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Succinate retention: the core Krebs dysfunction in immune-inflammatory disorders.

In 2004, in my first "Oxygen Homeostasis" column in Townsend Letter, I presented evidence to establish respiratory-to-fermentative (RTF) shift as the molecular basis of chronic fatigue in chronic inflammatory disorders. (1) Specifically, I presented data concerning 24-hour urinary excretion of Krebs cycle metabolites in 236 patients. Succinic acid was the metabolite of greatest interest, since its increased excretion occurred with the highest frequency.

In 2014, Chouchani et al. reported that ischemic accumulation of succinate controls redox dynamics of reperfusion injury through mitochondrial reactive oxygen species. (2) They recognized that this finding may have clinical significance for patients with inflammatory disorders. This report fully validated the two main conclusions drawn from my 2004 study: (1) respiratory-to-fermentative shift as the mitochondrial dysfunction in inflammatory-immune disorders; and (2) succinate retention as the Krebs cycle dysfunction of highest clinical interest.

Prompted by the report of Chouchani et al., I reviewed Krebs cycle data for an additional 315 patients seen since my 2004 Townsend report. My two sets of data (2004 and 2015 studies) were published online in Nature (Table 1). (3) These data are concordant and consistent with the succinate findings in the 2014 Nature report. They also support the inference of Chouchani et al. concerning the clinical significance of succinate retention.

In subsequent columns on oxygen homeostasis, based on the respiratory-to-fermentative shift model, I put forth my oxygen models of aging, inflammation, pain, diabetes, coronary heart disease, renal failure, insulin toxicity, hormone disorders, adrenal dysfunction, osteoporosis, allergy, and environmentally induced osteoporosis. (4-14)

Chouchani and colleagues specifically demonstrated that: (1) ischemic succinate accumulation develops due to reversed activity of succinate dehydrogenase triggered by fumarate overflow from purine nucleotide breakdown; and (2) succinate retention occurs partly due to reversal of the malate/aspartate shuttle. (2) These findings, as the investigators anticipated, will lead to the development of a novel class of drugs--"succinate drugs" seems to be good term for them--for preventing and/or or treating reperfusion injury. Undoubtedly, they will also shed light on the mechanisms of action of oxystatic therapies, nutrients, spice, herbs, and enzymes.

The following five distinctions between the 2004 and 2014 reports are noteworthy: (1) the subjects of investigation were human and mice respectively; (2) mitochondrial function was investigated in chronic disorders among humans and acute lesions in mice; (3) the pathologic entities understudy were inflammatory disorders and reperfusion ischemic injury respectively; (4) the intended approaches to restoration of oxygen homeostasis were integrated nondrug protocols and pharmacologic agents respectively; and (5) the seminal studies of Chouchani et al. dramatically advanced our understanding of impaired succinate pathways in reperfusion ischemic injury, whereas no evidence for similar impairment was developed in the 2004 study.

Scientific Basis of Holism in Healing

In my 2004 report, I noted that a report published in Nature established succinate and a-ketoglutarate as important signaling molecules. (15) Cells sense their environment through proteins in their membranes. One of the most important family members of such proteins is that of G-protein-coupled receptors (GPCR). GPR91, a member of GPCR family, serves as the ligand for succinate, while another member (GPR99) is the ligand for [alpha]-ketoglutarate. Through their dynamics with GPCRs, succinate and [alpha]-ketoglutarate serve important signaling pathways, including those that affect renin functions in the kidney. In an animal model, hypertension was produced by an increase in such signaling. These findings also underscored the importance of succinate retention in mitochondrial dysfunction and shed light on the broader clinical significance of RTF shift.

The Philosophy and Science of Holism in Healing

In 1980, I recognized the crucial need for ecologic thinking in clinical medicine and published a monograph titled Altered States of Bowel Ecology to focus on the centrality of the bowel in all deliberations of health/dis-ease/ disease continuum. (16) In this volume, I described my seed-feed-and-weed guidelines for restoring bowel ecology disrupted by heavy sugar intake, frequent use of antibiotics, neglect of mold and food allergy, and chronic stress.

