Quantifying small molecule phenotypic effects using mitochondrial morpho-functional fingerprinting and machine learning

Blanchet, Lionel; Smeitink, Jan A.M.; Vries, Sjenet E. van Emst de; Vogels, Caroline; Pellegrini, Mina; Jonckheere, An I.; Rodenburg, Richard J.; Buydens, L.M.C.; Beyrath, Julien; Willems, Peter H.G.M.; Koopman, Werner J.H.

doi:10.1038/srep08035

Cited by 42 publications

(40 citation statements)

References 49 publications

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“…Other antioxidants like vitamins C and E might also be beneficial in patients with mitochondrial diseases. An example is an analogue of vitamin E, trolox ornithylamide hydrochloride, when applied to fibroblasts from patients with Leigh syndrome reduced ROS levels and increased activities of mitochondrial complexes I, IV and citrate synthase(9). Nevertheless, efficacy of antioxidants in patients with mitochondrial diseases remains controversial.…”

Section: Existing Therapeutic Optionsmentioning

confidence: 99%

Emerging therapies for mitochondrial diseases

Hirano

Emmanuele

Quinzii

2018

Essays in Biochemistry

126

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For the vast majority of patients with mitochondrial diseases, only supportive and symptomatic therapies are available. However, in the last decade, due to extraordinary advances in defining the causes and pathomechanisms of these diverse disorders, new therapies are being developed in the laboratory and are entering human clinical trials. In this review, we highlight the current use of dietary supplement and exercise therapies as well as emerging therapies that may be broadly applicable across multiple mitochondrial diseases or tailored for specific disorders. Examples of non-tailored therapeutic targets include: activation of mitochondrial biogenesis, regulation of mitophagy and mitochondrial dynamics, bypass of biochemical defects, mitochondrial replacement therapy, and hypoxia. In contrast, tailored therapies are: scavenging of toxic compounds, deoxynucleoside and deoxynucleotide treatments, cell replacement therapies, gene therapy, shifting mitochondrial DNA mutation heteroplasmy, and stabilization of mutant mitochondrial transfer RNAs.

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Section: Existing Therapeutic Optionsmentioning

confidence: 99%

Emerging therapies for mitochondrial diseases

Hirano

Emmanuele

Quinzii

2018

Essays in Biochemistry

126

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“…Additional numerical descriptors will need to be incorporated in quantitative analysis of mitochondrial morphology and have their level of redundancy clearly assessed, in order to produce phenotypic ‘fingerprints’ or ‘mitograms’ at the level of individual mitochondria and mitochondrial networks, as recently anticipated (Blanchet et al, 2015; Iannetti et al, 2016). Development of a unified nomenclature of mitochondrial parameters and novel graphical representation systems might be useful in order to define how to best describe the morphology and dynamics of these organelles.…”

Section: Future Challengesmentioning

confidence: 99%

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

Aouacheria

Baghdiguian

Lamb

et al. 2017

Neurochemistry International

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The morphology of a population of mitochondria is the result of several interacting dynamical phenomena, including fission, fusion, movement, elimination and biogenesis. Each of these phenomena is controlled by underlying molecular machinery, and when defective can cause disease. New understanding of the relationships between form and function of mitochondria in health and disease is beginning to be unraveled on several fronts. Studies in mammals and model organisms have revealed that mitochondrial morphology, dynamics and function appear to be subject to regulation by the same proteins that regulate apoptotic cell death. One protein family that influences mitochondrial dynamics in both healthy and dying cells is the Bcl-2 protein family. Connecting mitochondrial dynamics with life-death pathway forks may arise from the intersection of Bcl-2 family proteins with the proteins and lipids that determine mitochondrial shape and function. Bcl-2 family proteins also have multifaceted influences on cells and mitochondria, including calcium handling, autophagy and energetics, as well as the subcellular localization of mitochondrial organelles to neuronal synapses. The remarkable range of physical or functional interactions by Bcl-2 family proteins is challenging to assimilate into a cohesive understanding. Most of their effects may be distinct from their direct roles in apoptotic cell death and are particularly apparent in the nervous system. Dual roles in mitochondrial dynamics and cell death extend beyond BCL-2 family proteins. In this review, we discuss many processes that govern mitochondrial structure and function in health and disease, and how Bcl-2 family proteins integrate into some of these processes.

