NDUFS3

Official Full Name

NADH:ubiquinone oxidoreductase core subunit S3

Organism

Homo sapiens

GeneID

4722

Background

This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone oxidoreductase (complex I). Mutations in this gene are associated with Leigh syndrome resulting from mitochondrial complex I deficiency.[provided by RefSeq, Apr 2009]

Synonyms

CI-30; MC1DN8;

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Detailed Information

NADH dehydrogenase [ubiquinone] ferrithionein 3 (NDUFS3) is the core subunit of mitochondrial complex I and is directly involved in the electron transport of the respiratory chain. Its expression levels in human tissues and organs are high and low. NDUFS3 is involved in the development of tumors and is closely related to the levels of reactive oxygen species (ROS), adenosine triphosphate (ATP) and Warburg effect.

Structure of NDUFS3

The human NDUFS3 gene is located in the nuclear genome 11p11.2. It is 19227 bp in length and has 7 exons and 6 introns. The NDUFS3 protein is present as a monomer or multimer and its function is closely related to phosphorylation and glycosylation. Tyr122 and Ser115 of NDUFS3 protein are common phosphorylation sites. The O-glycosylation modification of NDUFS3 is a glycosyltransferase. N-acetylglucosamine (GlcNAc) is added to the oxygen atom of Ser or Thr of the protein. Its sustained glycosylation state can affect the energy metabolism of mitochondria, and the number of glycosylation subunits is associated with cellular mitochondrial dysfunction.

MDM2 integrates cellular respiration and apoptotic signaling through NDUFS1 and the mitochondrial network. Figure 1. Summary of the post-transcriptional gene regulation mechanisms known to regulate ETC transcript abundance. (Sirey, T. M., et al. 2016)

The Role and Mechanism of NDUFS3 in Tumorigenesis and Development

NDUFS3 is lowly expressed in most tumor tissues such as renal cell carcinoma and serous ovarian cancer, and is significantly associated with survival and prognosis. The study found that NDUFS3 is under-expressed in human breast cancer HMC-1 (human mammary carcinoma-1) cells and highly expressed in highly invasive breast cancer necrotic tissue, which may be a marker of breast cancer invasion or metastasis. In addition, the expression of NDUFS3 in neuroblastoma, cervical cancer, osteosarcoma, gastric cancer and colorectal cancer is also high.

After overexpressing NDUFS3 in human melanoma A875 and SKMEL-110 cell lines, cell proliferation, anti-apoptosis and migration and invasion were enhanced. By knocking down NDUFS3 of A875 and SKMEL-110 cell lines, cell proliferation, anti-apoptosis and migration and invasion were significantly attenuated. The NDUFS3-deficient Hela cells were significantly inhibited in their proliferative capacity and were resistant to the synergistic induction of apoptosis by interferon beta and retinoic acid. In addition, NDUFS3-deficient Hela cells promote cell migration and invasion and increase intercellular adhesion-forming spheroid formation by inducing epithelial-mesenchymal transition (EMT). In contrast, the highly expressed NDUFS3 is one of the indicators of the invasive ability of highly invasive breast cancer cells.

NDUFS3 Affects Mitochondrial Energy Production

Mitochondria-derived adenosine triphosphate (ATP) is the most important energy substance for life activities. In breast cancer HMC-1 cells with low expression of NDUFS3 protein, the expression of ATP synthase subunit was down-regulated, accompanied by a decrease in ATP production. The high expression of NDUFS3 protein in neuroblastoma caused by NNMT can lead to increased mitochondrial ATP production, decreased ADP production, increased ATP/ADP ratio, and enhanced cell viability. After knockdown of NDUFS3 in human embryonic fetal kidney HEK cells, mitochondrial complex V expression is up-regulated and mitochondrial compensatory adaptation occurs to produce more ATP to meet cell proliferation requirements. ATP synthase is down-regulated in most tumor cells, accompanied by high expression of ATPase inhibitory factor 1 (IF1) to maintain a certain level of ATP and to adapt to cellular metabolism. It can be seen that NDUFS3 affects mitochondrial energy metabolism and further affects tumor development.

References:

Wirth, C. , Brandt, U. , Hunte, C. , & Zickermann, V. . (2016). Structure and function of mitochondrial complex i. Biochimica et Biophysica Acta (BBA) - Bioenergetics, S0005272816300329.
Sirey, T. M. , & Ponting, C. P. . (2016). Insights into the post-transcriptional regulation of the mitochondrial electron transport chain. Biochemical Society Transactions, 44(5), 1491-1498.
Suhane, S. , Kanzaki, H. , Arumugaswami, V. , Murali, R. , & Ramanujan, V. K. . (2013). Mitochondrial ndufs3 regulates the ros-mediated onset of metabolic switch in transformed cells. Biology Open, 2(3), 295-305.

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