bims-mevinf 2025-04-13 papers

J Virol. 2025 Apr 08. e0231024

Peste des petits ruminants virus (PPRV) induces ferroptosis via LONP1-mediated mitochondrial GPX4 degradation in cell culture.

Qiaodi Hou, Shuijin Cheng, Zhijun Li, Congshang Lei, Yan Chen, Mingzhuo Ma, Jinming Liu, Xiwen Chen, Lizhen Wang, Qinghong Xue, Xuefeng Qi.

Peste des petits ruminants virus (PPRV) is an important pathogen that seriously affects the productivity of small ruminants worldwide. Ferroptosis is a programmed cell death characterized by iron-dependent lipid peroxidation and the accumulation of reactive oxygen species (ROS). Emerging evidence has demonstrated that mitochondria play diverse roles in the process of ferroptosis, but the interaction between mitochondria and ferroptosis during virus infection remains largely unknown. Here, we demonstrate that PPRV induces ferroptosis, including Fe2+ overload, accumulation of lipid peroxidation, and shrinkage of mitochondria. Importantly, mitochondria play a crucial role in the process of PPRV-induced ferroptosis characterized by decreased mitochondrial GPX4 and lipid peroxidation in mitochondria. Mechanistically, PPRV infection downregulates mitochondrial Lon protease-1 (LONP1) expression, an important multifaceted enzyme that is essential for maintaining mitochondrial homeostasis and function, which leads to mitochondrial GPX4 degradation through the Nrf2/Keap pathway and accumulation of ROS in mitochondria. More importantly, PPRV-induced ferroptosis is tightly associated with inflammatory responses and enhanced virus replication. Overall, this study is the first to show that LONP1-mediated ferroptosis is involved in the inflammatory responses during PPRV infection.
IMPORTANCE: Peste des petits ruminants virus (PPRV) infection induces a transient but severe immunosuppression in the host, which threatens both small livestock and endangered susceptible wildlife populations in many countries. Despite extensive research, it is unknown whether PPRV causes ferroptosis and what the mechanism of regulation is. Our data provide the first direct evidence that the relationship between Lon protease-1 (LONP1)-mediated dysfunctional mitochondria and the consequent induction of ferroptosis is involved in PPRV-induced pathogenesis. Importantly, we demonstrate that PPRV infection induces ferroptosis via the LONP1-mediated GPX4 degradation and ROS accumulation in mitochondria, and PPRV-induced ferroptosis is tightly associated with inflammatory responses and enhanced virus replication levels. Taken together, our research has provided new insight into understanding the effect of ferroptosis on PPRV replication and pathogenesis and revealed a potential therapeutic target for antiviral intervention.

Keywords: LONP1; Peste des petits ruminants virus; ferroptosis; innate immunity; mitochondria

DOI: https://doi.org/10.1128/jvi.02310-24

J Med Virol. 2025 Apr;97(4): e70328

SARS-CoV-2 Membrane Protein Induces MARCHF1/GPX4-Mediated Ferroptosis by Promoting Lipid Accumulation.

Pei Sun, Qian Liu, Shuofeng Yuan, Xin-Tao Wang, Ye Qiu, Xing-Yi Ge.

The membrane protein (M), a key structural protein of SARS-CoV-2 that regulates virus assembly and morphogenesis, is involved in the pathological processes of multiple organ damage and metabolic disorders. This study aims to elucidate the mechanisms of M-mediated host ferroptosis and lipid accumulation during SARS-CoV-2 infection. Here, we detected that M protein enhances cellular sensitivity to ferroptosis. Additionally, we uncovered the pivotal role of perilipin-2 and sterol regulatory element-binding protein 1 in M-induced lipid accumulation. Xanthohumol, a cost-effective and orally available diacylglycerol acyltransferase inhibitor, alleviated triglyceride and total cholesterol accumulation, thereby counteracting the M-induced ferroptosis. Furthermore, we identified that the mitochondrial import inner membrane translocase subunit TIM23 and the mitochondrial import receptor subunit TOM20 homolog contribute to M-induced mitochondrial dysfunction. Notably, inhibiting lipid synthesis effectively reduced mitochondrial reactive oxygen species and transmembrane potential, indicating a cross-talk between lipid and ferro metabolic pathways. Mechanistically, glutathione peroxidase 4 (GPX4) interacts with SARS-CoV-2 M, leading to its subsequent degradation by the Membrane Associated Ring-CH-Type Finger 1 (MARCHF1) ubiquitin ligase. M-GPX4 interaction occurs at the R72 residue, which may represent a potential therapeutic target against SARS-CoV-2 infection. M modulates lipid accumulation and further impairs mitochondrial functions, ultimately resulting in ferroptosis through MARCHF1-GPX4 axis. Disrupting host-virus interactions along this pathway may provide a therapeutic strategy for SARS-CoV-2 infection.

