Nuclear Respiratory Factor 1 Controls Myocyte Enhancer Factor 2A Transcription to Provide a Mechanism for Coordinate Expression of Respiratory Chain Subunits

Diabetes Research Laboratory, Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2008; 283(18):11935-46. DOI: 10.1074/jbc.M707389200
Source: PubMed


Nuclear respiratory factors NRF1 and NRF2 regulate the expression of nuclear genes encoding heme biosynthetic enzymes, proteins
required for mitochondrial genome transcription and protein import, and numerous respiratory chain subunits. NRFs thereby
coordinate the expression of nuclear and mitochondrial genes relevant to mitochondrial biogenesis and respiration. Only two
of the nuclear-encoded respiratory chain subunits have evolutionarily conserved tissue-specific forms: the cytochrome c oxidase (COX) subunits VIa and VIIa heart/muscle (H) and ubiquitous (L) isoforms. We used genome comparisons to conclude
that the promoter regions of COX6AH and COX7AH lack NRF sites but have conserved myocyte enhancer factor 2 (MEF2) elements. We show that MEF2A mRNA is induced with forced expression of NRF1 and that the MEF2A 5′-regulatory region contains an evolutionarily conserved canonical element that binds endogenous NRF1 in chromatin immunoprecipitation
(ChIP) assays. NRF1 regulates MEF2A promoter-reporters according to overexpression, RNA interference underexpression, and promoter element mutation studies.
As there are four mammalian MEF2 isotypes, we used an isoform-specific antibody in ChIP to confirm MEF2A binding to the COX6AH promoter. These findings support a role for MEF2A as an intermediary in coordinating respiratory chain subunit expression in heart and muscle through a NRF1 → MEF2A → COXH transcriptional cascade. MEF2A also bound the MEF2A and PPARGC1A promoters in ChIP, placing it within a feedback loop with PGC1α in controlling NRF1 activity. Interruption of this cascade
and loop may account for striated muscle mitochondrial defects in mef2a null mice. Our findings also account for the previously described indirect regulation by NRF1 of other MEF2 targets in muscle
such as GLUT4.

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    • "ols cell metabolism , at least in part , through the regulation of Sirt1 expression . ERK5 activates the transcription factors of the MEF2 family , which bind to and activate the Sirt1 pro - moter in human leukemic cells . Interestingly , NRF1 induces MEF2 expression allowing regulation of mitochondrial genes that lack NRF1 or NRF2 binding sites ( Ramachandran et al . , 2008a ) . Thus , ERK5 activation can control expression of MEF2 proteins through the Sirt1 / PGC1␣ / NRF pathway , as suggested by our observation in Jurkat shERK5 cells , which express lower levels of MEF2 . ERK5 can also directly activate MEF transcriptional activity , which acti - vates its own promoter ( Ramachandran et al . , 2008b ) . T"
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