Multi-parametric analysis and modeling of relationships between mitochondrial morphology and apoptosis

Mitochondria exist as a network of interconnected organelles undergoing constant fission and fusion. Current approaches to study mitochondrial morphology are limited by low data sampling coupled with manual identification and classification of complex morphological phenotypes. Here we propose an int...

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Hauptverfasser: Reis, Yara (VerfasserIn) , Bernardo Faura, Martí (VerfasserIn) , Richter, Daniela (VerfasserIn) , Wolf, Thomas (VerfasserIn) , Brors, Benedikt (VerfasserIn) , Hamacher-Brady, Anne (VerfasserIn) , Eils, Roland (VerfasserIn) , Brady, Nathan (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 17 January 2012
In: PLOS ONE
Year: 2012, Jahrgang: 7, Heft: 1
ISSN:1932-6203
DOI:10.1371/journal.pone.0028694
Online-Zugang:Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1371/journal.pone.0028694
Verlag, kostenfrei, Volltext: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028694
Volltext
Verfasserangaben:Yara Reis, Marti Bernardo-Faura, Daniela Richter, Thomas Wolf, Benedikt Brors, Anne Hamacher-Brady, Roland Eils, Nathan R. Brady

MARC

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520 |a Mitochondria exist as a network of interconnected organelles undergoing constant fission and fusion. Current approaches to study mitochondrial morphology are limited by low data sampling coupled with manual identification and classification of complex morphological phenotypes. Here we propose an integrated mechanistic and data-driven modeling approach to analyze heterogeneous, quantified datasets and infer relations between mitochondrial morphology and apoptotic events. We initially performed high-content, multi-parametric measurements of mitochondrial morphological, apoptotic, and energetic states by high-resolution imaging of human breast carcinoma MCF-7 cells. Subsequently, decision tree-based analysis was used to automatically classify networked, fragmented, and swollen mitochondrial subpopulations, at the single-cell level and within cell populations. Our results revealed subtle but significant differences in morphology class distributions in response to various apoptotic stimuli. Furthermore, key mitochondrial functional parameters including mitochondrial membrane potential and Bax activation, were measured under matched conditions. Data-driven fuzzy logic modeling was used to explore the non-linear relationships between mitochondrial morphology and apoptotic signaling, combining morphological and functional data as a single model. Modeling results are in accordance with previous studies, where Bax regulates mitochondrial fragmentation, and mitochondrial morphology influences mitochondrial membrane potential. In summary, we established and validated a platform for mitochondrial morphological and functional analysis that can be readily extended with additional datasets. We further discuss the benefits of a flexible systematic approach for elucidating specific and general relationships between mitochondrial morphology and apoptosis. 
650 4 |a Apoptosis 
650 4 |a Apoptotic signaling cascade 
650 4 |a Decision trees 
650 4 |a Depolarization 
650 4 |a Drug therapy 
650 4 |a Membrane potential 
650 4 |a Mitochondria 
650 4 |a Mitochondrial membrane 
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