Friday, January 27, 2012

Mitochondrial Dysfunction

(Unlike the other posts I changed the reference count to reset at each sub-heading to make this post easier to edit)

Mitochondrial Dysfunction as a Mechanism of Disease 

There are many chronic diseases.  Some of them can be the result of similar mechanisms.  A perfect example of this are the autoimmune diseases, which share the common mechanism of autoimmunity, but manifest in remarkably different ways.  Another mechanism that can produce a wide variety of chronic diseases is mitochondrial dysfunction. 

Mitochondrial dysfunction is a potential mechanism behind many metabolic, age-related, neurodegenerative and psychiatric diseases or health conditions such as: aging [1], age-related macular degeneration [2], Alzheimer’s disease [3], amyotrophic lateral sclerosis [4], atherosclerosis [5], autism [6], bipolar disorder [7], cancer [8], cataracts [2], chronic fatigue syndrome [9], diabetic cardiomyopathy [10], nephropathy [11], neuropathy [12] and retinopathy [2], endothelial dysfunction [5], epilepsy [13], fibromyalgia [14], hearing loss [15], Huntington’s disease [16], hypertension [5], insulin resistance [17], major depressive disorder [7], male infertility [18], migraines [19], multiple sclerosis (?) [20], non-alcoholic fatty liver disease [21], obesity [22], Parkinson’s disease [23], schizophrenia [7] and type 2 diabetes [24]. 

Diseases and health condition stemming from mitochondrial dysfunction tend to occur in the brain, heart, liver and muscle.  A possible reason is that these parts of the body require a lot of aerobic metabolism and are therefore more dependent on their mitochondria. 

"Chronic mitochondrial oxidative stress on the peripheral tissues subsequently damages the retina, vascular endothelial cells, peripheral neurons, and the nephrons, leading to the clinical sequelae of end-stage diabetes. Thus chronic mitochondrial dysfunction can explain all of the features of type II diabetes, and is thus the likely cause of the disease" [1]

Mitochondria and Respiration 

A mitochondrion is an organelle within our cells.  Endosymbiosis is the theory to explain how some aerobic bacteria were engulfed by eukaryotic cells, but instead of being digested the bacteria became part of the eukaryotic cell.  Mitochondria have many bacterial features and their own separate DNA (mtDNA). 

The primary role of mitochondria is to generate most of our energy by aerobic respiration.  Mitochondria are also involved in detoxification and cellular signalling related to apoptosis and energy status. 

In the cytosol glucose is split from a 6 carbon molecule to a 3 carbon molecule called pyruvate.  Under anaerobic conditions (such as in intense exercise) pyruvate is fermented to lactate*.  The process from glucose to lactate can generate ATP quickly, but only a very small amount.  Under aerobic conditions pyruvate enters the mitochondria and helps form acetyl-CoA. 

Fatty acids are broken down in the mitochondria, two carbons at a time, each couple helps form another acetyl-CoA.  Acetyl-CoA donates 2 carbons to the citric acid cycle, which removes the carbons, generating a little more ATP and attaching the carbons to oxygen to form CO2.  Meanwhile the electrons from the hydrogen atoms are bound to electron carriers.  The electron carriers pass their electrons along the electron transport chain, which releases energy to pumps protons across the inner mitochondrial membrane.  Eventually there’s a lot of potential energy from lots of protons one side of the membrane and lots of electrons on the other side.  An enzyme called ATP synthase opens the gates causing protons to pair up with electrons to form hydrogen, which then bind with oxygen to form H2O.  As the protons flow through ATP synthase they release the potential energy, which ATP synthase uses to create lots of ATP.  Most ATP is generated this way.  (What the electron transport chain does is called oxidative phosphorylation (OXPHOS)) 

* Animals and bacteria ferment pyruvate to lactate.  Plants and fungi ferment pyruvate to ethanol. 

