Infection-induced peripheral mitochondria fission drives ER encapsulations that rescue bioenergetics

During infection, viruses rely on altering organelle shape, location, and abundance to modulate cellular functions. The prevalent pathogen human cytomegalovirus (HCMV) induces mitochondria fragmentation while paradoxically promoting respiration. Using super-resolution and cryo-electron tomography, we establish that HCMV infection induces peripheral mitochondria fission, the progeny of which form mitochondria-ER encapsulations (MENCs). Proteomics and metabolic assays demonstrate that MENC resident protein PTPIP51 promotes mitochondria health by regulating calcium transfer, membrane potential, and cellular respiration. MENCs stabilize pro-viral mitochondria-mitochondria contacts (MiMiCs) that facilitate the transfer of membrane potential and further increase respiration. Beyond infection, we show that metastatic melanoma cells, which exhibit similar fragmentation/respiration phenotypes, also form PTPIP51-enriched MENCs. Given the prevalence of mitochondria fragmentation in diverse disease states, MENCs can provide an explanation for uncharacterized facets of pathogenesis.