scholarly journals Localized Proteotoxic Stress in Mitochondrial Intermembrane Space and Matrix Elicits Sub-compartment Specific Response Pathways Governed by Unique Modulators

2020 ◽  
Author(s):  
Kannan Boosi Narayana Rao ◽  
Pratima Pandey ◽  
Rajasri Sarkar ◽  
Asmita Ghosh ◽  
Shemin Mansuri ◽  
...  
Keyword(s):  
Stress Response ◽  
Cellular Response ◽  
Protein Quality ◽  
Atp Synthesis ◽  
Specific Response ◽  
Intermembrane Space ◽  
Matrix Stress ◽  
Proteotoxic Stress ◽  
Tom Complex ◽  
The Matrix

AbstractThe complex double-membrane architecture of mitochondria is essential for its ATP synthesis function and divides the organelle into two sub-mitochondrial compartments, inter-membrane space (IMS) and matrix. The folding environments of IMS and matrix are significantly different owing to its dissimilar oxido-reductive environments and distinctly divergent protein quality control (PQC) machineries. Here, by inducing proteotoxic stress restricted to IMS or matrix by targeting three different stressor proteins, we show that the cellular response to IMS or matrix-localized misfolding stress is distinct and unique. IMS and matrix stress response pathways are quite effective in combatting stress despite significant stress-induced alteration in mitochondrial phenotypes. IMS misfolding stress leads to specific upregulation of IMS chaperones and components of TOM complex while matrix chaperones and cytosolic PQC components are upregulated during matrix stress. Notably, the amplitude of upregulation of mitochondrial chaperones is not overwhelming. We report that cells respond to mitochondrial stress through an adaptive mechanism by adjourning mitochondrial respiration while upregulating glycolysis as a compensatory pathway. We show that subunits of TOM complex act as specific modulators of IMS-stress response while Vms1 precisely modulates the matrix stress response.

scholarly journals Impact of Carcinogenic Chromium on the Cellular Response to Proteotoxic Stress

2019 ◽  
Vol 20 (19) ◽  
pp. 4901 ◽  
Author(s):  
Leonardo M. R. Ferreira ◽  
Teresa Cunha-Oliveira ◽  
Margarida C. Sobral ◽  
Patrícia L. Abreu ◽  
Maria Carmen Alpoim ◽  
...  
Keyword(s):  
Stress Response ◽  
Health Effects ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Chemical Properties ◽  
Adverse Health Effects ◽  
Proteotoxic Stress ◽  
Adverse Health ◽  
The Impact

Worldwide, several million workers are employed in the various chromium (Cr) industries. These workers may suffer from a variety of adverse health effects produced by dusts, mists and fumes containing Cr in the hexavalent oxidation state, Cr(VI). Of major importance, occupational exposure to Cr(VI) compounds has been firmly associated with the development of lung cancer. Counterintuitively, Cr(VI) is mostly unreactive towards most biomolecules, including nucleic acids. However, its intracellular reduction produces several species that react extensively with biomolecules. The diversity and chemical versatility of these species add great complexity to the study of the molecular mechanisms underlying Cr(VI) toxicity and carcinogenicity. As a consequence, these mechanisms are still poorly understood, in spite of intensive research efforts. Here, we discuss the impact of Cr(VI) on the stress response—an intricate cellular system against proteotoxic stress which is increasingly viewed as playing a critical role in carcinogenesis. This discussion is preceded by information regarding applications, chemical properties and adverse health effects of Cr(VI). A summary of our current understanding of cancer initiation, promotion and progression is also provided, followed by a brief description of the stress response and its links to cancer and by an overview of potential molecular mechanisms of Cr(VI) carcinogenicity.

scholarly journals Identification of ubiquitin Ser57 kinases regulating the oxidative stress response in yeast