The Role of Mitochondrial Dysfunction in Chronic Disease 

The process of breaking down carbohydrates and fat into carbon dioxide and water doesn’t always work perfectly.  Sometimes hydrogen peroxide (H2O2) is formed instead of water or superoxide (O2-) is formed by an electron binding to oxygen (O2) (a process called reduction) too soon.  Hydrogen peroxide and superoxide are two common reactive oxygen species (ROS).  ROS are involved in cellular signalling, but also steal electrons (a process called oxidation) from proteins, DNA and PUFA (lipid peroxidation), which damages cells and is called oxidative stress. 

To protect against ROS we have antioxidant enzymes such as superoxide dismutase (to convert superoxide to hydrogen peroxide), glutathione peroxidase and catalase (both convert hydrogen peroxide to water). 

If the antioxidant defences are overwhelmed these ROS are free to cause oxidative stress.  The mitochondria are most vulnerable due to their close proximity.  ROS inhibit ATP production and can damage mtDNA, leading to mutations*.  This initiates a positive feedback cycle whereby mutations in mtDNA compromise mitochondrial function, slow down the electron transport chain and lead to more ROS, more oxidative stress and more mutations [1]. 

Mitochondria generate roughly 90% of the endogenous ROS so mitochondrial ROS have a great capacity to cause damage [1].  Hydrogen peroxide and superoxide are less damaging than other oxidants but can from very damaging compounds.  Hydrogen peroxide can bind with metal ions to form a hydroxyl radical (OH-) and superoxide can combine with nitric oxide (NO) to form peroxynitrite (ONO2).  Mitochondrial ROS can increase pro-inflammatory cytokines [2] and insulin resistance [3]

Mitochondria can initiate apoptosis in response to energy deficiency, oxidative stress and elevated intracellular calcium ions (Ca2+), all of which can be a result of mitochondrial dysfunction.  Apoptosis and energy deficiency in a cluster of cells responsible for a specific function can result in chronic diseases such as: the pancreatic beta cells in type 2 diabetes**, the substantia nigra neurons in Parkinson’s disease and the diabetic '-opathies' (cardiomyopathy, neuropathy, nephropathy and retinopathy) [1].  The increase in calcium ions may lead to excitotoxity [4]

Mitochondrial dysfunction is strongly associated with and can cause endoplasmic reticulum (ER) stress and vice versa [5].  The ER is an organelle involved in the synthesis and folding of proteins (putting the protein in the right shape), the synthesis of lipids and steroid hormones, and more.  Protein unfolding occurs during ER stress as an adaptive mechanism, although prolonged ER stress will initiate apoptosis.  Prolonged ER stress stimulates the release of protein-tyrosine phosphatase 1B (PTP1B), which inhibits the signal transduction of leptin, leading to leptin resistance and obesity [6].  PTP1B also increases insulin resistance, gluconeogenesis, triglycerides and cholesterol [7] and promotes tumour growth [8]


Symptoms of these diseases and health conditions appear when the function and/or number of cells drop below a minimum threshold needed for normal functioning.  Mitochondrial dysfunction is major factor behind many progressive, degenerative diseases which usually manifest later in later life and can be described as accelerated aging.  More generally, mitochondrial dysfunction is also related to many aspects of aging and I think it is a main factor driving the aging process [1]

I've done some blog posts on mitochondrial dysfunction and obesity, cancer, cardiovascular disease, type 2 diabetes, Parkinson's disease and Alzheimer's disease

* Unlike nuclear DNA, mitochondrial DNA cannot be repaired [9] 

** Type 1 and type 2 diabetes involve a loss of pancreatic beta cell function (inadequate insulin released).  Gestational diabetes is different, in that there's no pancreatic damage (and there's rarely any glucose in the urine - what 'diabetes mellitus' means), just a higher level of insulin resistance to divert nutrients to the foetus, and so perhaps it should be called gestational insulin resistance instead.

