p53-mediated regulation of electron transport chain and nucleotide synthesis during Newcastle disease virus infection

TL;DR

The study shows how the p53 protein controls mitochondrial function during Newcastle disease virus infection, affecting viral replication and cell survival.

Contribution

The study reveals a novel role of p53 in regulating mitochondrial metabolism during NDV infection, influencing viral replication and metabolic stress.

Findings

NDV infection disrupts mitochondrial function and increases ROS production, especially in p53-null cells.

ETC impairment limits NDV replication by restricting nucleotide biosynthesis, not through energy depletion or ROS toxicity.

p53 protects mitochondrial function and precursor availability, shaping cellular susceptibility to NDV.

Abstract

Mitochondria and their electron transport chain (ETC) constitute the central machinery for cellular energy metabolism and biosynthetic regulation. Disruption of the ETC leads to reactive oxygen species (ROS) production and metabolic imbalance, but its precise role in viral replication and infection remains to be elucidated. In this study, we used Newcastle disease virus (NDV), an important avian pathogen and a promising oncolytic virus, as a model to explore its relationship with cellular mitochondrial metabolism. We demonstrate that NDV infection induces varying degrees of mitochondrial fragmentation, membrane potential dissipation, and ROS production, especially in p53-null H1299 cells compared to p53-wild-type A549 cells. ETC impairment restricts NDV replication primarily by limiting aspartate and pyrimidine nucleotide biosynthesis, rather than through ROS-mediated cytotoxicity or energy depletion. Notably, NDV replication in p53-null cells is highly sensitive to ETC complexes I and III inhibition, which can be rescued by exogenous aspartate or uridine supplementation. Mechanistically, p53 serves as a metabolic buffer, protecting mitochondrial function and maintaining precursor availability during viral infection. These findings elucidate the selective and differential utilization of mitochondrial ETC components by NDV and reveal that p53 status shapes cellular susceptibility to NDV-induced metabolic stress. Our work highlights mitochondrial metabolism and p53 as potential targets for antiviral and oncolytic strategies against NDV.

This study uncovers the intricate relationship between Newcastle disease virus (NDV) infection and host cell mitochondrial metabolism, with a particular emphasis on the pivotal regulatory role of p53. As both an important avian pathogen and a promising oncolytic virus, NDV disrupts mitochondrial function and the electron transport chain, leading to p53-mediated alterations in cellular energy metabolism and redox homeostasis. Our findings not only deepen the understanding of NDV-mitochondria interactions but also highlight the central role of p53 in viral infection and oncolytic mechanisms. These insights provide a theoretical foundation and novel therapeutic targets for antiviral and anticancer strategies based on p53 or mitochondrial pathways.

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