In 1983, I published a monograph titled Spontaneity of Oxidation in Nature and Aging, in which I proposed my oxidative theory of aging. (17) This spontaneity seemed to initiate and drive the redox dynamics in the body--the human equivalent of the second law of thermodynamics, so to speak--and appeared to be a highly plausible primal mechanism for disease initiation and progression. Within this evolutionary context, in 1987 I summarized my observations and reflections concerning the gating functions of biomembranes in a monograph titled Oxidative Leaky Cell Membrane Disorder. (18)

Human evolution may be visualized within the broader context of trillions of energetic events--steps, missteps, and countersteps--inevitably constituting the pathways of molecular complementarity and contrariety. A study of the history of oxygen on planet Earth led to my recognition of oxygen as the king of human biology (recognition of insulin as its minister of energy and metabolism would come 15 years later). In 1998, that work led to the publication of Nature's Preoccupation with Complementarity and Contrariety, the first volume of my 14-volume textbook, The Principles and Practice of Integrative Medicine. (19)

In closing, I point out that 30 years after I published Altered States of Bowel Ecology, the journal Nature fully endorsed that position in a 2010 article with the following words: "By 2020, personalized health care could involve doctors monitoring the metabolic activities of a patient's gut microbes and, possibly, modulating them therapeutically." (20) Next, consider the following words, again from Nature: "World Health Organization warns that world may be heading into a 'post-antibiotics era.'" (21)

One day, let us hope, the science and philosophy of holism in healing traditions will rise to yet a higher level --of the whole-body ecology--which looks at the body microbes as an integral part of the whole, which also needs to heal.


(1.) Ali M. Respiratory-to-fermentative (RTF) shift in ATP production in chronic energy deficit states. Townsend Lett. 2004 August/Sept.;64-65.

(2.) Chouchani ET, Pell VR, Gaude E, et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014;515:431-435. Available at n7527/full/nature13909.html.

(3.) Ali M. Comment on Chouchani et al. Ibid.

(4.) Ali M. The Dysox Model of Cancer. Aging Healthfully; 2004;7:3-11.

(5.) Ali M. Oxygen governs the inflammatory response and adjudicates the man-microbe conflicts. Townsend Lett. 2005;262:98-103.

(6.) Ali M. The oxygen view of pain: every chronic pain represents cells' cries for oxygen. Townsend Lett. 2005;258:46-48.

(7.) Ali M. The dysox model of diabetes and de-diabetization potential. Townsend Lett. 2007;286:137-145.

(8.) Ali M. Oxidative coagulopathy in fibromyalgia and chronic fatigue syndrome. Am J Clin Pathol. 1999; 112:566-567.

(9.) Ali M. The dysox model of renal insufficiency and improved renal function with oxystatic therapies. Townsend Lett. 2005;267:101-108.

(10.) Ali M. Cancer.

(11.) Ali M. Oxygen, insulin toxicity, inflammation, and the clinical benefits of chelation. Part 1. Townsend Lett. October 2009;315:105-109.

(12.) Ali M. The dysox model of adrenal dysfunction and gender devolution: the Cushingoid-Addisonian epidemic. Townsend Lett. 2008;305:117-121.

(13.) Ali M. Ali Recent advances in integrative allergy care. Curr Opin Otolaryngol Head Neck Surg. 2000;8:260-266.

(14.) Ali M. Oxidative coagulopathy in environmental illness. Environ Manag Health. 2000;11:175-191.

(15.) He W, Milao F J-P, Lin D C-H, et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature. 2004;429:188-193.

(16.) Ali M. Altered States of Bowel Ecology [monograph]. Teaneck, NJ; 1980.

(17.) Ali M. Spontaneity of Oxidation in Nature and Aging [monograph]. Teaneck, NJ; 1983.

(18.) Ali M. Leaky Cell Membrane Disorder [monograph]. Teaneck, NJ; 1987

(19.) Ali M. Nature's Preoccupation with Complementarity and Contrariety. The Principles and Practice of Integrative Medicine 1. 2nd ed. New York: Canary 21 Press; 2005.

(20.) Holt RD. 2020 visions: ecology. Nature. 2010;463:32.

(21.) The year in science. Nature. 2014;516:302.

Majid Ali, MD, is author of the 12-volume series The Principles and Practice of Integrative Medicine. He is also the founder of the YouTube Science, Health, and Healing Encyclopedia, and producer and host of the program "Science, Health, and Healing" on MNN TV and WBAI radio (New York). In addition, Dr. Ali is president of the Institute of Integrative Medicine and was formerly associate professor of pathology at Columbia University.
Table 1: Frequency of Increased * Urinary Excretion of Krebs Cycle
Metabolites In Chronic Inflammatory Disorders

Krebs Cycle Metabolites   2004 n = 236   2015 n = 315

Citric acid                   194            315
Succinic acid                  40             55
Aconitic acid                  24             45
Fumaric acid                   2              2
2-oxo-glutaric acid            1              2

* Levels of Krebs metabolites measured in mmol/mol creatinine. The
mean values of 24-hour urinary succinate excretion of patients and
20 control subjects were 80.3 and 8.7 mmol/mol creatinine,
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Author:Ali, Majid
Publication:Townsend Letter
Date:Nov 1, 2015
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