Restricted ADP movement in cardiomyocytes: Cytosolic diffusion obstacles are complemented with a small number of open mitochondrial voltage-dependent anion channels

Simson, Päivo; Jepihhina, Natalja; Laasmaa, Martin; Peterson, Pearu; Birkedal, Rikke; Vendelin, Marko

doi:10.1016/j.yjmcc.2016.04.012

Cited by 32 publications

(38 citation statements)

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“…On the other hand, diffusivity of ATP, ADP and AMP were set to a value 1% of that in the IMS region, compared to their cytosolic values. This was done to simulate low permeability of the VDACs (voltage depended anion channels) to these large anions as suggested by previous studies [10,20,21]. We also assumed that none of these large molecules can diffuse through the mitochondrial matrix due to intramatrix barriers like cristae structure and protein complexes [22].…”

Section: A High Resolution Two-dimensional Spatial Model Of Cardiac Bmentioning

confidence: 99%

“…The differences in spatial gradients of phosphagens can be attributed to the activity of creatine kinase (CK) enzyme isoforms in the IMS and myofibrils. Based on previous work by Vendelin et al[10,21], we assumed ADP, ATP and AMP diffusivity in the IMS region is 1% of their corresponding diffusivity in the cytosolic space. Despite restricted diffusivity, the estimated ADP and ATP gradients were less than one tenth of the gradients present in PCr and Cr (Fig 5A).…”

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Insights on the impact of mitochondrial organisation on bioenergetics in high-resolution computational models of cardiac cell architecture

Ghosh

Tran

Delbridge

et al. 2018

Preprint

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Recent electron microscopy data have revealed that cardiac mitochondria are not arranged in crystalline columns, but are organised with several mitochondria aggregated into columns of varying sizes often spanning the cell cross-section. This All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/327254 doi: bioRxiv preprint first posted online May. 22, 2018; raises the question -how does the mitochondrial arrangement affect the metabolite distributions within cardiomyocytes and their impact on force dynamics? Here we employed finite element modelling of cardiac bioenergetics, using computational meshes derived from electron microscope images, to address this question. Our results indicate that heterogeneous mitochondrial distributions can lead to significant spatial variation across the cell in concentrations of inorganic phosphate, creatine (Cr) and creatine phosphate (PCr). However, our model predicts that sufficient activity of the creatine kinase (CK) system, coupled with rapid diffusion of Cr and PCr, maintains near uniform ATP and ADP ratios across the cell cross sections. This homogenous distribution of ATP and ADP should also evenly distribute force production and twitch duration with contraction. These results suggest that the PCr shuttle, and associated enzymatic reactions, act to maintain uniform force dynamics in the cell despite the heterogeneous mitochondrial organization. However, our model also predicts that under hypoxia -activity of mitochondrial CK enzyme and diffusion of high-energy phosphate compounds may be insufficient to sustain uniform ATP/ADP distribution and hence force generation. Author SummaryMammalian cardiomyocytes contain a high volume of mitochondria, which maintains the continuous and bulk supply of ATP to sustain normal heart function. Previously, cardiac mitochondria were understood to be distributed in a regular, crystalline pattern, which facilitated a steady supply of ATP at different workloads. Using electron microscopy images of cell cross sections, we recently found that they are not regularly distributed inside cardiomyocytes. We created new spatially accurate computational models of cardiac cell bioenergetics and tested whether this All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/327254 doi: bioRxiv preprint first posted online May. 22, 2018; heterogeneous distribution of mitochondria causes non-uniform energy supply and contractile force production in the cardiomyocyte. We found that ATP and ADP concentrations remain uniform throughout the cell because of the activity of creatine kinase (CK) enzymes that convert ATP produced in the mitochondria into creatine phosphate...

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Section: A High Resolution Two-dimensional Spatial Model Of Cardiac Bmentioning

confidence: 99%

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Insights on the impact of mitochondrial organisation on bioenergetics in high-resolution computational models of cardiac cell architecture

Ghosh

Tran

Delbridge

et al. 2018

Preprint

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“…En los cardiomiocitos y otras células, el intercambio rápido de fosfato de creatina con carga negativa y de creatina neutra entre las mitocondrias y los sarcómeros es primordial para la disminución de la resistencia de la ruta de suministro de energía durante la fase sistólica (Wallimann, et al, 2011;Simson, et al, 2016). La resistencia metabólica de esta ruta citosólica del intercambio CrP 1-/Cr es mucho menor que la del intercambio por la electro-difusión del ATP 4y ADP 3-, sobre todo en concentraciones bajas de ADP 3en el citosol (Wallimann, et al, 2011).…”

Section: Generación Del Potencial De La Membrana Mitocondrial Externaunclassified

“…Para suministrar la energía al citosol, el ATP y el CrP producidos en las mitocondrias atraviesan la membrana mitocondrial externa en su forma aniónica. En varias demostraciones experimentales se ha visto cómo la membrana externa restringe significativamente el flujo entre las mitocondrias y el citosol de estos y otros metabolitos cargados (Vander Heiden, et al, 2000;Lemasters & Holmuhamedov, 2006;Rostovtseva & Bezrukov, 2012;Simson, et al, 2016).…”

