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.