2020 ◽  
Author(s):  
Nathaniel L. Hepowit ◽  
Kevin N. Pereira ◽  
Jessica M. Tumolo ◽  
Walter J. Chazin ◽  
Jason A. MacGurn
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Membrane Trafficking ◽  
Stress Responses ◽  
Protein Quality ◽  
Oxidative Stress Response ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Proteotoxic Stress ◽  
Substrate Proteins

ABSTRACTUbiquitination regulates many different cellular processes, including protein quality control, membrane trafficking, and stress responses. The diversity of ubiquitin functions in the cell is partly due to its ability to form chains with distinct linkages that can alter the fate of substrate proteins in unique ways. The complexity of the ubiquitin code is further enhanced by post-translational modifications on ubiquitin itself, the biological functions of which are not well understood. Here, we present genetic and biochemical evidence that serine 57 (Ser57) phosphorylation of ubiquitin functions in stress responses in Saccharomyces cerevisiae, including the oxidative stress response. We also identify and characterize the first known Ser57 ubiquitin kinases in yeast and human cells, and we report that two Ser57 ubiquitin kinases regulate the oxidative stress response in yeast. These studies implicate ubiquitin phosphorylation at the Ser57 position as an important modifier of ubiquitin function, particularly in response to proteotoxic stress.

scholarly journals Chemical-Genetic Interactions with the Proline Analog L-Azetidine-2-Carboxylic Acid in Saccharomyces cerevisiae

2020 ◽  
Vol 10 (12) ◽  
pp. 4335-4345
Author(s):  
Matthew D. Berg ◽  
Yanrui Zhu ◽  
Joshua Isaacson ◽  
Julie Genereaux ◽  
Raphaël Loll-Krippleber ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Amino Acid ◽  
Carboxylic Acid ◽  
Cellular Response ◽  
Protein Quality ◽  
Genetic Interaction ◽  
Genetic Interactions ◽  
Temperature Sensitive ◽  
Chemical Genetic ◽  
Proteotoxic Stress

Non-proteinogenic amino acids, such as the proline analog L-azetidine-2-carboxylic acid (AZC), are detrimental to cells because they are mis-incorporated into proteins and lead to proteotoxic stress. Our goal was to identify genes that show chemical-genetic interactions with AZC in Saccharomyces cerevisiae and thus also potentially define the pathways cells use to cope with amino acid mis-incorporation. Screening the yeast deletion and temperature sensitive collections, we found 72 alleles with negative chemical-genetic interactions with AZC treatment and 12 alleles that suppress AZC toxicity. Many of the genes with negative chemical-genetic interactions are involved in protein quality control pathways through the proteasome. Genes involved in actin cytoskeleton organization and endocytosis also had negative chemical-genetic interactions with AZC. Related to this, the number of actin patches per cell increases upon AZC treatment. Many of the same cellular processes were identified to have interactions with proteotoxic stress caused by two other amino acid analogs, canavanine and thialysine, or a mistranslating tRNA variant that mis-incorporates serine at proline codons. Alleles that suppressed AZC-induced toxicity functioned through the amino acid sensing TOR pathway or controlled amino acid permeases required for AZC uptake. Further suggesting the potential of genetic changes to influence the cellular response to proteotoxic stress, overexpressing many of the genes that had a negative chemical-genetic interaction with AZC suppressed AZC toxicity.

Abstract P334: Biophysical Properties Of A Novel Mitochondrial Large Ubiquitous Non-selective Amiloride Sensitive (luna) Current

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Enrique Balderas-Angeles ◽  
Thirupura Shankar ◽  
Anthony Balynas ◽  
Xue Yin ◽  
Dipayan Chaudhuri
Keyword(s):  
Ion Channels ◽  
Divalent Cations ◽  
Pressure Overload ◽  
Atp Synthesis ◽  
Intermembrane Space ◽  
Inner Mitochondrial Membrane ◽  
Patch Clamp Technique ◽  
Transport Chain ◽  
The Matrix ◽  
Established Cell

