Abstract
Mitochondrial malic enzyme 2 (ME2), which catalyzes the conversion of malate to pyruvate, is frequently upregulated during tumorigenesis and is a potential target for cancer therapy. However, the regulatory mechanism underlying ME2 activity is largely unknown. In this study, we demonstrate that ME2 is highly expressed in human colorectal cancer (CRC) tissues, and that ME2 knockdown inhibits the proliferation of CRC cells. Furthermore, we reveal that ME2 is succinylated and identify Sirtuins 5 (SIRT5) as an ME2 desuccinylase. Glutamine deprivation directly enhances the interaction of SIRT5 with ME2 and thus promotes SIRT5-mediated desuccinylation of ME2 at lysine 346, activating ME2 enzymatic activity. Activated ME2 significantly enhances mitochondrial respiration, thereby counteracting the effects of glutamine deprivation and supporting cell proliferation and tumorigenesis. Additionally, the levels of succinylated ME2 at K346 and SIRT5 in CRC tissues, which are negatively correlated, are associated with patient prognosis. These observations suggest that SIRT5-catalyzed ME2 desuccinylation is a key signaling event through which cancer cells maintain mitochondrial respiration and promote CRC progression under glutamine deficiency conditions, offering the possibility of targeting SIRT5-mediated ME2 desuccinylation for CRC treatment.
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Data availability
The full and uncropped western blots were uploaded as the Supplemental Material. Other datasets used and/or analyzed during the study are available from the corresponding author on reasonable request.
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Acknowledgements
We thank Professor Li Jia (Shanghai Institute of Materia Medica, Chinese Academy of Sciences) for providing the pRH-ME2 plasmids. We also thank Professor Yu Wei (Fudan University) for providing the SIRT5-HA and SIRT5-HA H158Y plasmids. This work was supported by the Natural Science Foundation of China (82002964, 82173063), China Postdoctoral Science Foundation (2022M711370), Wuxi Taihu Lake Talent Plan for Leading Talents in Medical and Health Profession, Wuxi Medical Key Discipline (ZDXK2021002) and Youth Program of Wuxi Medical Foundation (Q202123).
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CL, PT, and ZH designed the research. CL and PT performed most of the experiments. KC performed bioinformatic analyses. SY and BF collected clinical samples. ZH and CL supervised the project. CL, PT, FL, and ZH wrote the manuscript.
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All animal experiments were performed in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals and were approved by the Clinical Research Ethics Committees of Jiangnan University (JN. No20220515b0320730[151]).
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Teng, P., Cui, K., Yao, S. et al. SIRT5-mediated ME2 desuccinylation promotes cancer growth by enhancing mitochondrial respiration. Cell Death Differ 31, 65–77 (2024). https://doi.org/10.1038/s41418-023-01240-y
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DOI: https://doi.org/10.1038/s41418-023-01240-y