Section: Introductionunclassified

“…En la actualidad el concepto más aceptado para la regulación de la permeabilidad de la membrana externa es el "taponamiento" molecular de los VDAC, especialmente con la tubulina y otras proteínas mitocondriales o citosólicas (Liu & Colombini, 1992;Kmita, et al, 2003;Rostovtseva & Bezrukov, 2012;Rostovtseva, et al, 2015). En el más reciente ejemplo, hasta 98 % de los VDAC en la membrana externa de los cardiomiocitos podría verse taponado por la tubulina y el retículo sarcoplasmático muy cercano a las mitocondrias (Simson, et al, 2016). Sin embargo, los datos experimentales obtenidos en el estudio de Simson, et al (2016) no descartan que el "taponamiento" solo de una parte de los VDAC favorezca la generación del potencial de la membrana externa y la modulación eléctrica de su permeabilidad frente a varios metabolitos cargados de una manera dependiente del metabolismo energético (Lemeshko, 2014(Lemeshko, , 2016(Lemeshko, , 2017a, lo cual también facilita la unión dependiente del potencial de la tubulina con el VDAC (Rostovtseva & Bezrukov, 2012;Rostovtseva, et al, 2017).…”

Section: Introductionunclassified

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El papel de la membrana mitocondrial externa en el control del metabolismo energético celular

Lemeshko

2018

Rev. Acad. Colomb. Cienc. Ex. Fis. Nat.

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Hasta 95 % de la energía en las células eucariotas se produce en las mitocondrias, las cuales se componen de dos membranas, la interna y la externa. La principal función de la membrana interna es la fosforilación oxidativa. El trifosfato de adenosina (adenosine triphosphate, ATP) y el fosfato de creatina, producidos en las mitocondrias, se transfieren al citosol atravesando la membrana mitocondrial externa, básicamente a través de las porinas (voltagedependent anion cannel, VDAC). Dado que los mecanismos de generación del potencial eléctrico en esta membrana se desconocen, generalmente se asume que la compuerta eléctrica de los VDAC siempre está abierta. Sin embargo, el potencial de la membrana mitocondrial externa puede generarse de manera dependiente del metabolismo energético celular mediante diversos mecanismos. La generación de dicho potencial mediante los complejos VDAC-hexocinasa en las células cancerígenas, o la oxidación directa del NADH citosólico en las mitocondrias de la levadura Saccharomyces cerevisiae permiten explicar los efectos de Crabtree y Warburg como una supresión eléctrica de las mitocondrias. Según el modelo desarrollado, la prevención de la formación de los complejos VDAC-hexocinasa por acción de algunos factores podría causar efectos anti-Warburg y anticancerígenos. Además, este potencial positivo generado por los complejos VDAC-creatina-cinasa podría proteger las mitocondrias de los cardiomiocitos y de otras células frente a los niveles tóxicos de calcio en el citosol. Los mecanismos propuestos de generación del potencial de la membrana dependiente del metabolismo energético celular, sugieren que las propiedades eléctricas del VDAC tienen un papel importante en varios procesos fisiológicos y patofisiológicos. © 2018. Acad. Colomb. Cienc. Ex. Fis. Nat.

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Compartmentalization in cardiomyocytes modulates creatine kinase and adenylate kinase activities

Birkedal,

Branovets,

Vendelin

2024

FEBS Letters

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Intracellular molecules are transported by motor proteins or move by diffusion resulting from random molecular motion. Cardiomyocytes are packed with structures that are crucial for function, but also confine the diffusional spaces, providing cells with a means to control diffusion. They form compartments in which local concentrations are different from the overall, average concentrations. For example, calcium and cyclic AMP are highly compartmentalized, allowing these versatile second messengers to send different signals depending on their location. In energetic compartmentalization, the ratios of AMP and ADP to ATP are different from the average ratios. This is important for the performance of ATPases fuelling cardiac excitation‐contraction coupling and mechanical work. A recent study suggested that compartmentalization modulates the activity of creatine kinase and adenylate kinase in situ. This could have implications for energetic signaling through, for example, AMP‐activated kinase. It highlights the importance of taking compartmentalization into account in our interpretation of cellular physiology and developing methods to assess local concentrations of AMP and ADP to enhance our understanding of compartmentalization in different cell types.

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Restricted ADP movement in cardiomyocytes: Cytosolic diffusion obstacles are complemented with a small number of open mitochondrial voltage-dependent anion channels

Cited by 32 publications

References 53 publications

Insights on the impact of mitochondrial organisation on bioenergetics in high-resolution computational models of cardiac cell architecture

Insights on the impact of mitochondrial organisation on bioenergetics in high-resolution computational models of cardiac cell architecture

El papel de la membrana mitocondrial externa en el control del metabolismo energético celular

Compartmentalization in cardiomyocytes modulates creatine kinase and adenylate kinase activities

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