Role of Cardiolipins in the Inner Mitochondrial Membrane: Insight Gained through Atom-Scale Simulations

Róg, Tomasz; Martinez‐Seara, Hector; Munck, Nana; Orešič, Matej; Karttunen, Mikko; Vattulainen, Ilpo

doi:10.1021/jp8077369

Cited by 61 publications

(33 citation statements)

References 59 publications

(109 reference statements)

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“…diverse molecular species of cardiolipin have stimulated the investigation of numerous analytical and mathematical approaches to determine the importance of cardiolipin in biological function. Coarse-grained molecular dynamics, thermodynamics and thermal response, atomic force microscopy, and atomic-scale simulations have all been used to characterize structural orientation and interaction of cardiolipin in membrane dynamics (55)(56)(57)(58)(59)(60). More recently, mathematical models using linear algebraic representation have been used to explain the acyl selectivity of cardiolipin remodeling based on free energies ( 61 ).…”

Section: Discussionmentioning

confidence: 99%

Dynamic simulation of cardiolipin remodeling: greasing the wheels for an interpretative approach to lipidomics

Kiebish

Bell

Yang

et al. 2010

Journal of Lipid Research

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Lipids are critical for the regulation and control of cellular function, membrane dynamics, and signal transduction. The systematic identifi cation and analysis of all cellular lipids in a biological sample is embodied by the rapidly developing fi eld of lipidomics, which has been enabled by recent advances in mass spectrometry ( 1-3 ). A multidimensional MS-based shotgun lipidomics (MDMS-SL) approach for analysis of cellular lipidomes has been demonstrated as one of the most systematic and quantitative high-throughput platforms for global lipidomics capable of analyzing thousands of lipid molecular species directly from the lipid extracts of biological tissues ( 4, 5 ). Analysis of lipidomic data requires extensive use of bioinformatics and computational algorithms for the accurate identifi cation and quantifi cation of lipid molecular species and classes ( 5-9 ). However, most advances in bioinformatics in lipidomics have largely focused on lipid identifi cation rather than interpretation of alterations in biological function resulting in adaptive or pathologic changes in lipid metabolism ( 10 ). Thus, development of bioinformatic and systems biology approaches for the interpretation of lipidomic networks would signifi cantly advance the understanding of the roles of lipids in biological systems ( 3 ).Cardiolipin is a complex polyglycerophospholipid found almost exclusively in mitochondrial membranes of eukaryotic organisms ( 11 ). Cardiolipin is intricately involved in the effi cient production of ATP through utilizing the proton gradient as well as maintaining mitochondrial functionality ( 12-14 ). The diversity of cardiolipin molecular species varies markedly between tissues as well as among Abstract Cardiolipin is a class of mitochondrial specifi c phospholipid, which is intricately involved in mitochondrial functionality. Differences in cardiolipin species exist in a variety of tissues and diseases. It has been demonstrated that the cardiolipin profi le is a key modulator of the functions of many mitochondrial proteins. However, the chemical mechanism(s) leading to normal and/or pathological distribution of cardiolipin species remain elusive. Herein, we describe a novel approach for investigating the molecular mechanism of cardiolipin remodeling through a dynamic simulation. This approach applied data from shotgun lipidomic analyses of the heart, liver, brain, and lung mitochondrial lipidomes to model cardiolipin remodeling, including relative content, regiospecifi city, and isomeric composition of cardiolipin species. Generated cardiolipin profi les were nearly identical to those determined by shotgun lipidomics. Importantly, the simulated isomeric compositions of cardiolipin species were further substantiated through product ion analysis. Finally, unique enzymatic activities involved in cardiolipin remodeling were assessed from the parameters used in the dynamic simulation of cardiolipin profi les. Collectively, we described, verifi ed, and demonstrated a novel approach by integrating both lipidomic ana...

