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Mitophagy protein PINK1 suppresses colon tumor growth by metabolic reprogramming via p53 activation and reducing acetyl-CoA production

Abstract

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the US. Understanding the mechanisms of CRC progression is essential to improve treatment. Mitochondria is the powerhouse for healthy cells. However, in tumor cells, less energy is produced by the mitochondria and metabolic reprogramming is an early hallmark of cancer. The metabolic differences between normal and cancer cells are being interrogated to uncover new therapeutic approaches. Mitochondria targeting PTEN-induced kinase 1 (PINK1) is a key regulator of mitophagy, the selective elimination of damaged mitochondria by autophagy. Defective mitophagy is increasingly associated with various diseases including CRC. However, a significant gap exists in our understanding of how PINK1-dependent mitophagy participates in the metabolic regulation of CRC. By mining Oncomine, we found that PINK1 expression was downregulated in human CRC tissues compared to normal colons. Moreover, disruption of PINK1 increased colon tumorigenesis in two colitis-associated CRC mouse models, suggesting that PINK1 functions as a tumor suppressor in CRC. PINK1 overexpression in murine colon tumor cells promoted mitophagy, decreased glycolysis and increased mitochondrial respiration potentially via activation of p53 signaling pathways. In contrast, PINK1 deletion decreased apoptosis, increased glycolysis, and reduced mitochondrial respiration and p53 signaling. Interestingly, PINK1 overexpression in vivo increased apoptotic cell death and suppressed colon tumor xenograft growth. Metabolomic analysis revealed that acetyl-CoA was significantly reduced in tumors with PINK1 overexpression, which was partly due to activation of the HIF-1α-pyruvate dehydrogenase (PDH) kinase 1 (PDHK1)-PDHE1α axis. Strikingly, treating mice with acetate increased acetyl-CoA levels and rescued PINK1-suppressed tumor growth. Importantly, PINK1 disruption simultaneously increased xenografted tumor growth and acetyl-CoA production. In conclusion, mitophagy protein PINK1 suppresses colon tumor growth by metabolic reprogramming and reducing acetyl-CoA production.

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Fig. 1: PINK1 deficiency promotes colon tumorigenesis in an AOM/DSS-induced colitis-associated CRC mouse model.
Fig. 2: PINK1 deficiency promotes colon tumorigenesis in an DSS/Apc deletion-induced colitis-associated CRC mouse model.
Fig. 3: PINK1 is critical for cell death in CRC.
Fig. 4: PINK1 drives metabolic reprogramming in vitro.
Fig. 5: PINK1 overexpression suppresses colon tumor in vivo.
Fig. 6: PINK1 overexpression suppresses colon tumor growth by metabolic rewiring.
Fig. 7: Acetyl-CoA is a determinant metabolite in PINK1-repressed tumor growth.
Fig. 8: Working model for PINK1-suppressed colon tumor growth.

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Acknowledgements

This research was supported in part by the National Institutes of Health (P20 GM130422, K01DK114390), a Research Scholar Grant from the American Cancer Society (RSG-18-050-01-NEC), a Research Pilot Project Grant from University of New Mexico Environmental Health Signature Program and Superfund (P42 ES025589), a Shared Resources Pilot Project Award and a Research Program Support Pilot Project Award from UNM comprehensive cancer center (P30CA118100), a new investigator award from the Dedicated Health Research Funds at the University of New Mexico School of Medicine, and a Core Utilization Voucher Program award and a Metabolomic Studies Voucher Award from the Autophagy, Inflammation and Metabolism (AIM) Center of Biomedical Research Excellence (P20GM121176). We thank Dr. Jim Liu for providing us access to the SpectraMax M2 Microplate Reader, Dr. Laurie Hudson for providing us access to the microtome, Dr. Michael Paffett from the UNMCC Fluorescence Microscopy Core facility for helping with confocal imaging, Dr. Sharina P Desai from Scientific Cores off AIM center for helping with ImageStream analysis, and Dr. Jesse L Denson for proofreading the manuscript.

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Correspondence to Xiang Xue.

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Yin, K., Lee, J., Liu, Z. et al. Mitophagy protein PINK1 suppresses colon tumor growth by metabolic reprogramming via p53 activation and reducing acetyl-CoA production. Cell Death Differ (2021). https://doi.org/10.1038/s41418-021-00760-9

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