A Disease State Is Evolution-In-Reverse – A Bioenergetic View of the Nature of Chronic Disease

Majid Ali, M.D.

In 2004, I coined the term respiratory-to-fermentative to define the bioenergetic basis of immune-inflammatory diseases.

In the years following 2004, I extended my studies of Krebs cycle metabolites and reported the presence of the respiratory-to-fermentative (RTF) shift to varying degrees in all chronic disorders in which I examined Krebs cycle metabolism with 24-hour urinary excretion of Krebs metabolites.

Evolution in Reverse

Pathogenesis of chronic disease based on impaired Krebs cycle homeostasis, in a way can be rightly designated as molecular evolution-in-reverse. In this article, I present some of my earliest observations on the subject.

Syndromes of persistent and debilitating fatigue— fibromyalgia, chronic fatigue syndrome, persistent fatigue following chemotherapy for malignant disorders, and others — may be properly designated “chronic energy deficit states.” There is an enormous body of literature concerning clinical patterns, symptom-complexes, and putative etiologic agents.  In 1994, in The Canary and Chronic Fatigue, I marshaled extensive evidence for my view that accelerated oxidative molecular injury is the common energetic-molecular pathway among all etiologic factors for chronic fatigue syndrome.1

In this first column devoted to oxygen homeostasis, I furnish evidence for the hypothesis that chronic disabling fatigue is caused by a respiratory-to-fermentative (RTF) shift in adenosine triphosphate (ATP) production. As a consequence, there is a drastic (over 93%) reduction in the available cellular energy currency (ATP)

— only two moles of ATP per mole of glucose are generated in the fermentative mode as compared with approximately 30 moles of ATP per mole of glucose in the respiratory mode. In 1999, I introduced the term dysoxygenosis for this respiratory-to-fermentative shift in ATP production.2-4 I defined dysoxygenosis as a state of diminished cellular oxygen utilization resulting from function of enzymes involved in oxygen homeostasis (designated oxyenzymes) that leads to altered expressions of genes induced by hypoxic environment (designated oxygenes). The webs of oxyenzymes are vast, with each entity linked to every other through multiple pathways. The webs of oxygenes are seemingly far more complex. All such webs are exquisitely ‘aware’ of changes in oxygen availability in their microenvironment and vigorously respond to them. Some sense of the clinical significance of this may be obtained by considering the broad range of symptom-complexes of RTF shift in chronic energy deficit states.

Clear and unequivocal biochemical evidence for such shift can be readily established by measuring 24-hour urinary excretion of organic compounds (Tables 1). When the spectrum of organic acids included in the urinary profile is broad enough, not only is it possible to detect the presence of that shift, it is generally possible also to recognize defects in molecular pathways that set the stage for RTF shift (Tables 2 and 3).

Impaired Krebs Cycle

Of central importance in cellular energetics is the Krebs (citric acid, tricarboxylic acid) cycle. In health, this cycle is the true crossroads of both anabolic and catabolic energetics. It is the final common pathway for oxygen-driven breakdown of sugars, fats, and proteins for serving the energy needs of the body. It also provides for the oxygen-driven synthesis of the basic

building blocks for structural and functional molecules of the body. All steps in this cycle of energetics are catalyzed by a variety of enzymes and their cofactors. Metabolic pathways of carbohydrates, lipids, and proteins enter the cycle via acetyl CoA derived from pyruvic acid, fatty acids, and amino acids respectively. Theoretically, blockages at various levels in the Krebs cycle can be produced when the enzymatic pathways of the Krebs cycle are:

1. Impaired or inactivated by incremental oxidative stress of endogenous and exogenous factors;

2. Hampered by intracellular acidosis resulting from chronic oxidosis;

3. Impeded by the quality and quantity of substrates (discussed below);

4. Rendered inefficient by deficiency of metal cofactors; and

5. Clogged by mitochondrial uncoupling.

Increased Urinary Excretion of Krebs Intermediate

In clinical states associated with RTF shift, one or more of the above conditions exist in various combinations. However, to precisely determine the pathogenetic contribution of individual factors is not possible at this time — nor does that seem likely in the future given the breadth of the molecular webs involved and the kaleidoscopic changes that occur when something changes in one way. Increased excretion of acids in the Krebs cycle provides direct evidence for impaired function of enzymes involved in those pathways. Under physiological conditions, minute amounts of metabolic intermediates of both pathways are excreted in the urine.

