bims-resufa 2019-06-16 papers

Issue of 2019–06–16
two papers selected by
Vera Strogolova, Marquette University

Comput Struct Biotechnol J. 2019 ;17 654-660

Cytochrome c: Surfing Off of the Mitochondrial Membrane on the Tops of Complexes III and IV.

Gonzalo Pérez-Mejías, Alejandra Guerra-Castellano, Antonio Díaz-Quintana, Miguel A De la Rosa, Irene Díaz-Moreno.

The proper arrangement of protein components within the respiratory electron transport chain is nowadays a matter of intense debate, since altering it leads to cell aging and other related pathologies. Here, we discuss three current views-the so-called solid, fluid and plasticity models-which describe the organization of the main membrane-embedded mitochondrial protein complexes and the key elements that regulate and/or facilitate supercomplex assembly. The soluble electron carrier cytochrome c has recently emerged as an essential factor in the assembly and function of respiratory supercomplexes. In fact, a 'restricted diffusion pathway' mechanism for electron transfer between complexes III and IV has been proposed based on the secondary, distal binding sites for cytochrome c at its two membrane partners recently discovered. This channeling pathway facilitates the surfing of cytochrome c on both respiratory complexes, thereby tuning the efficiency of oxidative phosphorylation and diminishing the production of reactive oxygen species. The well-documented post-translational modifications of cytochrome c could further contribute to the rapid adjustment of electron flow in response to changing cellular conditions.

Keywords: Cytochrome c; Mitochondria; Phosphorylation; Reactive oxygen species; Respiratory supercomplexes

DOI: https://doi.org/10.1016/j.csbj.2019.05.002

Antimicrob Agents Chemother. 2019 Jun 10. pii: AAC.00374-19. [Epub ahead of print]

The novel arylamidine T-2307 selectively disrupts yeast mitochondrial function by inhibiting respiratory chain complexes.

Kohei Yamashita, Taiga Miyazaki, Yoshiko Fukuda, Junichi Mitsuyama, Tomomi Saijo, Shintaro Shimamura, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae.

The novel arylamidine T-2307 exhibits broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens. Previous studies have shown that T-2307 accumulates in yeast cells via a specific polyamine transporter and disrupts yeast mitochondrial membrane potential. Further, it has little effect on rat liver mitochondrial function. The mechanism by which T-2307 disrupts yeast mitochondrial function is poorly understood, and its elucidation may provide important information for developing novel antifungal agents. This study aimed to understand how T-2307 promotes yeast mitochondrial dysfunction and to investigate the selectivity of this mechanism between fungi and mammals. T-2307 inhibited the respiration of yeast whole cells and isolated yeast mitochondria in a dose-dependent manner. The similarity of the effects of T-2307 and respiratory chain inhibitors on mitochondrial respiration prompted us to investigate the effect of T-2307 on mitochondrial respiratory chain complexes. T-2307 particularly inhibited respiratory chain complexes III and IV not only in Saccharomyces cerevisiae but also in Candida albicans, indicating that T-2307 acts against pathogenic fungi in a manner similar to that of yeast. Conversely, T-2307 showed little effect on bovine respiratory chain complexes. Additionally, we demonstrated that the inhibition of respiratory chain complexes by T-2307 resulted in a decrease in the intracellular ATP levels in yeast cells. These results indicate that the inhibition of respiratory chain complexes III and IV is a key for selective disruption of yeast mitochondrial function and antifungal activity.

DOI: https://doi.org/10.1128/AAC.00374-19