bims-cytox1 2023-03-19 papers

Issue of 2023‒03‒19
four papers selected by
Gavin McStay
Liverpool John Moores University

Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00123-5. [Epub ahead of print]83(6): 890-910

Mitochondrial protein transport: Versatility of translocases and mechanisms.

Jakob D Busch, Laura F Fielden, Nikolaus Pfanner, Nils Wiedemann.

Biogenesis of mitochondria requires the import of approximately 1,000 different precursor proteins into and across the mitochondrial membranes. Mitochondria exhibit a wide variety of mechanisms and machineries for the translocation and sorting of precursor proteins. Five major import pathways that transport proteins to their functional intramitochondrial destination have been elucidated; these pathways range from the classical amino-terminal presequence-directed pathway to pathways using internal or even carboxy-terminal targeting signals in the precursors. Recent studies have provided important insights into the structural organization of membrane-embedded preprotein translocases of mitochondria. A comparison of the different translocases reveals the existence of at least three fundamentally different mechanisms: two-pore-translocase, β-barrel switching, and transport cavities open to the lipid bilayer. In addition, translocases are physically engaged in dynamic interactions with respiratory chain complexes, metabolite transporters, quality control factors, and machineries controlling membrane morphology. Thus, mitochondrial preprotein translocases are integrated into multi-functional networks of mitochondrial and cellular machineries.

DOI: https://doi.org/10.1016/j.molcel.2023.02.020

J Biol Phys. 2023 Mar 18.

Electrostatic effects on water-soluble fullerene derivatives interaction with cytochrome c and cytochrome c oxidase.

Darya A Poletaeva, Raisa A Kotelnikova, Irina I Faingold, Olga A Kraevaya, Pavel A Troshin, Alexander I Kotelnikov.

Water-soluble fullerene derivatives are good candidates for various biological applications such as anticancer or antimicrobial therapy, cytoprotection, enzyme inhibition, and many others. Their toxicity, both in tissue culture and in vivo, is a critical characteristic for the development and restriction of these applications. The effects of six water-soluble cationic and anionic polysubstituted fullerene derivatives on cytochrome c oxidase activity in rat brain mitochondria and the possibility of cytochrome c binding were studied. We found that the ability of these fullerene derivatives to bind with cytochrome c oxidase and charged molecules like eosin Y strongly depends on their electrostatic charge. As was shown, the cationic fullerene derivative inhibits cytochrome c oxidase that has the overall negative electrostatic potential completely, unlike anionic derivatives. Thus, it confirms the essential role of electrostatic interactions in the interaction of fullerene derivatives with the active site of enzymes. The results explore how cationic fullerene derivatives play a role in mitochondrial dysfunction, oxidative stress, and cytotoxicity.

Keywords: Cytochrome c; Cytochrome c oxidase; Cytotoxicity; Electrostatics; Fullerene derivatives

DOI: https://doi.org/10.1007/s10867-023-09631-5

Curr Vasc Pharmacol. 2023 Mar 15.

Protective role of cytochrome c oxidase 5A (COX5A) against mitochondrial disorder and oxidative stress in VSMC phenotypic modulation and neointima formation.

Haijing Guan, Jingwen Sun, Xiuying Liang, Wenjuan Yao.

BACKGROUND: The pathological role of cytochrome c oxidase 5A (COX5A) in vascular neointima formation remains unknown.AIM: This study aims to investigate the role of COX5A on Platelet-derived growth factor BB (PDGF-BB)-mediated smooth muscle phenotypic modulation and neointima formation and clarify the molecular mechanisms behind this effect.
METHOD: For in vitro assays, human aortic vascular smooth muscle cells (HA-VSMCs) were transfected with pcDNA3.1-COX5A and COX5A siRNA to overexpress and knockdown COX5A, respectively. Mitochondrial complex IV activity, oxygen consumption rate (OCR), H2O2 and ATP production, reactive oxygen species (ROS) generation, cell proliferation, and migration were measured. For in vivo assays, rats after balloon injury (BI) were injected with recombinant lentivirus carrying the COX5A gene. Mitochondrial COX5A expression, carotid arterial morphology, mitochondrial ultrastructure, and ROS were measured. Result &Discussion: The results showed that PDGF-BB reduced the level and altered the distribution of COX5A in mitochondria, as well as reduced complex IV activity, ATP synthesis, and OCR while increasing H2O2 synthesis, ROS production, and cell proliferation and migration. These effects were reversed by overexpression of COX5A and aggravated by COX5A knockdown. In addition, COX5A overexpression attenuated BI-induced neointima formation, muscle fiber area ratio, VSMC migration to the intima, mitochondrial ultrastructural damage, and vascular ROS generation.
CONCLUSION: The present study demonstrated that COX5A protects VSMCs against phenotypic modulation by improving mitochondrial respiratory function and attenuating mitochondrial damage, as well as reducing oxidative stress, thereby preventing neointima formation.

Keywords: COX5A; Mitochondrial respiratory chain; VSMC phenotypic modulation; intimal hyperplasia; oxidative stress

DOI: https://doi.org/10.2174/1570161121666230315142507

Front Pharmacol. 2023 ;14 1084564

Effect of Dl-3-n-butylphthalide on mitochondrial Cox7c in models of cerebral ischemia/reperfusion injury.

Jingjing Jia, Jianwen Deng, Haiqiang Jin, Jie Yang, Ding Nan, Zemou Yu, Weiwei Yu, Zhiyuan Shen, Yuxuan Lu, Ran Liu, Zhaoxia Wang, Xiaozhong Qu, Dong Qiu, Zhenzhong Yang, Yining Huang.

Several studies have demonstrated the protective effect of dl-3-n-Butylphthalide (NBP) against cerebral ischemia, which may be related to the attenuation of mitochondrial dysfunction. However, the specific mechanism and targets of NBP in cerebral ischemia/reperfusion remains unclear. In this study, we used a chemical proteomics approach to search for targets of NBP and identified cytochrome C oxidase 7c (Cox7c) as a key interacting target of NBP. Our findings indicated that NBP inhibits mitochondrial apoptosis and reactive oxygen species (ROS) release and increases ATP production through upregulation of Cox7c. Subsequently, mitochondrial respiratory capacity was improved and the HIF-1α/VEGF pathway was upregulated, which contributed to the maintenance of mitochondrial membrane potential and blood brain barrier integrity and promoting angiogenesis. Therefore, our findings provided a novel insight into the mechanisms underlying the neuroprotective effects of NBP, and also proposed for the first time that Cox7c exerts a critical role by protecting mitochondrial function.

Keywords: Dl-3-n-butylphthalide; ROS; cerebral ischemia/reperfusion; cytochrome c oxidase; mitochondrial dysfunction

DOI: https://doi.org/10.3389/fphar.2023.1084564