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Article ; Online: CMLS forum reviews: mitochondrial damage control.

Hamacher-Brady, Anne

Cellular and molecular life sciences : CMLS

2021 Volume 78, Issue 8, Page(s) 3763–3765

Abstract: Mitochondria supply cellular energy through oxidative phosphorylation and fulfill numerous additional functions that are fundamental to cellular homeostasis and stress responses. Mitochondrial malfunction, arising from inherent defects of the organelle ... ...

Abstract	Mitochondria supply cellular energy through oxidative phosphorylation and fulfill numerous additional functions that are fundamental to cellular homeostasis and stress responses. Mitochondrial malfunction, arising from inherent defects of the organelle itself, aging, or acute or chronic stress, can cause substantial damage to organismal health. For instance, mitochondrial malfunction contributes to inflammation, neurodegeneration, tumorigenesis and cardiovascular diseases. Therefore, various quality control mechanisms exist that support a functional mitochondrial organelle compartment. The CMLS Forum Reviews introduced here present a collection of articles covering select topics on basic mechanisms and pathophysiological contexts of mitochondrial damage control.
MeSH term(s)	Animals ; Apoptosis ; Autophagy ; Humans ; Mitochondria/metabolism ; Mitochondria/pathology ; Mitochondrial Dynamics ; Mitophagy ; Neoplasms/metabolism ; Neoplasms/pathology ; Unfolded Protein Response
Language	English
Publishing date	2021-03-12
Publishing country	Switzerland
Document type	Editorial ; Introductory Journal Article
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-021-03804-y
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Article: CMLS forum reviews: mitochondrial damage control

Hamacher-Brady, Anne

Cellular and molecular life sciences. 2021 Apr., v. 78, no. 8

2021

Abstract	Mitochondria supply cellular energy through oxidative phosphorylation and fulfill numerous additional functions that are fundamental to cellular homeostasis and stress responses. Mitochondrial malfunction, arising from inherent defects of the organelle itself, aging, or acute or chronic stress, can cause substantial damage to organismal health. For instance, mitochondrial malfunction contributes to inflammation, neurodegeneration, tumorigenesis and cardiovascular diseases. Therefore, various quality control mechanisms exist that support a functional mitochondrial organelle compartment. The CMLS Forum Reviews introduced here present a collection of articles covering select topics on basic mechanisms and pathophysiological contexts of mitochondrial damage control.
Keywords	carcinogenesis ; energy ; homeostasis ; inflammation ; mitochondria ; neurodegenerative diseases ; oxidative phosphorylation ; quality control
Language	English
Dates of publication	2021-04
Size	p. 3763-3765.
Publishing place	Springer International Publishing
Document type	Article
Note	NAL-AP-2-clean ; Editorial
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-021-03804-y
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Autophagy regulation and integration with cell signaling.

Hamacher-Brady, Anne

Antioxidants & redox signaling

2012 Volume 17, Issue 5, Page(s) 756–765

Abstract: Significance: Study over the past decade has revealed the critical role of autophagy in homeostatic and stress cell signaling. Autophagy is an intracellular process whereby double-membrane structures termed autophagosomes deliver cellular components to ... ...

Abstract	Significance: Study over the past decade has revealed the critical role of autophagy in homeostatic and stress cell signaling. Autophagy is an intracellular process whereby double-membrane structures termed autophagosomes deliver cellular components to lysosomes for their degradation. Recent advances: Targets of specific autophagy range from proteins to protein aggregates to organelles and intracellular pathogens. Accordingly, autophagy fulfills numerous physiological roles and its deregulation can underlie disease. Critical issues: Although autophagy is orchestrated by common core machinery, the discovery of distinct and highly varied autophagic programs reveals autophagy as a heterogeneous phenomenon, capable of specificity. Future directions: Here the molecular mechanisms of mammalian autophagy are reviewed, including recent advances in unraveling of its machinery, specificity, and regulation. With our increasing knowledge of autophagy mechanisms and signaling roles, we begin to work towards a systems understanding of autophagy.
MeSH term(s)	Animals ; Autophagy ; Humans ; Signal Transduction
Language	English
Publishing date	2012-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1483836-9
ISSN	1557-7716 ; 1523-0864
ISSN (online)	1557-7716
ISSN	1523-0864
DOI	10.1089/ars.2011.4410
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Zs.A 5488: Show issues

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Article ; Online: Study of Microbial Extracellular Vesicles:Separation by Density Gradients, Protection Assays and Labelling for Live Tracking.

