The depletion of TFAM and p-β-catenin(S552) in mitochondria in response to BoAHV-1 productive infection leads to decreased mitochondrial biogenesis

Varicellovirus bovinealpha (BoAHV) types 1(BoAHV-1) is one of the most significant viruses affecting cattle, causing substantial economic losses in the global cattle industry. Virus productive Infection in cell cultures leads to mitochondrial dysfunction, resulting in the overproduction of Reactive Oxygen Species (ROS), which act as inflammatory mediators and exert cytotoxic effects. But the underlying mechanisms remain poorly understood. Mitochondrial transcription factor A (TFAM) is a critical transcriptional activator of the mitochondrial DNA and plays a vital role in mitochondrial biogenesis. In this study, we report that virus acute Infection in calves (at 4 days post-infection) increases TFAM protein expression and its accumulation in the peri-nuclear region in a subset of trigeminal ganglia (TG) neurons. Similarly, virus productive Infection at later stages in MDBK cells also leads to increased TFAM protein expression and its accumulation in the nucleus. Using TFAM-specific siRNAs, we revealed that TFAM plays a significant role in BoAHV-1 productive Infection. Consistent with decreased mitochondrial biogenesis, TFAM protein accumulation in mitochondria was significantly reduced following viral Infection, which is corroborated by the reduced accumulation of TOM70 and Tim44 proteins in mitochondria. These proteins are key components of the mitochondrial membrane transport system that facilitates the translocation of TFAM into mitochondria. Interestingly, we found that a subset of β-catenin resides in mitochondria, and viral Infection decreases the accumulation of transcriptionally active β-catenin, p-β-catenin(S552), in mitochondria. This may contribute to decreased mitochondrial biogenesis, as the β-catenin-specific inhibitor iCRT14 reduces the protein expression of Cytb, a key regulator of mitochondrial biosynthesis. Collectively, we suggest that the depletion of both TFAM and p-β-catenin(S552) in mitochondria may contribute to the mitochondrial dysfunction induced by BoAHV-1 productive Infection.

BoAHV-1; Mitochondria dysfunction; TFAM.