Ischemic A/D transition of mitochondrial complex I and its role in ROS generation

Abstract

Mitochondrial complex I (NADH:ubiquinone oxidoreductase) is a key enzyme in cellular energy metabolism and provides approximately 40% of the proton-motive force that is utilized during mitochondrial ATP production. The dysregulation of complex I function – either genetically, pharmacologically, or metabolically induced – has severe pathophysiological consequences that often involve an imbalance in the production of reactive oxygen species (ROS). Slow transition of the active (A) enzyme to the deactive, dormant (D) form takes place during ischemia in metabolically active organs such as the heart and brain. The reactivation of complex I occurs upon reoxygenation of ischemic tissue, a process that is usually accompanied by an increase in cellular ROS production. Complex I in the D-form serves as a protective mechanism preventing the oxidative burst upon reperfusion. Conversely, however, the D-form is more vulnerable to oxidative/nitrosative damage. Understanding the so-called active/deactive (A/D) transition may contribute to the development of new therapeutic interventions for conditions like stroke, cardiac infarction, and other ischemia-associated pathologies. In this review, we summarize current knowledge on the mechanism of A/D transition of mitochondrial complex I considering recently available structural data and site-specific labeling experiments. In addition, this review discusses in detail the impact of the A/D transition on ROS production by complex I and the S-nitrosation of a critical cysteine residue of subunit ND3 as a strategy to prevent oxidative damage and tissue damage during ischemia–reperfusion injury. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt.

The novel targets of DL-3-n-butylphthalide predicted by similarity ensemble approach in combination with molecular docking study

“…Metformin, as an inhibitor of NADHubiquinone oxidoreductase, is proved to exert protective role in ischemic stroke through suppression of ROS (reactive oxygen species). NBP may suppress ROS by the mechanism relying on NADH-ubiquinone oxidoreductase in a manner of resembling metformin (15,16). Based on the paper we published in 2012 (2), NBP may prevent neurological deficits and cerebral injury following stroke as an anti-oxidant agent, which is in good agreement with our prediction.…”

Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes

“…Thus, NADH-derived electrons are inefficiently transferred to ubiquinone by deactive complex I (30,31), and subsequently to complex IV due to the low proportion of complex III in astrocytes. Moreover, given the low complex III abundance in astrocytes, it would be reasonable to speculate that ubiquinone pool would be favored toward its reduced status, a factor known to cause complex I deactivation (34). Whether a positive loop of complex I deactivation, which is promoted by ROS (34), takes place in astrocytes is a tempting possibility that remains to be explored.…”

Progress in understanding the molecular oxygen paradox – function of mitochondrial reactive oxygen species in cell signaling

“…Modification of either protein, which lowers complex I activity, would also limit electron transfer to the ubiquinone-binding site, another putative ROS forming site. As for increasing O 2˙− /H 2 O 2 production, another putative S-glutathionylation in complex I happens to be the ND3 subunit, which forms part of the ubiquinone binding pocket (Drose et al, 2016). Its S-glutathionylation could drive up O 2˙− /H 2 O 2 formation by allowing the over-reduction of the FMN prosthetic group.…”

“…However, under ischemic-reperfusion conditions other enzymes like complex I, PDH, and OGDH might also display different S-glutathionylation profiles which may favor higher than normal O 2˙− /H 2 O 2 production. For example, during ischemia, complex I transitions from an activate A-state to a deactivate D-state where a cysteine residue on the ND3 subunit becomes amenable to oxidative modification (Drose et al, 2016). This allows NADH to accumulate in the matrix of mitochondria.…”