584188; PMCID: PMC3089886.

https://pubmed.ncbi.nlm.nih.gov/21584188/ 

2) Wang PY, Ma J, Kim YC, Son AY, Syed AM, Liu C, Mori MP, Huffstutler RD, Stolinski JL, Talagala SL, Kang JG, Walitt BT, Nath A, Hwang PM. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2302738120. doi: 10.1073/pnas.2302738120. Epub 2023 Aug 14. PMID: 37579159; PMCID: PMC10450651.2) 

https://pubmed.ncbi.nlm.nih.gov/37579159/

3) Scoma ER, Da Costa RT, Leung HH, Urquiza P, Guitart-Mampel M, Hambardikar V, Riggs LM, Wong CO, Solesio ME. Human Prune Regulates the Metabolism of Mammalian Inorganic Polyphosphate and Bioenergetics. Int J Mol Sci. 2023 Sep 8;24(18):13859. doi: 10.3390/ijms241813859. PMID: 37762163; PMCID: PMC10531210.

https://pubmed.ncbi.nlm.nih.gov/37762163/

4) Missailidis D, Annesley SJ, Allan CY, Sanislav O, Lidbury BA, Lewis DP, Fisher PR. An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients. Int J Mol Sci. 2020 Feb 6;21(3):1074. doi: 10.3390/ijms21031074. PMID: 32041178; PMCID: PMC7036826.

https://pubmed.ncbi.nlm.nih.gov/32041178/