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ATP SYNTHASE PERIPHERAL STALK, SUBUNIT D; ATP5PD

ATP SYNTHASE PERIPHERAL STALK, SUBUNIT D; ATP5PD

Alternative titles; symbolsATP SYNTHASE, H+ TRANSPORTING, MITOCHONDRIAL F0 COMPLEX, SUBUNIT D; ATP5HHGNC Approved Gene Symbol: ATP5PDCytogenetic location: 17q25....

Alternative titles; symbols

  • ATP SYNTHASE, H+ TRANSPORTING, MITOCHONDRIAL F0 COMPLEX, SUBUNIT D; ATP5H

HGNC Approved Gene Symbol: ATP5PD

Cytogenetic location: 17q25.1 Genomic coordinates (GRCh38): 17:75,038,862-75,046,968 (from NCBI)

▼ Description
ATP5PD encodes subunit D of mitochondrial H(+)-ATP synthase, a multisubunit complex that uses a transmembrane protein gradient to form ATP (Higuti et al., 1993).

▼ Cloning and Expression
Higuti et al. (1993) cloned rat Atp5h. The predicted Atp5h precursor contains 161 amino acids and has a calculated molecular mass of 18.8 kD, and the mature protein contains 160 amino acids and has a calculated molecular mass of 18.6 kD. Atp5h is a hydrophilic protein. It shares high homology with its ortholog from bovine heart and slight similarity with its yeast ortholog, but no homology with subunits of bacterial or chloroplast ATP synthase.

▼ Gene Function
Song et al. (2018) subjected mouse and human tumor cells transformed with HPV oncoproteins to 3 sequential rounds of in vivo or in vitro selection by cognate cytotoxic T lymphocytes (CTLs) and found that immune editing of tumor cells could provoke resistance to chemotherapy, radiotherapy, and immunotherapy. Analyses by 2D protein electrophoresis and mass spectrometry revealed that ATP5H was downregulated in cognate CTL-treated cells (P3 cells) compared with untreated parental cells (P0). Both P3 mouse and human tumor cells gradually lost ATP5H at the transcriptional level through HDAC1 (601242)-mediated histone deacetylation over the course of immune editing. Knockdown of ATP5H in mouse or human P0 cells phenocopied P3 cells by converting the cells to an antiapoptotic, treatment-resistant, stem-like, and invasive phenotype. Downregulation of ATP5H in P3 cells or in ATP5H-knockdown P0 cells resulted in mitochondrial metabolic reprogramming, induced reactive oxygen species (ROS) accumulation, and resistance to cancer therapy, and restoration of ATP5H in ATP5H-knockdown cells reversed these effects. Corroborating these in vitro results, delivery of antioxidants also reversed immune and drug resistance in vivo, retarded tumor growth, and prolonged survival in mice. Molecular pathway analysis revealed that ROS mediated AKT (164730)/ERK (see 176948) signaling through expression of HIF1-alpha (HIF1A; 603348), and knockdown of HIF1A restored susceptibility of ATP5H-depleted mouse or human tumor cells to immunotherapy. Examination of a cisplatin-refractory variant of A2780 human ovarian cancer cells demonstrated that, as with immune editing, drug selection prompted loss of ATP synthase and resulted in resistance to therapies, which could be reversed by delivery of antioxidants. Expression analysis of ATP5H and HIF1A proteins in various types of human tumor cells demonstrated that the observed ATP5H/HIF1A metabolic reprogramming pathway was widely conserved among human cancers.

▼ Mapping
Gross (2018) mapped the ATP5PD gene to chromosome 17q25.1 based on an alignment of the ATP5PD sequence (GenBank AF070650) with the genomic sequence (GRCh38).

Tags: 17q25.1