Methylmalonic acid, a biochemical hallmark of methylmalonic acidurias but no inhibitor of mitochondrial respiratory chain.
Methylmalonic acidurias are biochemically characterized by an accumulation of methylmalonic acid and alternative metabolites. An impairment of energy metabolism plays a key role in the pathophysiology of this disease, resulting in neurodegeneration of the basal ganglia and renal failure. It has become the subject of intense debates whether methylmalonic acid is the major toxin, inhibiting respiratory chain complex II. To elucidate whether methylmalonic acid is a respiratory chain inhibitor, we used spectrophotometric analysis of complex II activity in submitochondrial particles from bovine heart, radiometric analysis of 14C-labeled substrates (pyruvate, malate, succinate), and analysis of ATP production in muscle from mice. Methylmalonic acid revealed no direct effects on the respiratory chain function, i.e. on single electron transferring complexes I-IV, ATPase, and mitochondrial transporters. However, we identified a variety of variables that must be carefully controlled to avoid an artificial inhibition of complex II activity. In summary, the study verifies our hypothesis that methylmalonic acid is not the major toxic metabolite in methylmalonic acidurias. Inhibition of respiratory chain and tricarboxylic acid cycle is most likely induced by synergistically acting alternative metabolites, in particular 2-methylcitric acid, malonic acid, and propionyl-CoA.
Kölker
Stefan
S
Department of General Pediatrics, Division of Metabolic and Endocrine Diseases, University Children's Hospital Heidelberg, D-69120 Heidelberg, Germany. Stefan_Koelker@med.uni-heidelberg.de
Schwab
Marina
M
Hörster
Friederike
F
Sauer
Sven
S
Hinz
Angela
A
Wolf
Nicole I
NI
Mayatepek
Ertan
E
Hoffmann
Georg F
GF
Smeitink
Jan A M
JA
Okun
Jürgen G
JG
D000214:Acyl Coenzyme A / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging; D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002951:Citrates / Q000378:metabolism; D002952:Citric Acid Cycle; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport; D005260:Female; D006863:Hydrogen-Ion Concentration; D008297:Male; D008314:Malonates / Q000378:metabolism; D008764:Methylmalonic Acid / Q000737:chemistry* / Q000652:urine; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D011773:Pyruvates / Q000378:metabolism; D013053:Spectrophotometry; D013997:Time Factors
D000214:Acyl Coenzyme A; D002951:Citrates; D008314:Malonates; D011773:Pyruvates; C009061:propionyl-coenzyme A; C031605:2-methylcitric acid; D000255:Adenosine Triphosphate; D008764:Methylmalonic Acid; C030290:malonic acid; D010100:Oxygen