Table 1 shows data for 24-hour urinary excretion of organic acids that comprise major intermediates of the Krebs cycle in a series of 236 patients with clinical features of dysoxygenosis—a sense of air hunger, fatigue, dry skin, orthostatic intolerance, disorders of mood, memory, and mentation, and other symptom-complexes encountered in energy disorders listed above. These data need to be considered in view of the Krebs cycle, which begins with reaction of acetyl CoA with oxaloacetate to form citrate with the following intermediates: cis-aconitate, isocitrate, á-ketoglutarate, succinate, fumarate, malate, and back to oxaloacetate.

Table 1. The Frequency of Increased* Urinary Excretion of Metabolites of the Krebs Cycle in 236 Patients with Dysoxygenosis

Citric acid

Succinic acid

Aconitic acid

Fumaric acid

2-oxo-glutaric acid






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

An Anaology of Ponds With Beaver Dams

In interpreting the data presented in Table 1, let us draw an analogy of ponds at five levels, eachdraining into the one a lower level. If the outflow of all ponds were to be impeded to equal degrees and there were to be a build-up of water levels behind the dams — by, let us say, dams built by beavers at the outlet of each pond — the quantity of water held back by the highest pond would be expected to be larger than in the pond in the second tier, and the amount of water held back in the second pond would be expected to be more than in the one below it, and so on. This can be reasonably deduced from the sequence of the dammed outlets of five ponds at different levels illustrated in Figure ).

Figure 1. The Multilevel Pond Analogy for Impaired Krebs Cycle: Succesive Dams on Five Levels Create Progressively Shrink the Ponds






Figure 2. Data Concerning Krebs Cycle Intermediates Shown in Table 1 Are Presented Schematically to Underscore the Effect of Sequential Damming of Multilayered Ponds Illustrated in Figure 1

                          Acetyl Co A (0)

     Malic acid (0)                     Oxaloacetic acid (0)

Fumaric acid (1)                              Citric acid (196)

                                               Succinic (40)

                        Aconitic acid (26)

Table 2. Increased* Urinary Excretion of Metabolites of Glycolysis in 236 Patients with Dysoxygenosis

Glyceric acid

2-hydroxybutyric aci

Lactic acid

Pyruvic acid





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

Table 3. Increased 24-Hour Urinary Excretion* of Miscellaneous Organic Acids in 100 Patients with Dysoxygenosis

Hippuric acid

2-oxoglutaric acid

Citramalic acid

Tartaric acid



Carboxycitric acid

Glycolic acid

Furan 2,5dicarboxylic acid

Malonic acid











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

From the above analogy, one can reasonably postulate that impairment or functional deficits involving enzyme of the Krebs cycle (Figure 1) at any stage of the cycle would be expected to be seen most clearly at the beginning of the cycle where the raw material (the primary substrate, acetyl CoA) enters the cycle. The cumulative blockages throughout the cycle would then be expected to result in inefficient processing of citrate with the consequent increased urinary excretion. That, indeed, turns out to be the case. Increased excretion of citric acid was seen more than four times as frequently as succinic acid, the next most commonly encountered acid. Next in order is aconitic acid, another acid produced during the early part of the cycle. Increased frequency of fumaric acid was seen in a single case and that of malic acid not at all. Though the order of frequency of increased urinary excretion seen in Table 1 does not exactly match the order of intermediates of the Krebs cycle, the general pattern clearly is consistent with the postulate of the proposed RTF shift.

Signaling Functions of Krebs Intermediates

The intermediates of Krebs cycle and glycolytic pathways have been regarded merely as metabolic pawns in cellular energetics. That would hardly be expected to be the case in view of Nature’s preoccupation with complementarity and contrariety. it was with great wonderment that I read a recent article in Nature that clearly established succinate and á-ketoglutarate as important signaling molecules.6 Cells sense their environment through proteins in their membranes. One of the most important family of such proteins is that of G-protein-coupled receptors (GPCR). It turns out that GPR91, one member of GPCR family, serves as the ligand for succinate while another member (GPR99) is the ligand for á-ketoglutarate. Through their dynamics with GPCRs, succinate and á-ketoglutarate serve important signaling pathways,7 including those that affect renin functions in the kidney. In an animal model, hypertension was produced by increment in such signaling.6 Future research in this area — seems safe to predict — will define additional signaling functions of metabolites of Krebs cycle, and shed further light on the clinical significance of RTF shift.

In closing two points may be added in brief. First, the RTF shift in ATP generation is not an all-or-none phenomenon. Thus, different cell populations in different tissue-organs with varying genetical predisposition may be involved in diverse clinical entities. Second, and evidently as a consequence of the first, clinical consequences of the shift can be expected to vary over a wide range. And that, indeed, is the case with chronic energy deficit state in different individuals.

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