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Section: Discussionmentioning

confidence: 99%

Dynamic simulation of cardiolipin remodeling: greasing the wheels for an interpretative approach to lipidomics

Kiebish

Bell

Yang

et al. 2010

Journal of Lipid Research

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“…Considering that the typical membrane thickness of mitochondria is in the range of 4–6 nm (Róg et al, 2009), interpolating the image to 2 nm pixel size does not generate data loss problems for the mitochondrial membrane as we justified in our pilot study (Mumcuoglu et al, 2012). …”

Section: Methodsmentioning

confidence: 99%

A validated active contour method driven by parabolic arc model for detection and segmentation of mitochondria

Tasel

Mumcuoglu

Hassanpour

et al. 2016

Journal of Structural Biology

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Recent studies reveal that mitochondria take substantial responsibility in cellular functions that are closely related to aging diseases caused by degeneration of neurons. These studies emphasize that the membrane and crista morphology of a mitochondrion should receive attention in order to investigate the link between mitochondrial function and its physical structure. Electron microscope tomography (EMT) allows analysis of the inner structures of mitochondria by providing highly detailed visual data from large volumes. Computerized segmentation of mitochondria with minimum manual effort is essential to accelerate the study of mitochondrial structure/function relationships. In this work, we improved and extended our previous attempts to detect and segment mitochondria from transmission electron microcopy (TEM) images. A parabolic arc model was utilized to extract membrane structures. Then, curve energy based active contours were employed to obtain roughly outlined candidate mitochondrial regions. Finally, a validation process was applied to obtain the final segmentation data. 3D extension of the algorithm is also presented in this paper. Our method achieved an average F-score performance of 0.84. Average Dice Similarity Coefficient and boundary error were measured as 0.87 and 14 nm respectively.

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“…1 The separation between the mitochondrial outer membrane and inner boundary 1 The range of typical mitochondrial membrane thickness is indicated in Rog et al, 2009 The preprocessing stage, Step (1), does noise reduction, contrast enhancement and normalization prior to Step (2). In Step (2), a double ridge energy function is calculated, which is the probability of being a double ridge (membrane) for every pixel, as well as the most probable angle.…”

Section: Mitochondria Detection Methodsmentioning

confidence: 99%

Computerized detection and segmentation of mitochondria on electron microscope images

Mumcuoglu

Hassanpour

Tasel

et al. 2012

Journal of Microscopy

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SummaryMitochondrial function plays an important role in the regulation of cellular life and death, including disease states. Disturbance in mitochondrial function and distribution can be accompanied by significant morphological alterations. Electron microscopy tomography (EMT) is a powerful technique to study the 3D structure of mitochondria, but the automatic detection and segmentation of mitochondria in EMT volumes has been challenging due to the presence of subcellular structures and imaging artifacts. Therefore, the interpretation, measurement and analysis of mitochondrial distribution and features have been time consuming, and development of specialized software tools is very important for high-throughput analyses needed to expedite the myriad studies on cellular events. Typically, mitochondrial EMT volumes are segmented manually using special software tools. Automatic contour extraction on large images with multiple mitochondria and many other subcellular structures is still an unaddressed problem. The purpose of this work is to develop computer algorithms to detect and segment both fully and partially seen mitochondria on electron microscopy images. The detection method relies on mitochondria's approximately elliptical shape and double membrane boundary. Initial detection results are first refined using active contours. Then, our seed point selection method automatically selects reliable seed points along the contour, and segmentation is finalized by automatically incorporating a live-wire graph search algorithm between these seed points. In our evaluations on four images containing multiple mitochondria, 52 ellipses are detected among which 42

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Role of Cardiolipins in the Inner Mitochondrial Membrane: Insight Gained through Atom-Scale Simulations

Cited by 61 publications

References 59 publications

Dynamic simulation of cardiolipin remodeling: greasing the wheels for an interpretative approach to lipidomics

Dynamic simulation of cardiolipin remodeling: greasing the wheels for an interpretative approach to lipidomics

A validated active contour method driven by parabolic arc model for detection and segmentation of mitochondria

Computerized detection and segmentation of mitochondria on electron microscope images

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