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Interactome of activated BAX in Senescent Cells.

ABSTRACT: We aimed to identify the interactome of activated BAX in the mitochondria of senescent cells. Our goal was to understand which factors can directly mediate the formation of BAX pores in senescent cells.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung, Fibroblast

SUBMITTER: Karolina Szczepanowska

LAB HEAD: Karolina Szczepanowska

PROVIDER: PXD040018 | Pride | 2023-08-13

REPOSITORIES: Pride

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Apoptotic stress causes mtDNA release during senescence and drives the SASP.

Victorelli Stella S Salmonowicz Hanna H Chapman James J Martini Helene H Vizioli Maria Grazia MG Riley Joel S JS Cloix Catherine C Hall-Younger Ella E Machado Espindola-Netto Jair J Jurk Diana D Lagnado Anthony B AB Sales Gomez Lilian L Farr Joshua N JN Saul Dominik D Reed Rebecca R Kelly George G Eppard Madeline M Greaves Laura C LC Dou Zhixun Z Pirius Nicholas N Szczepanowska Karolina K Porritt Rebecca A RA Huang Huijie H Huang Timothy Y TY Mann Derek A DA Masuda Claudio Akio CA Khosla Sundeep S Dai Haiming H Kaufmann Scott H SH Zacharioudakis Emmanouil E Gavathiotis Evripidis E LeBrasseur Nathan K NK Lei Xue X Sainz Alva G AG Korolchuk Viktor I VI Adams Peter D PD Shadel Gerald S GS Tait Stephen W G SWG Passos João F JF

Nature 20231011 7983

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we ...[more]

PMID: 37821702

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VDAC2 promotes BAX apoptotic activity

Project description:Intrinsic apoptosis is critical for normal physiology including the prevention of tumor formation. BAX and BAK, which are essential for mediating this process and for the cytotoxic action of many anti-cancer drugs, are thought to be regulated through similar mechanisms and act redundantly to drive apoptosis. Here we have established the various mitochondrial complexes that contain VDAC1, VDAC2, VDAC3 and BAX or BAK.

2018-10-29 | PXD011195 | Pride

The Conformational Stability of Pro-apoptotic BAX is Dictated by Discrete Residues of the Protein Core

Project description:BAX is a pro-apoptotic member of the BCL-2 family, which regulates the balance between cellular life and death. During homeostasis, BAX predominantly resides in the cytosol as a latent monomer but, in response to stress, transforms into an oligomeric protein that permeabilizes the mitochondria, leading to cell death. Because renegade BAX activation poses a grave risk to the cell, the architecture of BAX must ensure monomeric stability yet simultaneously enable conformational change upon stress signaling. The specific structural features that afford both stability and dynamic flexibility remain ill-defined and represent a critical control point of BAX regulation. Here, we identified a nexus of interactions involving four discrete residues of the BAX core α5 helix that are individually essential to maintaining the structure and latency of monomeric BAX and are collectively required for dimeric assembly. We compared the HDX MS profile of full-length recombinant wild-type BAX in solution with that of the BAX L113A, F114A, Y115A, and F116A single point mutants. In each case, we observed striking, regiospecific consequences of replacing the bulky hydrophobic residue with alanine. We also compared HDX in a construct of α2-α5 for the wt protein as well as mutants. The dual yet distinct roles of these residues reveals the intricacy of BAX conformational regulation and opportunities for therapeutic modulation.

2021-08-26 | PXD024479 | Pride

Covalent Inhibition of Pro-Apoptotic BAX

Project description:BCL-2-associated X protein (BAX) is a promising therapeutic target for activating or restraining apoptosis in diseases of pathologic cell survival or cell death, respectively. In response to cellular stress, BAX transforms from a quiescent cytosolic monomer into a toxic oligomer that permeabilizes the mitochondria, releasing key apoptogenic factors. The mitochondrial lipid trans-2-hexadecenal (t-2-hex) sensitizes BAX activation by covalent derivatization of cysteine 126 (C126). Here, we performed a disulfide tethering screen to discover C126-reactive molecules that modulate BAX activity. We identified covalent BAX inhibitor 1 (CBI1) as a compound that selectively derivatizes BAX at C126 and inhibits BAX activation by the physiologic ligand tBID and point mutagenesis. Biochemical and structural analyses revealed that CBI1 can inhibit BAX by a dual mechanism of action: conformational constraint and competitive blockade of lipidation. Hydrogen deuterium exchange mass spectrometry (HDX MS) showed that CBI1 derivatization of BAX C126 reversed the conformational changes caused by the auto-activating mutant F116A These data inform a pharmacologic strategy for blocking apoptosis in diseases of unwanted cell death by covalent targeting of BAX C126.

2024-01-19 | PXD040917 | Pride

MCL-1 Drives a Metabolic Dependency on Fatty Acid Oxidation in Cancer Independent of its Anti-Apoptotic Function

Project description:MCL-1 is an anti-apoptotic BCL-2 family protein essential to the survival of diverse cell types and is a major driver of cancer and chemoresistance. The unique oncogenic supremacy of MCL-1, as compared to its anti-apoptotic homologs, suggests that it has additional functions to complement apoptotic suppression. Here, we find that MCL-1-dependent hematologic cancer cells selectively rely on fatty acid oxidation (FAO) as a fuel source due to metabolic wiring enforced by MCL-1 itself. Importantly, this metabolic function is independent of anti-apoptotic activity, as demonstrated by metabolomic, proteomic, and genomic profiling of MCL-1-dependent leukemia cells lacking pro-apoptotic BAX and BAK. Genetic deletion of Mcl-1 results in selective downregulation of proteins within the FAO pathway, accompanied by cell death upon glucose deprivation despite apoptotic blockade. Our data reveal that MCL-1 drives a programmatic dependency on FAO in hematologic cancer cells, which can be effectively targeted by FAO inhibitors.