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“…Such a redox fingerprint may become a valuable tool for classification of cells from different pathological conditions or could lead to novel cell-based screening methods for diagnostic purposes. It has been shown that the combination of multiple morphological parameters of the mitochondrial network permits robust classification of different phenotypes using unsupervised as well as supervised data mining strategies Blanchet et al 2015). Indeed, hierarchical clustering has allowed for stratifying antiretroviral drug treatments based on mitochondrial morphology fingerprints .…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, hierarchical clustering has allowed for stratifying antiretroviral drug treatments based on mitochondrial morphology fingerprints . Likewise, learning methods (logistic regression and support vector machines learning) have been successfully used to discriminate between primary fibroblasts of a healthy individual and a Leigh Syndrome patient and to identify potential therapeutic compounds based on their mitochondrial morpho-functional phenotype (Blanchet et al 2015). These examples demonstrate the potential of integrated image-based redox profiling.…”

Section: Discussionmentioning

confidence: 99%

Integrated High-Content Quantification of Intracellular ROS Levels and Mitochondrial Morphofunction

Sieprath

Corne

Willems

et al. 2016

Advances in Anatomy, Embryology and Cell Biology

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Oxidative stress arises from an imbalance between the production of reactive oxygen species (ROS) and their removal by cellular antioxidant systems. Especially under pathological conditions, mitochondria constitute a relevant source of cellular ROS. These organelles harbor the electron transport chain, bringing electrons in close vicinity to molecular oxygen. Although a full understanding is still lacking, intracellular ROS generation and mitochondrial function are also linked to changes in mitochondrial morphology. To study the intricate relationships between the different factors that govern cellular redox balance in living cells, we have developed a high-content microscopy-based strategy for simultaneous quantification of intracellular ROS levels and mitochondrial morphofunction. Here, we summarize the principles of intracellular ROS generation and removal, and we explain the major considerations for performing quantitative microscopy analyses of ROS and mitochondrial morphofunction in living cells. Next, we describe our workflow and finally, we illustrate that a multiparametric readout enables the unambiguous classification of chemically perturbed cells as well as laminopathy patient cells. Principles of intracellular ROS generation and removalReactive oxygen species (ROS) are small, short-lived derivatives of molecular oxygen (O 2 ) of radical and non-radical nature (Halliwell and Gutteridge 2007 • ), nitrate radical (NO 3 • ) and many other nitrogen derivatives. ROS were originally described as molecular constituents of the defense system of phagocytic cells, but it has become clear that besides their damaging properties, they also function as signaling molecules and mediate a variety of other cellular responses including cell proliferation, differentiation, gene expression and migration (Lambeth 2004;Bartz and Piantadosi 2010). Intracellular ROS metabolismROS can be generated at various sites in the cell (Fig. 1A). This can be either deliberately, e.g. by NADPH oxidases (NOX), or as a byproduct, e.g. during normal cellular respiration in mitochondria (Babior 1999;Turrens 2003;Murphy 2009). The NOX family of NADPH oxidases (NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2) are proteins that transport electrons (e -) from NADPH across biological membranes (plasma or endomembranes) (Bedard and Krause 2007;Dupre-Crochet et al. 2013). The activation mechanisms and tissue distribution of the isoforms differ but they all use O 2 as e --acceptor, producing O 2•-. Through ROS generation, they play a role in many cellular processes including host defense, regulation of gene expression and cell differentiation (Bedard and Krause 2007). Despite their sometimes significant contribution to the global ROS pools, NOX are not the predominant source of intracellular ROS. Mitochondria are considered the major culprit, in particular under pathological conditions. Mitochondrial ROS are generated as a byproduct of the oxidative phosphorylation (OXPHOS, cf. below). Irrespective of its source, ROS production generally sta...

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Quantifying small molecule phenotypic effects using mitochondrial morpho-functional fingerprinting and machine learning

Cited by 42 publications

References 49 publications

Emerging therapies for mitochondrial diseases

Emerging therapies for mitochondrial diseases

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

Integrated High-Content Quantification of Intracellular ROS Levels and Mitochondrial Morphofunction

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