Reverse Electron Transport

What is RET?

RET stands for Reverse Electron Transport.

RET is produced when electrons from ubiquinol are transferred back to respiratory complex I, reducing NAD+ to NADH. This process generates a significant amount of ROS. (R1)

Recent studies have highlighted an important role for reverse electron transport (RET) in producing mtROS.

RET occurs when the pool of coenzyme Q (CoQ) is over‐reduced with electrons from respiratory complex II. In the presence of a high proton motive force (Δp), complex I reduces NAD+ to NADH with electrons received from the ubiquinol pool, generating a high level of mtROS. (R6)

Highlights

• Activates macrophages in response to bacterial infection
• Alters ETC in response to changes in energy supply
• May extend lifespan

RET has been shown to be instrumental for the activation of macrophages in response to bacterial infection, re-organization of the electron transport chain in response to changes in energy supply and adaptation of the carotid body to changes in oxygen levels. In Drosophila melanogaster, stimulating RET extends lifespan. (R1)

Oxidation of hydrogen sulfide

Although in mammals sulfide exposure is not thought to be quantitatively important outside the colonic mucosa, our study shows that a majority of mammalian cells, by means of the mitochondrial sulfide quinone reductase (SQR), avidly consume sulfide as a fuel.

The SQR activity was found in mitochondria isolated from mouse kidneys, liver, and heart. We demonstrate the precedence of the SQR over the mitochondrial complex I. This explains why the oxidation of the mineral substrate sulfide takes precedence over the oxidation of other (carbon-based) mitochondrial substrates. (R2)

Ketosis

Nutritional ketosis is likely to increase RET by altering the FADH2 to NADH ratio.

As the primary source of acetyl CoA shifts from glycolysis to β-oxidation and ketolysis, this ratio increases, more than doubling for β-oxidation of longerchain fatty acids.

Electrons from FADH2 reduce the CoQ pool through complex II and ETF-QO, thereby increasing RET. This induction of RET by alteration of substrate availability can also be influenced by configuration of mtETC complexes into supercomplexes.

Furthermore, succinate is generated during ketolysis by succinyl-CoA:3oxoacid CoA-transferase (SCOT), which also promotes RET by reducing the CoQ pool through complex II. (R3)

Damage of Complex I and loss of flavin

Energy failure due to alterations in mitochondrial metabolism and elevated production of reactive oxygen species (ROS) is one of the main causes of brain ischemia-reperfusion (IR) damage.

Ischemia resulted in the accumulation of succinate in tissues, which favors the process of reverse electron transfer (RET) when a fraction of electrons derived from succinate is directed to mitochondrial complex I for the reduction of matrix NAD+.

We demonstrate that in intact brain mitochondria oxidizing succinate, complex I became damaged and was not able to contribute to the physiological respiration.

This process is associated with a decline in ROS release and a dissociation of the enzyme’s flavin. This previously undescribed phenomenon represents the major molecular mechanism of injury in stroke and induction of oxidative stress after reperfusion. We also demonstrate that the origin of ROS during RET is flavin of mitochondrial complex I. (R4)

Succinate had also been shown to inhibit the oxidation of pyruvate and other NAD-linked respiratory substrates and cause an over-reduction of mitochondrial pyridine nucleotides. (R4)