Inverse Warburg effect
The term Inverse Warburg effect is used to describe the increase in oxidative phosphorylation observed in cortical regions of the brain during the presymptomatic phase of the neurodegenerative disorders, Alzheimer's disease [1][2][3] and Parkinson's disease.[4][5][6][7]
Basis[edit]
The main energy currency in living organisms is ATP, which must be continually generated to maintain cell viability. The energy is derived from two types of processes: oxidative phosphorylation, which provides 80% of the total energy, and glycolysis, which contributes the remaining ~20%.(Fig.1)
The Warburg effect and the Inverse Warburg effect are complementary modes of metabolic reprogramming observed in cancer cells (Fig.2) and in neurodegenerative disorders, respectively (Fig.3).
The Warburg effect is the empirical observation that most cancer cells predominantly generate energy by a high rate of glycolysis. Otto Warburg proposed that this phenomenon is the fundamental cause of cancer.[8] The model, now known as the Warburg Hypothesis, contends that the up-regulation of glycolysis compensates for energy deficiencies due to dysregulation in the mitochondria.
Neurodegenerative Disorders[edit]
The Inverse Warburg effect is the empirical observation that the presymptomatic phase of the neurodegenerative disorders - Alzheimer's disease [1][2][3] and Parkinson's disease [4][5][6][7] - is characterized by an enhanced rate of oxidative phosphorylation in certain cortical neurons.
Lloyd Demetrius and colleagues [9][10] postulated that this mode of metabolic reprogramming - the up-regulation of oxidative phosphorylation - is a primary cause of the sporadic forms of neurodegenerative disorders, such as Alzheimer's and Parkinson's. This proposition, now known as the Inverse Warburg Hypothesis, contends that neurodegenerative disorders are primarily metabolic diseases, which are the result of a cascade of three events: (i) mitochondrial dysregulation: deficits in energy production; (ii) metabolic reprogramming: a compensatory increase in oxidative phosphorylation to maintain adequate energy production; (iii) natural selection: competition between intact neurons defined by standard energy production, and mildly impaired neurons defined by a hyper-metabolic activity.
Cancer and Neurodegenerative Disorders: Inverse Association[edit]
Epidemiological studies have shown that cancer is inversely comorbid with both Alzheimer's disease (AD) and Parkinson's disease (PD) [11][12][13]: Prevalent AD or PD is associated with a reduced risk for cancer, while a history of cancer is related to a diminished risk for the neurodegenerative diseases. The molecular and bioenergetic basis for this inverse relation can be explained by invoking the Warburg effect as the fundamental cause of cancer and the Inverse Warburg effect as the primary cause of sporadic forms of AD and PD.[14]
Autoimmune Diseases[edit]
Neurons are unable to compensate for deficits in energy production through glycolysis, owing to the lack of activity of some glycolysis promoting enzymes.[15] Accordingly, neurons rely exclusively on oxidative phosphorilation to meet energy demands. Hence the response of neurons to mitochondrial dysfunction is characterized by the up-rgulation of Ox-Phos activity - the Inverse Warburg effect.
This mode of metabolic reprogramming is also observed in studies of autoimmune diseases.[16][17][18] T cells in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have a disease specific metabolic signature. RA T cells are described by low adenosine triphosphate and lactate levels, together with increased availability of the cellular reductant NAPDH. This metabolic signature, a characteristic of the Inverse Warburg effect, derives from insufficient activity of the glycolytic enzyme phosphofructokinase.
SLE T cells are characterized by excess production of reactive oxygen species. This metabolic signature, another feature of the Inverse Warburg effect is a result of the up-regulation in Ox-Phos activity.
Therapeutic interventions[edit]
The Inverse Warburg effect has given rise to the notion that neurodegenerative disorders and chronic autoimmune diseases may have their origin in bioenergetics. This realization sugests that these diseases may be prevented by means of metabolic intervention, that is the use of metabolites to maintain homeostatic conditions and regulate cellular metabolism.
