Cover Story Current Issue

Alterations in mitochondrial structure and function are commonly observed in adult-onset neurodegenerative diseases. In ALS, mitochondrial dysfunction impairs the efficiency of electron transport chain (ETC) activity and ATP production and leads to the accumulation of reactive oxygen and nitrogen species, abnormal handling of intracellular calcium and cytochrome C release and apoptosis. The extent to which these alterations in mitochondrial functionimpair cellular operations is unclear. Therapeutic intervention based on combating these mitochondrial abnormalities have displayed variable success in mouse models of ALS and humans, as reviewed in Vandoorne et al.

Sean-Patrick Riechers, Jelena Mojsilovic-Petrovic, Tayler B. Belton, Ram P. Chakrabarty, ... Robert G. Kalb

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Current Issue

Key features of inhibitor binding to the human mitochondrial pyruvate carrier hetero-dimer

Sotiria Tavoulari, Tom J.J. Schirris, Vasiliki Mavridou, Chancievan Thangaratnarajah, ... Edmund R.S. Kunji

Objective

The mitochondrial pyruvate carrier (MPC) has emerged as a promising drug target for metabolic disorders, including non-alcoholic steatohepatitis and diabetes, metabolically dependent cancers and neurodegenerative diseases. A range of structurally diverse small molecule inhibitors have been proposed, but the nature of their interaction with MPC is not understood, and the composition of the functional human MPC is still debated. The goal of this study was to characterise the human MPC protein in vitro, to understand the chemical features that determine binding of structurally diverse inhibitors and to develop novel higher affinity ones.

Methods

We recombinantly expressed and purified human MPC hetero-complexes and studied their composition, transport and inhibitor binding properties by establishing in vitro transport assays, high throughput thermostability shift assays and pharmacophoremodeling.

Results

We determined that the functional unit of human MPC is a hetero-dimer. We compared all different classes of MPC inhibitors to find that three closely arranged hydrogen bond acceptors followed by an aromatic ring are shared characteristics of all inhibitors and represent the minimal requirement for high potency. We also demonstrated that high affinity binding is not attributed to covalent bond formation with MPC cysteines, as previously proposed. Following the basic pharmacophore properties, we identified 14 new inhibitors of MPC, one outperforming compound UK5099 by tenfold. Two are the commonly prescribed drugs entacapone and nitrofurantoin, suggesting an off-target mechanism associated with their adverse effects.

Conclusions

This work defines the composition of human MPC and the essential MPC inhibitor characteristics. In combination with the functional assays we describe, this new understanding will accelerate the development of clinically relevant MPC modulators.

Key features of inhibitor binding to the human mitochondrial pyruvate carrier hetero-dimer

Sotiria Tavoulari, Tom J.J. Schirris, Vasiliki Mavridou, Chancievan Thangaratnarajah, ... Edmund R.S. Kunji

Objective

The mitochondrial pyruvate carrier (MPC) has emerged as a promising drug target for metabolic disorders, including non-alcoholic steatohepatitis and diabetes, metabolically dependent cancers and neurodegenerative diseases. A range of structurally diverse small molecule inhibitors have been proposed, but the nature of their interaction with MPC is not understood, and the composition of the functional human MPC is still debated. The goal of this study was to characterise the human MPC protein in vitro, to understand the chemical features that determine binding of structurally diverse inhibitors and to develop novel higher affinity ones.

Methods

We recombinantly expressed and purified human MPC hetero-complexes and studied their composition, transport and inhibitor binding properties by establishing in vitro transport assays, high throughput thermostability shift assays and pharmacophoremodeling.

Results

We determined that the functional unit of human MPC is a hetero-dimer. We compared all different classes of MPC inhibitors to find that three closely arranged hydrogen bond acceptors followed by an aromatic ring are shared characteristics of all inhibitors and represent the minimal requirement for high potency. We also demonstrated that high affinity binding is not attributed to covalent bond formation with MPC cysteines, as previously proposed. Following the basic pharmacophore properties, we identified 14 new inhibitors of MPC, one outperforming compound UK5099 by tenfold. Two are the commonly prescribed drugs entacapone and nitrofurantoin, suggesting an off-target mechanism associated with their adverse effects.

Conclusions

This work defines the composition of human MPC and the essential MPC inhibitor characteristics. In combination with the functional assays we describe, this new understanding will accelerate the development of clinically relevant MPC modulators.

2021 impact factor: 7.422

The 60 Second Metabolist

In this section authors briefly report on their work recently published in Molecular Metabolism.

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