Rationale: Exercise capacity is a physiological characteristic associated with protection from both cardiovascular and all-cause mortality. p53 regulates mitochondrial function and its deletion markedly diminishes exercise capacity, but the underlying genetic mechanism orchestrating this is unclear. Understanding the biology of how p53 improves exercise capacity may provide useful insights for improving both cardiovascular as well as general health. Objective: The purpose of this study was to understand the genetic mechanism by which p53 regulates aerobic exercise capacity. Methods and Results: Using a variety of physiological, metabolic, and molecular techniques, we further characterized maximum exercise capacity and the effects of training, measured various nonmitochondrial and mitochondrial determinants of exercise capacity, and examined putative regulators of mitochondrial biogenesis.As p53 Key Words: aerobic Ⅲ exercise Ⅲ mitochondrial DNA Ⅲ p53 Ⅲ TFAM A cross populations aerobic exercise capacity inversely correlates with cardiovascular disease and all-cause mortality. 1-3 Our report of a marked reduction in the maximal exercise capacity of p53 homozygous knockout (p53 Ϫ/Ϫ ) mice and subsequent confirmation by others provided physiological evidence for p53 as an important mediator of aerobic metabolism. 4,5 We previously showed that p53 promotes mitochondrial respiration in human and murine cells by regulating the transcription of Synthesis of Cytochrome c Oxidase 2 (SCO2), a gene essential for oxidative phosphorylation. 4,6 A concurrent report demonstrating that p53 directly suppresses glycolysis through TIGAR, a p53-dependent regulator of glycolysis and apoptosis, suggested that p53 can coordinate aerobic and glycolytic metabolism. 7 Multiple factors contribute to aerobic exercise capacity, but one major determinant is the mitochondrial content of skeletal muscle as demonstrated by a genetic selection experiment. 8 A recent study showed decreased mitochondrial density in the skeletal muscle of p53-deficient mice, 5 but the genetic mechanism orchestrating this change has remained unclear. A number of other studies have also associated p53 with exercise response and mitochondrial function. For example, p53 levels are increased after acute exercise, and the transition from glycolysis to oxidative metabolism during development is dependent on p53. 9,10 p53 can transactivate ribonucleotide reductase p53R2 (RRM2B) which is important for maintaining mtDNA in skeletal muscle. 11 Additionally, 2 recent studies have shown asso-
Most insects have telomeres that consist of pentanucleotide (TTAGG) telomeric repeats, which are synthesized by telomerase. However, all species in Diptera so far examined and several species in other orders of insect have lost the (TTAGG)n repeats, suggesting that some of them recruit telomerase-independent telomere maintenance. The silkworm, Bombyx mori, retains the TTAGG motifs in the chromosomal ends but expresses quite a low level of telomerase activity in all stages of various tissues. Just proximal to a 6-8-kb stretch of the TTAGG repeats in B. mori, more than 1000 copies of non-LTR retrotransposons, designated TRAS and SART families, occur among the telomeric repeats and accumulate. TRAS and SART are abundantly transcribed and actively retrotransposed into TTAGG telomeric repeats in a highly sequence-specific manner. They have three possible mechanisms to ensure specific integration into the telomeric repeats. This article focuses on the telomere structure and telomere-specific non-LTR retrotransposons in B. mori and discusses the mechanisms for telomere maintenance in this insect.
Previous studies have shown that transforming growth factor b (TGF-b) promotes receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclastogenesis. However, the underlying molecular mechanisms have not been elucidated. When TGF-b signals were blocked either by a specific inhibitor of TGF-b type 1 receptor kinase activity, SB431542, or by introducing a dominant-negative mutant of TGF-b type 2 receptor, RANKL-induced osteoclastogenesis was almost completely suppressed. Blockade of Smad signaling by overexpression of Smad7 or c-Ski markedly suppressed RANKL-induced osteoclastogenesis, and retroviral induction of an activated mutant of Smad2 or Smad3 reversed the inhibitory effect of SB431542. Immunoprecipitation analysis revealed that Smad2/3 directly associates with the TRAF6-TAB1-TAK1 molecular complex, which is generated in response to RANKL stimulation and plays an essential role in osteoclast differentiation. TRAF6-TAB1-TAK1 complex formation was not observed when TGF-b signaling was blocked. Analysis using deletion mutants revealed that the MH2 domain of Smad3 is necessary for TRAF6-TAB1-TAK1 complex formation, downstream signal transduction, and osteoclast formation. In addition, gene silencing of Smad3 in osteoclast precursors markedly suppressed RANKLinduced osteoclast differentiation. In summary, TGF-b is indispensable in RANKL-induced osteoclastogenesis, and the binding of Smad3 to the TRAF6-TAB1-TAK1 complex is crucial for RANKL-induced osteoclastogenic signaling. ß
Cancer cells often display defects in mitochondrial respiration, thus the identification of pathways that promote cell survival under this metabolic state may have therapeutic implications. Here, we report that the targeted ablation of mitochondrial respiration markedly increases expression of Polo-like kinase 2 (PLK2) and that it is required for the in vitro growth of these nonrespiring cells. Furthermore, we identify PLK2 as a kinase that phosphorylates Ser-137 of PLK1, which is sufficient to mediate this survival signal. In vivo, knockdown of PLK2 in an isogenic human cell line with a modest defect in mitochondrial respiration eliminates xenograft formation, indicating that PLK2 activity is necessary for growth of cells with compromised respiration. Our findings delineate a mitochondrial dysfunction responsive cell cycle pathway critical for determining cancer cell outcome.cell cycle ͉ respiration ͉ sco2
There have been two distinct formalisms of thermodynamics of information: one is the measurementfeedback formalism, which concerns bipartite systems with measurement and feedback processes, and the other is the information reservoir formalism, which considers bit sequences as a thermodynamic fuel. In this paper, we derive a second-law-like inequality by applying the measurement-feedback formalism to information reservoirs, which provides a stronger bound of extractable work than any other known inequality in the same setup. In addition, we demonstrate that the Mandal-Jarzynski model, which is a prominent model of the information reservoir formalism, is equivalent to a model obtained by the contraction of a bipartite system with autonomous measurement and feedback. Our results provide a unified view on the measurement-feedback and the information-reservoir formalisms.
