Mitochondria – May the Force Be With You

In Episode 1 of the Star Wars franchise (The Phantom Menace), Master Jedi Qui-Gon Jinn explains the origin of ‘The Force’, the source of the Jedi’s extraordinary abilities. It is derived, he says, from microscopic life forms called ‘midi-chlorians’ that dwell within all living cells. Whilst it is tempting to dismiss this idea as a convenient plot mechanism to explain a supernatural force, perhaps George Lucas knows more about biology than he is normally given credit for, and like many of the elements of the Star Wars films there may be a grain of truth to this idea. I recall the first time I watched the movie, having an epiphany in the middle of the cinema, that ‘midi-chlorians’ might be Jedi-speak for mitochondria, the tiny bacterium-like structures that populate our cells, and provide us with energy (or force…).

Aliens Amongst Us
One of the most important and earliest divisions of life was between the prokaryotes and eukaryotes. Prokaryotes are considered to be the original forms of life that developed on Earth, and are comprised of the Bacteria and Archae. They are simple structures, and are defined by what they are missing, which is the membrane-bound organelles like the nucleus, chloroplast and mitochondria found in eukaryotic cells. Prokaryotes are also almost universally single-celled organisms (although they are capable of forming communities protected by slime known as biofilms), whereas the development of the eukaryote allowed the subsequent development of multicellular, cooperative communities of cells that eventually led to higher forms of life.1 The leading theory for the development of eukaryotes is that of endosymbiosis, where the creation of a eukaryotic cell took place by the combination of a number of prokaryotic progenitor cells within a single cell. According to this theory, certain organelles originated as free-living bacteria that were taken inside another cell as endosymbionts.2 There are numerous lines of evidence that support this theory, including the fact that mitochondria have their own DNA which is similar to bacterial and different to nuclear DNA, that mitochondria form within cells via binary fission, and they have ribosomes similar to those found in bacteria.

The implication of this theory is that within all of our cells, we have alien bacterial ‘cells’ that were once free living but have now become incorporated into our cellular structure. The acquisition of these ‘cells’, which have become known as the organelle mitochondria, was a major step forward in the development of multicellular, complex organisms, as it allowed for a much greater amount of energy (ATP) to be produced from the available energy sources the cell acquired. Over time the nucleus of our cells has assumed control over some aspects of mitochondrial function and our cells have become dependent on the energy produced by mitochondria, to the point that neither can effectively survive independently without the other. Whilst this has been a remarkably successful marriage, it is starting to be recognised that bringing a powerful energy production source inside the cell, much like cooking with an open fire inside a house, can occasionally get out of control and burn the house down. Researchers are now beginning to identify a range of disorders that are of mitochondrial origin, and also therefore the need for therapies targeted to the mitochondria to combat these issues.

Fire in the Hole
Mitochondria provide energy to our cells in the form of ATP via aerobic respiration, or simply, the use of oxygen to burn fuel. This is dangerous work and needs to be carried out in highly controlled conditions, due to the high levels of potentially damaging oxygen radicals that are produced during the process. In mitochondria with poorly formed (or inadequately repaired) membranes, or in people with insufficient endogenous defence against these oxidants, damage to structures can take place. One of the first areas that is affected is the mitochondrial DNA (mtDNA), which due to its proximity to the source of the oxidants and its lack of effective repair mechanisms (unlike nuclear DNA), is particularly vulnerable to damage. Researchers believe that once mtDNA damage takes place, this accelerates radical production and the damage spreads to the rest of the cellular structures, eventually leading to dysfunctional cells and loss of healthy tissue.3

Loss of functional mitochondria diminishes cellular energy metabolism and can lead to conditions associated with physical and mental fatigue. Perhaps of more concern is that mitochondrial damage can also lead to cellular changes associated with cancer development or apoptosis (loss of cells).4 Over the last decade, mitochondrial dysfunction has been shown to be associated with or causative of diverse conditions including diabetic neuropathy, Alzheimer’s dementia, Autism, Parkinson’s disease, metabolic syndrome, dementia, stroke and migraine.5 mtDNA mutations have also been shown to be strongly associated with the initiation and progression of the ageing process and cognitive decline as seen in figure 1.6

Mannion_mito_Fig1

Figure 1.  mtDNA damage associated with cognitive decline and ageing.7

 

