A2E Inhibits Mitochondrial Function, Causes the Release of Pro-Apoptotic Proteins and Induces Apoptosis in Mammalian Cells

2001 ◽  
pp. 223-233 ◽  
Author(s):  
Christian Grimm ◽  
Marianne Suter ◽  
Andreas Wenzel ◽  
Marja Jäättela ◽  
Peter Esser ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Mammalian Cells ◽  
Apoptotic Proteins

scholarly journals Primary and Secondary Drug Screening Assays for Friedreich Ataxia

2011 ◽  
Vol 17 (3) ◽  
pp. 303-313 ◽  
Author(s):  
M. Grazia Cotticelli ◽  
Lynn Rasmussen ◽  
Nicole L. Kushner ◽  
Sara McKellip ◽  
Melinda Ingrum Sosa ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
High Throughput Screening ◽  
Mammalian Cells ◽  
Friedreich Ataxia ◽  
Krebs Cycle ◽  
C2c12 Cells ◽  
Transport Chain ◽  
Screening Assays ◽  
Yeast Mutants

Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardiodegenerative disorder for which there are no proven effective treatments. FRDA is caused by decreased expression and/or function of the protein frataxin. Frataxin chaperones iron in the mitochondrial matrix for the assembly of iron–sulfur clusters (ISCs), which are prosthetic groups critical for the function of the Krebs cycle and the mitochondrial electron transport chain (ETC). Decreased expression of frataxin or the yeast frataxin orthologue, Yfh1p, is associated with decreased ISC assembly, mitochondrial iron accumulation, and increased oxidative stress, all of which contribute to mitochondrial dysfunction. Using yeast depleted of Yfh1p, a high-throughput screening (HTS) assay was developed in which mitochondrial function was monitored by reduction of the tetrazolium dye WST-1 in a growth medium with a respiration-only carbon source. Of 101 200 compounds screened, 302 were identified that effectively rescue mitochondrial function. To confirm activities in mammalian cells and begin understanding mechanisms of action, secondary screening assays were developed using murine C2C12 cells and yeast mutants lacking specific complexes of the ETC, respectively. The compounds identified in this study have potential relevance for other neurodegenerative disorders associated with mitochondrial dysfunction, such as Parkinson disease.

Mitochondrial Function and Biogenesis in Cultured Mammalian Cells without Functional Respiratory Chains

1992 ◽  
pp. 97-105
Author(s):  
Coby Van den Bogert ◽  
Nicole H. Herzberg ◽  
Johannes N. Spelbrink ◽  
Henk L. Dekker ◽  
Brenda H. Groen ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Mammalian Cells ◽  
Respiratory Chains

scholarly journals RCAN1 Regulates Mitochondrial Function and Increases Susceptibility to Oxidative Stress in Mammalian Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Heshan Peiris ◽  
Daphne Dubach ◽  
Claire F. Jessup ◽  
Petra Unterweger ◽  
Ravinarayan Raghupathi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Function ◽  
Neurodegenerative Disorders ◽  
Mammalian Cells ◽  
Cell Function ◽  
Cellular Energy ◽  
Mitochondrial Ros ◽  
Ros Accumulation ◽  
The Brain ◽  
Increased Susceptibility

Mitochondria are the primary site of cellular energy generation and reactive oxygen species (ROS) accumulation. Elevated ROS levels are detrimental to normal cell function and have been linked to the pathogenesis of neurodegenerative disorders such as Down's syndrome (DS) and Alzheimer’s disease (AD). RCAN1 is abundantly expressed in the brain and overexpressed in brain of DS and AD patients. Data from nonmammalian species indicates that increased RCAN1 expression results in altered mitochondrial function and that RCAN1 may itself regulate neuronal ROS production. In this study, we have utilized mice overexpressing RCAN1RCAN1oxand demonstrate an increased susceptibility of neurons from these mice to oxidative stress. Mitochondria from these mice are more numerous and smaller, indicative of mitochondrial dysfunction, and mitochondrial membrane potential is altered under conditions of oxidative stress. We also generated a PC12 cell line overexpressing RCAN1PC12RCAN1. Similar toRCAN1oxneurons,PC12RCAN1cells have an increased susceptibility to oxidative stress and produce more mitochondrial ROS. This study demonstrates that increasing RCAN1 expression alters mitochondrial function and increases the susceptibility of neurons to oxidative stress in mammalian cells. These findings further contribute to our understanding of RCAN1 and its potential role in the pathogenesis of neurodegenerative disorders such as AD and DS.

