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Unravelling the mechanisms controlling heme supply and demand.

ABSTRACT: In addition to heme's role as the prosthetic group buried inside many different proteins that are ubiquitous in biology, there is new evidence that heme has substantive roles in cellular signaling and regulation. This means that heme must be available in locations distant from its place of synthesis (mitochondria) in response to transient cellular demands. A longstanding question has been to establish the mechanisms that control the supply and demand for cellular heme. By fusing a monomeric heme-binding peroxidase (ascorbate peroxidase, mAPX) to a monomeric form of green-fluorescent protein (mEGFP), we have developed a heme sensor (mAPXmEGFP) that can respond to heme availability. By means of fluorescence lifetime imaging, this heme sensor can be used to quantify heme concentrations; values of the mean fluorescence lifetime (τ_Mean) for mAPX-mEGFP are shown to be responsive to changes in free (unbound) heme concentration in cells. The results demonstrate that concentrations are typically limited to one molecule or less within cellular compartments. These miniscule amounts of free heme are consistent with a system that sequesters the heme and is able to buffer changes in heme availability while retaining the capability to mobilize heme when and where it is needed. We propose that this exchangeable supply of heme can operate using mechanisms for heme transfer that are analogous to classical ligand-exchange mechanisms. This exquisite control, in which heme is made available for transfer one molecule at a time, protects the cell against the toxic effect of excess heme and offers a simple mechanism for heme-dependent regulation in single-molecule steps.

SUBMITTER: Leung GC

PROVIDER: S-EPMC8179208 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In advanced age, the resting myocardial oxygen consumption rate (MVO2) and cardiac work (CW) in the rat remain intact. However, MVO2, CW and cardiac efficiency achieved at high demand are decreased with age, compared to maximal values in the young. Whether this deterioration is due to decrease in myocardial ATP demand, ATP supply, or the control mechanisms that match them remains controversial. Here we discuss evolving perspectives of age-related changes of myocardial ATP supply and demand mechanisms, and critique experimental models used to investigate aging. Specifically, we evaluate experimental data collected at the level of isolated mitochondria, tissue, or organism, and discuss how mitochondrial energetic mechanisms change in advanced age, both at basal and high energy-demand levels.

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Characterising Wildlife Trade Market Supply-Demand Dynamics.

Project description:The trade in wildlife products can represent an important source of income for poor people, but also threaten wildlife locally, regionally and internationally. Bushmeat provides livelihoods for hunters, traders and sellers, protein to rural and urban consumers, and has depleted the populations of many tropical forest species. Management interventions can be targeted towards the consumers or suppliers of wildlife products. There has been a general assumption in the bushmeat literature that the urban trade is driven by consumer demand with hunters simply fulfilling this demand. Using the urban bushmeat trade in the city of Kumasi, Ghana, as a case study, we use a range of datasets to explore the processes driving the urban bushmeat trade. We characterise the nature of supply and demand by explicitly considering three market attributes: resource condition, hunter behaviour, and consumer behaviour. Our results suggest that bushmeat resources around Kumasi are becoming increasingly depleted and are unable to meet demand, that hunters move in and out of the trade independently of price signals generated by the market, and that, for the Kumasi bushmeat system, consumption levels are driven not by consumer choice but by shortfalls in supply and consequent price responses. Together, these results indicate that supply-side processes dominate the urban bushmeat trade in Kumasi. This suggests that future management interventions should focus on changing hunter behaviour, although complementary interventions targeting consumer demand are also likely to be necessary in the long term. Our approach represents a structured and repeatable method to assessing market dynamics in information-poor systems. The findings serve as a caution against assuming that wildlife markets are demand driven, and highlight the value of characterising market dynamics to inform appropriate management.

| S-EPMC5024990 | biostudies-literature

Sickle cell microvascular paradox-oxygen supply-demand mismatch.

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LARP1 senses free ribosomes to coordinate supply and demand of ribosomal proteins

Project description:Terminal oligopyrimidine motif-containing (TOP) mRNAs encode all ribosomal proteins in mammals and are regulated to tune ribosome synthesis to cell state. Previous studies implicate LARP1 in 40S- or 80S-ribosome complexes that repress and stabilize TOP mRNAs. However, a mechanistic understanding of how LARP1 and TOP mRNAs interact with ribosomes to coordinate TOP mRNA outcomes is lacking. Here, we show that LARP1 senses the cellular supply of ribosomes by directly binding non-translating 80S ribosomes. Cryo-EM structures reveal a previously uncharacterized domain of LARP1 bound to and occluding the 40S mRNA channel and mutations at the LARP1-ribosome interface block formation of the 40S/80S-LARP1-TOP complexes. Free cytosolic ribosomes induce sequestration of TOP mRNAs in repressed 80S-LARP1-TOP complexes independent of alterations in mTOR signaling. Together, this work demonstrates a ribosome-sensing function of LARP1 that allows it to tune ribosome protein synthesis to the availability of free ribosomes.

