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

Abstract

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.