scholarly journals Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins

2016 ◽  
Vol 113 (12) ◽  
pp. E1673-E1682 ◽  
Author(s):  
Adi Neufeld-Cohen ◽  
Maria S. Robles ◽  
Rona Aviram ◽  
Gal Manella ◽  
Yaarit Adamovich ◽  
...  
Keyword(s):  
Mitochondrial Respiration ◽  
Energy Demand ◽  
Nutrient Utilization ◽  
Mitochondrial Enzymes ◽  
Mitochondrial Proteome ◽  
Clock Proteins ◽  
Circadian Control ◽  
Rate Limiting ◽  
Control Of Oscillations ◽  
Daily Changes

Mitochondria are major suppliers of cellular energy through nutrients oxidation. Little is known about the mechanisms that enable mitochondria to cope with changes in nutrient supply and energy demand that naturally occur throughout the day. To address this question, we applied MS-based quantitative proteomics on isolated mitochondria from mice killed throughout the day and identified extensive oscillations in the mitochondrial proteome. Remarkably, the majority of cycling mitochondrial proteins peaked during the early light phase. We found that rate-limiting mitochondrial enzymes that process lipids and carbohydrates accumulate in a diurnal manner and are dependent on the clock proteins PER1/2. In this conjuncture, we uncovered daily oscillations in mitochondrial respiration that peak during different times of the day in response to different nutrients. Notably, the diurnal regulation of mitochondrial respiration was blunted in mice lacking PER1/2 or on a high-fat diet. We propose that PERIOD proteins optimize mitochondrial metabolism to daily changes in energy supply/demand and thereby, serve as a rheostat for mitochondrial nutrient utilization.

scholarly journals Bioenergetic and autophagic control by Sirt3 in response to nutrient deprivation in mouse embryonic fibroblasts

2013 ◽  
Vol 454 (2) ◽  
pp. 249-257 ◽  
Author(s):  
Qiuli Liang ◽  
Gloria A. Benavides ◽  
Athanassios Vassilopoulos ◽  
David Gius ◽  
Victor Darley-Usmar ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Mitochondrial Respiration ◽  
Energy Demand ◽  
Mammalian Target Of Rapamycin ◽  
Protective Role ◽  
Nutrient Deprivation ◽  
Autophagy Flux ◽  
Jnk Pathway ◽  
Mouse Muscle

Sirt3 (sirtuin 3) is an NAD-dependent deacetylase localized to mitochondria. Sirt3 expression is increased in mouse muscle and liver by starvation, which could protect against the starvation-dependent increase in oxidative stress and protein damage. Damaged proteins and organelles depend on autophagy for removal and this is critical for cell survival, but the role of Sirt3 is unclear. To examine this, we used Sirt3-KO (knockout) mouse embryonic fibroblast cells, and found that, under basal conditions, Sirt3-KO cells exhibited increased autophagy flux compared with WT (wild-type) cells. In response to nutrient deprivation, both WT and KO cells exhibited increased basal and ATP-linked mitochondrial respiration, indicating an increased energy demand. Both cells exhibited lower levels of phosphorylated mTOR (mammalian target of rapamycin) and higher autophagy flux, with KO cells exhibiting lower maximal mitochondrial respiration and reserve capacity, and higher levels of autophagy than WT cells. KO cells exhibit higher phospho-JNK (c-Jun N-terminal kinase) and phospho-c-Jun than WT cells under starvation conditions. However, inhibition of JNK activity in Sirt3-KO cells did not affect LC3-I (light chain 3-I) and LC3-II levels, indicating that Sirt3-regulated autophagy is independent of the JNK pathway. Caspase 3 activation and cell death are significantly higher in Sirt3-KO cells compared with WT cells in response to nutrient deprivation. Inhibition of autophagy by chloroquine exacerbated cell death in both WT and Sirt3-KO cells, and by 3-methyadenine exacerbated cell death in Sirt3-KO cells. These data suggest that nutrient deprivation-induced autophagy plays a protective role in cell survival, and Sirt3 decreases the requirement for enhanced autophagy and improves cellular bioenergetics.