Mitochondrial Medicine

Traditionally, mitochondrial disease has been thought of as those diseases caused by an inherited defect in mtDNA, which is rare and has no established medical treatment.  It is starting to become clear however, that acquired mitochondrial dysfunction is associated with a broad range of conditions, and is far more common.  Acquired mitochondrial dysfunction is characterised by low ATP production, elevated levels of ROS and systemic inflammation – factors common to many chronic degenerative diseases.  So in this context mitochondrial dysfunction can be seen as a common and powerful underlying driver of many disorders of western diet, lifestyle and ageing.  Several researchers are working on strategies to correct this acquired dysfunction and their efforts can be broadly grouped into 2 areas.  The first is the stimulation of the division and replication of healthy mitochondria (mitogenesis) and the second is the repair and rebuilding of defective structures within the mitochondria.

One of the strategies that have been employed to increase mitogenesis is exercise – both resistance and aerobic methods have been shown to be of benefit.8  Exercise stimulates metabolic pathways in the cells mediated via the chemokine PGC1alpha that signal to the cell a need for greater energy production to meet the demands of the exercising muscle tissue.  This then triggers a range of processes which enhance mitochondrial number and activity, and the removal of old and damaged mitochondria from cells.  It is thought that many of the metabolic benefits of exercise come from this enhanced mitochondrial function.  In effect exercise is a mild stressor to the body, and this provokes an adaptive response which is designed to improve the ability of the body to cope with similar stressors in the future.  An important discovery is that there are a number of naturally occurring compounds which also activate the same pathways.  These are typically phytochemicals produced by plants as secondary metabolites to help the plant cope with stressful conditions.  It is thought that via co-evolution, our genes have learned to interpret the presence of these compounds in our food supply as a signal that the food supply is under threat, and to respond by triggering a range of defensive actions, including an increase in mitochondrial efficiency, to ensure maximum energy is extracted from the available calories (figure 2).9

 

Mannion_mito_Fig2

Figure 2.  Humans have evolved the ability to sense detrimental changes to the food supply from changes in the levels of secondary metabolites, and to modify their metabolism accordingly.

One of the key plants that has been shown to boost PGC1alpha levels and thus to stimulate mitogenesis is green tea extracts rich in phytochemicals including EGCG.  By increasing PGC1alpha, EGCG is able to improve mitochondrial numbers and efficiency, in addition to its powerful antioxidant benefits.10 Another is Yerba maté  (Ilex paraguariensis), which has been shown to boost PGC1alpha, inhibit mtDNA damage and in an animal study to support mitochondrial function in a model of a western diet (high calorie/high fat).11  A key nutrient with similar activity is lipoic acid, which is an essential cofactor for the oxidative phosphorylation process.  In animal and human studies lipoic acid has been shown to support PGC1alpha levels, enhance glucose disposal and mitogenesis.12,13

Mitochondrial Repair

Whilst mitogenesis is a very valuable strategy to enhance mitochondrial function, another important approach which has been trialled clinically is the provision of nutritional substrates for the repair and maintenance of mitochondria.  As previously discussed, mtDNA is highly vulnerable to oxidative damage and therefore the provision of targeted antioxidants is a high priority.  Another important difference with mitochondria is that their membranes, especially the inner membranes are much higher in phospholipids than other cellular membranes.  These membranes are subject to oxidative damage which leads to defects in the ability of the mitochondria to create the proton gradient across the inner membrane that is required for the production of ATP.

Professor Garth Nicolson has been researching the properties of cell membranes for his entire career (over 40 years) and was co-author of the seminal paper that established the ‘Singer–Nicolson fluid mosaic cell membrane model’ published in Science in 1972, still one of the most highly cited papers ever published.14 Professor Nicolson has in more recent years developed the concept of ‘lipid replacement therapy’, and has conducted a number of clinical trials administering a combination of essential fatty acids, phospholipids and antioxidants to patients with a range of mitochondria-based disorders.  In two trials conducted on patients with Chronic Fatigue Syndrome, it was found that the use of the supplement significantly improved fatigue scores in patients, with one trial reporting a 36% reduction after one week of treatment. In addition, mitochondrial function was also analysed and significant improvements were found in those using the phospholipid and fatty acid supplementation.15,16  In other trials Nicolson has shown beneficial effects from this formula in fatigue associated with cancer, and other researchers have demonstrated benefits with cognitive performance and Alzheimer’s dementia with some of the ingredients used separately.17,18

