Dataset Information

Mitochondrial origins of fractional control in regulated cell death.

ABSTRACT: Individual cells in clonal populations often respond differently to environmental changes; for binary phenotypes, such as cell death, this can be measured as a fractional response. These types of responses have been attributed to cell-intrinsic stochastic processes and variable abundances of biochemical constituents, such as proteins, but the influence of organelles is still under investigation. We use the response to TNF-related apoptosis inducing ligand (TRAIL) and a new statistical framework for determining parameter influence on cell-to-cell variability through the inference of variance explained, DEPICTIVE, to demonstrate that variable mitochondria abundance correlates with cell survival and determines the fractional cell death response. By quantitative data analysis and modeling we attribute this effect to variable effective concentrations at the mitochondria surface of the pro-apoptotic proteins Bax/Bak. Further, our study suggests that inhibitors of anti-apoptotic Bcl-2 family proteins, used in cancer treatment, may increase the diversity of cellular responses, enhancing resistance to treatment.

SUBMITTER: Santos LC

PROVIDER: S-EPMC6428895 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mitochondrial origins of fractional control in regulated cell death.

Santos Luís C LC Vogel Robert R Chipuk Jerry E JE Birtwistle Marc R MR Stolovitzky Gustavo G Meyer Pablo P

Nature communications 20190321 1

Individual cells in clonal populations often respond differently to environmental changes; for binary phenotypes, such as cell death, this can be measured as a fractional response. These types of responses have been attributed to cell-intrinsic stochastic processes and variable abundances of biochemical constituents, such as proteins, but the influence of organelles is still under investigation. We use the response to TNF-related apoptosis inducing ligand (TRAIL) and a new statistical framework ...[more]

PMID: 30899020

Similar Datasets

Project description:BackgroundCytoplasmic male sterility (CMS) is a maternally inherited failure to produce functional pollen that most commonly results from expression of novel, chimeric mitochondrial genes. In Zea mays, cytoplasmic male sterility type S (CMS-S) is characterized by the collapse of immature, bi-cellular pollen. Molecular and cellular features of developing CMS-S and normal (N) cytoplasm pollen were compared to determine the role of mitochondria in these differing developmental fates.ResultsTerminal deoxynucleotidyl transferase dUTP nick end labeling revealed both chromatin and nuclear fragmentation in the collapsed CMS-S pollen, demonstrating a programmed cell death (PCD) event sharing morphological features with mitochondria-signaled apoptosis in animals. Maize plants expressing mitochondria-targeted green fluorescent protein (GFP) demonstrated dynamic changes in mitochondrial morphology and association with actin filaments through the course of N-cytoplasm pollen development, whereas mitochondrial targeting of GFP was lost and actin filaments were disorganized in developing CMS-S pollen. Immunoblotting revealed significant developmental regulation of mitochondrial biogenesis in both CMS-S and N mito-types. Nuclear and mitochondrial genome encoded components of the cytochrome respiratory pathway and ATP synthase were of low abundance at the microspore stage, but microspores accumulated abundant nuclear-encoded alternative oxidase (AOX). Cytochrome pathway and ATP synthase components accumulated whereas AOX levels declined during the maturation of N bi-cellular pollen. Increased abundance of cytochrome pathway components and declining AOX also characterized collapsed CMS-S pollen. The accumulation and robust RNA editing of mitochondrial transcripts implicated translational or post-translational control for the developmentally regulated accumulation of mitochondria-encoded proteins in both mito-types.ConclusionsCMS-S pollen collapse is a PCD event coincident with developmentally programmed mitochondrial events including the accumulation of mitochondrial respiratory proteins and declining protection against mitochondrial generation of reactive oxygen species.

Project description:In this chapter, the various subroutines of regulated cell death are neatly described by highlighting apoptosis and subforms of regulated necrosis such as necroptosis, ferroptosis, pyroptosis, and NETosis. Typically, all forms of regulated necrosis are defined by finite rupture of the plasma cell membrane. Apoptosis is characterized by an enzymatic machinery that consists of caspases which cause the morphologic features of this type of cell death. Mechanistically, apoptosis can be instigated by two major cellular signalling pathways: an intrinsic pathway that is initiated inside cells by mitochondrial release of pro-apoptotic factors or an extrinsic pathway that is initiated at the cell surface by various death receptors. In necroptosis, the biochemical processes are distinct from those found in apoptosis; in particular, there is no caspase activation. As such, necroptosis is a kinase-mediated cell death that relies on “receptor-interacting protein kinase 3” which mediates phosphorylation of the pseudokinase “mixed lineage kinase domain-like protein.” While ferroptosis is an iron-dependent, oxidative form of regulated necrosis that is biochemically characterized by accumulation of ROS from iron metabolism, oxidase activity, and lipid peroxidation products, pyroptosis is defined as a form of cell death (predominantly of phagocytes) that develops during inflammasome activation and is executed by caspase-mediated cleavage of the pore-forming protein gasdermin D. Finally, NETosis refers to a regulated death of neutrophils that is characterized by the release of chromatin-derived weblike structures released into the extracellular space. The chapter ends up with a discussion on the characteristic feature of regulated necrosis: the passive release of large amounts of constitutive DAMPs as a consequence of final plasma membrane rupture as well as the active secretion of inducible DAMPs earlier during the dying process. Notably, per cell death subroutine, the active secretion of inducible DAMPs varies, thereby determining different immunogenicity of dying cells.

Dataset Information

Mitochondrial origins of fractional control in regulated cell death.

Publications

Mitochondrial origins of fractional control in regulated cell death.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets