Neuromuscular

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PATHWAYS: MITOCHONDRIAL

Fatty acid oxidation
Lactate metabolism
Oxidative phosphorylation
  Composition
    Complex I
    Complex II
    Complex III
    Complex IV
    Complex V
    Combined deficiencies
  Pathways
Mitochondrial disorders


OXIDATIVE PHOSPHORYLATION

Complex I Complex II Complex III Complex IV TCA cycle Coenzyme Q10
Modified from MW King

Mitochondrial respiratory chain
  • Location: Inner mitochondrial membrane
  • Composition
    • > 80 peptides organized in 5 enzymatic complexes (I-V)
    • Electron shuttle molecules: Coenzyme Q (CoQ); Cytochrome c (Cyt c)
  • Overall actions: Produces ATP from the reduction of oxygen to generate energy for cellular function
  • Pathway
    • Receives electrons generated by donors in intermediary metabolism
    • Electrons sequentially transferred through redox groups to final acceptor, oxygen
    • Free energy generated: Used to pump protons from mitochondrial matrix to intermembrane space
    • Generates electrochemical gradient across inner mitochondrial membrane
    • Protein flux back into mitochondrial matrix through Complex V is coupled to ATP synthesis
    • See: Animated diagram of proton pump & ATP synthesis
Other mitochondrial functions


MITOCHONDRIAL RESPIRATORY CHAIN: COMPOSITION
Complex I II III IV V
Enzyme NADH-CoQ
Reductase
Succinate-CoQ
Reductase
CoQ-Cytochrome C
Reductase
Cytochrome C
Oxidase
ATP Synthase
Inhibitor Rotenone
Amytal
TTFA malonate Antimycin A Cyanide
Carbon Monoxide
Azide
Oligomycin
Nuclear DNA
Subunits
39 4 10 10 ~14
Mitochondrial
DNA Subunits
7
ND1-6, ND4L
0 1
Cytochrome b
3
Cytochrome oxidase
I , II , III
2
ATPase 6
ATPase 8
Flavoprotein Flavin
mononucleotide
FAD (SDHA)      
Iron protein Iron Sulfur
(FeS) protein
NDUFS1
FeS protein
SDHB
Rieske FeS ;
Cytochrome
(Heme) b, c1
Cytochrome
(Heme) a, a3
 
Other features   Membrane proteins
Cytochrome b560
SDHC
SDHD
  Copper protein  


Disorders
General

Alpers
Alzheimer's/
  Parkinsonism
Cardiomyopathy
Deficiency
  Barth
  Lethal Infantile
Encephalopathy
Infantile CNS
Leber's
Leigh
Longevity
MELAS
MERRF
Myopathy ± CNS
PEO
Spinal cord
General

Kearns-Sayre
Leigh's
Myopathy
  Infantile
  ± CNS
Paraganglioma
Pheochromocytoma
General

Cardiomyopathy
Fatal infantile
GRACILE
Leber's
Myopathy
  ± CNS
PEO
General

Alper's
Ataxia
Deafness
Leber's
Leigh's
Myopathy
  Infantile
    Fatal
    Benign
  Adult
  Rhabdomyolysis
PEO, KSS, MNGIE
MERRF, MELAS
Cardiomyopathy
Encephalopathy
Leber's
Leigh
Multisystem
NARP
Notes
  • Most mitochondrial encephalomyopathies are associated with mutations in mitochondrial DNA
  • Nuclear mutations ® Defects in respiratory chain
  • ~ 1,000 mitochondrial peptides not involved in the respiratory chain: Encoded by nuclear DNA
    • Superoxide dismutase 2 (SOD2)
      • Intramitochondrial free radical scavenging enzyme
      • Degrades superoxide produced as a byproduct of oxidative phosphorylation




COMPLEX I (NADH-Ubiquinone Oxidoreductase): Features & Deficiency 1



COMPLEX II (Succinate Dehydrogenase-CoQ Oxoreductase): Features & Deficiency



COMPLEX III (CYTOCHROME REDUCTASE): Features & Deficiency

Complex III Features Complex III Functions Complex III disorders

COMPLEX IV (CYTOCHROME OXIDASE): Features & Deficiency

Complex IV Composition & Related Proteins Nuclear mutations Mitochondrial mutations Other syndromes associated with Complex IV deficiency


COMPLEX V (ATP Synthase): Features & Deficiency



Combined Complex Deficiencies


Complexes I, III, IV ± V Deficient
Complexes I, II & III Deficient

Lactate metabolism 4


Return to Neuromuscular Home Page
Return to Mitochondrial disorders

References
1. Human Mutation 2000;15:123-134, IUBMB Life 2011; Online July
2. Am J Hum Genet 2000;67
3. Curr Opin Neurol 2004;17:179–186
4. Sports Med 2007;37:341-343
5. J Child Neurol 2009 Jun 17

9/25/2013