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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

SUBMITTER: Will Hofstadter

LAB HEAD: William Hofstadter

PROVIDER: PXD038330 | Pride | 2024-07-25

REPOSITORIES: Pride

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			Action	DRS
	202109_IgG-IP_48hpi_BR1.raw	Raw
	202109_IgG-IP_72hpi_BR1.raw	Raw
	202109_IgG-IP_96hpi_BR1.raw	Raw
	202109_IgG-IP_Mock_BR1.raw	Raw
	202109_PTPIP51-IP_48hpi_BR1.raw	Raw

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Project description:The response of chicken to non-typhoidal Salmonella infection is becoming well characterised but the role of particular cell types in this response is still far from being understood. Therefore, in this study we characterised the response of chicken embryo fibroblasts (CEFs) to infection with two different S. Enteritidis strains by microarray analysis. The expression of chicken genes identified as significantly up- or down-regulated (≥3-fold) by microarray analysis was verified by real-time PCR followed by functional classification of the genes and prediction of interactions between the proteins using Gene Ontology and STRING Database. Finally the expression of the newly identified genes was tested in HD11 macrophages and in vivo in chickens. Altogether 19 genes were induced in CEFs after S. Enteritidis infection. Twelve of them were also induced in HD11 macrophages and thirteen in the caecum of orally infected chickens. The majority of these genes were assigned different functions in the immune response, however five of them (LOC101750351, K123, BU460569, MOBKL2C and G0S2) have not been associated with the response of chicken to Salmonella infection so far. K123 and G0S2 were the only 'non-immune' genes inducible by S. Enteritidis in fibroblasts, HD11 macrophages and in the caecum after oral infection. The function of K123 is unknown but G0S2 is involved in lipid metabolism and in β-oxidation of fatty acids in mitochondria. Increased levels of G0S2 might decrease the availability of fatty acids to mitochondria. In non-professional phagocytes such as CEFs, this may lead to the dysfunction of mitochondria, apoptosis of CEFs and release of intracellular Salmonella. In professional phagocytes, G0S2 might be involved in the control of mitochondrial respiration, resulting in a decrease of reactive oxygen species as respiration by-products and lower damage to tissue. In this study we were interested whether chicken embryo fibroblast (CEFs) respond to S. Enteritidis infection and to what extent their response differs from that of other cells and caecal tissue. To address this, we characterised the gene expression of CEFs after infection with two different wild-type S. Enteritidis strains of poultry origin - SE 147 and SE 11 - using Agilen custom 8×15K microarrays. In total, 13,681 probes were designed to characterise the expression of ~9,000 transcripts of Gallus gallus.

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

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