A Systems Level Analysis of Communications between Microbes and Host Mitochondrial Unfolded Protein Response
Objective:Mitochondrial dysfunction is widely implicated in various diseases and pathological conditions.The mito-chondrial unfolded protein response(UPRmt)is activated to maintain mitochondrial function when misfolded proteins accumulate.Recent findings have unveiled several factors that activate UPRmt.However,the precise mechanism underlying UPRmt activation by microbes,re-mains incompletely understood.To identify bacterial modifiers of host mitochondrial unfolded protein response.Methods:We developed an in vivo high-throughput screening assay to assess the impact of microbes on host mitochondrial unfolded protein response.We screened 3985 Escherichia coli single-gene deleted mutants.Results:Through first screening and further validation,we identified 88 E.coli single-gene deleted mutants and Agrococcus R98 that regulate UPRmt in C.elegans.88 E.coli genes are involved in various cellular processes,including signal transduction,RNA modification,and transport.Notably,40％of these genes are related to bacterial metabolism.fep G encodes a ferric enterobactin ABC transporter subunit,essential for retrieving insoluble Fe(Ⅲ)from environments.We supplemented C.elegans fed △fepG and other mutants with the iron and observed a repression of host UPRmt,suggesting that bacteria act through iron to trigger C.elegans mitochondrial unfolded protein response.However,iron supplementation did not inhibit the host UPRmt induced by Agrococcus R98,demonstrating that different species of bacteria stimulate the host UPRmt by different mechanisms.Conclu-sions:Our study sheds light on a systems-level understanding of how microbial metabolites regulate host mitochondrial unfolded protein response,laying a foundation for similar investigations in higher organisms.
C.elegansEscherichia coliMicrobe-host interactionMitochondrial unfolded protein responseIron metabolism
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