In the case of age-related neurodegenerative disorders, these interventions involve enhancing the activity of key metabolic enzymes which will maintain the selective advantage of healthy neurons, and thereby prevent the transition from normal aging to pathological aging.[19][20]
In the case of chronic autoimmune diseases, therapeutic interventions would involve a modification of the cell internal metabolism in t cells.[21]
References[edit]
- ↑ 1.0 1.1 Ashraf A, Fan Z, Brooks DJ, Edison P. Cortical hypermetabolism in MCI subjects: a compensatory mechanism? Eur J Nucl Med Mol Imaging. 42(3):447–58 (2015).
- ↑ 2.0 2.1 Ossenkoppele R, Madison C, Oh H, Wirth M, van Berckel BN, Jagust WJ. Is verbal episodic memory in elderly with amyloid deposits preserved through altered neuronal function? Cereb Cortex. 4(8):2210-8 (2014).
- ↑ 3.0 3.1 Bakkour A, Morris JC & Dickerson BC. The cortical signature of prodromal AD: thinning predicts mild AD dementia. Neurology. 72:1048-55 (2009).
- ↑ 4.0 4.1 Tang CS, Poston KL, Dhawan V & Eidelberg D. Abnormalities in Metabolic Network Activity Precede the Onset of Motor Symptoms in Parkinson's Disease. J Neurosci, 30(3): 1049–1056 (2010).
- ↑ 5.0 5.1 Pacelli C, Giguère N, Bourque M, Lévesque M,. Slack RS & Trudeau L. Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons. Current Biology, 25(18) R:797 (2015).
- ↑ 6.0 6.1 Caballero B, Sherman, SJ & Falk T. Insights into the mechanisms involvedin protective effects of VEGF-B in Dopaminergic Neurons. Parkinson's Disease, Article ID 4263795 (2017).
- ↑ 7.0 7.1 Oliveira L et al. Elevated α-synuclein caused by SNCA genetriplication impairs neuronal differentiation and maturation in Parkinson's patient-derived pluripotent stem cells. Cell Death and Disease, 6:e1994 (2015).
- ↑ Warburg O. On the origin of cancer cells. Science 123 (3191): 309–314 (1956).
- ↑ Demetrius LA & Simon DK. An inverse-Warburg effect and the origin of Alzheimer's disease. Biogerontology. 13(6):583-94 (2012).
- ↑ Demetrius LA, Magistretti PJ & Pellerin L. Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect. Front Physiol. 5: 522 (2015).
- ↑ Tabares-Seisdedos R & Rubinstein JL. Inverse cancer comorbidity: a serendipitous opportunity to gain insight into CNS disorders. Nat. Rev. Neuroscience. 14:293-304 (2013).
- ↑ Driver JA, Beiser A, Au R, Kreger BE, Splansky GL, Kurth T, Kiel DP, Lu KP, Seshadri S & Wolf PA. Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study. BMJ. 344:e1442 (2012).
- ↑ Beckera C, Brobert GP, Johansson S, d,. Jick SS & Meier CT. Cancer risk in association with Parkinson disease: A population-based study. Parkinsonism Relat Disord. (3): 186–190 (2009).
- ↑ Demetrius LA & Simon DK. The Inverse association between cancer and Alzheimer's: a bioenergetic mechanism. "Jour. Royal Soc. Interface". 10.20130006 (2013).
- ↑ Bolanos JP, Almedia A and Moncada S. Glycolysis: a bioenergetic or survival pathway? Trends Biochem Sci. 35(3):145-149 (2010).
- ↑ Yang Z, Matteson EL, Goronzy JJ & Weyand CM. T cell metabolism in autoimmune disease. Arthritis Research & Therapy. 17:29 (2015).
- ↑ Goronzy JJ, Shao L & Weyand CM. Immune aging and rheumatoid arthitis. Rheum. Dis. Clin. North Am. 36.297-310 (2010).
- ↑ Goronzy JJ & Weyand CM. Developments in the understanding of rheumatoid arthritis. Arthritis Res Ther. 11:249. (2009).
- ↑ Demetrius LA & Driver J. Preventing Alzheimer's by means of natural selection. Jour. Royal Soc. Interface.. Vol.12 DO1.10.1098 (2015)
- ↑ "A new understanding of Alzheimer's". Harvard Gazette. 2015-02-25. Retrieved 2017-08-05.
- ↑ Weyand CM, Jujii H, Shao L Goronzy JJ. Rejuvenating the immune system in rheumatic arthritis. Nat. Rev. Rheumatol. 5:583-588 (2009).
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