What are mitochondria?

• Mitochondria are cell organelles
• between 0.5 and 10 μmol long
• occupy between 3 and 30% of the cell volume
• its surface forms an area of ​​14,000 m²
• Cells contain up to 1000 mitochondria (depending on the function of the respective cell)

 

How is a mitochondrion structured?

• Contains its own “mDNA” (structure of DNA and ribosomes like bacteria)
• Small double-stranded DNA ring (v.a inherited from mother)
• 2 – 10 copies per mitochondrion
• Compact (approx. 1000 proteins; almost only coded sections)
• No histone protection
• Hardly any error detection and repair mechanisms
• Therefore, mitochondria can be easily damaged by oxidative & nitrosative stress (free radicals)!

 

What are the tasks of the mitochondria?

1. Energy production
   1. Mitochondria are power plants and engines of our cells: macronutrients (carbohydrates, proteins, fats) contain chemically bound energy that is not directly available to the cells (cf. "Oil"). This energy must first be processed outside the mitochondria. Like “gasoline” in an engine, the processed nutrients are burned (assisted by “cofactors”) to produce usable energy.
   2. 95% of cellular energy is produced in the mitochondria, ~ 65 kg ATP/day via oxidative phosphorylation, beta-oxidation and citrate cycle
   3. By-product of energy production: Free radicals, which lead to oxidative stress (physiologically 2-5% from oxygen; possibly. increasing up to 25%) à Problem: Risk of damage to 1.-3. caused by free radicals (oxidative damage in mitochondria 10-20 times more common than in nuclear genome)!
2. Involvement in important intracellular processes via mitochondrial DNA (mDNA), e.g.b:
   1. Control of cell functions (via calcium concentration)
   2. Protection of the rest of the cell from free radicals
   3. Signal function for the immune system (e.g.b virus defense)
   4. Involved in autophagy (mitophagy) and apoptosis
3. Provision of intermediate products for anabolic processes in the citrate cycle (such as keto acids, citric acid), e.g.b for amino and fatty acid biosynthesis, gluconeogenesis, heme formation

 

 

The four most important sources of energy production in the mitochondria:

 

Relevant co-factors for these 4 energy production processes:

Without the u.G The energy production processes in the mitochondria cannot take place without co-factors. Therefore, sufficient availability is important.a the following co-factors should be taken into account:

• B vitamins
• L-Carnitine
• Coenzyme Q10
• Magnesium
• Alpha lipoic acid (ALA)
• Sulfur
• Copper
• Calcium
• Iron
• Manganese

 

Ad 1: Beta-oxidation and the important role of L-carnitine:

• Energy metabolism: L-carnitine as a “biocarrier” of fatty acids into the mitochondria
  • Transport molecule for free long-chain fatty acids in mitochondria
  • 95% of the occurrence of L-carnitine in heart and Skeletal muscles, as there is a great need for energy and therefore “mitochondria”
  • Performance-enhancing
• Influence on blood lipid levels
• Membrane stabilizing, antioxidant and neuroprotective properties
• Immune system: increasing…
  • Lymphocyte proliferation
  • Phagocytosis activity of granulocytes and monocytes
  • Natural killer cell activity
• Detoxification function
  • Liver metabolism of toxic substances: transport molecule (“biocarrier”) of the toxic metabolites for excretion via the kidneys

 

Ad 4: The respiratory chain (oxidative phosphorylation) and the important role of coenzyme Q10:

• Energy metabolism: Coenzyme Q10 is a central component of the respiratory chain (electron transport chain) in the inner mitochondrial membrane (conversion of oxidized ubiquinone into reduced ubiquinol)
• Antioxidant
  • Reduces oxidative stress and its consequences (arteriosclerosis, cancer, accelerated aging, etc.)
  • Localization in mitochondria (particularly good and rapid local effect on oxygen radicals)
  • Involved in the reduction of oxidized vitamin E
• Mitochondrial disorders, oxidative stress and coenzyme Q10:

 

 

Mitochondrial dysfunction / mitochondrial diseases

• With mitochondrial dysfunction and mitochondrial diseases, there are varying degrees of metabolic defects in the mitochondria. The defects are divided into
  • primary (genetically determined)
  • secondary (acquired)
• Mitochondrial diseases are more common than expected: prevalence approx. 11.8 / 100,000

