Selective Mitochondrial Respiratory Complex I Subunit Deficiency Causes Tumor Immunogenicity.

Targeting 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 subunits Ndufs4 and Ndufs6 , but not other subunits, induces an immune-dependent tumor growth attenuation in mouse melanoma models. We show that deletion of Ndufs4 induces expression of the transcription factor Nlrc5 and 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 of Ndufs4 , or related CI subunits, increases T-cell mediated immunity and sensitivity to ICB.

Cell cycle regulation of ER membrane biogenesis protects against chromosome missegregation.

Failure to reorganize the endoplasmic reticulum (ER) in mitosis results in chromosome missegregation. Here, we show that accurate chromosome segregation in human cells requires cell cycle-regulated ER membrane production. Excess ER membranes increase the viscosity of the mitotic cytoplasm to physically restrict chromosome movements, which impedes the correction of mitotic errors leading to the formation of micronuclei. Mechanistically, we demonstrate that the protein phosphatase CTDNEP1 counteracts mTOR kinase to establish a dephosphorylated pool of the phosphatidic acid phosphatase lipin 1 in interphase. CTDNEP1 control of lipin 1 limits the synthesis of fatty acids for ER membrane biogenesis in interphase that then protects against chromosome missegregation in mitosis. Thus, regulation of ER size can dictate the biophysical properties of mitotic cells, providing an explanation for why ER reorganization is necessary for mitotic fidelity. Our data further suggest that dysregulated lipid metabolism is a potential source of aneuploidy in cancer cells.