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Wallace F. Marshall - One of the best experts on this subject based on the ideXlab platform.

  • testing the role of intraflagellar transport in flagellar length control using length altering mutants of chlamydomonas
    Philosophical Transactions of the Royal Society B, 2020
    Co-Authors: Kimberly A Wemmer, William B Ludington, Wallace F. Marshall
    Abstract:

    Cilia and flagella are ideal model Organelles in which to study the general question of Organelle Size control. Flagellar microtubules are steady-state structures whose Size is set by the balance of assembly and disassembly. Assembly requires intraflagellar transport (IFT), and measurements of IFT have shown that the rate of entry of IFT particles into the flagellum is a decreasing function of length. It has been proposed that this length dependence of IFT may be the basis for flagellar length control. Here, we test this idea by showing that three different long-flagella mutations in Chlamydomonas all cause increased IFT injection, thus confirming that IFT can influence length control. However, quantitative comparisons with mathematical models suggest that the increase in injection is not sufficient to explain the full increase in length seen in these mutants; hence, some other mechanism may be at work. One alternative mechanism that has been proposed is length-regulated binding of tubulin to the IFT particles. However, we find that the apparent length dependence of tubulin loading that has previously been reported may actually reflect length-dependent organization of IFT trains. This article is part of the Theo Murphy meeting issue 'Unity and diversity of cilia in locomotion and transport'.

  • Diffusion as a Ruler: Modeling Kinesin Diffusion as a Length Sensor for Intraflagellar Transport.
    Biophysical Journal, 2018
    Co-Authors: Nathan L Hendel, Matt Thomson, Wallace F. Marshall
    Abstract:

    An important question in cell biology is whether cells are able to measure Size, either whole cell Size or Organelle Size. Perhaps cells have an internal chemical representation of Size that can be used to precisely regulate growth, or perhaps Size is just an accident that emerges due to constraint of nutrients. The eukaryotic flagellum is an ideal model for studying Size sensing and control because its linear geometry makes it essentially one-dimensional, greatly simplifying mathematical modeling. The assembly of flagella is regulated by intraflagellar transport (IFT), in which kinesin motors carry cargo adaptors for flagellar proteins along the flagellum and then deposit them at the tip, lengthening the flagellum. The rate at which IFT motors are recruited to begin transport into the flagellum is anticorrelated with the flagellar length, implying some kind of communication between the base and the tip and possibly indicating that cells contain some mechanism for measuring flagellar length. Although it is possible to imagine many complex scenarios in which additional signaling molecules sense length and carry feedback signals to the cell body to control IFT, might the already-known components of the IFT system be sufficient to allow length dependence of IFT? Here we investigate a model in which the anterograde kinesin motors unbind after cargo delivery, diffuse back to the base, and are subsequently reused to power entry of new IFT trains into the flagellum. By mathematically modeling and simulating such a system, we are able to show that the diffusion time of the motors can in principle be sufficient to serve as a proxy for length measurement. We found that the diffusion model can not only achieve a stable steady-state length without the addition of any other signaling molecules or pathways, but also is able to produce the anticorrelation between length and IFT recruitment rate that has been observed in quantitative imaging studies.

  • Diffusion as a ruler: modeling kinesin diffusion as a length sensor for intraflagellar transport
    2017
    Co-Authors: Nathan L Hendel, Matt Thomson, Wallace F. Marshall
    Abstract:

