PMID- 37828426 OWN - NLM STAT- MEDLINE DCOM- 20231102 LR - 20231121 IS - 1689-1392 (Electronic) IS - 1425-8153 (Print) IS - 1425-8153 (Linking) VI - 28 IP - 1 DP - 2023 Oct 12 TI - MCCC2 is a novel mediator between mitochondria and telomere and functions as an oncogene in colorectal cancer. PG - 80 LID - 10.1186/s11658-023-00487-0 [doi] LID - 80 AB - BACKGROUND: The mitochondrial gene MCCC2, a subunit of the heterodimer of 3-methylcrotonyl-CoA carboxylase, plays a pivotal role in catabolism of leucine and isovaleric acid. The molecular mechanisms and prognostic value still need to be explored in the context of specific cancers, including colorectal cancer (CRC). METHODS: In vitro and in vivo cell-based assays were performed to explore the role of MCCC2 in CRC cell proliferation, invasion, and migration. Mitochondrial morphology, membrane potential, intracellular reactive oxygen species (ROS), telomerase activity, and telomere length were examined and analyzed accordingly. Protein complex formation was detected by co-immunoprecipitation (CO-IP). Mitochondrial morphology was observed by transmission electron microscopy (TEM). The Cancer Genome Atlas (TCGA) CRC cohort analysis, qRT-PCR, and immunohistochemistry (IHC) were used to examine the MCCC2 expression level. The association between MCCC2 expression and various clinical characteristics was analyzed by chi-square tests. CRC patients' overall survival (OS) was analyzed by Kaplan-Meier analysis. RESULTS: Ectopic overexpression of MCCC2 promoted cell proliferation, invasion, and migration, while MCCC2 knockdown (KD) or knockout (KO) inhibited cell proliferation, invasion, and migration. MCCC2 KD or KO resulted in reduced mitochondria numbers, but did not affect the gross ATP production in the cells. Mitochondrial fusion markers MFN1, MFN2, and OPA1 were all upregulated in MCCC2 KD or KO cells, which is in line with a phenomenon of more prominent mitochondrial fusion. Interestingly, telomere lengths of MCCC2 KD or KO cells were reduced more than control cells. Furthermore, we found that MCCC2 could specifically form a complex with telomere binding protein TRF2, and MCCC2 KD or KO did not affect the expression or activity of telomerase reverse transcriptase (TERT). Finally, MCCC2 expression was heightened in CRC, and patients with higher MCCC2 expression had favorable prognosis. CONCLUSIONS: Together, we identified MCCC2 as a novel mediator between mitochondria and telomeres, and provided an additional biomarker for CRC stratification. CI - (c) 2023. University of Wroclav. FAU - Liu, Wanjun AU - Liu W AD - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Road, Guangzhou, 510655, Guangdong, China. AD - Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. FAU - Chen, Si AU - Chen S AD - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Road, Guangzhou, 510655, Guangdong, China. FAU - Xie, Wenqing AU - Xie W AD - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Road, Guangzhou, 510655, Guangdong, China. AD - Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. FAU - Wang, Qian AU - Wang Q AD - Department of Intensive Care Unit, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Road, Guangzhou, 510655, China. FAU - Luo, Qianxin AU - Luo Q AD - Department of Intensive Care Unit, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Road, Guangzhou, 510655, China. FAU - Huang, Minghan AU - Huang M AD - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Road, Guangzhou, 510655, Guangdong, China. AD - Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. FAU - Gu, Minyi AU - Gu M AD - Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. AD - Scientific Journal Center, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Road, Guangzhou, 510655, China. FAU - Lan, Ping AU - Lan P AD - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Road, Guangzhou, 510655, Guangdong, China. lanping@mail.sysu.edu.cn. AD - Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Road, Guangzhou, 510655, China. lanping@mail.sysu.edu.cn. FAU - Chen, Daici AU - Chen D AUID- ORCID: 0000-0002-8872-0592 AD - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Road, Guangzhou, 510655, Guangdong, China. chendc3@mail.sysu.edu.cn. AD - Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. chendc3@mail.sysu.edu.cn. LA - eng GR - 31970703/National Natural Science Foundation of China/ GR - 2021A1515010544/Natural Science Foundation of Guangdong Province/ GR - 2022A1515012472/Natural Science Foundation of Guangdong Province/ PT - Journal Article DEP - 20231012 PL - England TA - Cell Mol Biol Lett JT - Cellular & molecular biology letters JID - 9607427 SB - IM MH - Humans MH - *Colorectal Neoplasms/genetics/metabolism MH - Telomere/genetics/metabolism MH - Oncogenes MH - Mitochondria/metabolism MH - Kaplan-Meier Estimate MH - Cell Proliferation/genetics MH - Cell Line, Tumor MH - Gene Expression Regulation, Neoplastic MH - Cell Movement/genetics PMC - PMC10571261 OTO - NOTNLM OT - Colorectal cancer OT - MCCC2 OT - Mitochondria OT - Telomere COIS- The authors declare no competing interests. EDAT- 2023/10/13 00:42 MHDA- 2023/11/02 12:45 PMCR- 2023/10/12 CRDT- 2023/10/12 23:39 PHST- 2023/03/20 00:00 [received] PHST- 2023/09/04 00:00 [accepted] PHST- 2023/11/02 12:45 [medline] PHST- 2023/10/13 00:42 [pubmed] PHST- 2023/10/12 23:39 [entrez] PHST- 2023/10/12 00:00 [pmc-release] AID - 10.1186/s11658-023-00487-0 [pii] AID - 487 [pii] AID - 10.1186/s11658-023-00487-0 [doi] PST - epublish SO - Cell Mol Biol Lett. 2023 Oct 12;28(1):80. doi: 10.1186/s11658-023-00487-0.