Progression of herpesvirus infection remodels mitochondrial organization and metabolism.

Viruses target mitochondria to promote their replication, and infection-induced stress during the progression of infection leads to the regulation of antiviral defenses and mitochondrial metabolism which are opposed by counteracting viral factors. The precise structural and functional changes that underlie how mitochondria react to the infection remain largely unclear. Here we show extensive transcriptional remodeling of protein-encoding host genes involved in the respiratory chain, apoptosis, and structural organization of mitochondria as herpes simplex virus type 1 lytic infection proceeds from early to late stages of infection. High-resolution microscopy and interaction analyses unveiled infection-induced emergence of rough, thin, and elongated mitochondria relocalized to the perinuclear area, a significant increase in the number and clustering of endoplasmic reticulum-mitochondria contact sites, and thickening and shortening of mitochondrial cristae. Finally, metabolic analyses demonstrated that reactivation of ATP production is accompanied by increased mitochondrial Ca2+ content and proton leakage as the infection proceeds. Overall, the significant structural and functional changes in the mitochondria triggered by the viral invasion are tightly connected to the progression of the virus infection. Author summary: Herpesviruses not only cause significant diseases but are also promising candidates for oncolytic therapy. The HSV-1 infection depends on the nuclear DNA replication, transcription machinery, and mitochondrial metabolism of the host cell. Late in lytic infection, HSV-1 induces major structural changes in nuclear structures, including host chromatin, and mitochondria. This study investigated time-dependent mitochondrial changes as HSV-1 infection proceeds from early to late infection. We show that infection leads to significant transcriptional modification of genes encoding proteins involved in the mitochondrial network, such as the respiratory chain, apoptosis, and the structural organization of mitochondria. Our findings indicate that infection leads to significant alterations in mitochondrial structure and function, including changes in mitochondrial morphology and distribution, thickening and shortening of cristae, an increase in the number and area of contact sites between mitochondria and the endoplasmic reticulum, as well as a rise in mitochondrial calcium ion content and proton leak. [ABSTRACT FROM AUTHOR]

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