bims-resufa 2021-10-10 papers

Issue of 2021–10–10
three papers selected by
Vera Strogolova, Strong Microbials, Inc

Curr Mol Pharmacol. 2021 Sep 28.

Cytochrome bc1-aa3 oxidase supercomplex as emerging and potential drug target against tuberculosis.

The cytochrome bc1-aa3 supercomplex plays an essential role in the cellular respiratory system of Mycobacterium Tuberculosis. It transfers electrons from menaquinol to cytochrome aa3 (Complex IV) via cytochrome bc1 (Complex III), which reduces the oxygen. The electron transfer from a variety of donors into oxygen through the respiratory electron transport chain is essential to pump protons across the membrane creating an electrochemical transmembrane gradient (proton motive force, PMF) that regulates the synthesis of ATP via the oxidative phosphorylation process. Cytochrome bc1-aa3 supercomplex in M. tuberculosis is, therefore, a major drug target for antibiotic action. In recent years, several respiratory chain components have been targeted for developing new candidate drugs, illustrating the therapeutic potential of obstructing energy conversion of M. tuberculosis. The recently available cryo-EM structure of mycobacterial cytochrome bc1-aa3 supercomplex with open and closed conformations has opened new avenues for understanding its structure and function for developing more effective, new therapeutics against pulmonary tuberculosis. In this review, we discuss the role and function of several components, subunits, and drug targeting elements of the supercomplex cytochrome bc1-aa3, and its potential inhibitors in detail.

Keywords: Mycobacterium Tuberculosis; QcrB; anti-TB agents; electron transport chain; oxidative phosphorylation

DOI: https://doi.org/10.2174/1874467214666210928152512

Nature. 2021 Oct 06.

Structure and assembly of the mammalian mitochondrial supercomplex CIII2CIV.

Irene Vercellino, Leonid A Sazanov.

The enzymes of the mitochondrial electron transport chain are key players of cell metabolism. Despite being active when isolated, in vivo they associate into supercomplexes1, whose precise role is debated. Supercomplexes CIII2CIV1-2 (refs. 2,3), CICIII2 (ref. 4) and CICIII2CIV (respirasome)5-10 exist in mammals, but in contrast to CICIII2 and the respirasome, to date the only known eukaryotic structures of CIII2CIV1-2 come from Saccharomyces cerevisiae11,12 and plants13, which have different organization. Here we present the first, to our knowledge, structures of mammalian (mouse and ovine) CIII2CIV and its assembly intermediates, in different conformations. We describe the assembly of CIII2CIV from the CIII2 precursor to the final CIII2CIV conformation, driven by the insertion of the N terminus of the assembly factor SCAF1 (ref. 14) deep into CIII2, while its C terminus is integrated into CIV. Our structures (which include CICIII2 and the respirasome) also confirm that SCAF1 is exclusively required for the assembly of CIII2CIV and has no role in the assembly of the respirasome. We show that CIII2 is asymmetric due to the presence of only one copy of subunit 9, which straddles both monomers and prevents the attachment of a second copy of SCAF1 to CIII2, explaining the presence of one copy of CIV in CIII2CIV in mammals. Finally, we show that CIII2 and CIV gain catalytic advantage when assembled into the supercomplex and propose a role for CIII2CIV in fine tuning the efficiency of electron transfer in the electron transport chain.

DOI: https://doi.org/10.1038/s41586-021-03927-z

Lab Invest. 2021 Oct 04.

ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis.

Kailiang Zhang, Rong Bao, Fengyuan Huang, Kevin Yang, Yishu Ding, Lothar Lauterboeck, Masasuke Yoshida, Qinqiang Long, Qinglin Yang.

Mitochondrial homeostasis is crucial for the function of pancreatic β-cells. ATP synthase inhibitory factor subunit 1 (IF1) is a mitochondrial protein interacting with ATP synthase to inhibit its enzyme activity. IF1 may also play a role in maintaining ATP synthase oligomerization and mitochondrial inner membrane formation. A recent study confirmed IF1 expresses in β-cells. IF1 knockdown in cultured INS-1E β-cells enhances glucose-induced insulin release. However, the role of IF1 in islet β-cells remains little known. The present study investigates islets freshly isolated from mouse lines with global IF1 knockout (IF1-/-) and overexpression (OE). The glucose-stimulated insulin secretion was increased in islets from IF1-/- mice but decreased in islets from IF1 OE mice. Transmitted Electronic Microscopic assessment of isolated islets revealed that the number of matured insulin granules (with dense core) was relatively higher in IF1-/-, but fewer in IF1 OE islets than those of controlled islets. The mitochondrial ultrastructure within β-cells of IF1 overexpressed islets was comparable with those of wild-type mice, whereas those in IF1-/- β-cells showed increased mitochondrial mass. Mitochondrial network analysis in cultured INS-1 β-cells showed a similar pattern with an increased mitochondrial network in IF1 knockdown cells. IF1 overexpressed INS-1 β-cells showed a compromised rate of mitochondrial oxidative phosphorylation with attenuated cellular ATP content. In contrast, INS-1 cells with IF1 knockdown showed markedly increased cellular respiration with improved ATP production. These results support that IF1 is a negative regulator of insulin production and secretion via inhibiting mitochondrial mass and respiration in β-cells. Therefore, inhibiting IF1 to improve β-cell function in patients can be a novel therapeutic strategy to treat diabetes.

DOI: https://doi.org/10.1038/s41374-021-00670-x