bims-cytox1 2024-12-22 papers

Arch Biochem Biophys. 2024 Dec 15. pii: S0003-9861(24)00393-X. [Epub ahead of print] 110271

High stability of the radical at the catalytic center of cytochrome c oxidase.

Adriana Tomkova, Erik Cizmar, Daniel Jancura, Marian Fabian.

In aerobic organisms, cellular respiration is associated with electron transfer through a respiratory system of membrane-bound complexes. This electron flow is terminated by the reduction of dioxygen to water by respiratory oxidases. Cytochrome c oxidase (CcO) is a widely distributed heme-copper-oxygen reductase (HCO) found in all mitochondria and some bacteria. However, the sequential reduction of O2 to water in CcO generates a protein-based radical at the catalytic heme a3-CuB site. To avoid the potential damage from the radical, CcO has apparently developed protective mechanisms. Protection by transfer of the highly oxidizing equivalent over considerable distances away from the catalytic site by redox-active Tyr/Trp chains has been previously demonstrated in bovine CcO. However, the rate of the radical migration from the catalytic center has not yet been determined for any HCO. In this work, we show that the radical escapes from the catalytic center of the ferryl PM intermediate of bovine CcO within minutes, which is much longer than the time of its functional reduction during cellular respiration. Apparently, this high stability has evolved to avoid the dissipation of energy released during the oxygen reduction with substrate electrons.

Keywords: cytochrome c oxidase; ferryl intermediates; free radical; lifetime of radical; oxidative damage

DOI: https://doi.org/10.1016/j.abb.2024.110271

Adv Sci (Weinh). 2024 Dec 10. e2408599

Enhanced Oxidative Phosphorylation Driven by TACO1 Mitochondrial Translocation Promotes Stemness and Cisplatin Resistance in Bladder Cancer.

Minhua Deng, Zhaohui Zhou, Jiawei Chen, Xiangdong Li, Zefu Liu, Jingwei Ye, Wensu Wei, Ning Wang, Yulu Peng, Xin Luo, Lijuan Jiang, Fangjian Zhou, Xianchong Zheng, Zhuowei Liu.

Chemoresistance poses a critical obstacle in bladder cancer (BCa) treatment, and effective interventions are currently limited. Elevated oxidative phosphorylation (OXPHOS) has been linked to cancer stemness, a determinant of chemoresistance. However, the mechanisms underlying increased OXPHOS during cancer cell chemoresistance remain unclear. This study revealed that the mitochondrial translational activator of cytochrome oxidase subunit 1 (TACO1) is linked to stemness and cisplatin resistance in BCa cells. Mechanistically, mitochondrial TACO1 enhances the translation of the mitochondrial cytochrome c oxidase I (MTCO1), promoting mitochondrial reactive oxygen species (mtROS) by upregulating OXPHOS, consequently driving cancer stemness and cisplatin resistance. Intriguingly, the mitochondrial translocation of TACO1 is mediated by the heat shock protein 90 β (HSP90β), a process that requires circFOXK2 as a scaffold for the TACO1-HSP90β interaction. The mutations at the binding sites of TACO1-circFOXK2-HSP90β disturb the ternary complex and inhibit cancer stemness and cisplatin resistance in BCa cells by suppressing the MTCO1/OXPHOS/mtROS axis. Clinically, BCa patients with increased mitochondrial TACO1 expression respond poorly to cisplatin treatment. This study elucidates the mechanisms by which TACO1 promotes BCa stemness and cisplatin resistance, providing a potential target for mitigating cisplatin resistance for BCa and a biomarker for predicting cisplatin response.

Keywords: TACO1; bladder cancer; cancer stemness; chemoresistance; oxidative phosphorylation

DOI: https://doi.org/10.1002/advs.202408599

Cell Death Dis. 2024 Dec 20. 15(12): 920

FXR-regulated COX6A2 triggers mitochondrial apoptosis of pancreatic β-cell in type 2 diabetes.

Lianqi Shao, Xiangchen Kong, Simian Lv, Xingsheng Shu, Xiaosong Ma, Xiaojiao Ai, Dan Yan, Ying Ying.

Pancreatic β-cell apoptosis plays a crucial role in the development of type 2 diabetes. Cytochrome c oxidase subunit 6A2 (COX6A2) and Farnesoid X Receptor (FXR) have been identified in pancreatic β-cells, however, whether they are involved in β-cell apoptosis is unclear. Here, we sought to investigate the role of FXR-regulated COX6A2 in diabetic β-cell apoptosis. We found that COX6A2 expression was increased in islets from diabetic animals, whereas FXR expression was suppressed. Notably, overexpression of COX6A2 facilitated β-cell apoptosis, whereas its deficiency attenuated this process and ameliorates type 2 diabetes, suggesting a pro-apoptotic role of COX6A2 in β-cells. Mechanistically, increased COX6A2 interacted with and enhanced the expression of voltage-dependent anion channel 1 (VDAC1), thereby promoting the mitochondrial translocation of Bax, leading to the release of cytochrome c from the mitochondria to the cytoplasm and ultimately causing β-cell apoptosis. Moreover, FXR negatively regulated COX6A2 expression through the inhibition of histone acetyltransferase p300 occupancy, diminishing histone H3 acetylation at lysine 27 on the Cox6a2 promoter. Furthermore, the deficiency of FXR intensified β-cell apoptosis under diabetic situations. Thus, it is probable that in diabetogenic environments, reduced FXR expression contributes to enhanced COX6A2 expression, culminating in β-cell apoptosis. These findings emphasize the essential involvement of the FXR/p300 pathway-controlled COX6A2 in β-cell apoptosis, revealing a previously undiscovered mechanism underlying diabetic β-cell apoptosis.

DOI: https://doi.org/10.1038/s41419-024-07302-4