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.
Highlights
Adenine nucleotide translocase (ANT) is an integral inner mitochondrial membrane protein that counter-exchanges newly synthesized ATP in the mitochondrial matrix for cytosolic ADP, allowing the proper function of oxidative phosphorylation (OXPHOS; for a review, see [1])
The principal finding of this study is that hANT3 is the main regulated hANT isoform in HeLa and HepG2 cells, which are not fully sensitive to growth factor deprivation or inhibition of growth by cell contact, respectively. hANT3 was upregulated by the induction of growth arrest as well as by forced acquisition of an oxidative metabolism
It has long been recognized that hANT2 expression is highly regulated. hANT2 was first cloned as an early response gene in human diploid fibroblasts [10] and is considered a marker of cell proliferation [13]
Summary
Adenine nucleotide translocase (ANT) is an integral inner mitochondrial membrane protein that counter-exchanges newly synthesized ATP in the mitochondrial matrix for cytosolic ADP, allowing the proper function of oxidative phosphorylation (OXPHOS; for a review, see [1]). In addition to this classical transport function, several lines of evidence indicate that ANT is involved in other cellular activities. HANT2 was first cloned in human fibroblasts as an early response gene [10], and it has been described as a marker of cell proliferation [13]
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