Coelho, Carolina / Vij, Raghav / Smith, Daniel Q / Brady, Nathan R / Hamacher-Brady, Anne / Casadevall, Arturo

Bio-protocol

2020 Volume 10, Issue 2, Page(s) e3502

Abstract: Extracellular vesicles (EVs) are produced by all domains of life including Bacteria, Archaea and Eukarya. EVs are critical for cellular physiology and contain varied cargo: virulence factors, cell wall remodeling enzymes, extracellular matrix components ... ...

Abstract	Extracellular vesicles (EVs) are produced by all domains of life including Bacteria, Archaea and Eukarya. EVs are critical for cellular physiology and contain varied cargo: virulence factors, cell wall remodeling enzymes, extracellular matrix components and even nucleic acids and metabolites. While various protocols for isolating EVs have been established for mammalian cells, the field is actively developing tools to study EVs in other organisms. In this protocol we describe our methods to perform density gradient purification of EVs in bacterial cells, allowing for separation of EV subpopulations, followed by protection assays for EV cargo characterization. Furthermore, we devised a protocol which incorporates a fluorescent conjugate of fatty acids into EVs, the first to allow
Language	English
Publishing date	2020-01-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325 ; 2331-8325
ISSN (online)	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.3502
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Article ; Online: Endolysosomal Targeting of Mitochondria Is Integral to BAX-Mediated Mitochondrial Permeabilization during Apoptosis Signaling.

Wang, Tim Sen / Coppens, Isabelle / Saorin, Anna / Brady, Nathan Ryan / Hamacher-Brady, Anne

Developmental cell

2020 Volume 53, Issue 6, Page(s) 627–645.e7

Abstract: Mitochondrial outer membrane permeabilization (MOMP) is a core event in apoptosis signaling. However, the underlying mechanism of BAX and BAK pore formation remains incompletely understood. We demonstrate that mitochondria are globally and dynamically ... ...

Abstract	Mitochondrial outer membrane permeabilization (MOMP) is a core event in apoptosis signaling. However, the underlying mechanism of BAX and BAK pore formation remains incompletely understood. We demonstrate that mitochondria are globally and dynamically targeted by endolysosomes (ELs) during MOMP. In response to pro-apoptotic BH3-only protein signaling and pharmacological MOMP induction, ELs increasingly form transient contacts with mitochondria. Subsequently, ELs rapidly accumulate within the entire mitochondrial compartment. This switch-like accumulation period temporally coincides with mitochondrial BAX clustering and cytochrome c release. Remarkably, interactions of ELs with mitochondria control BAX recruitment and pore formation. Knockdown of Rab5A, Rab5C, or USP15 interferes with EL targeting of mitochondria and functionally uncouples BAX clustering from cytochrome c release, while knockdown of the Rab5 exchange factor Rabex-5 impairs both BAX clustering and cytochrome c release. Together, these data reveal that EL-mitochondrial inter-organelle communication is an integral regulatory component of functional MOMP execution during cellular apoptosis signaling.
MeSH term(s)	Apoptosis ; Endosomes/metabolism ; Guanine Nucleotide Exchange Factors/metabolism ; Humans ; Lysosomes/metabolism ; MCF-7 Cells ; Mitochondria/metabolism ; Mitochondrial Permeability Transition Pore/metabolism ; Signal Transduction ; Ubiquitin-Specific Proteases/metabolism ; bcl-2-Associated X Protein/metabolism ; rab5 GTP-Binding Proteins/metabolism
Chemical Substances	BAX protein, human ; Guanine Nucleotide Exchange Factors ; Mitochondrial Permeability Transition Pore ; RABGEF1 protein, human ; bcl-2-Associated X Protein ; USP15 protein, human (EC 3.4.19.12) ; Ubiquitin-Specific Proteases (EC 3.4.19.12) ; RAB5C protein, human (EC 3.6.1.-) ; rab5 GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2020-06-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2054967-2
ISSN	1878-1551 ; 1534-5807
ISSN (online)	1878-1551
ISSN	1534-5807
DOI	10.1016/j.devcel.2020.05.014
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Zs.A 5742: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 76: Show issues

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Article ; Online: EMBO Workshop: Membrane Contact Sites in Health and Disease.

Bayer, Emmanuelle M / Calì, Tito / Giordano, Francesca / Hamacher-Brady, Anne / Pellegrini, Luca

Contact (Thousand Oaks (Ventura County, Calif.))

