H+ transport is an integral function of the mitochondrial ADP/ATP carrier

Bertholet, Ambre M.; Chouchani, Edward T.; Kazak, Lawrence; Angelin, Alessia; Fedorenko, Andriy; Long, Jonathan Z.; Vidoni, Sara; Garrity, Ryan; Cho, Joonseok; Terada, Naohiro; Wallace, Douglas C.; Spiegelman, Bruce M.; Kirichok, Yuriy

doi:10.1038/s41586-019-1400-3

Cited by 191 publications

(179 citation statements)

References 52 publications

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“…SS-31 binding to the ADT channel yet not functioning as an ADT inhibitor opens the possibility of therapeutic alteration of the balance of conformational states, potentially modulating proton leak and ADP/ATP exchange. As proposed in the recent report, the mechanism of proton leak through ADT is dependent on electrostatic interactions of the positively charged substrate binding site with a fatty acid (FA) co-factor, and competes with nucleotide transport through ADT [65]. Likewise, one can hypothesize that proton leak is prevented possibly through charge repulsion via two positively charged residues (Arginine and Lysine) in SS-31 ( Fig.…”

Section: Atp Production and Transport (Cv Ck And Adt)mentioning

confidence: 85%

“…Importantly, ADT was recently identified to support two distinct and competing transport modes involving ADP/ATP exchange and proton leak and thus, ADT connects coupled and uncoupled energy conversion mechanisms in mitochondria, respectively [65]. Studies have shown that proton leak through ADT was elevated in aged mitochondria and impairment of ADT was believed to play a central mechanism causing aged-related mitochondria defects [66][67][68].…”

Section: Atp Production and Transport (Cv Ck And Adt)mentioning

confidence: 99%

“…Insets show detailed view of salt bridge interaction between D232 residue and Arg residue in bSS-31 and aromatic stacking between Y187 and dimethyl tyrosine in bSS-31. D) Proposed model of FA-dependent proton leak via ADT shown on top[65], SS-31 binding of ADT possibly prevents proton leak with its two positively charged residues (bottom). E) SS-31 treatment increases ADP stimulated respiration in mitochondria isolated from old mice.…”

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confidence: 99%

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Mitochondrial protein interaction landscape of SS-31

Chavez

Tang

Campbell

et al. 2019

Preprint

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Mitochondrial dysfunction underlies the etiology of a broad spectrum of diseases including heart disease, cancer, neurodegenerative diseases, and the general aging process. Therapeutics that restore healthy mitochondrial function hold promise for treatment of these conditions. The synthetic tetrapeptide, elamipretide (SS-31), improves mitochondrial function, but mechanistic details of its pharmacological effects are unknown. Reportedly, SS-31 primarily interacts with the phospholipid cardiolipin in the inner mitochondrial membrane. Here we utilize chemical cross-linking with mass spectrometry to identify protein interactors of SS-31 in mitochondria. The SS-31-interacting proteins, all known cardiolipin binders, fall into two groups, those involved in ATP production through the oxidative phosphorylation pathway and those involved in 2-oxoglutarate metabolic processes. Residues cross-linked with SS-31 reveal binding regions that in many cases, are proximal to cardiolipin-protein interacting regions. These results offer the first glimpse of the protein interaction landscape of SS-31 and provide new mechanistic insight relevant to SS-31 mitochondrial therapy. Significance StatementSS-31 is a synthetic peptide that improves mitochondrial function and is currently undergoing clinical trials for treatments of heart failure, primary mitochondrial myopathy, and other mitochondrial diseases. SS-31 interacts with cardiolipin which is abundant in the inner mitochondrial membrane, but mechanistic details of its pharmacological effects are unknown. Here we apply a novel chemical cross-linking/mass spectrometry method to provide the first direct evidence for specific interactions between SS-31 and mitochondrial proteins. The identified SS-31 interactors are functional components in ATP production and 2-oxoglutarate metabolism and signaling, consistent with improved mitochondrial function resultant from SS-31 treatment. These results offer the first glimpse of the protein interaction landscape of SS-31 and provide new mechanistic insight relevant to SS-31 mitochondrial therapy.

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Section: Atp Production and Transport (Cv Ck And Adt)mentioning

confidence: 85%

Section: Atp Production and Transport (Cv Ck And Adt)mentioning

confidence: 99%

mentioning

confidence: 99%

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Mitochondrial protein interaction landscape of SS-31

Chavez

Tang

Campbell

et al. 2019

Preprint

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“…This suggests a role for other mechanisms that may also mediate proton leak, independent of UCPs. Notably, recent observations suggest that mitochondrial ADP/ATP carriers, also activated by FA, may be responsible for FA‐induced increase in leak respiration.…”

Section: Pathophysiology Of Disturbances In Mitochondrial Metabolismmentioning

confidence: 99%

“…The debate regarding the capacity of UCPs to uncouple mitochondria in the heart and the extent to which UCP3 is involved in the prevention of ROS formation remains unsettled. However, the correlation between UCP3 levels and FAO in the heart under obese/diabetic conditions does support a role for UCP3 under conditions of perturbed cardiac energy balance .…”

Section: Pathophysiology Of Disturbances In Mitochondrial Metabolismmentioning

confidence: 99%

Altered mitochondrial metabolism in the insulin‐resistant heart

et al. 2019

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Obesity‐induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA‐induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.

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Human mitochondrial uncoupling protein 3 functions as a metabolite transporter

De Leonardis,

Ahmed,

Vozza

et al. 2023

FEBS Letters

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Since its discovery, a major debate about mitochondrial uncoupling protein 3 (UCP3) has been whether its metabolic actions result primarily from mitochondrial inner membrane proton transport, a process that decreases respiratory efficiency and ATP synthesis. However, UCP3 expression and activity are induced by conditions that would seem at odds with inefficient ‘uncoupled’ respiration, including fasting and exercise. Here, we demonstrate that the bacterially expressed human UCP3, reconstituted into liposomes, catalyses a strict exchange of aspartate, malate, sulphate and phosphate. The R282Q mutation abolishes the transport activity of the protein. Although the substrate specificity and inhibitor sensitivity of UCP3 display similarity with that of its close homolog UCP2, the two proteins significantly differ in their transport mode and kinetic constants.

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H+ transport is an integral function of the mitochondrial ADP/ATP carrier

Cited by 191 publications

References 52 publications

Mitochondrial protein interaction landscape of SS-31

Mitochondrial protein interaction landscape of SS-31

Altered mitochondrial metabolism in the insulin‐resistant heart

Human mitochondrial uncoupling protein 3 functions as a metabolite transporter

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