Diagenode

Defective mitochondrial morphology and bioenergetic function in mice lacking the transcription factor YY1 in skeletal muscle


Blättler SM, Verdeguer F, Liesa M, Cunningham T, Vogel RO, Chim H, Liu H, Romanino K, Shirihai OS, Vazquez F, Rüegg MA, Shi Y, Puigserver P

Formation, distribution and maintenance of functional mitochondria are achieved through dynamic processes that strictly depend on transcription of nuclear genes encoding for mitochondrial proteins. A large number of these mitochondrial genes contain binding sites for the transcription factor YY1 in their proximal promoters but the physiological relevance is unknown. We report here that skeletal muscle specific YY1 knockout mice (YY1mKO) have severe defective mitochondrial morphology and oxidative function associated with exercise intolerance, signs of mitochondrial myopathy and short stature. Gene Set Enrichment Analysis (GSEA) revealed that the top pathways downregulated in YY1mKO mice were assigned to key metabolic and regulatory mitochondrial genes. This analysis was consistent with a profound decrease in mitochondrial proteins and OXPHOS bioenergetic function in these mice. In contrast to wild type mice, mTOR inactivation did not suppress mitochondrial genes in YY1mKO mice. Mechanistically, mTOR-dependent phosphorylation of YY1 resulted in a strong interaction between YY1 and the transcriptional co-activator PGC1α, a major regulator of mitochondrial function. These results underscore the important role of YY1 in the maintenance of mitochondrial function and how its inactivation might contribute to exercise intolerance and mitochondrial myopathies.

Tags
Bioruptor
Chromatin Shearing
ChIP-qPCR

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Published
June, 2012

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