*** There are many theories of why menopause exists, though the most basic purpose is to stop women reproducing.  Only mothers pass their mtDNA to their children. and menopause only affects women.  It's possible that menopause exists to stop women reproducing at an age when the body assumes there would be too many age-related mtDNA mutations, in order to prevent those mtDNA mutations from being passed on to their children.  It's well known that children from older mothers have a greater risk of certain diseases, so perhaps menopause is the body just drawing a line in the sand.  Menopause seems inevitable, so this is just an academic speculation 

Causes of Mitochondrial Dysfunction 

Causes of mitochondrial dysfunction tend to involve oxidative stress.  These can include: alcohol [1], excess calories [2], glucocorticoids [3], homocysteine [4], iron overload [5], lipopolysaccharides [6], nutrient deficiencies [7], pro-inflammatory cytokines [8], smoking [9], and statins* [10]. 

The efficiency of calories to ATP is determined by how coupled* the mitochondria are.  If mitochondria are tightly coupled then calories are efficiently converted to ATP and generate less heat, but excess calories will increase the production of ROS by slowing down the electron transport chain, allowing more opportunity for electrons to reduce O2 to superoxide.  Loosely coupled mitochondria are adaptations to cold climates as calories are less efficiently converted to ATP, but generate more heat (thermogenesis) and excess calories don’t increase the production of ROS as much.  People with tightly coupled mitochondria are at a much greater risk of mitochondrial dysfunction with excess calories [2]. 

Nutrient deficiencies in CoQ10 [10], glutathione [11], carnitine [12], taurine [13] or zinc [14] may lead to mitochondrial dysfunction.  Deficiencies in other nutrients that can act as mitochondrial antioxidants and/or support mitochondrial function may also lead to increased oxidative stress and mitochondrial dysfunction.  Nutrients important for mitochondria include: 

  • Glutathione and selenium to synthesise glutathione peroxidase.
  • Manganese to synthesise superoxide dismutase in the mitochondria (zinc and copper help synthesise superoxide dismutase elsewhere in the body)
  • Vitamins B2, B5, B6 and B7, iron, copper and zinc to synthesise heme in the mitochondria.  Heme is part of catalase and of complex IV in the electron transport chain to reduce ROS [15] 
  • FAD+ from riboflavin (B2), NAD+ from niacin (B3) and CoQ10 are electron carriers in the electron transport chain.  Also acetyl-CoA is derived from vitamin B5
  • CoQ10 [10], PQQ [16], lipoic acid [17], carnitine [18] carnosine [19], creatine [20], taurine [21], vitamin C and E are mitochondrial antioxidants and many have other functions as well

You can look where to find some of these nutrients on my nutrient database and check out this post for some of the others.  The general pattern is that animal foods and vegetables are the best sources.  The amino acid derivatives and CoQ10 are almost exclusively found in meats, which is logical because the muscle and organs contain many mitochondria.  Eat mitochondria to support your own.

* To lower cholesterol statins also block CoQ10 synthesis.  Mitochondrial dysfunction can follow from CoQ10 depletion and may explain some of their side effects such as an increased risk of diabetes and myopathy. 

** Tightly coupled mitochondria are more efficient at pumping protons into the inner mitochondrial membrane and also more efficient at using those protons as they go through ATP synthase to generate ATP [2]. 

*** Environmental toxins such as dioxins [22], heavy metal toxicity (aluminium [23] and mercury [24]), herbicides [25], pesticides [26] and welding fumes [27] can also have a role in mitochondrial dysfunction. 

Mitochondrial Biogenesis 

If mitochondrial numbers and/or function is low then a way to correct this is to increase mitochondrial biogenesis - the growth of new mitochondria.  AMP-activated protein kinase (AMPK) is an energy sensor that is released in response to low cellular energy (a high AMP:ATP ratio), it also increases mitophagy (autophagy of mitochondria) [1], glucose transport and fatty acid oxidation [2].  AMPK inreases PGC-1α, a protein that is largely responsible for mitochondrial biogenesis.  PGC-1α also increases fatty acid oxidation, oxidative phosphorylation, insulin sensitivity and energy expenditure [3]. 

Exercise* [4], ketogenic diets [5], fasting [6], calorie restriction [7], cold exposure [8] and non-ketogenic low carb diets [9] increase AMPK.  All of these signal energy scarcity, so are somewhat stressful for the body and may antagonise thyroid function is large amounts.  More is not always better. 

