Human adenine nucleotide translocases physically and functionally interact with respirasomes

TY - JOUR

T1 - Human adenine nucleotide translocases physically and functionally interact with respirasomes

AU - Lu, Ya Wen

AU - Acoba, Michelle Grace

AU - Selvaraju, Kandasamy

AU - Huang, Tai Chung

AU - Nirujogi, Raja S.

AU - Sathe, Gajanan

AU - Pandey, Akhilesh

AU - Claypool, Steven M.

N1 - Funding Information: This work was supported by National Institutes of Health Grant R01HL108882 to S.M.C. and predoctoral fellowships from the American Heart Association (12PRE11910004 to Y.-W.L. and 16PRE31140006 to M.G.A.). Publisher Copyright: © 2017 Shimamoto et al. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85020126947

U2 - 10.1091/mbc.E17-03-0195

DO - 10.1091/mbc.E17-03-0195

M3 - Article

C2 - 28404750

AN - SCOPUS:85020126947

SN - 1059-1524

VL - 28

SP - 1489

EP - 1506

JO - Molecular Biology of the Cell

JF - Molecular Biology of the Cell

IS - 11

ER -