Human adenine nucleotide translocases physically and functionally interact with respirasomes

Lu, Ya Wen; Acoba, Michelle Grace; Kandasamy, Selvaraju; Huang, Tai‐Chung; Nirujogi, Raja Sekhar; Sathe, Gajanan; Pandey, Akhilesh; Claypool, Steven M.

doi:10.1091/mbc.e17-03-0195

Cited by 44 publications

(58 citation statements)

References 81 publications

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“…However, it remains possible that these transporters can also export matrix copper and that our current assays lack the necessary components either in small molecules or interacting protein partners to stimulate this activity. SLC25A3 has been identified in multiple complexes in the IM, including the ATP synthasomes and respirasomes (42)(43)(44). The physical association of the respiratory chain complexes with other MCFs, most notably ANT1, is known to significantly affect both nucleotide transport rates and oxidative phosphorylation (44).…”

Section: Discussionmentioning

confidence: 99%

“…SLC25A3 has been identified in multiple complexes in the IM, including the ATP synthasomes and respirasomes (42)(43)(44). The physical association of the respiratory chain complexes with other MCFs, most notably ANT1, is known to significantly affect both nucleotide transport rates and oxidative phosphorylation (44). Therefore, further work is needed to elucidate the other components of this pathway involving SLC25A3, including the identity of possible metabolic products that could serve as modulators of transport and other transporters required to redistribute copper to the IMS.…”

Section: Discussionmentioning

confidence: 99%

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The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis

Boulet

Vest

Maynard

et al. 2018

Journal of Biological Chemistry

116

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Edited by Ruma BanerjeeCopper is required for the activity of cytochrome c oxidase (COX), the terminal electron-accepting complex of the mitochondrial respiratory chain. The likely source of copper used for COX biogenesis is a labile pool found in the mitochondrial matrix. In mammals, the proteins that transport copper across the inner mitochondrial membrane remain unknown. We previously reported that the mitochondrial carrier family protein Pic2 in budding yeast is a copper importer. The closest Pic2 ortholog in mammalian cells is the mitochondrial phosphate carrier SLC25A3. Here, to investigate whether SLC25A3 also transports copper, we manipulated its expression in several murine and human cell lines. SLC25A3 knockdown or deletion consistently resulted in an isolated COX deficiency in these cells, and copper addition to the culture medium suppressed these biochemical defects. Consistent with a conserved role for SLC25A3 in copper transport, its heterologous expression in yeast complemented copper-specific defects observed upon deletion of PIC2. Additionally, assays in Lactococcus lactis and in reconstituted liposomes directly demonstrated that SLC25A3 functions as a copper transporter. Taken together, these data indicate that SLC25A3 can transport copper both in vitro and in vivo.Mitochondrial dysfunction contributes to the pathogenesis of heart failure, neurodegenerative disorders, myopathies, and diabetes (1). Mitochondria are dynamic, double membranebound organelles with a semi-permeable outer membrane that allows exchange of metabolites between the cytosol and the intermembrane space (IMS).5 In contrast, the inner membrane (IM) that separates the IMS and the matrix is tightly sealed. Thus, numerous transporters are required to provide the matrix with a diverse range of substrates that are necessary to support metabolism, the biogenesis of iron-sulfur clusters, and the assembly of the electron transport chain (ETC) required for oxidative phosphorylation (2).Cytochrome c oxidase (COX) is the terminal electron-accepting complex of the ETC. Mammalian COX contains 14 major subunits, two of which bind three redox centers required for electron transfer (3). The catalytic core consists of the mitochondrially-encoded subunits COX1, COX2, and COX3. COX2 binds the binuclear Cu A site required for accepting electrons from cytochrome c. These electrons are then transferred to the cofactors of COX1, first to heme a and then to the heme a 3 -Cu B site where oxygen is bound. COX biogenesis requires Ͼ25 accessory proteins known as COX assembly factors (1). The overwhelming majority of ETC defects that underlie mitochondrial dysfunction and human disease is caused by pathogenic mutations in accessory factors (1). At least nine of these factors facilitate the insertion of the copper cofactors that are essential for the catalytic competence of the COX holoenzyme (4). In yeast, it has been demonstrated that the copper used for COX assembly comes from the matrix, and this matrix copper pool is conserved in mammals (5, 6). Howe...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis

Boulet

Vest

Maynard

et al. 2018

Journal of Biological Chemistry

116

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“…Other studies have found similar stability with oxidative phosphorylation proteins [17]. Two inhibitors of ANT exist, both blocking the ADP/ATP transport function: carboxyatractyloside (CATR) which is cell membrane-impermeable and bongkrekic acid (BKA), which is membrane-permeable.…”

Section: Ant Regulates Cellular Respiration and Atp Productionmentioning

confidence: 86%

Adenine Nucleotide Translocase regulates the airway epithelium, mitochondrial metabolism and ciliary function

Kliment

Nguyen

Kaltreider

et al. 2020

Preprint

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The authors have declared no conflicts of interest exist. AbstractAirway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive lung disease (COPD). COPD is the 4 th leading cause of death in the US and is impacted by cigarette smoking with no therapeutic options. We utilized a genetic selection approach in the amoeba Dictyostelium discoideum as a comparative discovery tool in lung biology to identify genetic protectors from cigarette smoke (CS). Adenine nucleotide translocase (ANT), a mitochondrial ADP/ATP transporter, was protective against CS in Dictyostelium and human bronchial epithelial cells. ANT2 gene expression is reduced in lung tissue from COPD patients and in a mouse smoking model. ANT1and ANT2 overexpression resulted in enhanced oxidative respiration and ATP flux. In addition to ANT's presence in the mitochondria, ANT1 and ANT2 reside at the plasma membrane in airway epithelial cells and this localization plays a role in how ANTs regulate airway homeostasis. ANT2 overexpression stimulates airway surface liquid hydration by ATP and maintains ciliary beating after CS exposure, which are key functions of the airway. Our study highlights the potential of ANT modulation in protecting from dysfunctional mitochondrial metabolism, airway hydration, and ciliary motility in COPD.

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“…hANT1 is mainly ex-pressed 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 [30]. The protein partners of the isoforms were found to be similar, and the absence of the main isoform hANT3 had no impact on the oxidative phosphorylation process [31]. However, the isoforms were found to be de-regulated in human tumors [2].…”

Section: Dissimilar Functions Of the Same Protein Isoformsmentioning

confidence: 95%

Protein isoforms. Origin, structure and functions.

Новосильная

2017

Biopolym. Cell

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Human adenine nucleotide translocases physically and functionally interact with respirasomes

Cited by 44 publications

References 81 publications

The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis

The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis

Adenine Nucleotide Translocase regulates the airway epithelium, mitochondrial metabolism and ciliary function

Protein isoforms. Origin, structure and functions.

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