2019 Volume 2

Language	English
Publishing date	2019-02-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2964312-0
ISSN	2515-2564 ; 2515-2564
ISSN (online)	2515-2564
ISSN	2515-2564
DOI	10.1177/2515256419825931
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Article ; Online: Autophagy capacity and sub-mitochondrial heterogeneity shape Bnip3-induced mitophagy regulation of apoptosis.

Choe, Sehyo Charley / Hamacher-Brady, Anne / Brady, Nathan Ryan

Cell communication and signaling : CCS

2015 Volume 13, Page(s) 37

Abstract: Background: Mitochondria are key regulators of apoptosis. In response to stress, BH3-only proteins activate pro-apoptotic Bcl2 family proteins Bax and Bak, which induce mitochondrial outer membrane permeabilization (MOMP). While the large-scale ... ...

Abstract	Background: Mitochondria are key regulators of apoptosis. In response to stress, BH3-only proteins activate pro-apoptotic Bcl2 family proteins Bax and Bak, which induce mitochondrial outer membrane permeabilization (MOMP). While the large-scale mitochondrial release of pro-apoptotic proteins activates caspase-dependent cell death, a limited release results in sub-lethal caspase activation which promotes tumorigenesis. Mitochondrial autophagy (mitophagy) targets dysfunctional mitochondria for degradation by lysosomes, and undergoes extensive crosstalk with apoptosis signaling, but its influence on apoptosis remains undetermined. The BH3-only protein Bnip3 integrates apoptosis and mitophagy signaling at different signaling domains. Bnip3 inhibits pro-survival Bcl2 members via its BH3 domain and activates mitophagy through its LC3 Interacting Region (LIR), which is responsible for binding to autophagosomes. Previously, we have shown that Bnip3-activated mitophagy prior to apoptosis induction can reduce mitochondrial activation of caspases, suggesting that a reduction to mitochondrial levels may be pro-survival. An outstanding question is whether organelle dynamics and/or recently discovered subcellular variations of protein levels responsible for both MOMP sensitivity and crosstalk between apoptosis and mitophagy can influence the cellular apoptosis decision event. To that end, here we undertook a systems biology analysis of mitophagy-apoptosis crosstalk at the level of cellular mitochondrial populations. Results: Based on experimental findings, we developed a multi-scale, hybrid model with an individually adaptive mitochondrial population, whose actions are determined by protein levels, embedded in an agent-based model (ABM) for simulating subcellular dynamics and local feedback via reactive oxygen species signaling. Our model, supported by experimental evidence, identified an emergent regulatory structure within canonical apoptosis signaling. We show that the extent of mitophagy is determined by levels and spatial localization of autophagy capacity, and subcellular mitochondrial protein heterogeneities. Our model identifies mechanisms and conditions that alter the mitophagy decision within mitochondrial subpopulations to an extent sufficient to shape cellular outcome to apoptotic stimuli. Conclusion: Overall, our modeling approach provides means to suggest new experiments and implement findings at multiple scales in order to understand how network topologies and subcellular heterogeneities can influence signaling events at individual organelle level, and hence, determine the emergence of heterogeneity in cellular decisions due the actions of the collective intra-cellular population.
MeSH term(s)	Animals ; Apoptosis ; Cell Line ; Cytochromes c/metabolism ; HeLa Cells ; Humans ; Membrane Proteins/metabolism ; Mice ; Mitochondria/metabolism ; Mitochondrial Degradation ; Mitochondrial Proteins/metabolism ; Models, Biological ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction
Chemical Substances	BNIP3 protein, human ; BNip3 protein, mouse ; Membrane Proteins ; Mitochondrial Proteins ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins c-bcl-2 ; Reactive Oxygen Species ; Cytochromes c (9007-43-6)
Language	English
Publishing date	2015-08-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1478-811X
ISSN (online)	1478-811X
DOI	10.1186/s12964-015-0115-9
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Mitophagy programs: mechanisms and physiological implications of mitochondrial targeting by autophagy.

Hamacher-Brady, Anne / Brady, Nathan Ryan

Cellular and molecular life sciences : CMLS

2015 Volume 73, Issue 4, Page(s) 775–795

Abstract: Mitochondria are an essential source of ATP for cellular function, but when damaged, mitochondria generate a plethora of stress signals, which lead to cellular dysfunction and eventually programmed cell death. Thus, a major component of maintaining ... ...

