The 2-Oxoacid Dehydrogenase Complexes in Mitochondria Can Produce Superoxide/Hydrogen Peroxide at Much Higher Rates Than Complex I

Abstract

Background: At the redox potential of NADH/NAD ϩ , at least four mitochondrial sites produce superoxide/H 2 O 2 .

Sites of Superoxide and Hydrogen Peroxide Production by Muscle Mitochondria Assessed ex Vivo under Conditions Mimicking Rest and Exercise

“…Mitochondria can produce superoxide or H 2 O 2 from at least 10 different sites (16,23). Which sites are the major producers in vivo is unknown.…”

“…The sites can be distinguished and studied in situ by providing electrons from appropriate substrates and using specific electron transport inhibitors to isolate them pharmacologically. In this way, at least 10 distinct sites have been characterized in rat skeletal muscle mitochondria (16). These sites are represented as red circles in Fig.…”

“…Complex I produces superoxide at two distinct sites: site I Q , a high capacity site, most obviously active during reverse transfer of electrons from ubiquinol to NADH (18,19,44,45); and site I F (18), now known to have much lower capacity (16). Complex III can produce superoxide at high rates from site III Qo (2,17).…”

“…1. In order of their maximum capacities, they are as follows: III Qo 4 in complex III (17); I Q (18,19) and II F (20) in complexes I and II; O F , P F , and B F in the 2-oxoglutarate, pyruvate, and branched-chain 2-oxoacid dehydrogenase complexes (16); G Q in mitochondrial glycerol phosphate dehydrogenase (21); I F in complex I (16); E F in ETF/ETF:Q oxidoreductase (22); and D Q in dihydroorotate dehydrogenase (23).…”

Human 2-Oxoglutarate Dehydrogenase Complex E1 Component Forms a Thiamin-derived Radical by Aerobic Oxidation of the Enamine Intermediate

“…The observation of a similar radical on E1o-ec (18) raised the possibility that such a radical also exists on the E1o-h. There have been several reports that mammalian OGDHc could be a major source of the reactive oxygen species (ROS), superoxide radical anion and hydrogen peroxide, in isolated brain and skeletal muscle mitochondria (5,19) and in the isolated synaptosomes (6), as was also confirmed with the isolated mammalian OGDHc (5,6). Based on experiments with spin-trapping techniques and using the isolated mammalian OGDHc with a modified flavin cofactor of E3, it was concluded that E3-bound FAD is responsible for the production of radical species by OGDHc (20).…”