Effect of varied extracellular P O 2 on muscle performance inXenopus single skeletal muscle fibers

1999 ◽  
Vol 86 (6) ◽  
pp. 1812-1816 ◽  
Author(s):  
Creed M. Stary ◽  
Michael C. Hogan
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Respiration ◽  
Muscle Fibers ◽  
Muscle Performance ◽  
Tetanic Force ◽  
Skeletal Muscle Fibers ◽  
Rate Limiting ◽  
Single Living ◽  
Initial Peak ◽  
Text Condition

The purpose of this study was to examine the development of fatigue in isolated, single skeletal muscle fibers when O2 availability was reduced but not to levels considered rate limiting to mitochondrial respiration. Tetanic force was measured in single living muscle fibers ( n = 6) from Xenopus laevis while being stimulated at increasing contraction rates (0.25, 0.33, 0.5, and 1 Hz) in a sequential manner, with each stimulation frequency lasting 2 min. Muscle fatigue (determined as 75% of initial maximum force) was measured during three separate work bouts (with 45 min of rest between) as the perfusate [Formula: see text] was switched between values of 30 ± 1.9, 76 ± 3.0, or 159 Torr in a blocked-order design. No significant differences were found in the initial peak tensions between the high-, intermediate-, and low-[Formula: see text] treatments (323 ± 22, 298 ± 27, and 331 ± 24 kPa, respectively). The time to fatigue was reached significantly sooner ( P < 0.05) during the 30-Torr treatment (233 ± 39 s) compared with the 76- (385 ± 62 s) or 159-Torr (416 ± 65 s) treatments. The calculated critical extracellular [Formula: see text]necessary to develop an anoxic core within these fibers was 13 ± 1 Torr, indicating that the extracellular[Formula: see text] of 30 Torr should not have been rate limiting to mitochondrial respiration. The magnitude of an unstirred layer (243 ± 64 μm) or an intracellular O2 diffusion coefficient (0.45 ± 0.04 × 10−5cm2/s) necessary to develop an anoxic core under the conditions of the study was unlikely. The earlier initiation of fatigue during the lowest extracellular[Formula: see text] condition, at physiologically high intracellular [Formula: see text] levels, suggests that muscle performance may be O2 dependent even when mitochondrial respiration is not necessarily compromised.

scholarly journals Changes in the mitochondrial phosphoproteome during mammalian hibernation

2013 ◽  
Vol 45 (10) ◽  
pp. 389-399 ◽  
Author(s):  
Dillon J. Chung ◽  
Beata Szyszka ◽  
Jason C. L. Brown ◽  
Norman P. A. Hüner ◽  
James F. Staples
Keyword(s):  
Protein Phosphorylation ◽  
Mitochondrial Respiration ◽  
Core Body Temperature ◽  
Mitochondrial Protein ◽  
Time Of Flight ◽  
Ground Squirrels ◽  
Mitochondrial Metabolism ◽  
Mitochondrial Enzymes ◽  
Phosphorylation State ◽  
Mammalian Hibernation

Mammalian hibernation involves periods of substantial suppression of metabolic rate (torpor) allowing energy conservation during winter. In thirteen-lined ground squirrels ( Ictidomys tridecemlineatus ), suppression of liver mitochondrial respiration during entrance into torpor occurs rapidly (within 2 h) before core body temperature falls below 30°C, whereas reversal of this suppression occurs slowly during arousal from torpor. We hypothesized that this pattern of rapid suppression in entrance and slow reversal during arousal was related to changes in the phosphorylation state of mitochondrial enzymes during torpor catalyzed by temperature-dependent kinases and phosphatases. We compared mitochondrial protein phosphorylation among hibernation metabolic states using immunoblot analyses and assessed how phosphorylation related to mitochondrial respiration rates. No proteins showed torpor-specific changes in phosphorylation, nor did phosphorylation state correlate with mitochondrial respiration. However, several proteins showed seasonal (summer vs. winter) differences in phosphorylation of threonine or serine residues. Using matrix-assisted laser desorption/ionization-time of flight/time of flight mass spectrometry, we identified three of these proteins: F1-ATPase α-chain, long chain-specific acyl-CoA dehydrogenase, and ornithine transcarbamylase. Therefore, we conclude that protein phosphorylation is likely a mechanism involved in bringing about seasonal changes in mitochondrial metabolism in hibernating ground squirrels, but it seems unlikely to play any role in acute suppression of mitochondrial metabolism during torpor.

