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Fatigue : (Mitochondria (Essential nutrients for mitochondrial function…

- - - - the tricarboxylic acid (TCA) cycle / Krebs / citric acid cycle
        
        The TCA cycle converts carbohydrates and fats into some ATP, but
        its major job is to produce the coenzymes NADH and FADH so that
        they, too, are entered into the ETC
      - the electron transport chain (ETC)
  - - - Primarily the SUPEROXIDE (O2–) radical
        • superoxide is transformed to HYROGEN PEROXIDE (H2O2) by MANGANSES SUPEROXIDE DISMUTASE (MnSOD) or COPPER/ZINCE SUPEROXIDE DISMUTASE (Cu/Zn SOD) and then to water
        by glutathione peroxidase (GPX) or peroxiredoxin III (PRX III). However, when these
        enzymes cannot convert ROS such as the superoxide radical to H2O fast enough,
        oxidative damage occurs and accumulates in the mitochondria
    - - lipids
      - proteins
        • decreases their affinity for substrates or coenzymes and thereby decrease their function
      - oxidative phosphorylation enzymes
        – mtDNA lipid membranes
    - - Hyperglycaemia induces mitochondrial superoxide production by
        endothelial cells
      - Inflammatory mediators such as TNF-α have been associated in vitro
        with mitochondrial dysfunction and increased ROS generation
  - - - N-acetyl carnitine / Acetyl-L-carnitine is one of the most critical
        nutrients for mitochondrial function
        
        Dosage
        
        Two to four grams per day
        – in split doses
        No advantage appears to exist in giving an oral dose greater than
        two grams at one time, with absorption studies indicating saturation
        at this dose
      - Red meat is the highest food source
        – Vegetarian sources are avocado and tempeh
      - serves several functions
        
        Assists in the transport of fat across cell membranes in muscle tissue for use
        as an energy source
        
        Is essential for mitochondrial fatty acid oxidation – primary fuel source for
        heart and skeletal muscles and to maintain CoA levels
        
        Improves blood sugar control/insulin sensitivity
        
        Involved in the protection of membrane structures and reduction of lactate
        production
        – Antioxidant – in the cell membrane preventing protein oxidation and pyruvate
        and lactate oxidative damage
        
        Prevents apoptosis of skeletal muscle cells
        – Neuroprotective
        – Lipid lowering
        
        Total cholesterol, triglycerides, LDL, apoproteins A1 and B
    - - an important nutrient for the mitochondria, both structurally
        and functionally, with lipoic acid actually forming a component of complex
        V within the electron transport chain
      - Complex V is also known by a separate name - ATP synthase - as the
        name implies, this complex produces ATP
      - Lipoic acid, therefore, is an essential and integral nutrient for ATP or
        energy production within the mitochondria and is fundamental in the
        treatment of fatigue
      - OTHER FUNCTIONS
        
        Facilitates citric acid cycle activity
        • Increases glucose uptake into the cells to be used as an energy source
        • Increases pyruvate and alpha-ketoglutarate availability
        • As an antioxidant, lipoic acid also protects mitochondrial structures
      - DOSE AND FOOD SOURC ES
        
        Dosage: 300 – 600 mg a day
        Food sources - red meat, organ meats, spinach, broccoli, potatoes, yams, carrots,
        beets, and yeast
    - - transfers phosphates from
        ADP to ATP and back again. This transfer of phosphates is the most fundamental step
        of energy creation and release
      - An underlying magnesium deficiency, even if subclinical, can result in chronic fatigue
        and symptoms similar to CFS
    - - Low levels of essential fatty acids (EFAs) appear to be a common finding
        in chronic fatigue syndrome
      - EPA component of fish oil induces mitochondrial growth, size and
        distribution
        • DHA component is essential for the structure of the electron transport
        chain complexes
      - Supplementing with fish oils regulates ion homeostasis, has an antioxidant
        benefit, improves oxygen usage and therefore improves ATP production
    - - VITAMIN E
        
        Vitamin E (VE) is a major chain breaking antioxidant that has been shown to reduce contraction
        -mediated oxidative damage
        
        VE deficiency impairs muscular endurance and
        alters muscle contractile properties following a prolonged series of contractions.
    - - Ubiquinone/Coenzyme Q10/CoQ10 is present in virtually all cells and in
        especially high concentrations in the heart, liver, kidney, and pancreas
      - Within the cell, 25 to 30 per cent of total coenzyme Q10 is found in the nucleus,
        40 to 50 per cent in the mitochondria, 15 to 20 per cent in the microsomes, and 5
        to 10 per cent in the cytosol
      - CoQ10 is essential for the shuttling of electrons along the electron transport
        chain
        – think of insulation on a wire, without adequate CoQ10 the highly reactive electrons fly off the
        electron transport chain – the ‘wire’ – causing oxidative damage and reducing energy
        production
      - shuttles electrons from complexes I and II to complex III
      - DOSE
        
        150 mg/day for six months to ten patients with mitochondrial
        cytopathies (such as chronic progressive external ophthalmoplegia
        and Leber’s hereditary optic neuropathy) resulted in improved
        mitochondrial function, but no dose response trial has been
        conducted.
        
