bims-cytox1 2025-12-14 papers

Antimicrob Agents Chemother. 2025 Dec 10. e0116125

The heme A synthase Cox15, as a target of redox-active 3-benzylmenadiones with antiparasitic activity.

Marcelo L Merli, Claudia Serot, Cindy Vallières, Julia A Cricco, Bogdan I Iorga, Elisabeth Davioud-Charvet, Brigitte Meunier.

Chagas disease, caused by Trypanosoma cruzi, is a neglected parasitic infection. The very limited arsenal of anti-T. cruzi treatments calls for the development of new drugs. Recently, a library of 3-benzylmenadione derivatives was synthesized, with cruzidione being the most efficient and specific compound against the parasite. To decipher its mode of action, we used the yeast Saccharomyces cerevisiae as a model. Evidence pinpointed at the heme A synthase Cox15 as a primary target of cruzidione: (i) a mutation in Cox15 (i.e., S429F) renders the yeast cells highly sensitive to the drug, (ii) treatment with cruzidione led to the loss of cytochrome c oxidase, an enzyme that relies on heme A as an essential cofactor, and (iii) replacement of the yeast Cox15 by T. cruzi enzyme resulted in a high sensitivity to cruzidione. We then investigated the effect of cruzidione in T. cruzi and observed a significant reduction in the heme contents, most likely involving the inhibition of the heme A synthase. This, in turn, led to a decrease in O2 consumption by the parasite. Finally, using the yeast model, we showed that, similar to what we previously found for the antimalarial benzylmenadione plasmodione, NADH-dehydrogenase plays a key role in cruzidione bioactivation. We proposed that the reduced benzoylmenadione metabolites, produced by the reaction with NADH-dehydrogenase, act as Cox15 inhibitors. This study, through the identification of the mode of action of cruzidione, highlighted Cox15 as a novel target for antiparasitic drugs.

Keywords: antiparasitic drug; drug mode of action; mitochondrial respiratory chain; yeast model

DOI: https://doi.org/10.1128/aac.01161-25

Biomed Opt Express. 2025 Sep 01. 16(9): 3797-3812

Quantification of oxidized and reduced cytochrome-c-oxidase by combining discrete-wavelength time-resolved and broadband continuous-wave near-infrared spectroscopy.

Rasa Eskandari, Natalie C Li, Saeed Samaei, Daniel Milej, Keith St Lawrence, Mamadou Diop.

Quantification of cytochrome-c-oxidase (CCO) can directly inform about cerebral metabolic capacity and function, but limited options currently exist for its in vivo assessment. Near-infrared spectroscopy (NIRS) has the potential to quantify CCO and its redox states, but hyperspectral absorption measurements are required due to their broad absorption profiles and low concentrations relative to hemoglobin. While this may be achieved with continuous-wave broadband NIRS (bNIRS), separating the signal contributions of absorption and scattering remains a challenge. Alternatively, time-resolved NIRS (trNIRS) can directly disentangle absorption and scattering but is typically constrained to a few wavelengths. This work aimed to develop an approach for quantifying absolute CCO concentration using discrete-wavelength trNIRS to calibrate bNIRS, yielding calibrated bNIRS (cbNIRS). Monte-Carlo simulations were conducted to validate the algorithm. Subsequently, a hybrid cbNIRS system was assembled, and tissue-mimicking phantoms were prepared with blood, Intralipid, and either yeast or sodium dithionite for validation. The simulations demonstrated that the algorithm can accurately measure absorption across the spectral range (error = 0.8 ± 0.4%). Further, the concentrations of CCO and its different redox states were estimated with an error of 7.9% or less. In the phantom experiments, the measured HbT concentration increased with the addition of blood, but not yeast nor sodium dithionite, and the value agreed with the expected concentration estimated from the packed cell volume of blood. A large increase in total CCO was measured only after the addition of yeast (1.8 ± 0.4 µM). Transitions in the oxygenation state of hemoglobin and redox state of CCO followed the expected trends as the phantom was deoxygenated and reoxygenated. Additionally, the sodium dithionite experiments confirmed that the COO signal measured with cbNIRS is not a result of crosstalk with the hemoglobin signal. This work demonstrates that absolute concentrations of both redox states of CCO can be quantified with high accuracy using cbNIRS. Future work will assess the feasibility of in vivo CCO measurements.

DOI: https://doi.org/10.1364/BOE.567105

Autophagy. 2025 Dec 08.

Mitochondrial protein COX5B orchestrates antiviral autophagy and apoptosis to restrict SRBSDV propagation in Sogatella furcifera.

Qing Bai, Yawen Ban, Lifei Zhao, Ting Cui, Xue Li, Tong Zhang, Guohui Zhou, Qingfa Wu.

Southern rice black-streaked dwarf virus (SRBSDV), a devastating plant pathogen transmitted by Sogatella furcifera, subverts host cellular machinery to establish persistent infection. While viral manipulation of mitochondrial dynamics and macroautophagic/autophagic pathways has been documented, host counterstrategies against such viral sabotage remain poorly understood. Here, we unveil a novel regulatory axis involving the viral protein P5-2, mitochondrial cytochrome c oxidase subunit COX5B, and the autophagy-related protein Atg3 during SRBSDV infection in S. furcifera. SRBSDV P5-2 localizes to host mitochondria, inducing mild structural damage and triggering mitochondrial stress. In response, COX5B is transcriptionally and translationally upregulated, exacerbating mitochondrial dysfunction to amplify autophagic flux. This enhanced autophagy facilitates the encapsulation of viral particles and damaged organelles within autophagosomes for subsequent lysosomal degradation. Intriguingly, COX5B directly interacts with P5-2, redirecting it to mitochondria and counteracting its autophagy-suppressive effects by sustaining Atg3-mediated autophagosome maturation. This interaction establishes COX5B as a molecular switch, tipping the balance toward antiviral autophagy rather than viral exploitation of mitophagy. Upregulation of COX5B induces suppression of class I phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, which mitigates its autophagy-inhibitory effects and promotes apoptosis to eliminate severely infected cells. Conversely, COX5B knockdown activates PI3K-Akt-mediated survival signaling, establishing a cytoprotective microenvironment that supports viral replication. Our study reveals a tripartite P5-2-COX5B-Atg3 axis modulating mitochondrial stress, autophagy, and apoptosis to balance viral persistence and host survival. This identifies COX5B as a central mitochondrial sentinel in insect antiviral immunity, demonstrating how host factors counteract viral sabotage via direct protein interactions, suggesting targets to disrupt viral transmission cycles.

Keywords: Antiviral autophagy; COX5B; PI3K-Akt-mTor pathway; SRBSDV; host-virus interaction; sogatella furcifera

DOI: https://doi.org/10.1080/15548627.2025.2601863