Faculty Collaboration Database

Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression. Cancer Res 2025 Sep 02;85(17):3313-3334

Date

06/20/2025

Pubmed ID

40540357

Pubmed Central ID

PMC12247146

DOI

10.1158/0008-5472.CAN-24-4042

Scopus ID

2-s2.0-105014771177 (requires institutional sign-in at Scopus site)   12 Citations

Abstract

UNLABELLED: Bioactive ceramide induces cell death in part by promoting mitophagy. C18-ceramide levels are commonly reduced in head and neck squamous cell carcinoma, which correlates with poor prognosis, suggesting the potential of harnessing ceramide for cancer treatment. In this study, we evaluated the ability of the ceramide analog D-erythro-14-(1-pyridinium)-N-octadecanoyl-sphingosine selenite (LCL768) to induce mitophagy and metabolic stress in head and neck squamous cell carcinoma. Mechanistically, LCL768 induced ceramide synthase 1 (CerS1)-mediated endogenous C18-ceramide accumulation in mitochondria to mediate mitophagy, which did not require the CerS1 transporter p17/PERMIT but was dependent on DRP1 activation via nitrosylation at C644. DRP1 facilitated the anchoring of the endoplasmic reticulum (ER) and mitochondrial membranes by promoting the association between phosphatidylethanolamine in the ER and cardiolipin in mitochondrial membranes. Mutations of Drp1 that prevented its binding to ER and mitochondrial membranes blocked CerS1/C18-ceramide mitochondrial accumulation, inhibiting LCL768-mediated mitophagy. In addition, LCL768-driven mitophagy altered mitochondrial metabolism, resulting in fumarate depletion and leading to tumor suppression in vivo. Exogenous fumarate supplementation prevented LCL768-mediated mitophagy, mitochondrial trafficking of CerS1, ER-mitochondrial tethering, and tumor suppression in mice. Fumarate metabolism was associated with PARKIN succination at a catalytic cysteine (Cys431), inhibiting its association with PINK1 and ubiquitin, thereby preventing mitophagy. LCL768-induced fumarate depletion attenuated PARKIN succination to promote PARKIN activation and mitophagy, indicating a feedforward mechanism that regulates mitophagy and fumarate metabolism through PARKIN succination. These data provide a mechanism whereby LCL768/CerS1-C18-ceramide-mediated mitophagy and tumor suppression are regulated by Drp1 nitrosylation, fumarate depletion, and PARKIN succination, providing a metabolic stress signature for lethal mitophagy.

SIGNIFICANCE: The identification of a metabolic link between ceramide-induced mitophagy, fission, and fumarate depletion reveals an effective tumor suppressive strategy for head and neck squamous cell carcinoma.

Author List

Oleinik NV, Atilgan FC, Kassir MF, Lee HG, Janneh AH, Wofford W, Walton C, Szulc ZM, Hill EG, Alekseyenko AV, Cimen H, Hartman JH, Voelkel-Johnson C, Lilly MB, Lemasters JJ, Frizzell N, Yu XZ, Mehrotra S, Ogretmen B

Author

Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Line, Tumor
Ceramides
Dynamins
Endoplasmic Reticulum
Humans
Membrane Proteins
Mice
Mice, Nude
Mitochondria
Sphingosine N-Acyltransferase
Stress, Physiological
Xenograft Model Antitumor Assays