📒 Scialo 2017
Role of mitochondrial reverse electron transport in ROS signaling: potential roles in health and disease1
- low levels of ROS having beneficial effects through stimulation of mitohormesis and high levels causing oxidative damage and contributing to aging
- few studies describing how much ROS each respiratory complex produces in vivo due to the lack of resolution with these type of measurements
- in vitro, CI generates ROS exclusively into the mitochondrial matrix, while CIII can produce ROS into either the matrix or intermembrane space
- Reverse electron transpor (RET) was considered an in vitro experimental artifact until recently.
- high ratio of ubiquinol(QH2) to ubiquinone(Q) and a high proton motive force ($\Delta p$) is required to produce RET.
WHERE ARE ROS PRODUCED WITHIN CI
- Feeding glutamate or pyruvate: forward electron transport (FET)
- Add rotenone => FMN (IF site) reduced => ROS formation
- independent of both the redox state of CoQ and $\Delta p$
- Feeding high concentration succinate: reverse electron transport (RET)
- Add rotenone => IQ site blocked => reduced ROS formation
- dependent on both the redox state of CoQ and $\Delta p$
- ROS formation @ IF or IQ site?
- How ROS are generated (i.e., in forward or reverse direction) at CI affects how several proteins are oxidized
- Site specific antioxidants fpor treatment?
- positive effects of metformin are caused by a site-specific inhibition of CI that triggers a specific ROS signal.
RET and health
- RET-derived ROS is a good metabolic indicator
- redox state of CoQ (electron flow through the ETC)
- proton motive force: mitochondrial energy state
- O2 concentration (linear relationship)
- Inhibition of differentiation of myoblasts into myotubes by rotenone
- ETC supercomplex reflects metabolic supply and needs
- CI+ CIII + CIV, CI+ CIII and CIII + CIV, in addition to CIV alone
- Glucose: NAH / FADH2 = 5 vs lipid: 2
- Under lipid diet, RET-ROS promotes the degradation of CI increasing the association between CIII and CIV, which is more efficient for the oxidation of fatty acids.
- macrophages reorganize their RC, decreasing the levels of CI and increasing activity of CII for inflammatory response
- switching to producing ATP via glycolysis instead of OXPHOS
- Suppression of RET-ROS inhibits the generation of pro-inflammatory cytokines required to fight bacterial infection
- sensing of oxygen levels by the carotid body (CB)
- hypoxia: CII activity increased, RET
- Drosophila extends lifespan by induction of RET-ROS in vivo
- Ectopic expression of NDI1 => Q pool more reduced => RET (blockable by rotenone)
- co-expression of NDI1 with a mitochondrially-targeted catalase abolished lifespan ext ension conferred by NDI1
- Hypoxia-reperfusion injury
- excess of ROS produced via RET due to succinate accumulates in ischemic tissues
- Inhibition of CII with dimethyl-malonate or CI with rotenone protects the heart during ischemia-reperfusion
- new generation of antioxidants that specifically neutralize ROS produced at the IQ site within CI also alleviate the effects of ischemia-reperfusion in the heart