bims-minimp 2022-05-08 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2022–05–08
eleven papers selected by
Hanna Salmonowicz, International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

High-content high-throughput imaging reveals distinct connections between mitochondrial morphology and functionality for OXPHOS complex I, III, and V inhibitors.
Stress Responses Elicited by Misfolded Proteins Targeted to Mitochondria.
The mitoXplorer 2.0 update: integrating and interpreting mitochondrial expression dynamics within a cellular context.
The activator/repressor Hap1 binds to the yeast eIF5A-encoding gene TIF51A to adapt its expression to the mitochondrial functional status.
Novel roles of RTN4 and CLIMP-63 in regulating mitochondrial structure, bioenergetics and apoptosis.
Mitochondria supply sub-lethal signals for cytokine secretion and DNA-damage in H. pylori infection.
Letting go of damaged mitochondria.
The chaperone Clusterin in neurodegeneration-friend or foe?
Resilience integrates concepts in aging research.
Mitochondria-derived peptides in aging and healthspan.
The MFN1 and MFN2 mitofusins promote clustering between mitochondria and peroxisomes.

Cell Biol Toxicol. 2022 May 04.

High-content high-throughput imaging reveals distinct connections between mitochondrial morphology and functionality for OXPHOS complex I, III, and V inhibitors.

Wanda van der Stel, Huan Yang, Sylvia E le Dévédec, Bob van de Water, Joost B Beltman, Erik H J Danen.

  Cells can adjust their mitochondrial morphology by altering the balance between mitochondrial fission and fusion to adapt to stressful conditions. The connection between a chemical perturbation, changes in mitochondrial function, and altered mitochondrial morphology is not well understood. Here, we made use of high-throughput high-content confocal microscopy to assess the effects of distinct classes of oxidative phosphorylation (OXPHOS) complex inhibitors on mitochondrial parameters in a concentration and time resolved manner. Mitochondrial morphology phenotypes were clustered based on machine learning algorithms and mitochondrial integrity patterns were mapped. In parallel, changes in mitochondrial membrane potential (MMP), mitochondrial and cellular ATP levels, and viability were microscopically assessed. We found that inhibition of MMP, mitochondrial ATP production, and oxygen consumption rate (OCR) using sublethal concentrations of complex I and III inhibitors did not trigger mitochondrial fragmentation. Instead, complex V inhibitors that suppressed ATP and OCR but increased MMP provoked a more fragmented mitochondrial morphology. In agreement, complex V but not complex I or III inhibitors triggered proteolytic cleavage of the mitochondrial fusion protein, OPA1. The relation between increased MMP and fragmentation did not extend beyond OXPHOS complex inhibitors: increasing MMP by blocking the mPTP pore did not lead to OPA1 cleavage or mitochondrial fragmentation and the OXPHOS uncoupler FCCP was associated with OPA1 cleavage and MMP reduction. Altogether, our findings connect vital mitochondrial functions and phenotypes in a high-throughput high-content confocal microscopy approach that help understanding of chemical-induced toxicity caused by OXPHOS complex perturbing chemicals.

Keywords:  ATP; Machine learning; Membrane potential; Mitochondria; Morphology

DOI:  https://doi.org/10.1007/s10565-022-09712-6
J Mol Biol. 2022 Apr 29. pii: S0022-2836(22)00198-X. [Epub ahead of print] 167618

Stress Responses Elicited by Misfolded Proteins Targeted to Mitochondria.

Kannan Boosi Narayana Rao, Pratima Pandey, Rajasri Sarkar, Asmita Ghosh, Shemin Mansuri, Mudassar Ali, Priyanka Majumder, K Ranjith Kumar, Arjun Ray, Swasti Raychaudhuri, Koyeli Mapa.

  The double-membrane-bound architecture of mitochondria, essential for ATP production, sub-divides the organelle into inter-membrane space (IMS) and matrix. IMS and matrix possess contrasting oxido-reductive environments and discrete protein quality control (PQC) machineries resulting inherent differences in their protein folding environments. To understand the nature of stress response elicited by equivalent proteotoxic stress to these sub-mitochondrial compartments, we took misfolding and aggregation-prone stressor proteins and fused it to well described signal sequences to specifically target and impart stress to yeast mitochondrial IMS or matrix. We show, mitochondrial proteotoxicity leads to growth arrest of yeast cells of varying degrees depending on nature of stressor proteins and the intra-mitochondrial location of stress. Next, by employing transcriptomics and proteomics, we report a comprehensive stress response elicited by stressor proteins specifically targeted to mitochondrial matrix or IMS. A general response to proteotoxic stress by mitochondria-targeted misfolded proteins is mitochondrial fragmentation, and an adaptive abrogation of mitochondrial respiration with concomitant upregulation of glycolysis. Beyond shared stress responses, specific signatures due to stress within mitochondrial sub-compartments are also revealed. We report that stress-imparted by bipartite signal sequence-fused stressor proteins to IMS, leads to specific upregulation of IMS-chaperones and TOM complex components. In contrast, matrix-targeted stressors lead to specific upregulation of matrix-chaperones and cytosolic PQC components. Finally, by systematic genetic interaction using deletion strains of differentially upregulated genes, we found prominent modulatory role of TOM complex components during IMS-stress response. In contrast, VMS1 markedly modulates the stress response originated from matrix.