Keywords: SARS‐CoV‐2 membrane protein; ferroptosis; glutathione peroxidase 4; lipid accumulation; mitochondrial damage

DOI: https://doi.org/10.1002/jmv.70328

J Leukoc Biol. 2025 Apr 11. pii: qiaf042. [Epub ahead of print]

Mitochondrial fusion reduces T cell susceptibility to HIV infection through citrate modulation.

Zichen Song, Jiangrong Wang, Zhihang Zheng, Zhixiang He, Jingna Xun, Ling Gu, Yinzhong Shen, Jun Chen.

Inhibiting the metabolic activity of CD4+ T cells can effectively reduce HIV infection. Mitochondria, as critical organelles in eukaryotic metabolism, play a significant role in the progression of many diseases. The change of mitochondrial dynamics is an important process of mitochondrial regulation of cell metabolic activity. However, it remains uncertain whether regulating mitochondrial dynamics is a viable approach to reducing HIV infection. In this study, we demonstrated that promoting mitochondrial fusion in Jurkat cells through treatment with the mitochondrial fusion promoter M1 and the dynamin-related protein 1 (Drp1) inhibitor Mdivi1 conferred resistance to single-round VSVG-HIVNL4-3-GFP viral infection. Targeted metabolomics analysis revealed and subsequently confirmed the potential involvement of citrate in reducing HIV infection, which has been subsequently verified. And we found that plasma citrate level was negatively associated with HIV disease progression. Multi-omics results showed that citric acid leads to a decrease in the level of nucleotide metabolism in Jurkat cells. In conclusion, increased citrate levels resulting from mitochondrial fusion significantly impair the ability of HIV to infect cells, which may due to regulate nucleotide metabolism.

Keywords: HIV; citrate; mitochondrial dynamic; nucleotide metabolism

DOI: https://doi.org/10.1093/jleuko/qiaf042

Int J Biol Macromol. 2025 Apr 07. pii: S0141-8130(25)03419-1. [Epub ahead of print] 142867

3β-hydroxysteroid-Δ24 reductase integrates cholesterol metabolism and innate immune to promote PRRSV replication.

Yuchao Yan, Changyan Li, Qun Jie, Junyang Zhang, Yijia Liu, Yong Li, Daqing Cui, Depin Hua, Jinhai Huang.

Cholesterol metabolism is a strategy used by PRRSV to inhibit host antiviral innate immunity. However, the key enzymes or the natural products and mechanisms involved have not been well elucidated. Here, we show that PRRSV infection upregulated DHCR24, the rate-limiting enzyme in the cholesterol synthesis pathway, to increase virus proliferation. We further elucidated that PRRSV Nsp4 interacts with the FAD domain of DHCR24, promoting its expression and increasing cellular cholesterol levels. In addition, U18666A treatment inhibited DHCR24 enzyme activity, significantly reduced cell cholesterol content and PRRSV replication, and exogenous cholesterol supplementation could rescued this effect. We also found that DHCR24 is a negative regulator of type I interferon (IFN-I) production upon viral infection. Mechanistically, DHCR24 interacts with TBK1 and disrupts the interaction of TBK1-IRF3, thereby inhibiting IRF3 phosphorylation and nuclear translocation. Taken together, these findings elucidate that DHCR24 is utilized by PRRSV to regulate host cholesterol content, inhibit the innate immune response, and promote virus proliferation.

Keywords: Cholesterol metabolism; DHCR24; Innate immune; PRRSV

DOI: https://doi.org/10.1016/j.ijbiomac.2025.142867

Cell Mol Life Sci. 2025 Apr 07. 82(1): 141

Heat shock protein 60 manipulates Foot-and-Mouth disease virus replication by regulating mitophagy.

Jianli Tang, Sahibzada Waheed Abdullah, Shiqi Sun, Huichen Guo.

Mitochondria serve as the hubs of cellular signaling, energetics, and redox balance under physiological conditions. Mitochondria play an essential role in defending against pathogenic infections upon virus invasion. As a critical intracellular physiological process, mitophagy is crucial for maintaining mitochondrial homeostasis. Accumulating evidence suggests that mitophagy contributes to modulating viral infection. In our previous study, we reported that heat shock protein 60 (HSP60) is involved in orchestrating autophagy; however, the underlying mechanisms remain elusive. Here, we examined the role of HSP60 in priming mitophagy to regulate foot-and-mouth disease virus (FMDV) replication. We first reported that mitophagy was elicited post-FMDV infection and further restricted FMDV replication. Regarding HSP60, our results showed that HSP60 depletion triggered Parkin-dependent mitophagy via activating dynamin-related protein 1 (Drp1) phosphorylation at Ser616 and promoting Drp1 translocation to mitochondria. Furthermore, calmodulin-dependent protein kinase II (CaMKII) was essential for phosphorylating Drp1 at Ser616 in HSP60-depleted cells. Taken together, HSP60 manipulates FMDV replication by governing mitophagy. Importantly, HSP60 could be a promising antiviral target for controlling FMDV infection.

Keywords: Dynamin-related protein 1; Foot-and-Mouth disease virus; Heat shock protein 60; Mitophagy; Parkin

DOI: https://doi.org/10.1007/s00018-025-05623-x