scholarly journals A method to identify and validate mitochondrial modulators using mammalian cells and the worm C. elegans

2014 ◽  
Vol 4 (1) ◽  
Author(s):  
Pénélope A. Andreux ◽  
Laurent Mouchiroud ◽  
Xu Wang ◽  
Virginija Jovaisaite ◽  
Adrienne Mottis ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Mammalian Cells ◽  
Screening Strategy ◽  
Culture Conditions ◽  
Metabolic Effects ◽  
Mitochondrial Activity ◽  
Exact Nature ◽  
C Elegans ◽  
Beneficial Effects ◽  
Multiple Parameters

Abstract Mitochondria are semi-autonomous organelles regulated by a complex network of proteins that are vital for many cellular functions. Because mitochondrial modulators can impact many aspects of cellular homeostasis, their identification and validation has proven challenging. It requires the measurement of multiple parameters in parallel to understand the exact nature of the changes induced by such compounds. We developed a platform of assays scoring for mitochondrial function in two complementary models systems, mammalian cells and C. elegans. We first optimized cell culture conditions and established the mitochondrial signature of 1,200 FDA-approved drugs in liver cells. Using cell-based and C. elegans assays, we further defined the metabolic effects of two pharmacological classes that emerged from our hit list, i.e. imidazoles and statins. We found that these two drug classes affect respiration through different and cholesterol-independent mechanisms in both models. Our screening strategy enabled us to unequivocally identify compounds that have toxic or beneficial effects on mitochondrial activity. Furthermore, the cross-species approach provided novel mechanistic insight and allowed early validation of hits that act on mitochondrial function.

scholarly journals Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals

2017 ◽  
Vol 216 (7) ◽  
pp. 2027-2045 ◽  
Author(s):  
Pedro M. Quirós ◽  
Miguel A. Prado ◽  
Nicola Zamboni ◽  
Davide D’Amico ◽  
Robert W. Williams ◽  
...  
Keyword(s):  
Stress Response ◽  
Mitochondrial Function ◽  
Mammalian Cells ◽  
Ribosomal Proteins ◽  
Cellular Metabolism ◽  
Mitochondrial Diseases ◽  
Mitochondrial Translation ◽  
Mitochondrial Stress ◽  
Main Regulator

Mitochondrial stress activates a mitonuclear response to safeguard and repair mitochondrial function and to adapt cellular metabolism to stress. Using a multiomics approach in mammalian cells treated with four types of mitochondrial stressors, we identify activating transcription factor 4 (ATF4) as the main regulator of the stress response. Surprisingly, canonical mitochondrial unfolded protein response genes mediated by ATF5 are not activated. Instead, ATF4 activates the expression of cytoprotective genes, which reprogram cellular metabolism through activation of the integrated stress response (ISR). Mitochondrial stress promotes a local proteostatic response by reducing mitochondrial ribosomal proteins, inhibiting mitochondrial translation, and coupling the activation of the ISR with the attenuation of mitochondrial function. Through a trans–expression quantitative trait locus analysis, we provide genetic evidence supporting a role for Fh1 in the control of Atf4 expression in mammals. Using gene expression data from mice and humans with mitochondrial diseases, we show that the ATF4 pathway is activated in vivo upon mitochondrial stress. Our data illustrate the value of a multiomics approach to characterize complex cellular networks and provide a versatile resource to identify new regulators of mitochondrial-related diseases.

scholarly journals Prohibitins and Ras2 protein cooperate in the maintenance of mitochondrial function during yeast aging.