Active thyroid hormone (T3) [10], BCAAs [11], butyric acid [12], PQQ [13], and a combination of lipoic acid and carnitine [14] increase PGC-1α (perhaps through AMPK independent mechanisms?).  This list is comprised of generally health promoting molecules 

* Based on the studies in an MDA post: endurance and HIIT (30 sprint, 240 off) increases MB, resistance enhances MB from endurance, but resistance alone may not and walking does not increase MB.  My guess it that whatever gets you breathing hardest will increase MB the most.  High doses of vitamin C supplementation (1000 mg daily) reduces exercise induced mitochondrial biogenesis [14].

Summary 

Mitochondrial dysfunction is a mechanism behind many metabolic, age-related, neurodegenerative and psychiatric diseases or health conditions. It can be caused by an excess of calories, nutrient deficiencies and various means of oxidative stress.  Mitochondrial dysfunction is a vicious cycle whereby oxidative stress damages mtDNA, leading to worse mitochondrial function and more oxidative stress.  Many nutrients that support mitochondrial function are found in meats and vegetables. A diet rich in these nutrients and measures that increase mitochondrial biogenesis and reduce oxidative stress will help prevent, and may reverse, mitochondrial dysfunction and other related diseases.

Further Reading:
(1) A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine

15 comments:

  1. Glad to have found your blog via your comment at Stephan's. Looking forward to having it be a regular read!

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  2. Lots of food for thought here. I found this from your comment on my blog. I'll be bookmarking this one to read more thoroughly when I have some time. Nice blog Steven!

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  3. Found you via Jaminet's blog. Awesome read, Steven! I am here to stay!

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  4. Wow, very interesting material. I have seen some assorted info along these lines, but the way this is presented is a very cohesive and seems complete.

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  5. Awesome job,

    one question: how do I decouple my mitochondria, I'd like to lose weight and be warmer.

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    1. Thanks DancinPete. Unfortunately I think there's a very strong genetic influnece.

      PGC-1a increases uncoupling proteins, but many things that increase AMPK/PGC-1a also somewhat downregulate thyroid function (calorie resistion, fasting, low carb), which would be in conflict of your goals.

      Some exercise, mild cold exposure and increasing thyroid function should produce the desired effect.

      It's hard to give a good answer without knowing more information (current diet, exercise, sleep, health problems, etc).

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  6. Great info - thanks. It seems mitochondria are a lot more complex than we knew. We are having fantastic results with APS Therapy as
    the therapy creates action potentials and ramps up the ATP both of which suffer from mitochondrial dysfunction. You can check it out on my blog http://nzhealthnews.blogspot.co.nz/
    Also there is a new book called Vitamin D Is This The Miracle Vitamin by Ian Wishart linking a lack of Vitamin D and mitachondrial dysfunction.

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  7. You don't mention fibromyalgia in your post - but i suspect this is also a huge issue with FMS and Chronic Myofascial Pain. Do you concur? I have fibro and CMP, and have always felt much better on a low carb diet.

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    Replies
    1. Hi Heka, the point of this post wasn't to say how mitochondrial dysfunction can cause each chronic disease, but rather more of a basic overview.

      Mitochondrial dysfunction does seem to be a factor in fibromyalgia but isn't the only one. Chris Kresser has mentioned problems with methylation and the therapeutic effect of low dose naltrexone. And fibromyalgia is associated with autoimmune diseases which suggests one or more of the mechanisms that cause AI diseases (immune dysfunction, intestinal permeability, infections) are a potential factor in fibromyalgia.

      Beyond that I don't know that much on fibromyalgia or CMP, though I plan to research fibromyalgia at some time. I hope you manage to reverse them as they both sound like awful diseases to have.

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  8. wouldn't the mitochondria in animal protein be destroyed when we cook the meat? How can "eating mitochondria produce mitochondria"???

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    Replies
    1. Yes, but their nutrients/antioxidants should be available, which is why I said 'Eat mitochondria to support your own'

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  9. It is generally cause due to diabetes, alcohol abuse, hormonal causes, stress, cycling, nervousness and depression.
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