2023-10-28 | GSE246077 | GEO

The dynamics of supply and demand in mRNA translation.

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Microbial substrate preference dictated by energy demand, not supply.

Project description:Growth substrates that maximize energy yield are widely thought to be utilized preferentially by microorganisms. However, observed distributions of microorganisms and their activities often deviate from predictions based solely on thermodynamic considerations of substrate energy supply. Here we present observations of the bioenergetics and growth yields of a metabolically flexible, thermophilic strain of the archaeon Acidianus when grown autotrophically on minimal medium with hydrogen (H2) or elemental sulfur (S°) as an electron donor, and S° or ferric iron (Fe3+) as an electron acceptor. Thermodynamic calculations indicate that S°/Fe3+ and H2/Fe3+ yield three- and four-fold more energy per mol electron transferred, respectively, than the H2/S° couple. However, biomass yields in Acidianus cultures provided with H2/S° were eight-fold greater than when provided S°/Fe3+ or H2/Fe3+, indicating the H2/S° redox couple is preferred. Indeed, cells provided with all three growth substrates (H2, Fe3+, and S°) grew preferentially by reduction of S° with H2. We conclude that substrate preference is dictated by differences in the energy demand of electron transfer reactions in Acidianus when grown with different substrates, rather than substrate energy supply.

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Measuring labor supply and demand shocks during COVID-19.

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Measuring Labor Supply and Demand Shocks during COVID-19.

Project description: Not available

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Unravelling and controlling hidden imprint fields in ferroelectric capacitors.

Project description:Ferroelectric materials have a spontaneous polarization that can point along energetically equivalent, opposite directions. However, when ferroelectric layers are sandwiched between different metallic electrodes, asymmetric electrostatic boundary conditions may induce the appearance of an electric field (imprint field, Eimp) that breaks the degeneracy of the polarization directions, favouring one of them. This has dramatic consequences on functionality of ferroelectric-based devices such as ferroelectric memories or photodetectors. Therefore, to cancel out the Eimp, ferroelectric components are commonly built using symmetric contact configuration. Indeed, in this symmetric contact configuration, when measurements are done under time-varying electric fields of relatively low frequency, an archetypical symmetric single-step switching process is observed, indicating Eimp???0. However, we report here on the discovery that when measurements are performed at high frequency, a well-defined double-step switching is observed, indicating the presence of Eimp. We argue that this frequency dependence originates from short-living head-to-head or tail-to-tail ferroelectric capacitors in the device. We demonstrate that we can modulate Eimp and the life-time of head-to-head or tail-to-tail polarization configurations by adjusting the polarization screening charges by suitable illumination. These findings are of relevance to understand the effects of internal electric fields on pivotal ferroelectric properties, such as memory retention and photoresponse.

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Unravelling the functional development of vertebrate pathways controlling gaze.

Project description:Animals constantly redirect their gaze away or towards relevant targets and, besides these goal-oriented responses, stabilizing movements clamp the visual scene avoiding image blurring. The vestibulo-ocular (VOR) and the optokinetic reflexes are the main contributors to gaze stabilization, whereas the optic tectum integrates multisensory information and generates orienting/evasive gaze movements in all vertebrates. Lampreys show a unique stepwise development of the visual system whose understanding provides important insights into the evolution and development of vertebrate vision. Although the developmental emergence of the visual components, and the retinofugal pathways have been described, the functional development of the visual system and the development of the downstream pathways controlling gaze are still unknown. Here, we show that VOR followed by light-evoked eye movements are the first to appear already in larvae, despite their burrowed lifestyle. However, the circuits controlling goal-oriented responses emerge later, in larvae in non-parasitic lampreys but during late metamorphosis in parasitic lampreys. The appearance of stabilizing responses earlier than goal-oriented in the lamprey development shows a stepwise transition from simpler to more complex visual systems, offering a unique opportunity to isolate the functioning of their underlying circuits.

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