2003 ◽  
Vol 50 (4) ◽  
pp. 1039-1056 ◽  
Author(s):  
Paul A Kirchman ◽  
Michael V Miceli ◽  
Roger L West ◽  
James C Jiang ◽  
Sangkyu Kim ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Life Span ◽  
Mitochondrial Function ◽  
Mammalian Cells ◽  
Mitochondrial Morphology ◽  
Inner Mitochondrial Membrane ◽  
Yeast Saccharomyces Cerevisiae ◽  
Replicative Life Span ◽  
Mitochondrial Integrity ◽  
Yeast Aging

The yeast Saccharomyces cerevisiae has a finite replicative life span. Yeasts possess two prohibitins, Phb1p and Phb2p, in similarity to mammalian cells. These proteins are located in the inner mitochondrial membrane, where they are involved in the processing of newly-synthesized membrane proteins. We demonstrate that the elimination of one or both of the prohibitin genes in yeast markedly diminished the replicative life span of cells that lack fully-functional mitochondria, while having no effect on cells with functioning mitochondria. This deleterious effect was suppressed by the deletion of the RAS2 gene. The expression of PHB1 and PHB2 declined gradually up to 5-fold during the life span. Cells in which PHB1 was deleted in conjunction with the absence of a mitochondrial genome displayed remarkable changes in mitochondrial morphology, distribution, and inheritance. This loss of mitochondrial integrity was not seen in cells devoid of PHB1 but possessing an intact mitochondrial genome. In a subset of the cells, the changes in mitochondrial integrity were associated with increased production of reactive oxygen species, which co-localized with the altered mitochondria. The mitochondrial deficits described above were all suppressed by deletion of RAS2. Our data, together with published information, are interpreted to provide a unified view of the role of the prohibitins in yeast aging. This model posits that the key initiating event is a decline in mitochondrial function, which leads to progressive oxidative damage that is exacerbated in the absence of the prohibitins. This aggravation of the initial damage is ameliorated by the suppression of the production of mitochondrial proteins in the absence of Ras2p signaling of mitochondrial biogenesis.

scholarly journals Central roles of apoptotic proteins in mitochondrial function

Oncogene ◽  
2012 ◽  
Vol 32 (22) ◽  
pp. 2703-2711 ◽  
Author(s):  
S M Kilbride ◽  
J H M Prehn
Keyword(s):  
Mitochondrial Function ◽  
Apoptotic Proteins

The regulation of mitochondrial function in mammalian cells by Ca2+ ions

1988 ◽  
Vol 16 (4) ◽  
pp. 523-527 ◽  
Author(s):  
JAMES G. McCORMACK ◽  
RICHARD M. DENTON
Keyword(s):  
Mitochondrial Function ◽  
Mammalian Cells

scholarly journals Historical perspective: phosphatidylserine and phosphatidylethanolamine from the 1800s to the present

2018 ◽  
Vol 59 (6) ◽  
pp. 923-944 ◽  
Author(s):  
Jean E. Vance
Keyword(s):  
Mitochondrial Function ◽  
Mammalian Cells ◽  
Isotope Labeling ◽  
Threshold Level ◽  
Ether Lipids ◽  
Membrane Contact Sites ◽  
Outer Leaflet ◽  
Physiological Processes ◽  
Membrane Contact

This article provides a historical account of the discovery, chemistry, and biochemistry of two ubiquitous phosphoglycerolipids, phosphatidylserine (PS) and phosphatidylethanolamine (PE), including the ether lipids. In addition, the article describes the biosynthetic pathways for these phospholipids and how these pathways were elucidated. Several unique functions of PS and PE in mammalian cells in addition to their ability to define physical properties of membranes are discussed. For example, the translocation of PS from the inner to the outer leaflet of the plasma membrane of cells occurs during apoptosis and during some other specific physiological processes, and this translocation is responsible for profound life-or-death events. Moreover, mitochondrial function is severely impaired when the PE content of mitochondria is reduced below a threshold level. The discovery and implications of the existence of membrane contact sites between the endoplasmic reticulum and mitochondria and their relevance for PS and PE metabolism, as well as for mitochondrial function, are also discussed. Many of the recent advances in these fields are due to the use of isotope labeling for tracing biochemical pathways. In addition, techniques for disruption of specific genes in mice are now widely used and have provided major breakthroughs in understanding the roles and metabolism of PS and PE in vivo.

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