A sufficient statistic is a significant concept in statistics, which means a probability variable that has sufficient information required for an inference task. We investigate the roles of sufficient statistics and related quantities in stochastic thermodynamics. Specifically, we prove that for general continuous-time bipartite networks, the existence of a sufficient statistic implies that an informational quantity called the sensory capacity takes the maximum. Since the maximal sensory capacity imposes a constraint that the energetic efficiency cannot exceed one-half, our result implies that the existence of a sufficient statistic is inevitably accompanied by energetic dissipation. We also show that, in a particular parameter region of linear Langevin systems there exists the optimal noise intensity at which the sensory capacity, the information-thermodynamic efficiency, and the total entropy production are optimized at the same time. We apply our general result to a model of sensory adaptation of E. coli and find that the sensory capacity is nearly maximal with experimentally realistic parameters.
The anti-apoptotic molecule Bcl-2 inhibits apoptosis by preventing cytochrome c release from mitochondria. Although several studies have indicated the importance of Bcl-2 in maintaining skeletal integrity, the detailed cellular and molecular mechanisms remain elusive. Bcl-2 ؊/؊ mice are growth-retarded and exhibit increased bone volume of the primary spongiosa, mainly due to the decreased number and dysfunction of osteoclasts. Osteoblast function is also impaired in Bcl-2 ؊/؊ mice.Ex vivo studies on osteoblasts and osteoclasts showed that Bcl-2 promoted the differentiation, activation, and survival of both cell types. Because Bcl-2 ؊/؊ mice die before 6 weeks of age due to renal failure and cannot be compared with adult wild type mice, we generated Bcl-2 ؊/؊ Bim ؉/؊ mice, in which a single Bim allele was inactivated, and compared them with theirBcl-2 ؉/؊ Bim ؉/؊ littermates. Loss of a single Bim allele restored normal osteoclast function in Bcl-2 ؊/؊ mice but did not restore the impaired function of osteoblasts, and the mice exhibited osteopenia. These data demonstrate that Bcl-2 promotes the differentiation, activity, and survival of both osteoblasts and osteoclasts. The balance between Bcl-2 and Bim regulates osteoclast apoptosis and function, whereas other pro-apoptotic members are important for osteoblasts.
Most eukaryotic cellular mRNAs are monocistronic; however, many retroviruses and long terminal repeat (LTR) retrotransposons encode multiple proteins on a single RNA transcript using ribosomal frameshifting. Non-long terminal repeat (non-LTR) retrotransposons are considered the ancestor of LTR retrotransposons and retroviruses, but their translational mechanism of bicistronic RNA remains unknown. We used a baculovirus expression system to produce a large amount of the bicistronic RNA of SART1, a non-LTR retrotransposon of the silkworm, and were able to detect the second open reading frame protein (ORF2) by Western blotting. The ORF2 protein was translated as an independent protein, not as an ORF1-ORF2 fusion protein.We revealed by mutagenesis that the UAAUG overlapping stop-start codon and the downstream RNA secondary structure are necessary for efficient ORF2 translation. Increasing the distance between the ORF1 stop codon and the ORF2 start codon decreased translation efficiency. These results are different from the eukaryotic translation reinitiation mechanism represented by the yeast GCN4 gene, in which the probability of reinitiation increases as the distance between the two ORFs increases. The translational mechanism of SART1 ORF2 is analogous to translational coupling observed in prokaryotes and viruses. Our results indicate that translational coupling is a general mechanism for bicistronic RNA translation.In many retroviruses and retrotransposons, gag protein and pol protein are encoded in different open reading frames (ORFs) on a single RNA transcript (4, 14). They translate these two proteins as gag-pol polyproteins. Retroviruses, such as human immunodeficiency virus type 1 and human T-cell lymphotropic virus type 1, have a Ϫ1 translational frameshift signal, and Ty1, one of the yeast long terminal repeat (LTR) retrotransposons, has a ϩ1 frameshift signal to translate gagpol polyproteins (4, 14). The signal for retroviral Ϫ1 frameshifting in RNA is composed of two structures, a slippery sequence where the frameshifting takes place and the downstream stem-loop or pseudoknot structure (16). The general slippery sequence in retroviruses is the heptamer nucleotide sequence X XXY YYZ. The tRNA initially bound to XXY slips to bind to XXX at the P site, and the tRNA initially bound to YYZ slips to bind to YYY at the A site. The mechanism for ϩ1 frameshifting in Ty1 is entirely different from the retroviral Ϫ1 frameshifting. A codon for low available tRNA interrupts the translation elongation and induces the tRNA slippage (15).Non-LTR retrotransposons are considered the ancestor of LTR retrotransposons and retroviruses (25). Although more ancient classes of non-LTR retrotransposons have a single ORF, the recently branched non-LTR retrotransposons usually have two ORFs (24). The first ORF (ORF1) of the latter type of non-LTR retrotransposons encodes a gag-like protein and the second ORF (ORF2) a pol-like protein, which are similar to LTR retrotransposons and retroviruses. ORF2 encodes two essential catalytic do...
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