Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1α: Modulation by p38 MAPK

Melina Fan, James Rhee, Julie St-Pierre, Christoph Handschin, Pere Puigserver, Jiandie Lin, Sibylle Jäeger, Hediye Erdjument-Bromage, Paul Tempst, Bruce M. Spiegelman

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The transcriptional coactivator PPAR gamma coactivator 1 α (PGC-1α) is a key regulator of metabolic processes such as mitochondrial biogenesis and respiration in muscle and gluconeogenesis in liver. Reduced levels of PGC-1α in humans have been associated with type II diabetes. PGC-1α contains a negative regulatory domain that attenuates its transcriptional activity. This negative regulation is removed by phosphorylation of PGC-1α by p38 MAPK, an important kinase downstream of cytokine signaling in muscle and β-adrenergic signaling in brown fat. We describe here the identification of p160 myb binding protein (p160 MBP) as a repressor of PGC-1α. The binding and repression of PGC-1α by p160MBP is disrupted by p38 MAPK phosphorylation of PGC-1α. Adenoviral expression of p160MBP in myoblasts strongly reduces PGC-1α's ability to stimulate mitochondrial respiration and the expression of the genes of the electron transport system. This repression does not require removal of PGC-1α from chromatin, suggesting that p160 MBP is or recruits a direct transcriptional suppressor. Overall, these data indicate that p160MBP is a powerful negative regulator of PGC-1α function and provide a molecular mechanism for the activation of PGC-1α by p38 MAPK. The discovery of p160MBP as a PGC-1α regulator has important implications for the understanding of energy balance and diabetes.

    Original languageEnglish (US)
    Pages (from-to)278-289
    Number of pages12
    JournalGenes & development
    Volume18
    Issue number3
    DOIs
    StatePublished - Feb 1 2004

    Keywords

    • Mitochondria
    • Mybbp1a
    • p38 MAPK
    • PGC-1α
    • Repressor

    ASJC Scopus subject areas

    • Genetics
    • Developmental Biology

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