    An important question in cell biology is whether cells are able to measure Size, either whole cell Size or Organelle Size. Perhaps cells have an internal chemical representation of Size that can be used to precisely regulate growth, or perhaps Size is just an accident that emerges due to constraint of nutrients. The eukaryotic flagellum is an ideal model for studying Size sensing and control because its linear geometry makes it essentially one-dimensional, greatly simplifying mathematical modeling. The assembly of flagella is regulated by intraflagellar transport (IFT), in which kinesin motors carry cargo adaptors for flagellar proteins along the flagellum and then deposit them at the tip, lengthening the flagellum. The rate at which IFT motors are recruited to begin transport into the flagellum is anticorrelated with the flagellar length, implying some kind of communication between the base and the tip and possibly indicating that cells contain some mechanism for measuring flagellar length. Although it is possible to imagine many complex scenarios in which additional signaling molecules sense length and carry feedback signals to the cell body to control IFT, might the already-known components of the IFT system be sufficient to allow length dependence of IFT? Here, we investigate a model in which the anterograde kinesin motors unbind after cargo delivery, diffuse back to the base, and are subsequently reused to power entry of new IFT trains into the flagellum. By modeling such a system at three different levels of abstraction we are able to show that the diffusion time of the motors can in principle be sufficient to serve as a proxy for length measurement. In all three implementations, we found that the diffusion model can not only achieve a stable steady-state length without the addition of any other signaling molecules or pathways, but also is able to produce the anticorrelation between length and IFT recruitment rate that has been observed in quantitative imaging studies.

  • scaling properties of cell and Organelle Size
    Organogenesis, 2010
    Co-Authors: Yeehung M Chan, Wallace F. Marshall
    Abstract:

    How Size is controlled is a fundamental question in biology. In this review, we discuss the use of scaling relationships-for example, power-laws of the form y∝x(α)-to provide a framework for comparison and interpretation of Size measurements. Such analysis can illustrate the biological and physical principles underlying observed trends, as has been proposed for the allometric dependence of metabolic rate or limb structure on organism mass. Techniques for measuring Size at smaller length-scales continue to improve, leading to more data on the control of Size in cells and Organelles. Size scaling of these structures is expected to influence growth patterns, functional capacity and intracellular transport. Furthermore, Organelles such as the nucleus, mitochondria and endoplasmic reticulum show widely varying morphologies that affect their scaling properties. We provide brief summaries of these issues for individual Organelles, and conclude with a discussion on how to apply this concept to better understand the mechanisms of Size control in the cellular environment.

  • building the cell design principles of cellular architecture
    Nature Reviews Molecular Cell Biology, 2008
    Co-Authors: Susanne M Rafelski, Wallace F. Marshall
    Abstract:

    The astounding structural complexity of a cell arises from the action of a relatively small number of genes, raising the question of how this complexity is achieved. Self-organizing processes combined with simple physical constraints seem to have key roles in controlling Organelle Size, number, shape and position, and these factors then combine to produce the overall cell architecture. By examining how these parameters are controlled in specific cell biological examples we can identify a handful of simple design principles that seem to underlie cellular architecture and assembly.

Nathan L Hendel - One of the best experts on this subject based on the ideXlab platform.

  • speed and diffusion of kinesin 2 are competing limiting factors in flagellar length control model
    Biophysical Journal, 2020
    Co-Authors: Nathan L Hendel
    Abstract:

    Abstract Flagellar length control in Chlamydomonas is a tractable model system for studying the general question of Organelle Size regulation. We have previously proposed that the diffusive return of the kinesin motor that powers intraflagellar transport can play a key role in length regulation. Here, we explore how the motor speed and diffusion coefficient for the return of kinesin-2 affect flagellar growth kinetics. We find that the system can exist in two distinct regimes, one dominated by motor speed and one by diffusion coefficient. Depending on length, a flagellum can switch between these regimes. Our results indicate that mutations can affect the length in distinct ways. We discuss our theory’s implication for flagellar growth influenced by beating and provide possible explanations for the experimental observation that a beating flagellum is usually longer than its immotile mutant. These results demonstrate how our simple model can suggest explanations for mutant phenotypes.