Abstract	Mitochondria are an essential source of ATP for cellular function, but when damaged, mitochondria generate a plethora of stress signals, which lead to cellular dysfunction and eventually programmed cell death. Thus, a major component of maintaining cellular homeostasis is the recognition and removal of dysfunctional mitochondria through autophagy-mediated degradation, i.e., mitophagy. Mitophagy further constitutes a developmental program, and undergoes a high degree of crosstalk with apoptosis. Reduced mitochondrial quality control is linked to disease pathogenesis, suggesting the importance of process elucidation as a clinical target. Recent work has revealed multiple mitophagy programs that operate independently or undergo crosstalk, and require modulated autophagy receptor activities at outer membranes of mitochondria. Here, we review these mitophagy programs, focusing on pathway mechanisms which recognize and target mitochondria for sequestration by autophagosomes, as well as mechanisms controlling pathway activities. Furthermore, we provide an introduction to the currently available methods for detecting mitophagy.
MeSH term(s)	Amino Acid Sequence ; Animals ; Autophagy ; Humans ; Membrane Proteins/analysis ; Membrane Proteins/metabolism ; Microtubule-Associated Proteins/analysis ; Microtubule-Associated Proteins/metabolism ; Mitochondria/metabolism ; Mitochondria/pathology ; Mitophagy ; Models, Molecular ; Molecular Sequence Data ; Protein Interaction Maps ; Proto-Oncogene Proteins/analysis ; Proto-Oncogene Proteins/metabolism ; Signal Transduction ; Ubiquitin/analysis ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/analysis ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	BNIP3 protein, human ; Membrane Proteins ; Microtubule-Associated Proteins ; Proto-Oncogene Proteins ; Ubiquitin ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; parkin protein (EC 2.3.2.27)
Language	English
Publishing date	2015-11-26
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-015-2087-8
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Article ; Online: Bax/Bak-dependent, Drp1-independent Targeting of X-linked Inhibitor of Apoptosis Protein (XIAP) into Inner Mitochondrial Compartments Counteracts Smac/DIABLO-dependent Effector Caspase Activation.

Hamacher-Brady, Anne / Brady, Nathan Ryan

The Journal of biological chemistry

2015 Volume 290, Issue 36, Page(s) 22005–22018

Abstract: Efficient apoptosis requires Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), which releases death-promoting proteins cytochrome c and Smac to the cytosol, which activate apoptosis and inhibit X-linked inhibitor of apoptosis protein ...

Abstract	Efficient apoptosis requires Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), which releases death-promoting proteins cytochrome c and Smac to the cytosol, which activate apoptosis and inhibit X-linked inhibitor of apoptosis protein (XIAP) suppression of executioner caspases, respectively. We recently identified that in response to Bcl-2 homology domain 3 (BH3)-only proteins and mitochondrial depolarization, XIAP can permeabilize and enter mitochondria. Consequently, XIAP E3 ligase activity recruits endolysosomes into mitochondria, resulting in Smac degradation. Here, we explored mitochondrial XIAP action within the intrinsic apoptosis signaling pathway. Mechanistically, we demonstrate that mitochondrial XIAP entry requires Bax or Bak and is antagonized by pro-survival Bcl-2 proteins. Moreover, intramitochondrial Smac degradation by XIAP occurs independently of Drp1-regulated cytochrome c release. Importantly, mitochondrial XIAP actions are activated cell-intrinsically by typical apoptosis inducers TNF and staurosporine, and XIAP overexpression reduces the lag time between the administration of an apoptotic stimuli and the onset of mitochondrial permeabilization. To elucidate the role of mitochondrial XIAP action during apoptosis, we integrated our findings within a mathematical model of intrinsic apoptosis signaling. Simulations suggest that moderate increases of XIAP, combined with mitochondrial XIAP preconditioning, would reduce MOMP signaling. To test this scenario, we pre-activated XIAP at mitochondria via mitochondrial depolarization or by artificially targeting XIAP to the intermembrane space. Both approaches resulted in suppression of TNF-mediated caspase activation. Taken together, we propose that XIAP enters mitochondria through a novel mode of mitochondrial permeabilization and through Smac degradation can compete with canonical MOMP to act as an anti-apoptotic tuning mechanism, reducing the mitochondrial contribution to the cellular apoptosis capacity.
MeSH term(s)	Animals ; Apoptosis Regulatory Proteins ; Blotting, Western ; Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology ; Caspases/metabolism ; Cells, Cultured ; Cytochromes c/metabolism ; Dynamins ; Embryo, Mammalian/cytology ; Enzyme Activation ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; GTP Phosphohydrolases/genetics ; GTP Phosphohydrolases/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; MCF-7 Cells ; Mice, Knockout ; Microscopy, Fluorescence ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Permeability/drug effects ; Protein Transport ; X-Linked Inhibitor of Apoptosis Protein/genetics ; X-Linked Inhibitor of Apoptosis Protein/metabolism ; bcl-2 Homologous Antagonist-Killer Protein/genetics ; bcl-2 Homologous Antagonist-Killer Protein/metabolism ; bcl-2-Associated X Protein/genetics ; bcl-2-Associated X Protein/metabolism
Chemical Substances	Apoptosis Regulatory Proteins ; DIABLO protein, human ; Intracellular Signaling Peptides and Proteins ; Microtubule-Associated Proteins ; Mitochondrial Proteins ; X-Linked Inhibitor of Apoptosis Protein ; bcl-2 Homologous Antagonist-Killer Protein ; bcl-2-Associated X Protein ; Carbonyl Cyanide m-Chlorophenyl Hydrazone (555-60-2) ; Cytochromes c (9007-43-6) ; Caspases (EC 3.4.22.-) ; GTP Phosphohydrolases (EC 3.6.1.-) ; DNM1L protein, human (EC 3.6.5.5) ; Dynamins (EC 3.6.5.5)
Language	English
Publishing date	2015-07-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M115.643064
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Article ; Online: Agent-Based Modeling of Mitochondria Links Sub-Cellular Dynamics to Cellular Homeostasis and Heterogeneity.

