Long chain fatty acyl-CoA modulation of H2O2 release at mitochondrial complex I

Abstract

Complex I is responsible for most of the mitochondrial H(2)O(2) release, low during the oxidation of the NAD linked substrates and high during succinate oxidation, via reverse electron flow. This H(2)O(2) production appear physiological since it occurs at submillimolar concentrations of succinate also in the presence of NAD substrates in heart (present work) and rat brain mitochondria (Zoccarato et al., Biochem J, 406:125-129, 2007). Long chain fatty acyl-CoAs, but not fatty acids, act as strong inhibitors of succinate dependent H(2)O(2) release. The inhibitory effect of acyl-CoAs is independent of their oxidation, being relieved by carnitine and unaffected or potentiated by malonyl-CoA. The inhibition appears to depend on the unbound form since the acyl-CoA effect decreases at BSA concentrations higher than 2 mg/ml; it is not dependent on DeltapH or Deltap and could depend on the inhibition of reverse electron transfer at complex I, since palmitoyl-CoA inhibits the succinate dependent NAD(P) or acetoacetate reduction.

Inhibitors of Succinate: Quinone Reductase/Complex II Regulate Production of Mitochondrial Reactive Oxygen Species and Protect Normal Cells from Ischemic Damage but Induce Specific Cancer Cell Death

“…However, the results of Zoccarato's group (58,59,67,85) revealed that these assumptions are incorrect since the co-presence of glutamate plus malate does not impede H 2 O 2 generation by low succinate but rather acts to enhance H 2 O 2 production and when glutamate plus malate and succinate are all being oxidized together, electrons from glutamate plus malate are still continuing to move through Complex I (because Complex I still continues oxidizing NADH making NAD + available for further 2-OG oxidation). Therefore, it appears likely that the succinate-promoted H 2 O 2 production is a direct consequence of the succinate-dependent elevation of the mitochondrial UQH 2 /UQ ratio and perhaps, to a lower extent, of the reduced level of the Complex I flavin.…”

“…More recent evidence suggests that long-chain fatty acyl-CoAs also directly inhibit ROS production by inhibiting mitochondrial matrix enzyme complexes (58). Thus, long-chain fatty acyl-CoAs, but not FFAs, acted as strong inhibitors of succinate-dependent H 2 O 2 release.…”

“…Hence, reverse electron transfer does not explain nor account for the very high levels of succinate-driven ROS production under more physiological conditions of either intact mitochondria or whole cells, which are orders of magnitude higher than those produced by the forward reaction of Complex I. Studies from Zoccarato's group (58,59,67) provide the basis for a suitable alternative and a more plausible and energetically favourable explanation for the high succinate-induced ROS production, which will be identified in detail below. First, their results need to be described in detail based on data obtained from heart or brain mitochondria respiring on both NADH and succinate (likely to reflect the more common situation as it would occur in vivo).…”

Oxygen radicals shaping evolution: Why fatty acid catabolism leads to peroxisomes while neurons do without it

“…Complex II itself is not a source of significant radical formation (as seems to hold true for ETF:CoQ reductase and glycerol-3-phosphate dehydrogenase, as described below) but 'activates' complex I [5,6]. The same group also showed succinate activation of radical formation to be suppressed by long chain FA acylCoAs [13]. This seems surprising as levels of FADH 2 could possibly rise even further under these circumstances, but is easily explained by the fact that these compounds are not found to be oxidized under these conditions and, furthermore, they uncouple the isolated mitochondria due to their hydrophobicity.…”

“…The crucial extra complication, however, is that more electrons entering complex I with less acceptors available (a high CoQH 2 /CoQ ratio), would lead to 'electron spill'. In isolated mitochondria, reverse electron transport (RET) is involved [13,14]. Radical formation taking place inside a 'proto mitochondrial' cell instead of peripherally, as occurring in bacterial respiration, only makes matters much worse.…”