Care for Your Prehistoric Friends

In previous articles I have discussed the concept that humans are a super-organism, comprised of a large array of species of bugs living in, on and around us.  Given the right diet and environment, we grow the right bugs and these serve us well.  It is apparent now that even within our most basic unit of life, our cells, we are the product of a hybridisation that occurred many millions of years ago between several classes of bugs.  We should rejoice in the fact that our progenitors were able to make the most of a convenient combination of skills and become the dominant life form on the planet.  With this however comes the acceptance that we have imported trillions of small furnaces into the cells that comprise our body, and that without the correct care they can and do burn out of control and cause damage to our tissues – literally from the inside out.  Therefore to manage the various diseases associated with mitochondrial dysfunction, and even more importantly to prevent them in the first place, we need to provide optimal mitochondrial support to our patients.  This includes:

  • A herbal and nutritional combination based on green tea to stimulate mitogenesis and provide an antioxidant protective effect for mtDNA;
  • A liquid combination of EFA’s, antioxidants and phospholipids to replace damaged mitochondrial membranes and build healthy new mitochondria;
  • A highly bioavailable source of CoQ10;
  • Avoid toxins and chemicals which damage the mitochondria and
  • Exercise at a moderate level to increase mitogenesis.

Take care of your patients’ mitochondria, and in turn they will take care of your patients’ energy requirements and keep them healthy for years to come.

 

References
[1] http://en.wikipedia.org/wiki/Prokaryote
[2] http://en.wikipedia.org/wiki/Endosymbiotic_theory
[3] Wei YH, Wu SB, Ma YS, Lee HC. Respiratory function decline and DNA mutation in mitochondria, oxidative stress and altered gene expression during aging. Chang Gung Med J. 2009;32(2):113-32.
[4] Seyfried TN, Shelton LM. Cancer as a metabolic disease. Nutr Metab (Lond). 2010:27;7:7
[5] Brand MD.  Assessing mitochondrial dysfunction in cells.  Biochem J. (2011) 435, 297-312.
[6] Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science. 2005; 309:481–484. [PubMed: 16020738]
[7] Kraytsberg Y, et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet. 2006 May;38(5):518-20.
[8] Handschin C, Spiegelman BM. The role of exercise and PGC1alpha in inflammation and chronic disease. Nature. 2008 Jul 24;454(7203):463-9
[9] Howitz KT, Sinclair DA. Xenohormesis: sensing the chemical cues of other species. Cell. 2008 May 2;133(3):387-91.
[10] Van Aller GS, Carson JD, Tang W, Peng H, Zhao L, Copeland RA, et al. Epigallocatechin gallate (EGCG), a major component of green tea, is a dual phosphoinositide-3-kinase/mTOR inhibitor. Biochem Biophys Res Commun. 2011 Mar 11;406(2):194-9.
[11] Pang J, Choi Y, Park T. Ilex paraguariensis extract ameliorates obesity induced by high-fat diet: potential role of AMPK in the visceral adipose tissue. Arch Biochem Biophys. 2008 Aug 15;476(2):178-85.
[12] Lee WJ, Song KH, Koh EH, Won JC, Kim HS, Park HS, et al. Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle. Biochem Biophys Res Commun. 2005 Jul 8;332(3):885-91.
[13] Alpha-lipoic acid. Monograph. Altern Med Rev. 2006 Sep;11(3):232-7.
[14] Singer SJ, Nicolson GL.  The fluid mosaic model of the structure of cell membranes. Science.  1972 Feb 18;175(4023):720-31.
[15] Nicolson GL. Lipid Replacement therapy with a glycophospholipid-antioxidant-vitamin formulation significantly reduces fatigue within one week. JANA 2010; 13(1):11-15.
[16] Agadjanyan M, et al. Nutritional Supplement (NT Factor™) Restores Mitochondrial Function and Reduces Moderately Severe Fatigue in Aged Subjects. J Chronic Fatigue Syndr 2003; 11(3): 23-36.
[17] Nicolson GL, Conklin KA. Reversing mitochondrial dysfunction, fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy. Clin Exp Metastasis. 2008;25(2):161-9.
[18] Söderberg M, Edlund C, Kristensson K, Dallner G. Fatty acid composition of brain phospholipids in aging and in Alzheimer's disease. Lipids. 1991 Jun;26(6):421-5.

 

 

 

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