Interferon stimulated gene MCL-1 inhibits FMDV replication by modulating mitochondrial dynamics and blocking autophagy

Authors: MOGULOTHU, AISHWARYA - UNIVERSITY OF CONNECTICUT; HICKMAN, DANIELLE - EMD MILLIPORE; ATTREED, SARAH; AZZINARO, PAUL; RODRIGUEZ-CALZADA, MONICA - OAK RIDGE INSTITUTE FOR SCIENCE AND EDUCATION (ORISE); DITTMANN, MEIKE - NEW YORK UNIVERSITY SCHOOL OF MEDICINE; DE LOS SANTOS, TERESA - U.S. DEPARTMENT OF AGRICULTURE (USDA); SZCZEPANEK, STEPHEN - UNIVERSITY OF CONNECTICUT; MEDINA, GISSELLE

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/2/2025
Publication Date: 6/4/2025
Citation: Mogulothu, A., Hickman, D., Attreed, S.E., Azzinaro, P.A., Rodriguez-Calzada, M., Dittmann, M., De Los Santos, T., Szczepanek, S., Medina, G.N. 2025. Interferon stimulated gene MCL-1 inhibits FMDV replication by modulating mitochondrial dynamics and blocking autophagy. Journal of Virology. Article e00581-25. https://doi.org/10.1128/jvi.00581-25.
DOI: https://doi.org/10.1128/jvi.00581-25

Interpretive Summary: In our recent study, we investigated the role of the gene MCL-1 in combating the Foot and Mouth Disease Virus (FMDV), a major threat to livestock health. We found that MCL-1 significantly reduces the virus's replication in pig cells, lowering viral levels by about 10,000 times. This discovery is important for developing new strategies to control FMDV outbreaks.

Technical Abstract: Interferons and the interferon stimulated genes (ISGs) they induce are effective in reducing the replication of Foot and Mouth Disease Virus (FMDV). In this study, we demonstrated that the ISG MCL-1 inhibits FMDV replication by reducing viral titers by approximately 4 logs in porcine cells overexpressing MCL-1. We explore the regulatory pathways associated with MCL-1 to determine the specific antiviral mechanism against FMDV. Our findings indicate that the antiviral mechanism does not involve apoptosis regulation or alterations in cell cycle phase heterogeneity. Analysis of mitochondrial function through mitochondrial oxygen consumption rate demonstrate that MCL-1 causes increased mitochondrial respiration and ATP production, while FMDV infection reduces both measures. Additionally, MCL-1 overexpression resulted in elongated mitochondrial morphology, contrasting with the fragmentation and punctate morphology observed during FMDV infection. Importantly, these changes in mitochondrial dynamics were independent of MCL-1’s regulation of mitochondrial calcium flux. We also evaluated autophagy and found that MCL-1 overexpression suppresses this process, which is a necessary for FMDV replication. Furthermore, MCL-1overexpression led to increased expression of other ISGs upon RLR stimulation, establishing an antiviral state in porcine cells. Our data indicates that MCL-1 is a potent antiviral ISG against MCL-1 and highlights the importance of mitochondrial dynamics and autophagy in FMDV replication