Inner mitochondrial membrane (IMM) ion channels and transporters account for communication of the matrix with the intermembrane space (IMS) and the cytosol. Transport of solutes and ions is keep under strict regulation mainly because small changes in solute concentrations could generate changes in mitochondrial volume or membrane potential (ΔΨ m ), interrupting ATP synthesis and leading to mitochondrial damage. The list of recently discovered mitochondrial ion channels has been growing in the past decades. In this work, using the patch-clamp technique we observed the activity of a novel mitochondrial current, named here LUNA current, in mitoplasts (IMM striped of outer membrane) from mouse liver, spleen, brain and heart, as well as established cell lines. LUNA is a novel non-selective cation current (K + >Na + >NMDG + >H + ) active at depolarized membrane potentials. The basal activity of whole-mitoplast LUNA currents from wild type mice hearts changed from 445±106 pA/pF to 1232±287 pA/pF upon chelation of external divalent cations (Ca 2+ and Mg 2+ ). Moreover, the activity of LUNA is independent of the mitochondrial Ca 2+ uniporter and of the non-selective reactive oxygen species modulator channel (ROMO1). In the heart, the activity of LUNA was enhanced in both the Tfam -KO mice, which have impaired electron transport chain (ETC) activity and are a model for mitochondrial cardiomyopathies, and mice with cardiac pressure overload due to transverse aortic constriction (TAC) compared to sham-operated hearts (729±197; n=7 vs 283±137 pA/pF). LUNA current is reversibly inhibited by amiloride with no sensitivity to the vast majority of common K + , Na + and Ca 2+ channels and ETC inhibitors. The molecular identity of mitochondrial LUNA current remains to be determined.

scholarly journals Identification of ubiquitin Ser57 kinases regulating the oxidative stress response in yeast

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Nathaniel L Hepowit ◽  
Kevin N Pereira ◽  
Jessica M Tumolo ◽  
Walter J Chazin ◽  
Jason A MacGurn
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Membrane Trafficking ◽  
Stress Responses ◽  
Protein Quality ◽  
Oxidative Stress Response ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Proteotoxic Stress ◽  
Substrate Proteins

Ubiquitination regulates many different cellular processes, including protein quality control, membrane trafficking, and stress responses. The diversity of ubiquitin functions in the cell is partly due to its ability to form chains with distinct linkages that can alter the fate of substrate proteins in unique ways. The complexity of the ubiquitin code is further enhanced by post-translational modifications on ubiquitin itself, the biological functions of which are not well understood. Here, we present genetic and biochemical evidence that serine 57 (Ser57) phosphorylation of ubiquitin functions in stress responses in Saccharomyces cerevisiae, including the oxidative stress response. We also identify and characterize the first known Ser57 ubiquitin kinases in yeast and human cells, and we report that two Ser57 ubiquitin kinases regulate the oxidative stress response in yeast. These studies implicate ubiquitin phosphorylation at the Ser57 position as an important modifier of ubiquitin function, particularly in response to proteotoxic stress.

Cell type-specific response to growth on soft materials

2005 ◽  
Vol 98 (4) ◽  
pp. 1547-1553 ◽  
Author(s):  
Penelope C. Georges ◽  
Paul A. Janmey
Keyword(s):  
Cellular Response ◽  
Biological Significance ◽  
Soft Materials ◽  
Cell Types ◽  
Specific Response ◽  
Mechanical Stimuli ◽  
The Matrix ◽  
Applied Forces ◽  
Tissue Systems

