Calcium-mediated mitochondrial fission and mitophagy drive glycolysis to facilitate arterivirus proliferation.

Mitochondria, recognized as the "powerhouse" of cells, play a vital role in generating cellular energy through dynamic processes such as fission and fusion. Viruses have evolved mechanisms to hijack mitochondrial function for their survival and proliferation. Here, we report that infection with the swine arterivirus porcine reproductive and respiratory syndrome virus (PRRSV), manipulates mitochondria calcium ions (Ca²⁺) to induce mitochondrial fission and mitophagy, thereby reprogramming cellular energy metabolism to facilitate its own replication. Mechanistically, PRRSV-induced mitochondrial fission is caused by elevated levels of mitochondria Ca²⁺, derived from the endoplasmic reticulum (ER) through inositol 1,4,5-triphosphate receptor (IP3R)—voltage-dependent anion channel 1 (VDAC1)—mitochondrial calcium uniporter (MCU) channels. This process is associated with increased mitochondria-associated membranes (MAMs), mediated by the upregulated expression of sigma non-opioid intracellular receptor 1 (SIGMAR1). Elevated mitochondria Ca²⁺ further activates the Ca²⁺/CaM-dependent protein kinase kinase β (CaMKKβ)—AMP-activated protein kinase (AMPK)—dynamin-related protein 1 (DRP1) signaling pathway, which interacts with mitochondrial fission protein 1 (FIS1) and mitochondrial dynamics proteins of 49 kDa (MiD49) to promote mitochondrial fission. PRRSV infection, alongside mitochondrial fission, triggers mitophagy via the PTEN-induced putative kinase 1 (PINK1)-Parkin RBR E3 ubiquitin (Parkin) pathway, promoting cellular glycolysis and excessive lactate production to facilitate its own replication. This study reveals the mechanism by which mitochondrial Ca²⁺ regulates mitochondrial function during PRRSV infection, providing new insights into the interplay between the virus and host cell metabolism. Author summary: PRRSV poses a major threat to the global swine industry, and no effective vaccines or antiviral drugs have been developed. A deep understanding of the PRRSV replication mechanism is essential for devising effective strategies to control this disease. The present work presents a detailed map of PRRSV infection, focusing on mitochondrial Ca²⁺, mitochondrial morphology, and glucose metabolism. Experimental findings reveal that viral infection induces alterations in fission and mitophagy through the elevation of mitochondrial Ca²⁺ levels. Furthermore, the study characterizes the regulatory mechanism of Ca²⁺ within mitochondria, influencing mitochondrial morphology during PRRSV infection. These mitochondrial alterations, coupled with reprogramming of cellular glucose metabolism, support the replication of the virus within host cells. This study provides insights into the interplay among the virus, mitochondrial morphology, and host cell metabolism, offering promise for guiding future research and informing therapeutic interventions against PRRSV. [ABSTRACT FROM AUTHOR]