Dataset Information

Environmentally induced differential amplification of mitochondrial populations.

ABSTRACT: Resistance to the drug rutamycin, an inhibitor of mitochondrial ATPase, has been shown to be cytoplasmically inherited in a mouse fibroblast line (TL) on fusion of the cytoplast (enTL) with a nucleated recipient A9 [Lichtor & Getz (1978) Proc. Natl. Acad. Sci. U.S.A. 75, 324-328]. The cytoplasmic hybrid (cybrid) so formed may be readily grown in the presence [CY(+)] or absence [CY(-)] of rutamycin. The ATPase of TL mitochondria is similarly resistant to rutamycin whether grown in the presence or absence of antibiotic. The ATPase of CY(+) mitochondria is resistant to rutamycin, but CY(-) mitochondrial ATPase is sensitive to rutamycin. Nevertheless, CY(-) can be readily grown in rutamycin after a brief lag. The pH optima of mitochondrial ATPase are 8.0 for A9 and CY(-) cells and 7.5 for TL cells, whereas the pH optimum for CY(+) spans the optima of A9 and TL. The TL mitochondrial NADH-cytochrome c reductase is resistant to rotenone, whereas that of A9 mitochondria is sensitive to this agent. CY(-) and CY(+) mitochondria are sensitive and resistant respectively to rotenone. Growth of cybrids in rutamycin for 2 weeks results in a 2-3-fold increase in mitochondrial mass, measured on the basis of electron microscopic morphometry, mitochondrial membrane enzyme assays, mass of cardiolipin, and quantification of mitochondrial DNA. These data suggest that the cybrid harbours two populations of mitochondria and that the proportions of the two populations dramatically influence morphology, growth and mitochondrial phenotype in the cybrid. Selective pressure appears to induce these changes through the differential amplification of mitochondria.

SUBMITTER: Tonsgard JH

PROVIDER: S-EPMC1131752 | biostudies-other | 1990 Sep

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

Project description:Necroptosis is a form of programmed cell death that critically depends on RIP3 and MLKL. However, the contribution of mitochondria to necroptosis is still poorly understood. In the present study, we discovered that mitochondrial perturbations play a critical role in Smac mimetic/Dexamethasone (Dexa)-induced necroptosis independently of death receptor ligands. We demonstrate that the Smac mimetic BV6 and Dexa cooperate to trigger necroptotic cell death in acute lymphoblastic leukemia (ALL) cells that are deficient in caspase activation due to absent caspase-8 expression or pharmacological inhibition by the caspase inhibitor zVAD.fmk, since genetic silencing or pharmacological inhibition of RIP3 or MLKL significantly rescue BV6/Dexa-induced necroptosis. In addition, RIP3 or MLKL knockout mouse embryonic fibroblasts (MEFs) are protected from BV6/Dexa/zVAD.fmk-induced cell death. In contrast, antagonistic antibodies against the death receptor ligands TNFα, TRAIL or CD95 ligand fail to rescue BV6/Dexa-triggered cell death. Kinetic studies revealed that prior to cell death BV6/Dexa treatment causes hyperpolarization of the mitochondrial membrane potential (MMP) followed by loss of MMP, reactive oxygen species (ROS) production, Bak activation and disruption of mitochondrial respiration. Importantly, knockdown of Bak significantly reduces BV6/Dexa-induced loss of MMP and delays cell death, but not ROS production, whereas ROS scavengers attenuate Bak activation, indicating that ROS production occurs upstream of BV6/Dexa-mediated Bak activation. Consistently, BV6/Dexa treatment causes oxidative thiol modifications of Bak protein. Intriguingly, knockdown or knockout of RIP3 or MLKL protect ALL cells or MEFs from BV6/Dexa-induced ROS production, Bak activation, drop of MMP and disruption of mitochondrial respiration, demonstrating that these mitochondrial events depend on RIP3 and MLKL. Thus, mitochondria might serve as an amplification step in BV6/Dexa-induced necroptosis. These findings provide new insights into the role of mitochondrial dysfunctions during necroptosis and have important implications for the development of novel treatment approaches to overcome apoptosis resistance in ALL.

Project description:Background Density-dependent regulation is ubiquitous in population dynamics, and its potential interaction with environmental stochasticity complicates the characterization of the random component of population dynamics. Yet, this issue has not received attention commensurate with its relevance for descriptive and predictive modeling of population dynamics. Here we use a Bayesian modeling approach to investigate the contribution of density regulation to population variability in stochastic environments. Methods We analytically derive a formula linking the stationary variance of population abundance/density under Gompertz regulation in a stochastic environment with constant variance to the environmental variance and the strength of density feedback, to investigate whether and how density regulation affects the stationary variance. We examine through simulations whether the relationship between stationary variance and density regulation inferred analytically under the Gompertz model carries over to the Ricker model, widely used in population dynamics modeling. Results The analytical decomposition of the stationary variance under stochastic Gompertz dynamics implies higher variability for strongly regulated populations. Simulation results demonstrate that the pattern of increasing population variability with increasing density feedback found under the Gompertz model holds for the Ricker model as well, and is expected to be a general phenomenon with stochastic population models. We also analytically established and empirically validated that the square of the autoregressive parameter of the Gompertz model in AR(1) form represents the proportion of stationary variance due to density dependence. Discussion Our results suggest that neither environmental stochasticity nor density regulation can alone explain the patterns of population variability in stochastic environments, as these two components of temporal variation interact, with a tendency for density regulation to amplify the magnitude of environmentally induced population fluctuations. This finding has far-reaching implications for population viability. It implies that intense intra-specific resource competition increases the risk of environment-driven population collapse at high density, making opportune harvesting a sensible practice for improving the resistance of managed populations such as fish stocks to environmental perturbations. The separation of density-dependent and density-independent processes will help improve population dynamics modeling, while providing a basis for evaluating the relative importance of these two categories of processes that remains a topic of long-standing controversy among ecologists.

Dataset Information

Environmentally induced differential amplification of mitochondrial populations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets