Human mitochondrial carriers of the SLC25 family function as monomers exchanging substrates with a ping-pong kinetic mechanism

The EMBO Journal, Journal Year: 2024, Volume and Issue: 43(16), P. 3450 - 3465

Published: June 27, 2024

Language: Английский

---

Structure of mitochondrial pyruvate carrier and its inhibition mechanism

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Language: Английский

---

The mitochondrial pyruvate carrier at the crossroads of intermediary metabolism

AJP Endocrinology and Metabolism, Journal Year: 2022, Volume and Issue: 323(1), P. E33 - E52

Published: May 30, 2022

Pyruvate metabolism, a central nexus of carbon homeostasis, is an evolutionarily conserved process and aberrant pyruvate metabolism associated with contributes to numerous human metabolic disorders including diabetes, cancer, heart disease. As product glycolysis, primarily generated in the cytosol before being transported into mitochondrion for further metabolism. entry mitochondrial matrix critical step efficient generation reducing equivalents ATP biosynthesis glucose, fatty acids, amino acids from pyruvate. However, many years, identity carrier protein(s) that remained mystery. In 2012, molecular-genetic identification (MPC), heterodimeric complex composed protein subunits MPC1 MPC2, enabled studies shed light on physiological processes regulated by A better understanding mechanisms regulating transport affected may enable novel therapeutics modulate flux treat variety disorders. Herein, we review our current knowledge MPC, discuss recent advances various tissue cell types, address some outstanding questions relevant this field.

Language: Английский

---

Fifty years of the mitochondrial pyruvate carrier: New insights into its structure, function, and inhibition

Acta Physiologica, Journal Year: 2023, Volume and Issue: 238(4)

Published: June 27, 2023

Abstract The mitochondrial pyruvate carrier (MPC) resides in the inner membrane, where it links cytosolic and metabolism by transporting produced glycolysis into matrix. Due to its central metabolic role, has been proposed as a potential drug target for diabetes, non‐alcoholic fatty liver disease, neurodegeneration, cancers relying on metabolism. Little is known about structure mechanism of MPC, proteins involved were only identified decade ago technical difficulties concerning their purification stability have hindered progress functional structural analyses. unit MPC hetero‐dimer comprising two small homologous membrane proteins, MPC1/MPC2 humans, with alternative complex MPC1L/MPC2 forming testis, but are found throughout tree life. predicted topology each protomer consists an amphipathic helix followed three transmembrane helices. An increasing number inhibitors being identified, expanding pharmacology providing insights inhibitory mechanism. Here, we provide critical composition, structure, function summarize different classes molecule therapeutics.

Language: Английский

---

A mitochondrial carrier transports glycolytic intermediates to link cytosolic and mitochondrial glycolysis in the human gut parasite Blastocystis

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Jan. 5, 2024

Stramenopiles form a clade of diverse eukaryotic organisms, including multicellular algae, the fish and plant pathogenic oomycetes, such as potato blight Phytophthora, human intestinal protozoan Blastocystis. In most eukaryotes, glycolysis is strictly cytosolic metabolic pathway that converts glucose to pyruvate, resulting in production NADH ATP (Adenosine triphosphate). contrast, stramenopiles have branched which enzymes pay-off phase are located both cytosol mitochondrial matrix. Here, we identify carrier Blastocystis can transport glycolytic intermediates, dihydroxyacetone phosphate glyceraldehyde-3-phosphate, across inner membrane, linking branches glycolysis. Comparative analyses with phylogenetically related oxoglutarate (SLC25A11) dicarboxylate (SLC25A10) show intermediate has lost its ability canonical substrates malate oxoglutarate. lacks several key components oxidative phosphorylation required for generation ATP, complexes III IV, synthase, ADP/ATP carriers. The presence matrix generates powers energy-requiring processes, macromolecular synthesis, well NADH, used by complex I generate proton motive force drive import proteins molecules. Given unique substrate specificity central role carbon energy metabolism, intermediates identified here represents specific drug pesticide target against stramenopile pathogens, great economic importance.

Language: Английский

---

The Hepatic Mitochondrial Pyruvate Carrier as a Regulator of Systemic Metabolism and a Therapeutic Target for Treating Metabolic Disease

Biomolecules, Journal Year: 2023, Volume and Issue: 13(2), P. 261 - 261

Published: Jan. 31, 2023

Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product glycolysis in the cytosol, it must be transported into mitochondrial matrix for energy stored this nutrient to fully harnessed generate ATP or become building block new biomolecules. Given requirement import, is not surprising that pyruvate carrier (MPC) has emerged as target therapeutic intervention variety diseases characterized by altered and In review, we focus on role MPC related pathways liver regulating hepatic systemic metabolism summarize current state targeting pathway treat liver. Available evidence suggests inhibiting hepatocytes other cells produces beneficial effects treating type 2 diabetes nonalcoholic steatohepatitis. We also highlight areas where our understanding incomplete regarding pleiotropic inhibition.