2022-10-03 | PXD031364 | Pride

Methylome analysis of nerd1-1 mutant seedlings

Project description:DNA methylation profiling in nerd1-1 mutant seedlings 2 biological replicates in dye-swap - MeDIP-chip

2012-12-20 | E-GEOD-35344 | biostudies-arrayexpress

Methylome analysis of Arabidopsis thaliana Col-0 primary root

Project description:DNA methylation profiling in Col-0 wild type primary root 2 biological replicates in dye-swap - MeDIP-chip

2012-12-07 | E-GEOD-36750 | biostudies-arrayexpress

Methylome analysis of epiRIL344 BC1-S1 to BC1-S6 aerial part

Project description:DNA methylation profiling in epiRIL344 BC1-S1 to BC1-S6 aerial part (epiRIL344_BC1-S1 - epiRIL344_BC1-S2 - epiRIL344_BC1-S3 - epiRIL344_BC1-S4 - epiRIL344_BC1-S5 - epiRIL344_BC1-S6) Keywords: Genome binding/occupancy profiling by genome tiling array 1 biological replicate in dye-swap - MeDIP-chip

2012-09-03 | E-GEOD-37285 | biostudies-arrayexpress

Transcriptome and methylome analyses of the nerd1-1 mutant

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2012-12-20 | E-GEOD-35346 | biostudies-arrayexpress

Methylome analysis of 123 epiRILs, WT and ddm1 mutant aerial part

Project description:DNA methylation profiling in 123 epiRILs, WT and ddm1 mutant aerial part (epiRIL008 - epiRIL011 - epiRIL014 - epiRIL018 - epiRIL020 - epiRIL024 - epiRIL036 - epiRIL046 - epiRIL052 - epiRIL053 - epiRIL054 - epiRIL055 - epiRIL060 - epiRIL062 - epiRIL064 - epiRIL069 - epiRIL070 - epiRIL071 - epiRIL073 - epiRIL092 - epiRIL093 - epiRILv94 - epiRIL095 - epiRIL098 - epiRIL099 - epiRIL101 - epiRIL108 - epiRIL112 - epiRIL114 - epiRIL118 - epiRIL122 - epiRIL137 - epiRIL144 - epiRIL147 - epiRIL148 - epiRIL150 - epiRIL159 - epiRIL164 - epiRIL166 - epiRIL169 - epiRIL170 - epiRIL172 - epiRIL183 - epiRIL193 - epiRIL195 - - epiRIL202 - epiRIL208 - epiRIL215 - epiRIL216 - epiRIL218 - epiRIL222 - epiRIL225 - epiRIL229 - epiRIL232 - epiRIL238 - epiRIL244 - epiRIL252 - epiRIL257 - epiRIL258 - epiRIL260 - epiRIL262 - epiRIL275 - epiRIL276 - epiRIL277 - epiRIL297 - epiRIL305 - epiRIL315 - epiRIL323 - epiRIL326 - epiRIL333 - epiRIL340 - epiRIL344 - epiRIL350 - epiRIL356 - epiRIL362 - epiRIL361 - epiRIL363 - epiRIL366 - epiRIL368 - epiRIL371 - epiRIL375 - epiRIL391 - epiRIL393 - epiRIL394 - epiRIL400 - epiRIL408 - epiRIL410 - epiRIL425 - epiRIL432 - epiRIL434 - epiRIL437 - epiRIL438 - epiRIL439 - epiRIL454 - epiRIL458 - epiRIL466 - epiRIL467 - epiRIL471 - epiRIL473 - epiRIL477 - epiRIL480 - epiRIL488 - epiRIL492 - epiRIL493 - epiRIL494 - epiRIL495 - epiRIL497 - epiRIL500 - epiRIL503 - epiRIL506 - epiRIL508 - epiRIL523 - epiRIL538 - epiRIL539 - epiRIL556 - epiRIL558 - epiRIL559 - epiRIL561 - epiRIL567 - epiRIL570 - epiRIL572 - epiRIL573 - epiRIL579 - wt - ddm1 mutant) Keywords: Genome binding/occupancy profiling by genome tiling array 1 biological replicate in dye-swap - MeDIP-chip

2012-09-03 | E-GEOD-37284 | biostudies-arrayexpress

A landscape of mouse mitochondrial small non-coding RNAs

Project description:Small noncoding RNAs (ncRNAs), particularly miRNAs, play key roles in a plethora of biological processes both in health and disease. Although largely operative in the cytoplasm, emerging data indicate their shuttling in different subcellular compartments. Given the central role of mitochondria in cellular homeostasis, here we systematically profiled their small ncRNAs content across mouse tissues that largely rely on mitochondria functioning. The ubiquitous presence of piRNAs in mitochondria (mitopiRNA) of somatic tissues is reported for the first time, supporting the idea of a strong and general connection between mitochondria biology and piRNA pathways. Then, we found groups of tissue-shared and tissue-specific mitochondrial miRNAs (mitomiRs), potentially related to the “basic” or “cell context dependent” biology of mitochondria. Overall, this large data platform will be useful to deepen the knowledge about small ncRNAs processing and their governed regulatory networks contributing to mitochondria functions.

2023-09-01 | E-MTAB-12911 | biostudies-arrayexpress

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