title: Changes in the expression of the human adenine nucleotide translocase isoforms condition cellular metabolic/proliferative status.
abstract: Human cells express four mitochondrial adenine nucleotide translocase (hANT) isoforms that are tissue-specific and developmentally regulated. hANT1 is mainly expressed in terminally differentiated muscle cells; hANT2 is growth-regulated and is upregulated in highly glycolytic and proliferative cells; and hANT3 is considered to be ubiquitous and non-specifically regulated. Here, we studied how the expression of hANT isoforms is regulated by proliferation and in response to metabolic stimuli, and examined the metabolic consequences of their silencing and overexpression. In HeLa and HepG2 cells, expression of hANT3 was upregulated by shifting metabolism towards oxidation or by slowed growth associated with contact inhibition or growth-factor deprivation, indicating that hANT3 expression is highly regulated. Under these conditions, changes in hANT2 mRNA expression were not observed in either HeLa or HepG2 cells, whereas in SGBS preadipocytes (which, unlike HeLa and HepG2 cells, are growth-arrest-sensitive cells), hANT2 mRNA levels decreased. Additionally, overexpression of hANT2 promoted cell growth and glycolysis, whereas silencing of hANT3 decreased cellular ATP levels, limited cell growth and induced a stress-like response. Thus, cancer cells require both hANT2 and hANT3, depending on their proliferation status: hANT2 when proliferation rates are high, and hANT3 when proliferation slows.
authors: Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain aleixgavalda@ub.edu.
authors: Aleix
authors: http://orcid.org/0000-0001-8421-3174
authors: A
authors: Gavaldà-Navarro
authors: Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain.
authors: Teresa
authors: T
authors: Mampel
authors: Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain.
authors: Octavi
authors: O
authors: Viñas
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics; D049109:Cell Proliferation; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006019:Glycolysis; D006031:Glycosylation; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007527:Isoenzymes; D000226:Mitochondrial ADP, ATP Translocases / Q000235:genetics* / Q000378:metabolism*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D012333:RNA, Messenger; D000226:Mitochondrial ADP, ATP Translocases
keywords: adenine nucleotide translocase; cell proliferation; cell stress response; gene expression; glycolysis; mitochondria