BVDV utilizes PGC-1α downregulation to remodel the mitochondrial metabolic microenvironment, enhancing viral replication and impairing host immunity.

Bovine viral diarrhea virus (BVDV) is a major pathogen affecting global livestock production, and virus-induced mitochondrial remodeling is closely associated with viral replication. However, the role of PGC-1α-mediated mitochondrial quality control in cytopathic BVDV strain NADL infection remains unclear. MDBK cells were infected with CP BVDV(NADL) to establish an in vitro infection model. Mitochondrial morphology, function, mitophagy levels, and the expression of related proteins were examined using transmission electron microscopy, fluorescence staining, confocal microscopy, Western blotting, and the pADV-CMV-FH-cox8-EGFP-mCherry vector dual-fluorescence system. PGC-1α expression was manipulated by plasmid-mediated overexpression or shRNA-mediated knockdown.Viral replication was quantified by qRT-PCR, and IFN-β secretion was assessed by ELISA. CP BVDV(NADL) infection caused mitochondrial structural damage and dysfunction, accompanied by persistent downregulation of PGC-1α and its downstream target TFAM. Meanwhile, Drp1 expression was increased, shifting mitochondrial dynamics toward excessive fission. CP BVDV(NADL) infection also markedly enhanced PINK1-mediated mitophagy. Functionally, PGC-1α overexpression restored mitochondrial homeostasis, inhibited PINK1-dependent mitophagy, reduced IFN-β expression, and ultimately suppressed CP BVDV(NADL) replication. Conversely, PGC-1α interference further promoted mitophagy and increased mPTP opening. These findings demonstrate for the first time that CP BVDV(NADL) promotes viral replication by manipulating PGC-1α-mediated mitochondrial quality control. This mechanism reveals a novel metabolic strategy used by BVDV and provides potential therapeutic targets for controlling CP BVDV(NADL) infection.