 

Causes of mitochondrial dysfunction

(adapted from guidelines of the German Society for Neurology)

• Disorders of mitochondrial energy production
  • In particular the two energy production processes oxidative phosphorylation (4) and fatty acid breakdown (1)
  • Risk high due to radical formation and involvement of many enzymes
  • As a result of
    • Primary: defects in nuclear genes or mutations in mtDNA, e.g.b singular mtDNA deletions or mtDNA-tRNA point mutations
    • Secondary:
      • Errors in energy generation or process control, e.g.b due to metabolic disorders, metabolites, pollutants, deficiency of coenzyme Q 10, L-carnitine, antioxidants and cofactors
      • Epigenetic influences (e.g.b from the environment)

 

Symptoms

• Symptoms of classic mitochondrial diseases occur primarily.a on in tissues with a high dependence on mitochondrial energy production and high energy requirements, e.g. in the area:
  • Eyes (Seeing)
  • ENT (inner ear)
  • Central nervous system (CNS) and peripheral nervous system
  • Heart and skeletal muscles
  • Pancreas
  • Kidney
  • Liver
• “Typical” symptoms as indications of mitochondrial disorders (Source: (Zeviani and Carelli 2003):
  • Adults:
    • Fatigue
    • Weakness
    • Difficulty concentrating
    • Depressed mood
    • Disorders of sensory perception
    • Myopathies
    • Joint pain
  • Children:
    • generalized muscle hypotonia (“floppy infant”)
    • psychomotor developmental delay
    • Lactic acidosis
    • Cardiopulmonary failure

Diagnostics

Laboratory normal values ​​of the parameters relevant to mitochondrial function:

Mitochondria
ATP intracellular Pyruvate Lactate Lactate-pyruvate Q10 L-carnitine LDH (serum) Active mitochondria (cf. Mitochondrial activity)	2-8 μmol/l 39-82 μmol/l 5-20 mg/dl (0.55-2.2 mmol/l) <20:1 (ideal 10: 1) 0.5-2.5 mg/l 20-50 mcmol/l < 245 U/l > 99%
Inflammation
sensitive CRP IL-6 IL-8 IL-10 (T cells) TNF-α (macrophages)	< 5 mg/dl < 5 pg/ml < 2 pg/ml < 1072 pg/ml < 0.5 pg/ml or <8.1 pg/ml
Oxidative stress / Nitrosative (NO) stress
Total antioxidant status (TAS, antioxidant capacity) in serum MDA (malondialdehyde) in EDTA plasma Hydroperoxides (1 FORT = 7.6 mcmol/l H2O2)	1.3-1.7 mmol/l 0.36-1.42 μmol/l <230 FORT
Nitrotyrosine (correlative for peroxynitrite formation) Holo-transcobalamin in serum (B12 = NO scavenger) or methylmalonic acid (B12 deficiency marker) in urine	< 10 nmol/l < 50 pmol/l < 2 nmol/mol Crea

 

 

Micronutrient therapy for mitochondrial dysfunction:

• Antioxidant enzymes such as SOD, peroxidases, catalases (“1. Defense line”)
• Coenzyme Q10 (energy and radical protection)
• L-Carnitine (Energy)
• Vitamins C, D and E, selenium, zinc and secondary plant substances (“2. Line of defense”: radical protection, anti-inflammatory)
• Cofactors (v.a Vitamin B complex)
• Possible dosage recommendation:

Active ingredient	Dose
Vitamin C Vitamin E Selenium Polyphenols (e.g.b Resveratrol) Coenzyme Q 10	3 x 0.5-1 g 200-400 mg 100 μg 40-125 mg 60-150 mg
Vit. B1 / B2 / B3 Vit. B6 / B12 / folic acid / Vit B5	50-100 mg / 10-100 mg / 50-75 mg 50-100 mg / 1 mg / 1 mg / 10-100 mg
Zinc Manganese Magnesium Unsaturated fatty acids L-carnitine	20-60 mg 2-30 mg 300-500 mg 1-3 g 1-3 g
α-lipoic acid	200-600 mg