Dalmasso, Giovanni / Marin Zapata, Paula Andrea / Brady, Nathan Ryan / Hamacher-Brady, Anne

PloS one

2017 Volume 12, Issue 1, Page(s) e0168198

Abstract: Mitochondria are semi-autonomous organelles that supply energy for cellular biochemistry through oxidative phosphorylation. Within a cell, hundreds of mobile mitochondria undergo fusion and fission events to form a dynamic network. These morphological ... ...

Abstract	Mitochondria are semi-autonomous organelles that supply energy for cellular biochemistry through oxidative phosphorylation. Within a cell, hundreds of mobile mitochondria undergo fusion and fission events to form a dynamic network. These morphological and mobility dynamics are essential for maintaining mitochondrial functional homeostasis, and alterations both impact and reflect cellular stress states. Mitochondrial homeostasis is further dependent on production (biogenesis) and the removal of damaged mitochondria by selective autophagy (mitophagy). While mitochondrial function, dynamics, biogenesis and mitophagy are highly-integrated processes, it is not fully understood how systemic control in the cell is established to maintain homeostasis, or respond to bioenergetic demands. Here we used agent-based modeling (ABM) to integrate molecular and imaging knowledge sets, and simulate population dynamics of mitochondria and their response to environmental energy demand. Using high-dimensional parameter searches we integrated experimentally-measured rates of mitochondrial biogenesis and mitophagy, and using sensitivity analysis we identified parameter influences on population homeostasis. By studying the dynamics of cellular subpopulations with distinct mitochondrial masses, our approach uncovered system properties of mitochondrial populations: (1) mitochondrial fusion and fission activities rapidly establish mitochondrial sub-population homeostasis, and total cellular levels of mitochondria alter fusion and fission activities and subpopulation distributions; (2) restricting the directionality of mitochondrial mobility does not alter morphology subpopulation distributions, but increases network transmission dynamics; and (3) maintaining mitochondrial mass homeostasis and responding to bioenergetic stress requires the integration of mitochondrial dynamics with the cellular bioenergetic state. Finally, (4) our model suggests sources of, and stress conditions amplifying, cell-to-cell variability of mitochondrial morphology and energetic stress states. Overall, our modeling approach integrates biochemical and imaging knowledge, and presents a novel open-modeling approach to investigate how spatial and temporal mitochondrial dynamics contribute to functional homeostasis, and how subcellular organelle heterogeneity contributes to the emergence of cell heterogeneity.
MeSH term(s)	Computer Simulation ; Homeostasis ; Membrane Fusion ; Mitochondria/physiology ; Models, Biological ; Organelle Biogenesis
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0168198
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