MPC1 is essential for PGC-1α-induced mitochondrial respiration and biogenesis.
Biochem J
; 475(10): 1687-1699, 2018 05 18.
Article
en En
| MEDLINE
| ID: mdl-29669911
ABSTRACT
Mitochondrial pyruvate carrier (MPC), which is essential for mitochondrial pyruvate usage, mediates the transport of cytosolic pyruvate into mitochondria. Low MPC expression is associated with various cancers, and functionally associated with glycolytic metabolism and stemness. However, the mechanism by which MPC expression is regulated is largely unknown. In this study, we showed that MPC1 is down-regulated in human renal cell carcinoma (RCC) due to strong suppression of peroxisome proliferator-activated receptor-gamma co-activator (PGC)-1 alpha (PGC-1α). We also demonstrated that overexpression of PGC-1α stimulates MPC1 transcription, while depletion of PGC-1α by siRNA suppresses MPC expression. We found that PGC-1α interacts with estrogen-related receptor-alpha (ERR-α) and recruits it to the ERR-α response element motif located in the proximal MPC1 promoter, resulting in efficient activation of MPC1 expression. Furthermore, the MPC inhibitor, UK5099, blocked PGC-1α-induced pyruvate-dependent mitochondrial oxygen consumption. Taken together, our results suggest that MPC1 is a novel target gene of PGC-1α. In addition, low expression of PGC-1α in human RCC might contribute to the reduced expression of MPC, resulting in impaired mitochondrial respiratory capacity in RCC by limiting the transport of pyruvate into the mitochondrial matrix.
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Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Consumo de Oxígeno
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Carcinoma de Células Renales
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Regulación Neoplásica de la Expresión Génica
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Proteínas de Transporte de Membrana Mitocondrial
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Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma
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Mitocondrias
Límite:
Humans
Idioma:
En
Revista:
Biochem J
Año:
2018
Tipo del documento:
Article