Many cell types respond to forces as acutely as they do to chemical stimuli, but the mechanisms by which cells sense mechanical stimuli and how these factors alter cellular structure and function in vivo are far less explored than those triggered by chemical ligands. Forces arise both from effects outside the cell and from mechanochemical reactions within the cell that generate stresses on the surface to which the cells adhere. Several recent reviews have summarized how externally applied forces may trigger a cellular response (Silver FH and Siperko LM. Crit Rev Biomed Eng 31: 255–331, 2003; Estes BT, Gimble JM, and Guilak F. Curr Top Dev Biol 60: 91–126, 2004; Janmey PA and Weitz DA. Trends Biochem Sci 29: 364–370, 2004). The purpose of this review is to examine the information available in the current literature describing the relationship between a cell and the rigidity of the matrix on which it resides. We will review recent studies and techniques that focus on substrate compliance as a major variable in cell culture studies. We will discuss the specificity of cell response to stiffness and discuss how this may be important in particular tissue systems. We will attempt to link the mechanoresponse to real pathological states and speculate on the possible biological significance of mechanosensing.

Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells

2019 ◽  
Vol 2 (1) ◽  
pp. 44-66 ◽  
Author(s):  
Dun-Xian Tan ◽  
Russel. J. Reiter
Keyword(s):  
Ischemia Reperfusion ◽  
Surface Membrane ◽  
Strong Association ◽  
Membrane Receptors ◽  
Melatonin Receptors ◽  
Metabolic Enzyme ◽  
Intermembrane Space ◽  
Antitumor Effects ◽  
The Matrix ◽  
Surprising Discovery

     It was a surprising discovery when mitochondria, as the power houses of cells, were also found to synthesize the potent mitochondrial targeted antioxidant, melatonin. The melatonin synthetic enzyme serotonin N-acetyltransferase (SNAT) was found in matrix and also in the intermembrane space of mitochondria. We hypothesize that the melatonin synthesis occurs in the matrix due to substrate (N-acetyl co-enzyme A) availability while the intermembrane space may serve as the recycling pool of SNAT to regulate the melatonin circadian rhythm. Another surprise was that the melatonin membrane receptors, including MT1 and MT2, were also present in mitochondria. The protective effects of melatonin against neuronal injury induced by brain ischemia/reperfusion were proven to be mainly mediated by mitochondrial melatonin receptors rather than the cell surface membrane receptors which is contrary to the classical principle. In addition, melatonin metabolic enzyme has also been identified in the mitochondria. This enzyme can convert melatonin to N-acetylserotonin to strengthen the antitumor effects of melatonin. Thus, mitochondria are the generator, battle ground and metabolic sites of melatonin. The biological significance of the strong association between mitochondria and melatonin should be intensively investigated. 

Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells

2019 ◽  
Vol 2 (1) ◽  
pp. 44-66 ◽  
Author(s):  
Dun-Xian Tan ◽  
Russel. J. Reiter
Keyword(s):  
Ischemia Reperfusion ◽  
Surface Membrane ◽  
Strong Association ◽  
Membrane Receptors ◽  
Melatonin Receptors ◽  
Metabolic Enzyme ◽  
Intermembrane Space ◽  
Antitumor Effects ◽  
The Matrix ◽  
Surprising Discovery

     It was a surprising discovery when mitochondria, as the power houses of cells, were also found to synthesize the potent mitochondrial targeted antioxidant, melatonin. The melatonin synthetic enzyme serotonin N-acetyltransferase (SNAT) was found in matrix and also in the intermembrane space of mitochondria. We hypothesize that the melatonin synthesis occurs in the matrix due to substrate (N-acetyl co-enzyme A) availability while the intermembrane space may serve as the recycling pool of SNAT to regulate the melatonin circadian rhythm. Another surprise was that the melatonin membrane receptors, including MT1 and MT2, were also present in mitochondria. The protective effects of melatonin against neuronal injury induced by brain ischemia/reperfusion were proven to be mainly mediated by mitochondrial melatonin receptors rather than the cell surface membrane receptors which is contrary to the classical principle. In addition, melatonin metabolic enzyme has also been identified in the mitochondria. This enzyme can convert melatonin to N-acetylserotonin to strengthen the antitumor effects of melatonin. Thus, mitochondria are the generator, battle ground and metabolic sites of melatonin. The biological significance of the strong association between mitochondria and melatonin should be intensively investigated. 

