PRUNE1 is involved in Myalgic encephalomyelitis and in exercise biology

Eleven genes may be involved in Myalgic encephalomyelitis (ME) (1):
WASF3, NUP98, PRUNE1, KIRREL3, TNK2, EIF3C, HOXA1, PMS2P5, HDAC7, FFAR3, MAP3K2.

ME patients have Post Exertional Malaise (PEM). PEM is the worsening of symptoms following even minor physical or mental exertion that would have been tolerated previously. Symptoms typically worsen 12 to 48 hours after activity. PEM can last for days or even weeks (2). Cardiopulmonary and metabolic responses during a 2-day CPET in myalgic encephalomyelitis showed the problems (3).

In a preprint page 12 and 13 (4):
Molecular Landscape of Modality-Specific Exercise Adaptation in Human Skeletal Muscle through Large-Scale Multi-OMICs Integration

you can read this, quote:

"Exercise modality-specific analyses revealed 13 intersected genes (CLIC1, SMTNL1, MRPL23, ITGA7, IFITM3, IGFBP7, SLC41A3, CHTOP, CTBP1, PRUNE1, THY1, RPRD1B, and PODXL) associated with aerobic exercise across all OMIC layers, excluding mRNA followed by inactivity."

"However, five genes (CLIC1, IFITM3, PRUNE1, RPRD1B and PODXL) appear to be newly associated with aerobic exercise training."

"PRUNE1 is implicated in various cellular processes, including cell proliferation, mitigation and survival. Its expression has been shown to be positively correlated with tumour metastasis (Ferrucci et al., 2024). Although there is no direct evidence linking PRUNE1 to exercise, its involvement in cellular processes such as cell proliferation, differentiation, and tissue repair can be indirectly associated with exercise. Exercise-induced muscle adaptation and repair processes could potentially be influenced by the mechanisms in which PRUNE1 is involved, highlighting its relevance in the context of exercise biology."

Further reading: 

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

Is TNK2 involved in the function of ATP synthase in Myalgic encephalomyelitis?

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) https://www.cdc.gov/me-cfs/hcp/clinical-care/treating-the-most-disruptive-symptoms-first-and-preventing-worsening-of-symptoms.html

3) Keller B, Receno CN, Franconi CJ, Harenberg S, Stevens J, Mao X, Stevens SR, Moore G, Levine S, Chia J, Shungu D, Hanson MR. Cardiopulmonary and metabolic responses during a 2-day CPET in myalgic encephalomyelitis/chronic fatigue syndrome: translating reduced oxygen consumption to impairment status to treatment considerations. J Transl Med. 2024 Jul 5;22(1):627. doi: 10.1186/s12967-024-05410-5. PMID: 38965566; PMCID: PMC11229500.

https://pubmed.ncbi.nlm.nih.gov/38965566/

4) PREPRINT
Molecular Landscape of Modality-Specific Exercise Adaptation in Human Skeletal Muscle through Large-Scale Multi-OMICs Integration
Macsue Jacques, Shanie Landen, Adam P Sharples, Andrew Garnham, Ralf Schittenhelm, Joel Stele, Aino Heikkinen, Elina Sillanpää, Miina Ollikainen, James Broatch, Navabeh Zarekookandeh, Ola Hanson, Ola Ekström, Olof Asplund, Séverine Lamon, Sarah E. Alexander, Cassandra Smith, Carlie Bauer, Mary N. Woessner, Itamar Levinger, Andrew E Teschendorff, Linn Gillberg, Ida Blom, Jørn Wulff Helge, Nicholas R Harvey, Larisa M Haupt, Lyn R Griffiths, Atul S. Deshmukh, Kirsi H Pietiläinen, Päivi Piirilä, Robert AE Seaborne, Bernadette Jones-Freeman, Nir Eynon
bioRxiv 2024.07.14.603458; doi: https://doi.org/10.1101/2024.07.14.603458

https://www.biorxiv.org/content/10.1101/2024.07.14.603458v1.supplementary-material

Is TNK2 involved in the function of ATP synthase in Myalgic encephalomyelitis?

Eleven genes may be involved in Myalgic encephalomyelitis (ME) (1):

WASF3, NUP98, PRUNE1, KIRREL3, TNK2, EIF3C, HOXA1, PMS2P5, HDAC7, FFAR3, MAP3K2.

WASF3 and PRUNE1 are involved in mitochondrial dysfunction as previously described:

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

Is TNK2 also involved in regulation af mitochondrial function in ME?

In cancer cells TNK2 controls the ATP synthase (2), quote:
"The challenge of rapid macromolecular synthesis enforces the energy-hungry cancer cell mitochondria to switch their metabolic phenotypes, accomplished by activation of oncogenic tyrosine kinases. Precisely how kinase activity is directly exploited by cancer cell mitochondria to meet high-energy demand, remains to be deciphered. Here we show that a non-receptor tyrosine kinase, TNK2/ACK1 (tyrosine kinase non receptor 2), phosphorylated ATP5F1A (ATP synthase F1 subunit alpha) at Tyr243 and Tyr246 (Tyr200 and 203 in the mature protein, respectively) that not only increased the stability of complex V, but also increased mitochondrial energy output in cancer cells. Further, phospho-ATP5F1A (p-Y-ATP5F1A) prevented its binding to its physiological inhibitor, ATP5IF1 (ATP synthase inhibitory factor subunit 1), causing sustained mitochondrial activity to promote cancer cell growth. TNK2 inhibitor, (R)-9b reversed this process..."

If TNK2 is involved in ME and the control of ATP synthase, then TNK2 is not phosphorylating ATP5F1A. And hypothetically TNK2 may be downregulated.

In NK cells from ME patients, TNK2 is on top of the list of downregulated kinases (table 3 in ref 3). 

Is expression of TNK2 in ME involved in the function of ATP synthase?

Further reading: 

A Review of the Inhibition of the Mitochondrial ATP Synthase by IF1 in vivo: Reprogramming Energy Metabolism and Inducing Mitohormesis

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) Chouhan S, Sawant M, Weimholt C, Luo J, Sprung RW, Terrado M, Mueller DM, Earp HS, Mahajan NP. TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability. Autophagy. 2023 Mar;19(3):1000-1025. doi: 10.1080/15548627.2022.2103961. Epub 2022 Jul 27. PMID: 35895804; PMCID: PMC9980697.

https://pubmed.ncbi.nlm.nih.gov/35895804/

3) Chacko A, Staines DR, Johnston SC, Marshall-Gradisnik SM. Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients. Gene Regul Syst Bio. 2016 Aug 28;10:85-93. doi: 10.4137/GRSB.S40036. PMID: 27594784; PMCID: PMC5003121.

https://pubmed.ncbi.nlm.nih.gov/27594784/

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/