Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries

Abstract

Infection with human cytomegalovirus (HCMV) profoundly affects cellular metabolism. Like in tumor cells, HCMV infection increases glycolysis, and glucose carbon is shifted from the mitochondrial tricarboxylic acid cycle to the biosynthesis of fatty acids. However, unlike in many tumor cells, where aerobic glycolysis is accompanied by suppression of mitochondrial oxidative phosphorylation, HCMV induces mitochondrial biogenesis and respiration. Here, we affinity purified mitochondria and used quantitative mass spectrometry to determine how the mitochondrial proteome changes upon HCMV infection. We found that the mitochondrial transcription and translation systems are induced early during the viral replication cycle. Specifically, proteins involved in biogenesis of the mitochondrial ribosome were highly upregulated by HCMV infection. Inhibition of mitochondrial translation with chloramphenicol or knockdown of HCMV-induced ribosome biogenesis factor MRM3 abolished the HCMV-mediated increase in mitochondrially encoded proteins and significantly impaired viral growth under bioenergetically restricting conditions. Our findings demonstrate how HCMV manipulates mitochondrial biogenesis to support its replication.

Human Cytomegalovirus Alters Host Cell Mitochondrial Function during Acute Infection

“…8). These data are consistent with previous reports showing increased mitochondrial biogenesis and upregulation of mitochondrial transcription and translation pathways (39,42,54).…”

“…A significant increase in glycolysis may suggest less reliance on or a decrease in mitochondrial respiration. Previous studies have indicated that mitochondria are altered during HCMV infection (25,39,42). We observed that OXPHOS activity was increased in HCMV-infected cells, as measured by the oxygen consumption rate (OCR) using the Seahorse XF e 24 platform ( Fig.…”

“…Previous studies have observed that HCMV infection induced mitochondrial fragmentation and biogenesis (25,(39)(40)(41). Also, mitochondrial transcription and translation machineries have been reported to be highly upregulated using transcriptome sequencing approaches (25,(42)(43)(44). However, it is unclear if host mitochondria are directly involved or even required for HCMV replication.…”

Single-cell transcriptome analysis of CD34+stem cell-derived myeloid cells identifies a CFU-GEMM-like population permissive to human cytomegalovirus infection

“…We initially reported the up-regulation of numerous genes with functions in mitochondrial oxidative phosphorylation, fatty acid β-oxidation, and malate-aspartate, ATP, and citrate transport systems in infected fibroblasts at late times pi [53]. Our findings were subsequently confirmed and expanded by a number of studies in fibroblasts and other cell types [101–104]. To our knowledge, the current work is the first report showing that a strong transcriptional induction of this type of genes also occurs in myeloid cells and at early times post-entry (Fig 7), making it a hallmark of CMV infection in different cell types and a requirement for successful viral replication.…”

The influence of macrophage growth factors on Theiler’s Murine Encephalomyelitis Virus (TMEV) infection and activation of macrophages

“…glycolysis) [21]. Because glycolysis has been shown to be required for efficient replication of viruses including dengue virus, cytomegalovirus, Semliki Forest virus, Sindbis, Adenovirus, and Hepatitis C virus and poliovirus, the Warburg effect may be purposely enhanced by viral infections to increase energy and metabolite production required for virus replication and inhibition of apoptosis in host cells [5, 22, 24, 30, 45, 66]. …”