IDH, GOT and ME

Fluge, Mella et al. have shown that ME is associated with defective oxidative metabolism - most likely involving impaired pyruvate dehydrogenase (PDH) function (1).

A study showed that PDH suppression shifted the source of lipogenic acetyl-CoA from glucose to glutamine, and this compensatory pathway required a net reductive isocitrate dehydrogenase (IDH) flux to produce a source of glutamine-derived acetyl-CoA for fatty acid. Levels of intra- and extracellular aspartate and alanine were enhanced (2).

Another study showed that inhibition of the mitochondrial pyruvate carrier in the retina caused accumulation of aspartate at the expense of glutamate. The mitochondrial glutamate oxoglutarate transaminase (GOT2) - also knowns as aspartate aminotransferase - became upregulated (3).

Expression of IDH-proteins (IDH3A, IDH3B and IDHP) and of GOT2 have been found upregulated in ME (4).

A proteomic study on cerebrospinal fluid from ME/CFS patients has shown (5):

• IDH1, CFS:2, normal value 4
• GOT1, CFS:39, normal value 29
• GOT2, CFS:1, normal value 6

Armstrong et al have shown increased aspartate, decreased glutamate and a potentially reduced provision of acetyl-CoA for the TCA-cycle (6).

Glutamate is important as a neurotransmitter and as a substrate for glutathione synthesis. Depletion of glutamate correlates with cell death in the retina (3).

Shungu et al. have found elevated ventricular lactate and decreased glutathione in CFS patients (7).

I have noticed that some ME patients develop an early age-related degeneration of the retina. Could dysregulated metabolism be involved?

The aspartate aminotransferase blood test (ASAT) is usually normal in ME patients. Could there be a local tissue-specific dysregulayion?

If glutamate decreases, what happens to the glutamate-NO-cGMP pathway in the brain?

References:

1. Fluge et al: Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy / chronic fatigue syndrome. JCI Insight. 2016; 1(21):e89376. Doi 10.1172/jci.insight.89276
2. Rajagopalan et al. Metabolic plasticity maintains proliferation in pyruvate dehydrogenase deficient cells. Cancer & Metabolism (2015) 3:7
3. Du et al. Inhibition of mitochondrial pyruvate transport by Zaprinast couses massive accumulation of aspartate at the expence of glutamate in the retina. Journal of Biological Chemistry 288,50,dec 2013
4. Ciregia et al.
   Translational Psychiatry (2016), 6, e904
   doi:10.1038/tp.2016.184
5. Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issue 2
6. Armstrong et al. Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in CFS. Metabolomics, 2015, 11:1626-1639.
7. Dikoma C Shungu et al. Increased Ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder oathophysiology. NMR Biomed (2012)