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Organelles play diverse roles within a cell, both during homeostasis and in response to internal and external stimuli. These functions can be tuned to the specific needs of the cell through the remodeling of organelle shape, composition, abundance, distribution, or interactions. Due to their importance for many critical cellular functions, organelle remodeling is commonly dysregulated in diverse disease states, including viral infection. Viruses rely on host processes to replicate and therefore must dysregulate organelles and organelle remodeling to promote a more suitable cellular environment for their replication and spread. The prevalent pathogen human cytomegalovirus (HCMV) takes this remodeling to the extreme, restructuring nearly the entire organelle landscape across its replication cycle. However, in many cases, the mechanism underpinning an HCMV-induced organelle remodeling event and the impact of that alteration on cellular function and viral replication is limited.
I sought to elucidate the mechanisms of organelle remodeling and the structure-function relationships of organelles throughout HCMV infection by integrative quantitative microscopy with mass spectrometry-based proteomics and functional assays. An outstanding question in the field has been how HCMV paradoxically induces mitochondria fragmentation concurrent with the upregulation of respiration. Here, I establish that HCMV elevates respiration in a fragmented mitochondria population by suppressing mitochondria fusion and concurrently upregulating peripheral fission. Downstream of this distinct fragmentation mechanism, I find that mitochondria engage in ER and inter-mitochondrial contacts that function to prevent mitochondria degradation and promote mitochondria bioenergetics. To determine whether HCMV-induced remodeling of mitochondria and other organelles is consistent across infections in different cell types, I compared protein and organelle dysregulation during infections in fibroblast and epithelial cells, two common sites for primary HCMV infection. Despite the baseline proteomic differences in these cell types, I find that protein abundances become more similar as infection progresses, concomitant with similar remodeling to mitochondria, peroxisomes, and cholesterol trafficking. Through an analysis of the HCMV virus microenvironment, I further find that pro-viral and host immune factors differentially modulate peroxisome morphology in nearby uninfected cells. These findings highlight the diverse ways in which viral infections can rewire existing cellular functions towards promoting virus replication.
