Nuclear Respiratory Factor 1 Controls Myocyte Enhancer Factor 2A Transcription to Provide a Mechanism for Coordinate Expression of Respiratory Chain Subunits
ABSTRACT 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.
- SourceAvailable from: Martin Villalba
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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"
ABSTRACT: Cancer cell metabolism differs from that of non-transformed cells in the same tissue. This specific metabolism gives tumor cells growing advantages besides the effect in increasing anabolism. One of these advantages is immune evasion mediated by a lower expression of the mayor histocompatibility complex class I molecules. The extracellular-signal-regulated kinase-5 regulates both mayor histocompatibility complex class I expression and metabolic activity. However, the mechanisms underlying are largely unknown. We show here that extracellular-signal-regulated kinase-5 regulates the transcription of the NADH(+)-dependent histone deacetylase silent mating type information regulation 2 homolog 1 (Sirtuin 1) in leukemic Jurkat T cells. This involves the activation of the transcription factor myocyte enhancer factor-2 and its binding to the sirt1 promoter. In addition, extracellular-signal-regulated kinase-5 is required for T cell receptor-induced and oxidative stress-induced full Sirtuin 1 expression. Extracellular-signal-regulated kinase-5 induces the expression of promoters containing the antioxidant response elements through a Sirtuin 1-dependent pathway. On the other hand, down modulation of extracellular-signal-regulated kinase-5 expression impairs the anti-oxidant response. Notably, the extracellular-signal-regulated kinase-5 inhibitor BIX02189 induces apoptosis in acute myeloid leukemia tumor cells without affecting T cells from healthy donors. Our results unveil a new pathway that modulates metabolism in tumor cells. This pathway represents a promising therapeutic target in cancers with deep metabolic layouts such as acute myeloid leukemia.The International Journal of Biochemistry & Cell Biology 05/2014; 53. DOI:10.1016/j.biocel.2014.05.026 · 4.24 Impact Factor
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- "Downstream targets of PGC-1α, including the nuclear respiratory factors 1 and 2 (Nrf-1 and Nrf-2), also showed significant increases during hibernation (Fig. 2B) (Scarpulla, 2002; Wu et al., 1999). By activating Nrf-1, PGC-1α also coordinates the increase of the GLUT4 isoform of the glucose transporter, which allows rapid glucose uptake into the muscle cell (Baar et al., 2003; Ramachandran et al., 2008; Wende et al., 2007). "
ABSTRACT: Skeletal muscle atrophy is a very common clinical challenge in many disuse conditions. Maintenance of muscle mass is crucial to combat debilitating functional consequences evoked from these clinical conditions. In contrast, hibernation represents a physiological state in which there is natural protection against disuse atrophy despite prolonged periods of immobilization and lack of nutrient intake. Even though peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1-α (PGC-1α) is a central mediator in muscle remodeling pathways, its role in the preservation of skeletal muscle mass during hibernation remains unclear. Since PGC-1α regulates muscle fiber type formation and mitochondrial biogenesis, we analyzed muscles of 13-lined ground squirrels. We find that animals in torpor exhibit a shift to slow-twitch Type I muscle fibers. This switch is accompanied by activation of the PGC-1α-mediated endurance exercise pathway. In addition, we observe increased antioxidant capacity without evidence of oxidative stress, a marked decline in apoptotic susceptibility, and enhanced mitochondrial abundance and metabolism. These results show that activation of the endurance exercise pathway can be achieved in vivo despite prolonged periods of immobilization, and therefore might be an important mechanism for skeletal muscle preservation during hibernation. This PGC-1α regulated pathway may be a potential therapeutic target promoting skeletal muscle homeostasis and oxidative balance to prevent muscle loss in a variety of inherited and acquired neuromuscular disease conditions.Experimental Neurology 01/2013; 247. DOI:10.1016/j.expneurol.2013.01.005 · 4.62 Impact Factor
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- "NRF-1 regulates many nuclear-encoded genes required for the expression of the mitochondrial electron transport chain, mtDNA transcription and replication  , genes for heme biosynthesis   and for mitochondrial protein importation and assembly . NRF-1 regulates MEF2A expression in muscle, which controls muscle-specific cytochrome c oxidase subunits and other muscle-specific MEF2 target genes . NRF-1 is also transcriptionally regulated by Nrf2 and NRF-1 induction by Nrf2 is followed by the induction of Tfam and mitochondrial transcription . "
ABSTRACT: The cell renews, adapts, or expands its mitochondrial population during episodes of cell damage or periods of intensified energy demand by the induction of mitochondrial biogenesis. This bigenomic program is modulated by redox-sensitive signals that respond to physiological nitric oxide (NO), carbon monoxide (CO), and mitochondrial reactive oxygen species production. This review summarizes our current ideas about the pathways involved in the activation of mitochondrial biogenesis by the physiological gases leading to changes in the redox milieu of the cell, with an emphasis on the responses to oxidative stress and inflammation. The cell’s energy supply is protected from conditions that damage mitochondria by an inducible transcriptional program of mitochondrial biogenesis that operates in large part through redox signals involving the nitric oxide synthase and the heme oxygenase-1/CO systems. These redox events stimulate the coordinated activities of several multifunctional transcription factors and coactivators also involved in the elimination of defective mitochondria and the expression of counterinflammatory and antioxidant genes, such as IL10 and SOD2, as part of a unified damage-control network. The redox-regulated mechanisms of mitochondrial biogenesis schematically outlined in the graphical abstract link mitochondrial quality control to an enhanced capacity to support the cell’s metabolic needs while improving its resistance to metabolic failure and avoidance of cell death during periods of oxidative stress.Free Radical Biology and Medicine 12/2012; 53(11):2043–2053. DOI:10.1016/j.freeradbiomed.2012.09.014 · 5.71 Impact Factor