The human cytomegalovirus protein pUL13 targets mitochondrial cristae architecture to increase cellular respiration during infection

Cora N. Betsinger, Connor S.R. Jankowski, William A. Hofstadter, Joel D. Federspiel, Clayton J. Otter, Pierre M. Jean Beltran, Ileana M. Cristea

Research output: Contribution to journalArticlepeer-review

Abstract

Viruses modulate mitochondrial processes during infection to increase biosynthetic precursors and energy output, fueling virus replication. In a surprising fashion, although it triggers mitochondrial fragmentation, the prevalent pathogen human cytomegalovirus (HCMV) increases mitochondrial metabolism through a yet-unknown mechanism. Here, we integrate molecular virology, metabolic assays, quantitative proteomics, and superresolution confocal microscopy to define this mechanism. We establish that the previously uncharacterized viral protein pUL13 is required for productive HCMV replication, targets the mitochondria, and functions to increase oxidative phosphorylation during infection. We demonstrate that pUL13 forms temporally tuned interactions with the mitochondrial contact site and cristae organizing system (MICOS) complex, a critical regulator of cristae architecture and electron transport chain (ETC) function. Stimulated emission depletion superresolution microscopy shows that expression of pUL13 alters cristae architecture. Indeed, using live-cell Seahorse assays, we establish that pUL13 alone is sufficient to increase cellular respiration, not requiring the presence of other viral proteins. Our findings address the outstanding question of how HCMV targets mitochondria to increase bioenergetic output and expands the knowledge of the intricate connection between mitochondrial architecture and ETC function.

Original languageEnglish (US)
Article numbere2101675118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number32
DOIs
StatePublished - Aug 10 2021

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • HCMV
  • Metabolism
  • Mitochondria
  • PUL13
  • Proteomics

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