  • speed and diffusion of kinesin 2 are competing limiting factors in flagellar length control model
    bioRxiv, 2019
    Co-Authors: Nathan L Hendel
    Abstract:

    Flagellar length control in Chlamydomonas is a tractable model system for studying the general question of Organelle Size regulation. We have previously proposed that diffusive return of the kinesin motor that powers intraflagellar transport can play a key role in length regulation. Here we explore how the motor speed and diffusion coefficient for the return of kinesin-2 affect flagellar growth kinetics. We find that the system can exist in two distinct regimes, one dominated by motor speed and one by diffusion coefficient. Depending on length, a flagellum can switch between these regimes. Our results indicate that mutations can affect length in distinct ways. We discuss our theory9s implication for flagellar growth influenced by beating and provide possible explanations for the experimental observation that a beating flagellum is usually longer than its immotile mutant. These results demonstrate how our simple model can suggest explanations for mutant phenotypes.

  • Diffusion as a Ruler: Modeling Kinesin Diffusion as a Length Sensor for Intraflagellar Transport.
    Biophysical Journal, 2018
    Co-Authors: Nathan L Hendel, Matt Thomson, Wallace F. Marshall
    Abstract:

    An important question in cell biology is whether cells are able to measure Size, either whole cell Size or Organelle Size. Perhaps cells have an internal chemical representation of Size that can be used to precisely regulate growth, or perhaps Size is just an accident that emerges due to constraint of nutrients. The eukaryotic flagellum is an ideal model for studying Size sensing and control because its linear geometry makes it essentially one-dimensional, greatly simplifying mathematical modeling. The assembly of flagella is regulated by intraflagellar transport (IFT), in which kinesin motors carry cargo adaptors for flagellar proteins along the flagellum and then deposit them at the tip, lengthening the flagellum. The rate at which IFT motors are recruited to begin transport into the flagellum is anticorrelated with the flagellar length, implying some kind of communication between the base and the tip and possibly indicating that cells contain some mechanism for measuring flagellar length. Although it is possible to imagine many complex scenarios in which additional signaling molecules sense length and carry feedback signals to the cell body to control IFT, might the already-known components of the IFT system be sufficient to allow length dependence of IFT? Here we investigate a model in which the anterograde kinesin motors unbind after cargo delivery, diffuse back to the base, and are subsequently reused to power entry of new IFT trains into the flagellum. By mathematically modeling and simulating such a system, we are able to show that the diffusion time of the motors can in principle be sufficient to serve as a proxy for length measurement. We found that the diffusion model can not only achieve a stable steady-state length without the addition of any other signaling molecules or pathways, but also is able to produce the anticorrelation between length and IFT recruitment rate that has been observed in quantitative imaging studies.

  • Diffusion as a ruler: modeling kinesin diffusion as a length sensor for intraflagellar transport
    2017
    Co-Authors: Nathan L Hendel, Matt Thomson, Wallace F. Marshall
    Abstract:

    An important question in cell biology is whether cells are able to measure Size, either whole cell Size or Organelle Size. Perhaps cells have an internal chemical representation of Size that can be used to precisely regulate growth, or perhaps Size is just an accident that emerges due to constraint of nutrients. The eukaryotic flagellum is an ideal model for studying Size sensing and control because its linear geometry makes it essentially one-dimensional, greatly simplifying mathematical modeling. The assembly of flagella is regulated by intraflagellar transport (IFT), in which kinesin motors carry cargo adaptors for flagellar proteins along the flagellum and then deposit them at the tip, lengthening the flagellum. The rate at which IFT motors are recruited to begin transport into the flagellum is anticorrelated with the flagellar length, implying some kind of communication between the base and the tip and possibly indicating that cells contain some mechanism for measuring flagellar length. Although it is possible to imagine many complex scenarios in which additional signaling molecules sense length and carry feedback signals to the cell body to control IFT, might the already-known components of the IFT system be sufficient to allow length dependence of IFT? Here, we investigate a model in which the anterograde kinesin motors unbind after cargo delivery, diffuse back to the base, and are subsequently reused to power entry of new IFT trains into the flagellum. By modeling such a system at three different levels of abstraction we are able to show that the diffusion time of the motors can in principle be sufficient to serve as a proxy for length measurement. In all three implementations, we found that the diffusion model can not only achieve a stable steady-state length without the addition of any other signaling molecules or pathways, but also is able to produce the anticorrelation between length and IFT recruitment rate that has been observed in quantitative imaging studies.