scholarly journals Exploring the multiple roles of guardian of the genome: P53

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Wasim Feroz ◽  
Arwah Mohammad Ali Sheikh
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Crucial Role ◽  
Cellular Response ◽  
Genotoxic Stress ◽  
Specific Response ◽  
Main Body ◽  
Repair System ◽  
Tumour Suppression

Abstract Background Cells have evolved balanced mechanisms to protect themselves by initiating a specific response to a variety of stress. The TP53 gene, encoding P53 protein, is one of the many widely studied genes in human cells owing to its multifaceted functions and complex dynamics. The tumour-suppressing activity of P53 plays a principal role in the cellular response to stress. The majority of the human cancer cells exhibit the inactivation of the P53 pathway. In this review, we discuss the recent advancements in P53 research with particular focus on the role of P53 in DNA damage responses, apoptosis, autophagy, and cellular metabolism. We also discussed important P53-reactivation strategies that can play a crucial role in cancer therapy and the role of P53 in various diseases. Main body We used electronic databases like PubMed and Google Scholar for literature search. In response to a variety of cellular stress such as genotoxic stress, ischemic stress, oncogenic expression, P53 acts as a sensor, and suppresses tumour development by promoting cell death or permanent inhibition of cell proliferation. It controls several genes that play a role in the arrest of the cell cycle, cellular senescence, DNA repair system, and apoptosis. P53 plays a crucial role in supporting DNA repair by arresting the cell cycle to purchase time for the repair system to restore genome stability. Apoptosis is essential for maintaining tissue homeostasis and tumour suppression. P53 can induce apoptosis in a genetically unstable cell by interacting with many pro-apoptotic and anti-apoptotic factors. Furthermore, P53 can activate autophagy, which also plays a role in tumour suppression. P53 also regulates many metabolic pathways of glucose, lipid, and amino acid metabolism. Thus under mild metabolic stress, P53 contributes to the cell’s ability to adapt to and survive the stress. Conclusion These multiple levels of regulation enable P53 to perform diversified roles in many cell responses. Understanding the complete function of P53 is still a work in progress because of the inherent complexity involved in between P53 and its target proteins. Further research is required to unravel the mystery of this Guardian of the genome “TP53”.

scholarly journals A discrete pathway for the transfer of intermembrane space proteins across the outer membrane of mitochondria

2014 ◽  
Vol 25 (25) ◽  
pp. 3999-4009 ◽  
Author(s):  
Agnieszka Gornicka ◽  
Piotr Bragoszewski ◽  
Piotr Chroscicki ◽  
Lena-Sophie Wenz ◽  
Christian Schulz ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Mitochondrial Membrane ◽  
Alternative Pathway ◽  
Intermembrane Space ◽  
Outer Mitochondrial Membrane ◽  
Membrane Translocation ◽  
Tom Complex ◽  
Precursor Proteins ◽  
Core Components

Mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria with the help of protein translocases. For the majority of precursor proteins, the role of the translocase of the outer membrane (TOM) and mechanisms of their transport across the outer mitochondrial membrane are well recognized. However, little is known about the mode of membrane translocation for proteins that are targeted to the intermembrane space via the redox-driven mitochondrial intermembrane space import and assembly (MIA) pathway. On the basis of the results obtained from an in organello competition import assay, we hypothesized that MIA-dependent precursor proteins use an alternative pathway to cross the outer mitochondrial membrane. Here we demonstrate that this alternative pathway involves the protein channel formed by Tom40. We sought a translocation intermediate by expressing tagged versions of MIA-dependent proteins in vivo. We identified a transient interaction between our model substrates and Tom40. Of interest, outer membrane translocation did not directly involve other core components of the TOM complex, including Tom22. Thus MIA-dependent proteins take another route across the outer mitochondrial membrane that involves Tom40 in a form that is different from the canonical TOM complex.

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