Induction of delta-aminolevulinic acid synthetase in muscle by exercise or thyroxine

1979 ◽  
Vol 236 (3) ◽  
pp. R180-R183 ◽  
Author(s):  
J. O. Holloszy ◽  
W. W. Winder
Keyword(s):  
Thyroid Hormones ◽  
Aminolevulinic Acid ◽  
Treadmill Running ◽  
Synthetase Activity ◽  
Mitochondrial Enzymes ◽  
Vigorous Exercise ◽  
Ala Synthetase ◽  
Rate Limiting ◽  
Rate Controlling Step ◽  
Mitochondrial Cytochromes

There is evidence that delta-aminolevulinic acid (ALA) synthetase is the rate-limiting enzyme in heme biosynthesis. Accumulation of the apoproteins of the mitochondrial cytochromes appears to be regulated by availability of heme. Exercise and thyrotoxicosis bring about increases in the cytochromes, and in other mitochondrial enzymes, in muscle. In this context, we have examined the effects of exercise and of thyroid hormones on ALA synthetase activity in skeletal muscle. Treadmill running and injection of thyroid hormones both resulted in significant increases in muscle ALA synthetase activity. A rise in ALA synthetase activity was evident within 17 h after a bout of vigorous exercise and 14 h after a single injection of thyroid hormones. The increase in ALA synthetase preceded the increase in cytochrome c, which was used as a mitochondrial marker. These results are compatible with the hypothesis that a relationship exists between heme synthesis and mitochondrial growth in which the rate-controlling step is ALA synthetase activity.

scholarly journals Circadian Control of Kisspeptin and a Gated GnRH Response Mediate the Preovulatory Luteinizing Hormone Surge

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 595-606 ◽  
Author(s):  
Wilbur P. Williams ◽  
Stephan G. Jarjisian ◽  
Jens D. Mikkelsen ◽  
Lance J. Kriegsfeld
Keyword(s):  
Neural Circuit ◽  
Time Of Day ◽  
Circadian System ◽  
Cellular Activity ◽  
Lh Surge ◽  
Gating Mechanism ◽  
Circadian Control ◽  
Maximal Sensitivity ◽  
Luteinizing Hormone Surge ◽  
Daily Changes

Abstract In spontaneously ovulating rodents, the preovulatory LH surge is initiated on the day of proestrus by a timed, stimulatory signal originating from the circadian clock in the suprachiasmatic nucleus (SCN). The present studies explored whether kisspeptin is part of the essential neural circuit linking the SCN to the GnRH system to stimulate ovulation in Syrian hamsters (Mesocricetus auratus). Kisspeptin neurons exhibit an estrogen-dependent, daily pattern of cellular activity consistent with a role in the circadian control of the LH surge. The SCN targets kisspeptin neurons via vasopressinergic (AVP), but not vasoactive intestinal polypeptide-ergic, projections. Because AVP administration can only stimulate the LH surge during a restricted time of day, we examined the possibility that the response to AVP is gated at the level of kisspeptin and/or GnRH neurons. Kisspeptin and GnRH activation were assessed after the administration of AVP during the morning (when AVP is incapable of initiating the LH surge) and the afternoon (when AVP injections stimulate the LH surge). Kisspeptin, but not GnRH, cellular activity was up-regulated after morning injections of AVP, suggesting that time-dependent sensitivity to SCN signaling is gated within GnRH but not kisspeptin neurons. In support of this possibility, we found that the GnRH system exhibits pronounced daily changes in sensitivity to kisspeptin stimulation, with maximal sensitivity in the afternoon. Together these studies reveal a novel mechanism of ovulatory control with interactions among the circadian system, kisspeptin signaling, and a GnRH gating mechanism of control.

scholarly journals Identification of Light-Sensitive Phosphorylation Sites on PERIOD That Regulate the Pace of Circadian Rhythms in Drosophila

2015 ◽  
Vol 36 (6) ◽  
pp. 855-870 ◽  
Author(s):  
Evrim Yildirim ◽  
Joanna C. Chiu ◽  
Isaac Edery
Keyword(s):  
Nuclear Accumulation ◽  
Phosphorylation Sites ◽  
Nuclear Entry ◽  
Content Type ◽  
Behavioral Rhythms ◽  
Clock Proteins ◽  
Clock Component ◽  
Localization Signal ◽  
Main Components ◽  
Daily Changes