Hani N Sabbah - One of the best experts on this subject based on the ideXlab platform.

  • abstract 12977 neladenoson a partial adenosine a1 receptor agonist improves mitochondrial function in left ventricular cardiomyocytes isolated from dogs with chronic heart failure
    Circulation, 2016
    Co-Authors: Hani N Sabbah, Ramesh C Gupta, Vinita Singhgupta, Kefei Zhang, Jiang Xu, Barbara Albrechtkupper
    Abstract:

    Background: Mitochondria (MITO) of failing cardiomyocytes (CMs) manifest structural and functional abnormalities characterized by hyperplasia, reduced Organelle Size and reduced respiration. These ...

  • abnormal mitochondrial respiration in failed human myocardium
    Journal of Molecular and Cellular Cardiology, 2000
    Co-Authors: Victor G Sharov, Anastassia Todor, Norman H Silverman, Sidney Goldstein, Hani N Sabbah
    Abstract:

    Chronic heart failure (HF) is associated with morphologic abnormalities of cardiac mitochondria including hyperplasia, reduced Organelle Size and compromised structural integrity. In this study, we examined whether functional abnormalities of mitochondrial respiration are also present in myocardium of patients with advanced HF. Mitochondrial respiration was examined using a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles obtained from myocardium of failed explanted human hearts due to ischemic (ICM, n=9) or idiopathic dilated (IDC, n=9) cardiomyopathy. Myocardial specimens from five normal donor hearts served as controls (CON). Basal respiratory rate, respiratory rate after addition of the substrates glutamate and malate (V(SUB)), state 3 respiration (after addition of ADP, V(ADP)) and respiration after the addition of atractyloside (V(AT)) were measured in scar-free muscle bundles obtained from the subendocardial (ENDO) and subepicardial (EPI) thirds of the left ventricular (LV) free wall, interventricular septum and right ventricular (RV) free wall. There were no differences in basal and substrate-supported respiration between CON and HF regardless of etiology. V(ADP)was significantly depressed both in ICM and IDC compared to CON in all the regions studied. The respiratory control ratio, V(ADP)/V(AT), was also significantly decreased in HF compared to CON. In both ICM and IDC, V(ADP)was significantly lower in ENDO compared to EPI. The results indicate that mitochondrial respiration is abnormal in the failing human heart. The findings support the concept of low myocardial energy production in HF via oxidative phosphorylation, an abnormality with a potentially impact on global cardiac performance.

  • 965 49 abnormal mitochondrial respiration in myocardium of dogs with chronic heart failure
    Journal of the American College of Cardiology, 1995
    Co-Authors: Victor G Sharov, Norman H Silverman, Hani N Sabbah, Jane M Cook, Ramesh C Gupta, Michael Lesch, Sidney Goldstein
    Abstract:

    We previously showed that abnormalities of mitochondria (M IT) exist in the failing heart and include hyperplasia, reduced Organelle Size and structural injury. In the present study, we examined MIT respiration in LV tissue obtained from 11 normal (NL) dogs and 8 dogs with heart failure (HF) produced by intracoronary microembolizations (LV ejection fraction 23 ± 3%). Tissue specimen (30 mg) were obtained from the subendocardial (ENDO) and subepicardial (EPI) halves of the LV wall. Basal (V o ) and state 3 (maximal) respiration (V ADP , after addition of 1 mM ADP) were measured with an oxygraph and Clark electrode using saponin skinned fiber bundles (0.2–0.3 mm). Respiratory rate was calculated in ngatoms of oxygen/min/mg of noncollagen protein. The respiration control ratio (RCR) was calculated as V ADP /V o . V o V ADP V ADP /V o ENDO EPI ENDO EPI ENDO EPI NL 9 ± 2 7 ± 1 46 ± 6 47 ± 1 6 ± 1 7 ± 1 HF 6 ± 1 6 ± 1 20 ± 5 22 ± 5 4 ± 1 4 ± 1 P-value l0.07 l0.5 l0.001 l0.005 l0.04 l0.004 MIT state 3 respiration is significantly reduced in myocardium of dogs with chronic HF. The observed reduction in the RCR confirms the presence of injury to inner MIT membrane. The abnormalities in MIT oxygen utilization support the concept of low energy production in the failing heart.

