bims-cytox1 2022-12-18 papers

Issue of 2022‒12‒18
three papers selected by
Gavin McStay
Liverpool John Moores University

Chem Sci. 2022 Nov 23. 13(45): 13489-13498

Cardiolipin, and not monolysocardiolipin, preferentially binds to the interface of complexes III and IV.

Robin A Corey, Noah Harrison, Philllp J Stansfeld, Mark S P Sansom, Anna L Duncan.

The mitochondrial electron transport chain comprises a series of protein complexes embedded in the inner mitochondrial membrane that generate a proton motive force via oxidative phosphorylation, ultimately generating ATP. These protein complexes can oligomerize to form larger structures called supercomplexes. Cardiolipin (CL), a conical lipid, unique within eukaryotes to the inner mitochondrial membrane, has proven essential in maintaining the stability and function of supercomplexes. Monolysocardiolipin (MLCL) is a CL variant that accumulates in people with Barth syndrome (BTHS). BTHS is caused by defects in CL biosynthesis and characterised by abnormal mitochondrial bioenergetics and destabilised supercomplexes. However, the mechanisms by which MLCL causes pathogenesis remain unclear. Here, multiscale molecular dynamics characterise the interactions of CL and MLCL with yeast and mammalian mitochondrial supercomplexes containing complex III (CIII) and complex IV (CIV). Coarse-grained simulations reveal that both CL and MLCL bind to sites at the interface between CIII and CIV of the supercomplex. Free energy perturbation calculations show that MLCL interaction is weaker than that of CL and suggest that interaction with CIV drives this difference. Atomistic contact analyses show that, although interaction with CIII is similar for CL and MLCL, CIV makes more contacts with CL than MLCL, demonstrating that CL is a more successful "glue" between the two complexes. Simulations of the human CIII2CIV supercomplex show that this interface site is maintained between species. Our study suggests that MLCL accumulation in people with BTHS disrupts supercomplex stability by formation of relatively weak interactions at the interface lipid binding site.

DOI: https://doi.org/10.1039/d2sc04072g

Cells. 2022 Nov 24. pii: 3756. [Epub ahead of print]11(23):

Destabilizing COXIV in Müller Glia Increases Retinal Glycolysis and Alters Scotopic Electroretinogram.

Nana Yaa Nsiah, Denise M Inman.

Müller glia (MG), the principal glial cell of the retina, have a metabolism that defies categorization into glycolytic versus oxidative. We showed that MG mount a strong hypoxia response to ocular hypertension, raising the question of their relative reliance on mitochondria for function. To explore the role of oxidative phosphorylation (OXPHOS) in MG energy production in vivo, we generated and characterized adult mice in which MG have impaired cytochrome c oxidase (COXIV) activity through knockout of the COXIV constituent COX10. Histochemistry and protein analysis showed that COXIV protein levels were significantly lower in knockout mouse retina compared to control. Loss of COXIV activity in MG did not induce structural abnormalities, though oxidative stress was increased. Electroretinography assessment showed that knocking out COX10 significantly impaired scotopic a- and b-wave responses. Inhibiting mitochondrial respiration in MG also altered the retinal glycolytic profile. However, blocking OXPHOS in MG did not significantly exacerbate retinal ganglion cell (RGC) loss or photopic negative response after ocular hypertension (OHT). These results suggest that MG were able to compensate for reduced COXIV stability by maintaining fundamental processes, but changes in retinal physiology and metabolism-associated proteins indicate subtle changes in MG function.

Keywords: Müller glia; electroretinogram; glaucoma; glycolysis; metabolism; oxidative phosphorylation

DOI: https://doi.org/10.3390/cells11233756

Adv Exp Med Biol. 2022 ;1395 367-372

On the Mechanism of Sustained Mitochondrial Membrane Potential Without Functioning Complex IV.

Eiji Takahashi, Yoshihisa Yamaoka.

In intact mitochondria, the transport of electrons, respiration and generation of proton gradients across the inner membrane (proton motive force) are mutually coupled, according to Peter Mitchell's hypothesis on oxidative phosphorylation. Thus, the inhibition of electron transport at either respiratory complex III or IV in the electron transport chain leads to failure in producing proton motive force along with the abolition of respiration. Here, we determined the mitochondrial membrane potential (MMP), as a measure of proton motive force, and cellular respiration in various cultured cells and demonstrated that inhibition of complex IV by KCN abolished mitochondrial respiration while MMP was sustained. These results are unexpected and appear incompatible with Mitchell's chemiosmotic hypothesis.

Keywords: Electron transport; Mitchell’s chemiosmotic hypothesis; Mitochondria; Proton motive force

DOI: https://doi.org/10.1007/978-3-031-14190-4_60