mitochondrial diseases

Etiologies

 A. mitochondrial genome anomalies

• whole mitochondrial proteome anomalies
  • tRNA gene anomalies
  • rRNA gene anomalies
  • deletions of the mitochondrial genome

• specific protein of respiratory chain anomalies
  • punctual mutations of the mitochondrial genome
  • deletions of the mitochondrial genome

 B. nuclear gene anomalies

• B-1. nuclear mutations of genes encoding electron transport proteins (structure genes of respiratory chain complex) - anomalies of the strucure of respiratory chain (mutations of 12 out of 38 subunits coded bu nuclear genes)
  • complex I deficiency
    • Leigh syndrome or Leigh-like syndromes (lethal and precocious necrotizing encephalopathy)

• • complex II deficiency
    • SDH-flavoprotein deficiency or SDHA deficiency
    • Leigh syndrome

• • complex III deficiency
  • complex IV deficiency

• B-2. resipratory chain complex assembly anomalies (nuclear mutations of genes encoding mitochondrial enzymes - proteins of assembling of respiratory chain, incorporation of cofactors, heme, iron, copper)
  • complex I assembling (38 subunits coded by nDNA, 7 subunits coded by mtDNA)
    • NDUFAF1
    • NDUFAF2
    • C6orf66
    • C20orf7
    • ACAD9

• • complex II assembling
    • NDUFAF2

• • complex III assembling
    • SDHAF1
    • BCS1L (iron-sulfur protein assembly)
    • TTC19

• • complex IV assembling
    • SURF1
    • SCO1
    • COX10
    • SCO2
    • LRPPRC
    • FASTKD2
    • TACO1

• • complex V assembling
    • TMEM70
    • ATP12

• • iron-sulfur protein assembly
    • Friedreich ataxia

• B-3. mtDNA maintenance anomalies (nuclear genes)
  • mtDNA multiple deletions (frequent autosomal dominant progressive external ophtalmoplegia - adPEO)
    • POLG1
    • POLG2
    • ANT1
    • OPA1

• • mtDNA depletion (hepatocerebral form, myopathic form, encephalomyopathic form, mitochondrial neurogastrointestinal encephalomyopathy/MNGIE)
    • POLG
    • PEO1
    • DGUOK
    • MPV17
    • RRM2B
    • TK2
• TP

• B-4. maturation and traduction of mitochondrial proteins
  • mtDNA mutations
    • tRNA mutations
      • tRNA-Leu(UUR) - 3243A>G (MT-TL1) (MELAS syndrome)

• • • rRNA mutations

• • nuclear genes (12 mutated nuclear genes)
    • mitochondrial traduction elongation factors
      • GFM1/EFG1
      • TUFM/EFTu
      • TSFM/EFTs

• • • tRNA modifier genes
      • PUS1
      • TRMU

• • • mitochondrial tRNA synthases
      • RARS2
      • DARS2
      • YARS2
      • HARS2

• • • unknown function proteins
      • C12Orf65

• B-5. mitochondrial protein importation
  • TIMM8A - Mohr-Tranebjaerg syndrome (X-linked deafness and dystonia)
  • DNAJC19 (dilated cardiomyopathy with ataxia)

• B-6. mitochondrial lipid anomalies
  • ubiqinone (coenzyme Q10) anomalies
    • PDSS1
    • PDSS2
    • COQ2
    • COQ9
    • CABC1
    • tafzzine naomalies: Barth syndrome (cardiolipine synthesis deficiency)

Types

 mitochondrial respiratory chain anomalies - oxidative phosphorylation anomalies - OXPHOS disorders
 defects of transport through the mitochondrial membrane
 defects of substrates utilization
 defects of Krebs cycle
 fatty acid oxydation anomalies
 urea cycle anomalies
 carnitine palmityl-transferase pyruvate dehydrogenase
 mitochondrial DNA depletion syndrome

Localization

 mitochondrial hepatopathies
 mitochondrial myopathies
 mitochondrial encephalopathies
 mitochondrial encephalomyopathies
 multiple symmetrical lipomatosis
 Barth Syndrome

• down-regulation of Bid protein in parallel to the genetic deficiency in cardiolipin remodeling

Classification (Mancuso, Filosto, 2007)

 mtDNA rearrangements

• sporadical mtDNA rearrangements
  • Kearns-Sayre syndrome (KSS)
  • Pearson syndrome
  • sporadical chronic progressive external ophtalmoplegia (sporadical CPEO)

• maternal transmitted mtDNA rearrangements
  • maternal transmitted chronic progressive external ophtalmoplegia (maternal transmitted CPEO)
  • systemic syndromes
  • diabetes mellitus and deafness (DAD)
    • this combination at an early age can be due to mitochondrial disease
    • Diabetes mellitus and deafness can also be found together for other reasons

 mtDNA punctual mutations

• mtDNA punctual mutations of genes coding for proteins
  • Leber hereditary optic neuropathy (LHON)
  • neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP)
  • Leigh syndrome

• mtDNA punctual mutations of genes coding for tRNA
  • mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS syndrome)
  • myoclonic epilepsy with ragged red fibers (MERRF)
  • myoneurogenic gastrointestinal encephalopathy (MNGIE)
  • cardiomyopathy and myopathy
  • chronic progressive external ophtalmoplegia (CPEO)
  • isolated myopathy
  • diabetes mellitus and deafness (DAD)
  • sensorial deafness
  • hypertrophic cardiomyopathy
  • tubulopathy
  • massive hepatic necrosis

• mtDNA punctual mutations of genes coding for rRNA
  • aminosid-induced non syndromal deafness
  • hypertrophic cardiomyopathy

Nota bene: Conditions such as Friedreich ataxia can affect the mitochondria, but are not associated with mitochondrial proteins.

See also

 mitochondrial protein synthesis diseases
 mitochondrial respiratory chain diseases

References

 Dimauro S, Schon EA. Mitochondrial Disorders in the Nervous System. Annu Rev Neurosci. 2008 Mar 10; PMID: 18333761

 Rotig A, Lebon S, Zinovieva E, Mollet J, Sarzi E, Bonnefont JP, Munnich A. Molecular diagnostics of mitochondrial disorders. Biochim Biophys Acta. 2004 Dec 6;1659(2-3):129-35. PMID: 15576044

 Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet. 2005 May;6(5):389-402. PMID: 15861210

 Jacobs HT. Disorders of mitochondrial protein synthesis. Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R293-301. PMID: 12928485

 Rotig A, Munnich A. Genetic features of mitochondrial respiratory chain disorders. J Am Soc Nephrol. 2003 Dec;14(12):2995-3007. PMID: 14638899