Succinate Retention – Molecular Biology of Oxygen

Majid Ali, M.D.

Below is the letter which I received about my Krebs Cycle Studies.


[Nature] Your post has been approved

Date: 6/19/2015 3:21:05 A.M. Pacific Daylight Time

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Dear Majid Ali,

The following post you wrote on the Nature website has been approved by the moderator:

Chouchani et al demonstrated ischaemic succinate accumulation due to reversed activity of succinate dehydrogenase triggered by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle.1 They recognized that their findings may have clinical significance for patients with inflammatory disorders. In 2004, I reported a survey of 24-hour urinary excretion of Krebs cycle metabolites in 236 patients with chronic inflammatory-immune disorders and noted the high frequency of increased urinary succinate excretion.2 The report by Chouchani et al prompted me to review Krebs cycle data for 315 patients seen with such disorders since the previous and succinate values in twenty control subjects.

My 2004 and 2015 data presented in Table are concordant as for the frequency of patients with increased retention of succinate as the specific Krebs cycle metabolite and support inference of Chouchani et al about its clinical relevance to mitoc hondrial dysfunction in patients with chronic inflammatory-immune disorders. The mean values of 24-hour urinary succinate excretion of patients and twenty control subjects were 80.3 and 8.7 mmol/mol creatinine respectively.

One noteworthy finding in my data is the much higher frequency of succinate retention among women than among males (61 women, 34 males). Many autoimmune disorders occur with higher frequency in women. A relationship among these female preponderances, if any, remains unclear.

Table 1. The Frequency of Increased* Urinary Excretion of Krebs Cycle Metabolites In Chronic Inflammatory Disorders (N=236, 2004; N=351, 2015).

Krebs Metabolites 2004 n=236 2015 n=315

2004 Report Data n= 236

Citric acid 194

Succinic acid 40

Aconitic acid 24

Fumaric acid 2

2-oxo-glutaric acid 1

New 2015 data n= 315

Citric acid 315

Succinic acid 55

Aconitic acid 45

Fumaric acid 2

2-oxo-glutaric acid 2

Increases beyond the laboratory range for the general population. Levels of acids measured in mmol/mol creatinine.

References:

1. Chouchani ET, Victoria R. Pell VR, Edoardo Gaude E, et. al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431?435

2. Ali M. Respiratory-to-Fermentative (RTF) Shift in ATP Production in Chronic Energy Deficit States. Townsend Letter for Doctors and Patients. 2004. August/Sept. issue. 64-65.

Thank you for contributing,

-Nature editors

**************

Dear Majid Ali,

The following post you wrote on the Nature website has been approved by the moderator:

Chouchani et al demonstrated ischaemic succinate accumulation due to reversed activity of succinate dehydrogenase triggered by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle.1 They recognized that their findings may have clinical significance for patients with inflammatory disorders. In 2004, I reported a survey of 24-hour urinary excretion of Krebs cycle metabolites in 236 patients with chronic inflammatory-immune disorders and noted the high frequency of increased urinary succinate excretion.2 The report by Chouchani et al prompted me to review Krebs cycle data for 315 patients seen with such disorders since the previous and succinate values in twenty control subjects.

My 2004 and 2015 data presented in Table are concordant as for the frequency of patients with increased retention of succinate as the specific Krebs cycle metabolite and support inference of Chouchani et al about its clinical relevance to mitoc hondrial dysfunction in patients with chronic inflammatory-immune disorders. The mean values of 24-hour urinary succinate excretion of patients and twenty control subjects were 80.3 and 8.7 mmol/mol creatinine respectively.

One noteworthy finding in my data is the much higher frequency of succinate retention among women than among males (61 women, 34 males). Many autoimmune disorders occur with higher frequency in women. A relationship among these female preponderances, if any, remains unclear.

Table 1. The Frequency of Increased* Urinary Excretion of Krebs Cycle Metabolites In Chronic Inflammatory Disorders (N=236, 2004; N=351, 2015).

Krebs Metabolites 2004 n=236 2015 n=315

2004 Report Data n= 236

Citric acid 194

Succinic acid 40

Aconitic acid 24

Fumaric acid 2

2-oxo-glutaric acid 1

New 2015 data n= 315

Citric acid 315

Succinic acid 55

Aconitic acid 45

Fumaric acid 2

2-oxo-glutaric acid 2

Increases beyond the laboratory range for the general population. Levels of acids measured in mmol/mol creatinine.

References:

1. Chouchani ET, Victoria R. Pell VR, Edoardo Gaude E, et. al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431?435

2. Ali M. Respiratory-to-Fermentative (RTF) Shift in ATP Production in Chronic Energy Deficit States. Townsend Letter for Doctors and Patients. 2004. August/Sept. issue. 64-65.

Thank you for contributing,

-Nature editors

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