Language: Английский

---

UK5099 Inhibits the NLRP3 Inflammasome Independently of its Long‐Established Target Mitochondrial Pyruvate Carrier

Advanced Science, Journal Year: 2024, Volume and Issue: 11(33)

Published: July 1, 2024

Targeting NLRP3 inflammasome has been recognized as a promising therapeutic strategy for the treatment of numerous common diseases. UK5099, long-established inhibitor mitochondrial pyruvate carrier (MPC), is previously found to inhibit macrophage inflammatory responses independent MPC expression. However, mechanisms by which UK5099 remain unclear. Here, it shown that potent in both mouse and human primary macrophages. selectively suppresses activation but not NLRC4 or AIM2 inflammasomes. Of note, retains activities on macrophages devoid expression, indicating this inhibitory effect MPC-independent. Mechanistically, abrogates mitochondria-NLRP3 interaction turn inhibits assembly inflammasome. Further, single dose persistently reduces IL-1β production an endotoxemia model. Importantly, structure modification reveals are unrelated existence activated double bond within molecule. Thus, study uncovers unknown molecular target only offers new candidate NLRP3-driven diseases also confounds its use immunometabolism studies.

Language: Английский

---

Advances in the Development of Mitochondrial Pyruvate Carrier Inhibitors for Therapeutic Applications

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 223 - 223

Published: Feb. 3, 2025

The mitochondrial pyruvate carrier (MPC) is a transmembrane protein complex critical for cellular energy metabolism, enabling the transport of from cytosol into mitochondria, where it fuels citric acid cycle. By regulating this essential entry point carbon MPC pivotal maintaining balance and metabolic flexibility. Dysregulation activity has been implicated in several disorders, including type 2 diabetes, obesity, cancer, underscoring its potential as therapeutic target. This review provides an overview complex, examining structural components, regulatory mechanisms, biological functions. We explore current understanding transcriptional, translational, post-translational modifications that modulate function highlight clinical relevance dysfunction neurodegenerative diseases. Progress development MPC-targeting therapeutics discussed, with focus on challenges designing selective potent inhibitors. Emphasis placed modern approaches identifying novel inhibitors, particularly virtual screening computational strategies. establishes foundation further research medicinal chemistry promoting advances structure-based drug design to develop

Language: Английский

---

Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier

Science Advances, Journal Year: 2025, Volume and Issue: 11(16)

Published: April 18, 2025

The mitochondrial pyruvate carrier transports pyruvate, produced by glycolysis from sugar molecules, into the matrix, as a crucial transport step in eukaryotic energy metabolism. is drug target for treatment of cancers, diabetes mellitus, neurodegeneration, and metabolic dysfunction–associated steatotic liver disease. We have solved structure human MPC1L/MPC2 heterodimer inward- outward-open states cryo–electron microscopy, revealing its alternating access rocker-switch mechanism. has central binding site which contains an essential lysine histidine residue, important ΔpH-dependent also determined poses three chemically distinct inhibitor classes, exploit same state mimicking interactions using aromatic stacking interactions.

Language: Английский

---

The mitochondrial pyruvate carrier complex potentiates the efficacy of proteasome inhibitors in multiple myeloma

Blood Advances, Journal Year: 2023, Volume and Issue: 7(14), P. 3485 - 3500

Published: March 15, 2023

Multiple myeloma (MM) is a hematological malignancy that emerges from antibody-producing plasma B cells. Proteasome inhibitors, including the US Food and Drug Administration-approved bortezomib (BTZ) carfilzomib (CFZ), are frequently used for treatment of patients with MM. Nevertheless, significant proportion MM refractory or develop resistance to this class which represents challenge in clinic. Thus, identifying factors determine potency proteasome inhibitors paramount importance bolster their efficacy Using genome-wide CRISPR-based screening, we identified subunit mitochondrial pyruvate carrier (MPC) complex, MPC1, as common modulator BTZ response 2 distinct human cell lines vitro. We noticed CRISPR-mediated deletion pharmacological inhibition MPC complex enhanced BTZ/CFZ-induced death minimal impact on cycle progression. In fact, targeting compromised bioenergetic capacity cells, accompanied by reduced proteasomal activity, thereby exacerbating BTZ-induced cytotoxicity Importantly, observed RNA expression levels several regulators metabolism were altered advanced stages they correlated poor patient prognosis. Collectively, study highlights survival cells responses inhibitors. These findings establish potential target an unappreciated strategy increase

Language: Английский

---