Sidney Goldstein - One of the best experts on this subject based on the ideXlab platform.

  • abnormal mitochondrial respiration in failed human myocardium
    Journal of Molecular and Cellular Cardiology, 2000
    Co-Authors: Victor G Sharov, Anastassia Todor, Norman H Silverman, Sidney Goldstein, Hani N Sabbah
    Abstract:

    Chronic heart failure (HF) is associated with morphologic abnormalities of cardiac mitochondria including hyperplasia, reduced Organelle Size and compromised structural integrity. In this study, we examined whether functional abnormalities of mitochondrial respiration are also present in myocardium of patients with advanced HF. Mitochondrial respiration was examined using a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles obtained from myocardium of failed explanted human hearts due to ischemic (ICM, n=9) or idiopathic dilated (IDC, n=9) cardiomyopathy. Myocardial specimens from five normal donor hearts served as controls (CON). Basal respiratory rate, respiratory rate after addition of the substrates glutamate and malate (V(SUB)), state 3 respiration (after addition of ADP, V(ADP)) and respiration after the addition of atractyloside (V(AT)) were measured in scar-free muscle bundles obtained from the subendocardial (ENDO) and subepicardial (EPI) thirds of the left ventricular (LV) free wall, interventricular septum and right ventricular (RV) free wall. There were no differences in basal and substrate-supported respiration between CON and HF regardless of etiology. V(ADP)was significantly depressed both in ICM and IDC compared to CON in all the regions studied. The respiratory control ratio, V(ADP)/V(AT), was also significantly decreased in HF compared to CON. In both ICM and IDC, V(ADP)was significantly lower in ENDO compared to EPI. The results indicate that mitochondrial respiration is abnormal in the failing human heart. The findings support the concept of low myocardial energy production in HF via oxidative phosphorylation, an abnormality with a potentially impact on global cardiac performance.

  • 965 49 abnormal mitochondrial respiration in myocardium of dogs with chronic heart failure
    Journal of the American College of Cardiology, 1995
    Co-Authors: Victor G Sharov, Norman H Silverman, Hani N Sabbah, Jane M Cook, Ramesh C Gupta, Michael Lesch, Sidney Goldstein
    Abstract:

    We previously showed that abnormalities of mitochondria (M IT) exist in the failing heart and include hyperplasia, reduced Organelle Size and structural injury. In the present study, we examined MIT respiration in LV tissue obtained from 11 normal (NL) dogs and 8 dogs with heart failure (HF) produced by intracoronary microembolizations (LV ejection fraction 23 ± 3%). Tissue specimen (30 mg) were obtained from the subendocardial (ENDO) and subepicardial (EPI) halves of the LV wall. Basal (V o ) and state 3 (maximal) respiration (V ADP , after addition of 1 mM ADP) were measured with an oxygraph and Clark electrode using saponin skinned fiber bundles (0.2–0.3 mm). Respiratory rate was calculated in ngatoms of oxygen/min/mg of noncollagen protein. The respiration control ratio (RCR) was calculated as V ADP /V o . V o V ADP V ADP /V o ENDO EPI ENDO EPI ENDO EPI NL 9 ± 2 7 ± 1 46 ± 6 47 ± 1 6 ± 1 7 ± 1 HF 6 ± 1 6 ± 1 20 ± 5 22 ± 5 4 ± 1 4 ± 1 P-value l0.07 l0.5 l0.001 l0.005 l0.04 l0.004 MIT state 3 respiration is significantly reduced in myocardium of dogs with chronic HF. The observed reduction in the RCR confirms the presence of injury to inner MIT membrane. The abnormalities in MIT oxygen utilization support the concept of low energy production in the failing heart.

