Contents

πŸ“’ Scialo 2017

Role of mitochondrial reverse electron transport in ROS signaling: potential roles in health and disease1

Sciwheel

Introduction

  • 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

https://www.frontiersin.org/files/Articles/273331/fphys-08-00428-HTML-r1/image_m/fphys-08-00428-g001.jpg

  • 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

https://www.frontiersin.org/files/Articles/273331/fphys-08-00428-HTML-r1/image_m/fphys-08-00428-g002.jpg

  • 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

Reference


  1. ScialΓ² F, FernΓ‘ndez-Ayala DJ, Sanz A. Role of Mitochondrial Reverse Electron Transport in ROS Signaling: Potential Roles in Health and Disease. Front Physiol. 2017;8:428. Published 2017 Jun 27. doi:10.3389/fphys.2017.00428 PMC5486155 ↩︎