TY - JOUR
T1 - Advances in the Development of Mitochondrial Pyruvate Carrier Inhibitors for Therapeutic Applications
AU - Politte, Henry
AU - Maram, Lingaiah
AU - Elgendy, Bahaa
N1 - Publisher Copyright:
© 2025 by the authors.
PY - 2025/2
Y1 - 2025/2
N2 - The mitochondrial pyruvate carrier (MPC) is a transmembrane protein complex critical for cellular energy metabolism, enabling the transport of pyruvate from the cytosol into the mitochondria, where it fuels the citric acid cycle. By regulating this essential entry point of carbon into mitochondrial metabolism, MPC is pivotal for maintaining cellular energy balance and metabolic flexibility. Dysregulation of MPC activity has been implicated in several metabolic disorders, including type 2 diabetes, obesity, and cancer, underscoring its potential as a therapeutic target. This review provides an overview of the MPC complex, examining its structural components, regulatory mechanisms, and biological functions. We explore the current understanding of transcriptional, translational, and post-translational modifications that modulate MPC function and highlight the clinical relevance of MPC dysfunction in metabolic and neurodegenerative diseases. Progress in the development of MPC-targeting therapeutics is discussed, with a focus on challenges in designing selective and potent inhibitors. Emphasis is placed on modern approaches for identifying novel inhibitors, particularly virtual screening and computational strategies. This review establishes a foundation for further research into the medicinal chemistry of MPC inhibitors, promoting advances in structure-based drug design to develop therapeutics for metabolic and neurodegenerative diseases.
AB - The mitochondrial pyruvate carrier (MPC) is a transmembrane protein complex critical for cellular energy metabolism, enabling the transport of pyruvate from the cytosol into the mitochondria, where it fuels the citric acid cycle. By regulating this essential entry point of carbon into mitochondrial metabolism, MPC is pivotal for maintaining cellular energy balance and metabolic flexibility. Dysregulation of MPC activity has been implicated in several metabolic disorders, including type 2 diabetes, obesity, and cancer, underscoring its potential as a therapeutic target. This review provides an overview of the MPC complex, examining its structural components, regulatory mechanisms, and biological functions. We explore the current understanding of transcriptional, translational, and post-translational modifications that modulate MPC function and highlight the clinical relevance of MPC dysfunction in metabolic and neurodegenerative diseases. Progress in the development of MPC-targeting therapeutics is discussed, with a focus on challenges in designing selective and potent inhibitors. Emphasis is placed on modern approaches for identifying novel inhibitors, particularly virtual screening and computational strategies. This review establishes a foundation for further research into the medicinal chemistry of MPC inhibitors, promoting advances in structure-based drug design to develop therapeutics for metabolic and neurodegenerative diseases.
KW - MPC (mitochondrial pyruvate carrier)
KW - MPC inhibitors
KW - drug design
KW - energy metabolism
KW - medicinal chemistry
KW - metabolic disorders (e.g., diabetes, obesity, and cancer)
KW - neurodegenerative disorders
KW - pyruvate transport
KW - therapeutic target
KW - virtual screening
UR - http://www.scopus.com/inward/record.url?scp=85219177869&partnerID=8YFLogxK
U2 - 10.3390/biom15020223
DO - 10.3390/biom15020223
M3 - Review article
C2 - 40001526
AN - SCOPUS:85219177869
SN - 2218-273X
VL - 15
JO - Biomolecules
JF - Biomolecules
IS - 2
M1 - 223
ER -