The main components regulating the pace of circadian (≅24 h) clocks in animals are PERIOD (PER) proteins, transcriptional regulators that undergo daily changes in levels and nuclear accumulation by means of complex multisite phosphorylation programs. In the present study, we investigated the function of two phosphorylation sites, at Ser826 and Ser828, located in a putative nuclear localization signal (NLS) on theDrosophila melanogasterPER protein. These sites are phosphorylated by DOUBLETIME (DBT;Drosophilahomolog of CK1δ/ε), the key circadian kinase regulating the daily changes in PER stability and phosphorylation. Mutant flies in which phosphorylation at Ser826/Ser828 is blocked manifest behavioral rhythms with periods slightly longer than 1 h and with altered temperature compensation properties. Intriguingly, although phosphorylation at these sites does not influence PER stability, timing of nuclear entry, or transcriptional autoinhibition, the phospho-occupancy at Ser826/Ser828 is rapidly stimulated by light and blocked by TIMELESS (TIM), the major photosensitive clock component inDrosophilaand a crucial binding partner of PER. Our findings identify the first phosphorylation sites on core clock proteins that are acutely regulated by photic cues and suggest that some phosphosites on PER proteins can modulate the pace of downstream behavioral rhythms without altering central aspects of the clock mechanism.

Effect of Chromium Chelavite supplementation on the metabolism of glycogen and lipid in adult Merino sheep

1998 ◽  
Vol 49 (1) ◽  
pp. 137 ◽  
Author(s):  
G. E. Gardner ◽  
G. Smith ◽  
D. W. Pethick
Keyword(s):  
Muscle Glycogen ◽  
Energy Demand ◽  
Subcutaneous Fat ◽  
Whole Body ◽  
Regular Exercise ◽  
Muscle Tissues ◽  
Citrate Lyase ◽  
Acid Chelate ◽  
Rate Limiting ◽  
Muscle Glycogen Concentration

This experiment investigated the effect of exercise and chromium supplementation on muscle glycogen and subcutaneous fat metabolism. The design of the experiment was a 2×2 factorial with chromium and regular exercise as the treatments. Forty-three Merino wethers (2 years old) were maintained for 10 weeks on a diet based on barley and lupin grain fed at 2·2 times maintenance. The ration was supplemented with 0 or 1 mg/kg DM of chromium, as Chromium Chelavite amino acid chelate. For regular exercise the animals were worked at approximately 60% maximum whole body oxygen consumption for 2 h, 3 times per week, which increased the estimated weekly energy demand by about 9%. Chromium increased the activity ofATP citrate lyase, a marker of the glucose-insulin axis, by 30%, but decreased the fat depth GR, the fat depth over the 12th rib, by 20%. There was no effect on the activity of acetyl CoA carboxylase, the major rate-limiting enzyme of lipogenesis. Thus the potential for glucose contribution to fat synthesis increased but the subcutaneous fat depth decreased, indicating that chromium may cause the redistribution of fat within the carcass due to changes in insulin sensitivity. The chromium treatment did not effect growth rate, carcass weight, or muscle glycogen concentration. Chromium supplementation tended to prevent a decline in the concentration of chromium in the kidney, caused by exercise. The level of exercise was only sufficient to cause a glycogen loading response in one of the muscle tissues sampled, the m. semimembranosis. Chromium Chelavite supplementation may be a useful tool for reducing the subcutaneous fat depth of mature ruminants, and may promote the redistribution of fat to other locations within the carcass.

Study on the effect of fengycin on the respiration and metabolic mechanism of Penicillium expansum

2021 ◽  
Vol 11 (12) ◽  
pp. 2047-2051
Author(s):  
Ruimin Fu ◽  
Hong Zhang ◽  
Wei Tang ◽  
Xue Yang ◽  
Ding Wang ◽  
...  
Keyword(s):  
Total Protein ◽  
Colorimetric Method ◽  
Nutrient Utilization ◽  
Total Sugar ◽  
Penicillium Expansum ◽  
Mitochondrial Enzymes ◽  
Respiratory Metabolism ◽  
Mitochondrial Complex ◽  
Enzyme Activity Assay ◽  
Biuret Method

This study investigate the inhibiting effect of fengycin on respiration and nutrient utilization of Penicillium expansum. The respiratory inhibition rate of the P. expansum was determined by the test of dissolved oxygen fengycin, The effect of fengycin treatment on the activity of P. expansum mitochondrial complex enzyme was detected by mitochondrial enzyme activity assay. The ability of fengycin treatment to P. expansum the utilization of total sugar and total protein was determined by DNS colorimetric method and biuret method. After fengycin treatments, the TCA pathway of respiratory metabolism in P. expansum was inhibited. Besides, fengycin could block the gene expression in P. expansum by binding P. expansum mitochondrial complex enzyme II and III related genes. Therefore, the activity of mitochondrial enzymes was affected. With the increasement of fengycin concentration, the absorption and utilization capacity of P. expansum to total sugar and total protein decreased significantly. Fengycin could inhibit the respiratory metabolism and reduce the biochemical metabolism level in P. expansum and finally caused the growth inhibition.