        =in the elderly this dose needs to be higher - 100-300 mg
        each day is recommended.
    - - Lauric acid found predominantly in breast milk and coconut oil, may be useful in therapy
        for post-viral or infection related fatigue.
      - • Monolaurin disrupts the lipid coat or membrane of enveloped virus’s and other
        infectious agents which may prevent infection.
      - Supplemental range is between 60- 3000mg three times daily. A maintenance dose of
        600-1200mg is suggested. Not for use during preganancy/breastfeeding.
- - - - Elevated levels of antibodyin people with CFS-like symptoms, most of
        whom had had a history of infectious mononucleosis a few years earlier
    - - Human herpes virus-6
      - Inoue-Melnick virus
      - Brucella
      - Borrelia burgdorferi
      - Giardia lamblia
      - Cytomegalovirus
        – Enterovirus
        – Retrovirus
    - - Elevated levels of antibodies to viral proteins
        • Decreased natural killer cell activity
        • Low or elevated antibody levels
        • Increased or decreased levels of circulating immune complexes
        • Increased cytokine (e.g. interleukin 2) levels
        • Increased or decreased interferon levels
        • Altered T helper cell to T suppressor cell ratio
    - - This may occur secondary to mitochondrial dysfunction
        • Dysfunction of hormonal, sleep, and autonomic control (all centred in the
        hypothalamus) and energy-production centres may explain the large
        number of symptoms and why most patients have a similar set of
        complaints
    - - KINDLING THEORY
        
        a heuristic model for understanding the etiology of Myalgic
        Encephalomyelitis/chronic fatigue syndrome (ME/CFS)
        
        Kindling occurs when an organism is exposed repeatedly to an initially sub-threshold stimulus
        resulting in hypersensitivity and spontaneous seizure-like activity
        
        Among patients with ME/CFS, chronically repeated low-intensity stimulation due to an infectious
        illness might cause kindling of the limbic-hypothalamic-pituitary axis
        
        Kindling might also occur by
        high-intensity stimulation (e.g., brain trauma) of the limbic-hypothalamic-pituitary axis. Once this
        system is charged or kindled, it can sustain a high level of arousal with little or no external
        stimulus and eventually this could lead to hypocortisolism
      - Seizure activity may spread to adjacent structures of the limbic-hypothalamic-pituitary axis in the
        brain, which might be responsible for the varied symptoms that occur among patients with
        ME/CFS. In addition, kindling may also be responsible for high levels of oxidative stress, which
        has been found in patients with ME/CFS.
      - CENTRAL NERVOUS SYSTEM SENSITISATION
        
        The observation of central sensitisation in CFS is in line with our
        current understanding of CFS
        • The presence of central sensitisation in CFS corroborates with the
        presence of several psychological influences on the illness, the
        presence of infectious agents and immune dysfunctions and the
        dysfunctional hypothalamus-pituitary-adrenal axis as seen in these
        severely debilitated patients
      - ANALOGY
        
        Analogy used for patients
        If the energy demands on your body are more than it can meet, your body “blows a
        fuse.” The ensuing fatigue forces you to use less energy, protecting you from
        harm. On the other hand, although a circuit breaker may protect the circuitry in
        the home, it does little good if you do not know how to turn it back on, or that it
        even exists
        • Research in genetic mitochondrial diseases shows not simply myopathic
        changes, but also marked hypothalamic disruption. As energy stores are
        depleted, hypothalamic dysfunction occurs early on
      - SHIN
        
        – Sleep
        – Hormonal support – thyroid, adrenal, DHEA, testosterone,
        oestrogen
        – Infections/Immune dysfunction
        – Nutritional support
        
        OXIDATIVE STRESS?
        
        The role of oxidative stress in
        CFS is an important area for current and future research as it suggests the use of
        antioxidants in the management of CFS. Specifically, the dietary supplements
        glutathione, N-acetylcysteine, alpha-lipoic acid, oligomeric proanthocyanidins,
        Ginkgo biloba, and Vaccinium myrtillus (bilberry) may be beneficial
        
        NUTRITIONAL DEFICIENCIES?
        
        A detailed review of the literature suggests a number of marginal nutritional deficiencies
        may have etiologic relevance. These include deficiencies of various B vitamins, vitamin C,
        magnesium, sodium, zinc, L-tryptophan, L-carnitine, coenzyme Q10, and essential fatty
        acids. Any of these nutrients could be marginally deficient in CFS patients, a finding that
        appears to be primarily due to the illness process rather than to inadequate diets.