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 area covers 14,000 m².
• Cells contain up to 1000 mitochondria (depending on the function of the respective cell).

What is the structure of a mitochondrion?

• Contains its own "mDNA" (structure of DNA and ribosomes as in bacteria)
• Small double-stranded DNA ring (v.a(inherited through the mother)
• 2–10 copies per mitochondrion
• Compact (approx. 1000 proteins; almost exclusively coded sequences)
• No histone protection
• Hardly any fault detection and repair mechanisms
• Therefore, mitochondria can easily be damaged by oxidative processes. & nitrosative stress (free radicals) can damage them!

What are the functions of mitochondria?

1. Energy generation
   1. Mitochondria are the powerhouses and engines of our cells: Macronutrients (carbohydrates, proteins, fats) contain chemically bound energy that is not directly available to the cells (compare to "oil"). This energy must first be processed outside the mitochondria. Like "gasoline" in an engine, the processed nutrients are burned (with the support of "cofactors") to generate usable energy.
   2. 95% of cellular energy is produced in the mitochondria, ~65 kg ATP/day via oxidative phosphorylation, beta-oxidation and citric acid cycle.
   3. A byproduct of energy production is free radicals, which lead to oxidative stress (physiologically 2-5% of oxygen; possibly increasing to 25%). Problem: The risk of damage to cells 1-3 from free radicals is high (oxidative damage in mitochondria is 10-20 times more frequent than in nuclear DNA)!
2. Involvement in important intracellular processes via mitochondrial DNA (mDNA), z.B.:
   1. Control of cell functions (via calcium concentration)
   2. Protection of the rest of the cell from free radicals
   3. Signaling function for the immune system (z.B( . Virus defense)
   4. Involved in autophagy (mitophagy) and apoptosis
3. Provision of intermediates for anabolic processes in the citric acid cycle (such as keto acids, citric acid), z.B. for amino and fatty acid biosynthesis, gluconeogenesis, heme formation

The four most important sources of energy production in mitochondria:

Relevant co-factors for these 4 energy generation processes:

Without the u.gCofactors cannot catalyze energy production processes in the mitochondria. Therefore, sufficient availability is essential. v.aThe following co-factors should be considered:

• 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, because there is a high energy demand and therefore a high "mitochondrial demand" there.
  • Performance-enhancing
• Influence on blood lipid levels
• Membrane-stabilizing, antioxidant and neuroprotective properties
• Immune system: Increased…
  • Lymphocyte proliferation
  • Phagocytic activity of granulocytes and monocytes
  • Natural killer cell activity
• detoxification function
  • Liver metabolism of toxic substances: Transport molecule ("biocarrier") of 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 to 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 dysfunction, oxidative stress and coenzyme Q10:

Mitochondrial dysfunction/Mitochondrial diseases

• Mitochondrial dysfunction and mitochondrial diseases involve varying degrees of metabolic defects in the mitochondria. These defects are categorized as follows:
  • primary (genetically determined)
  • secondary (acquired)
• Mitochondrial diseases are more common than previously thought: prevalence approximately 11.8/100,000

Causes of mitochondrial dysfunction

(adapted from guidelines of the German Society for Neurology)

• Disruptions in mitochondrial energy production
  • In particular, the two energy production processes oxidative phosphorylation (4) and fatty acid degradation (1)
  • High risk due to radical formation and the involvement of many enzymes
  • As a result of
    • Primary: defects in nuclear genes or mutations in mtDNA, z.Bsingular mtDNA deletions or mtDNA-tRNA point mutations
    • Secondary:
      • Errors in energy generation or process control, z.B. due to metabolic disorders, metabolites, pollutants, deficiency of coenzyme Q10, L-carnitine, antioxidants and cofactors
      • Epigenetic influences (z.B(from the environment)

Symptoms

• Symptoms of classic mitochondrial diseases occur v.a...in tissues with a high dependence on mitochondrial energy production and high energy demand, e.g. in the area of:
  • Eyes (sight)
  • ENT (inner ear)
  • Central nervous system (CNS) and peripheral nervous system
  • Cardiac and skeletal muscles
  • pancreas
  • kidney
  • liver
• “Typical” symptoms as indicators of mitochondrial disorders (Source: (Zeviani et al.)Carelli 2003):
  • Adult:
    • fatigue
    • weakness
    • Concentration problems
    • Depressed mood
    • Sensory perception disorders
    • Myopathies
    • Joint pain
  • Children:
    • generalized muscle hypotonia ("floppy infant")
    • psychomotor developmental delay
    • Lactic acidosis
    • Cardiopulmonary failure

Diagnostics

Normal laboratory values ​​for parameters relevant to mitochondrial function:

Mitochondria
ATP intracellular Pyruvate lactate Lactate-pyruvate Q10 L-Carnitine LDH (Serum) Active mitochondria (see 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 mmol/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 (correlate 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 creatinine

Micronutrient therapy for mitochondrial dysfunction:

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

Active ingredient	dose
Vitamin C Vitamin E selenium Polyphenols (z.B. Resveratrol) Coenzyme Q10	3 x 0.5-1 g 200-400 mg 100 μg 40-125 mg 60-150 mg
Vit. B1/B2/B3 Vit.Vitamin B6/B12/Folic acid/Vitamin B5	50-100mg/10-100mg/50-75mg 50-100mg/1mg/1mg/10-100mg
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