Selective Mitochondrial Respiratory Complex I Subunit Deficiency Causes Tumor Immunogenicity

Author:

Liang Jiaxin,Vitale TevisORCID,Zhang Xixi,Jackson Thomas D.,Yu Deyang,Jedrychowski Mark,Gygi Steve P.ORCID,Widlund Hans R.ORCID,Wucherpfennig Kai W.,Puigserver PereORCID

Abstract

AbstractTargeting of specific metabolic pathways in tumor cells has the potential to sensitize them to immune-mediated attack. Here we provide evidence for a specific means of mitochondrial respiratory Complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of the CI subunitsNdufs4andNdufs6, but not other subunits, induces an immune-dependent tumor growth attenuation in mouse melanoma models. We show that deletion ofNdufs4induces expression of the transcription factorNlrc5and genes in the MHC class I antigen presentation and processing pathway. This induction of MHC-related genes is driven by an accumulation of pyruvate dehydrogenase-dependent mitochondrial acetyl-CoA downstream of CI subunit deletion. This work provides a novel functional modality by which selective CI inhibition restricts tumor growth, suggesting that specific targeting ofNdufs4, or related CI subunits, increases T-cell mediated immunity and sensitivity to ICB.

Publisher

Cold Spring Harbor Laboratory

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