Skeletal muscle respiratory capacity is enhanced in rats consuming an obesogenic Western diet

2012 ◽  
Vol 302 (12) ◽  
pp. E1541-E1549 ◽  
Author(s):  
Erin J. Stephenson ◽  
Donny M. Camera ◽  
Trisha A. Jenkins ◽  
Sepideh Kosari ◽  
Jong Sam Lee ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Energy Demand ◽  
Citrate Synthase ◽  
Blood Glucose Concentration ◽  
Control Diet ◽  
Fasting Blood Glucose ◽  
Western Diet ◽  
Mitochondrial Enzymes ◽  
Serum Triglycerides ◽  
Respiratory Capacity

Obesity-induced lipid oversupply promotes skeletal muscle mitochondrial biogenesis. Previous investigations have utilized extreme high-fat diets (HFD) to induce such mitochondrial perturbations despite their disparity from human obesogenic diets. Here, we evaluate the effects of Western diet (WD)-induced obesity on skeletal muscle mitochondrial function. Long-Evans rats were given ad libitum access to either a WD [40% energy (E) from fat, 17% protein, and 43% carbohydrate (30% sucrose); n = 12] or a control diet (CON; 16% of E from fat, 21% protein, and 63% carbohydrate; n = 12) for 12 wk. Rats fed the WD consumed 23% more E than CON ( P = 0.0001), which was associated with greater increases in body mass (23%, P = 0.0002) and adiposity (17%, P = 0.03). There were no differences in fasting blood glucose concentration or glucose tolerance between diets, although fasting insulin was increased by 40% ( P = 0.007). Fasting serum triglycerides were also elevated in WD (86%, P = 0.001). The maximal capacity of the electron transfer system was greater following WD (37%, P = 0.02), as were the maximal activities of several mitochondrial enzymes (citrate synthase, β-hydroxyacyl-CoA dehydrogenase, carnitine palmitoyltransferase). Protein expression of citrate synthase, UCP3, and individual respiratory complexes was greater after WD ( P < 0.05) despite no differences in the expression of peroxisome proliferator-activated receptor (PPAR)α, PPARδ, or PPARγ coactivator-1 mRNA or protein abundance. We conclude that the respiratory capacity of skeletal muscle is enhanced in response to the excess energy supplied by a WD. This is likely due to an increase in mitochondrial density, which at least in the short term, and in the absence of increased energy demand, may protect the tissue from lipid-induced impairments in glycemic control.

scholarly journals FRQ-CK1 interaction determines the period of circadian rhythms in Neurospora

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Xiao Liu ◽  
Ahai Chen ◽  
Angélica Caicedo-Casso ◽  
Guofei Cui ◽  
Mingjian Du ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Stable Complex ◽  
Circadian Period ◽  
Feedback Process ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Clock Proteins ◽  
Rate Limiting

Abstract Circadian clock mechanisms have been extensively investigated but the main rate-limiting step that determines circadian period remains unclear. Formation of a stable complex between clock proteins and CK1 is a conserved feature in eukaryotic circadian mechanisms. Here we show that the FRQ-CK1 interaction, but not FRQ stability, correlates with circadian period in Neurospora circadian clock mutants. Mutations that specifically affect the FRQ-CK1 interaction lead to severe alterations in circadian period. The FRQ-CK1 interaction has two roles in the circadian negative feedback loop. First, it determines the FRQ phosphorylation profile, which regulates FRQ stability and also feeds back to either promote or reduce the interaction itself. Second, it determines the efficiency of circadian negative feedback process by mediating FRQ-dependent WC phosphorylation. Our conclusions are further supported by mathematical modeling and in silico experiments. Together, these results suggest that the FRQ-CK1 interaction is a major rate-limiting step in circadian period determination.

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