Human adenine nucleotide translocases physically and functionally interact with respirasomes
Journal
Molecular Biology of the Cell
Journal Volume
28
Journal Issue
11
Pages
1489-1506
Date Issued
2017
Author(s)
Abstract
Members of the adenine nucleotide translocase (ANT) family exchange ADP for ATP across the mitochondrial inner membrane, an activity that is essential for oxidative phosphorylation (OXPHOS). Mutations in or dysregulation of ANTs is associated with progressive external ophthalmoplegia, cardiomyopathy, nonsyndromic intellectual disability, apoptosis, and the Warburg effect. Binding partners of human ANTs have not been systematically identifed. The absence of such information has prevented a detailed molecular understanding of the assorted ANT-associated diseases, including insight into their disparate phenotypic manifestations. To fll this void, in this study, we defne the interactomes of two human ANT isoforms. Analogous to its yeast counterpart, human ANTs associate with heterologous partner proteins, including the respiratory supercomplex (RSC) and other solute carriers. The evolutionarily conserved ANT-RSC association is particularly noteworthy because the composition, and thereby organization, of RSCs in yeast and human is different. Surprisingly, absence of the major ANT isoform only modestly impairs OXPHOS in HEK293 cells, indicating that the low levels of other isoforms provide functional redundancy. In contrast, pharmacological inhibition of OXPHOS expression and function inhibits ANT-dependent ADP/ATP exchange. Thus ANTs and the OXPHOS machinery physically interact and functionally cooperate to enhance ANT transport capacity and mitochondrial respiration. ? 2017 Shimamoto et al.
SDGs
Other Subjects
adenine nucleotide translocase; heat shock protein; protein; respiratory supercomplex protein; solute carrier protein; unclassified drug; adenine nucleotide translocase; adenosine diphosphate; adenosine triphosphate; isoprotein; allele; Article; controlled study; HEK293 cell line; human; human cell; liquid chromatography-mass spectrometry; mitochondrial respiration; molecular weight; open reading frame; oxidative phosphorylation; polyacrylamide gel electrophoresis; priority journal; protein function; protein protein interaction; protein purification; apoptosis; genetics; HeLa cell line; metabolism; mitochondrial membrane; mitochondrion; structure activity relation; Adenosine Diphosphate; Adenosine Triphosphate; Apoptosis; HEK293 Cells; HeLa Cells; Humans; Mitochondria; Mitochondrial ADP, ATP Translocases; Mitochondrial Membranes; Oxidative Phosphorylation; Protein Isoforms; Structure-Activity Relationship
Publisher
American Society for Cell Biology
Type
journal article