Victor G Sharov - One of the best experts on this subject based on the ideXlab platform.

  • abnormal mitochondrial respiration in failed human myocardium
    Journal of Molecular and Cellular Cardiology, 2000
    Co-Authors: Victor G Sharov, Anastassia Todor, Norman H Silverman, Sidney Goldstein, Hani N Sabbah
    Abstract:

    Chronic heart failure (HF) is associated with morphologic abnormalities of cardiac mitochondria including hyperplasia, reduced Organelle Size and compromised structural integrity. In this study, we examined whether functional abnormalities of mitochondrial respiration are also present in myocardium of patients with advanced HF. Mitochondrial respiration was examined using a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles obtained from myocardium of failed explanted human hearts due to ischemic (ICM, n=9) or idiopathic dilated (IDC, n=9) cardiomyopathy. Myocardial specimens from five normal donor hearts served as controls (CON). Basal respiratory rate, respiratory rate after addition of the substrates glutamate and malate (V(SUB)), state 3 respiration (after addition of ADP, V(ADP)) and respiration after the addition of atractyloside (V(AT)) were measured in scar-free muscle bundles obtained from the subendocardial (ENDO) and subepicardial (EPI) thirds of the left ventricular (LV) free wall, interventricular septum and right ventricular (RV) free wall. There were no differences in basal and substrate-supported respiration between CON and HF regardless of etiology. V(ADP)was significantly depressed both in ICM and IDC compared to CON in all the regions studied. The respiratory control ratio, V(ADP)/V(AT), was also significantly decreased in HF compared to CON. In both ICM and IDC, V(ADP)was significantly lower in ENDO compared to EPI. The results indicate that mitochondrial respiration is abnormal in the failing human heart. The findings support the concept of low myocardial energy production in HF via oxidative phosphorylation, an abnormality with a potentially impact on global cardiac performance.

  • 965 49 abnormal mitochondrial respiration in myocardium of dogs with chronic heart failure
    Journal of the American College of Cardiology, 1995
    Co-Authors: Victor G Sharov, Norman H Silverman, Hani N Sabbah, Jane M Cook, Ramesh C Gupta, Michael Lesch, Sidney Goldstein
    Abstract:

    We previously showed that abnormalities of mitochondria (M IT) exist in the failing heart and include hyperplasia, reduced Organelle Size and structural injury. In the present study, we examined MIT respiration in LV tissue obtained from 11 normal (NL) dogs and 8 dogs with heart failure (HF) produced by intracoronary microembolizations (LV ejection fraction 23 ± 3%). Tissue specimen (30 mg) were obtained from the subendocardial (ENDO) and subepicardial (EPI) halves of the LV wall. Basal (V o ) and state 3 (maximal) respiration (V ADP , after addition of 1 mM ADP) were measured with an oxygraph and Clark electrode using saponin skinned fiber bundles (0.2–0.3 mm). Respiratory rate was calculated in ngatoms of oxygen/min/mg of noncollagen protein. The respiration control ratio (RCR) was calculated as V ADP /V o . V o V ADP V ADP /V o ENDO EPI ENDO EPI ENDO EPI NL 9 ± 2 7 ± 1 46 ± 6 47 ± 1 6 ± 1 7 ± 1 HF 6 ± 1 6 ± 1 20 ± 5 22 ± 5 4 ± 1 4 ± 1 P-value l0.07 l0.5 l0.001 l0.005 l0.04 l0.004 MIT state 3 respiration is significantly reduced in myocardium of dogs with chronic HF. The observed reduction in the RCR confirms the presence of injury to inner MIT membrane. The abnormalities in MIT oxygen utilization support the concept of low energy production in the failing heart.