Keywords:  Mitochondrial Unfolded Protein Response; Molecular Chaperone; Protein misfolding; Proteostasis; Proteotoxic stress; Ribosome Quality Control; Stress Response; TOM complex; Vms1

DOI:  https://doi.org/10.1016/j.jmb.2022.167618
Nucleic Acids Res. 2022 May 07. pii: gkac306. [Epub ahead of print]

The mitoXplorer 2.0 update: integrating and interpreting mitochondrial expression dynamics within a cellular context.

Fabio Marchiano, Margaux Haering, Bianca Hermine Habermann.

Mitochondria are subcellular organelles present in almost all eukaryotic cells, which play a central role in cellular metabolism. Different tissues, health and age conditions are characterized by a difference in mitochondrial structure and composition. The visual data mining platform mitoXplorer 1.0 was developed to explore the expression dynamics of genes associated with mitochondrial functions that could help explain these differences. It, however, lacked functions aimed at integrating mitochondria in the cellular context and thus identifying regulators that help mitochondria adapt to cellular needs. To fill this gap, we upgraded the mitoXplorer platform to version 2.0 (mitoXplorer 2.0). In this upgrade, we implemented two novel integrative functions, network analysis and transcription factor enrichment, to specifically help identify signalling or transcriptional regulators of mitochondrial processes. In addition, we implemented several other novel functions to allow the platform to go beyond simple data visualization, such as an enrichment function for mitochondrial processes, a function to explore time-series data, the possibility to compare datasets across species and an IDconverter to help facilitate data upload. We demonstrate the usefulness of these functions in three specific use cases. mitoXplorer 2.0 is freely available without login at http://mitoxplorer2.ibdm.univ-mrs.fr.

DOI: https://doi.org/10.1093/nar/gkac306
FEBS Lett. 2022 May 01.

The activator/repressor Hap1 binds to the yeast eIF5A-encoding gene TIF51A to adapt its expression to the mitochondrial functional status.

Marina Barba-Aliaga, Paula Alepuz.

  Mitochondrial activity adapts to cellular energetic and metabolic demands; its dysfunction is a hallmark of aging and many human diseases. The evolutionarily conserved translation elongation factor eIF5A is involved in maintaining mitochondrial function. In humans, eIF5A is encoded by two highly homologous but differentially expressed genes; in yeast, these are TIF51A and TIF51B. We show that yeast transcription factor Hap1 constitutively binds to the TIF51A promoter to activate its expression under respiration, but represses its expression under non-respiration conditions by recruiting the co-repressor Tup1. Hap1 indirectly regulates TIF51B expression by binding to and activating the TIF51B-repressor genes ROX1 and MOT3 under respiration and repressing them under non-respiration. Thus, the levels of eIF5A isoforms are adapted to the mitochondrial functional status.

Keywords:   TIF51A ; TIF51B ; Hap1; Tup1; eIF5A; mitochondrial respiration; translation; yeast

DOI:  https://doi.org/10.1002/1873-3468.14366
Cell Death Dis. 2022 May 04. 13(5): 436

Novel roles of RTN4 and CLIMP-63 in regulating mitochondrial structure, bioenergetics and apoptosis.

Rachel J Carter, Mateus Milani, Alison J Beckett, Shiyu Liu, Ian A Prior, Gerald M Cohen, Shankar Varadarajan.

The recruitment of DRP1 to mitochondrial membranes prior to fission is facilitated by the wrapping of endoplasmic reticulum (ER) membranes around the mitochondria. To investigate the complex interplay between the ER membranes and DRP1 in the context of mitochondrial structure and function, we downregulate two key ER shaping proteins, RTN4 and CLIMP-63, and demonstrate pronounced mitochondrial hyperfusion and reduced ER-mitochondria contacts, despite their differential regulation of ER architecture. Although mitochondrial recruitment of DRP1 is unaltered in cells lacking RTN4 or CLIMP-63, several aspects of mitochondrial function, such as mtDNA-encoded translation, respiratory capacity and apoptosis are significantly hampered. Further mechanistic studies reveal that CLIMP-63 is required for cristae remodeling (OPA1 proteolysis) and DRP1-mediated mitochondrial fission, whereas both RTN4 and CLIMP-63 regulate the recruitment of BAX to ER and mitochondrial membranes to enable cytochrome c release and apoptosis, thereby performing novel and distinct roles in the regulation of mitochondrial structure and function.

DOI: https://doi.org/10.1038/s41419-022-04869-8
Cell Death Differ. 2022 May 03.

Mitochondria supply sub-lethal signals for cytokine secretion and DNA-damage in H. pylori infection.

Benedikt Dörflinger, Mohamed Tarek Badr, Aladin Haimovici, Lena Fischer, Juliane Vier, Arlena Metz, Bianca Eisele, Peter Bronsert, Konrad Aumann, Jens Höppner, Collins Waguia Kontchou, Ishita Parui, Arnim Weber, Susanne Kirschnek, Georg Häcker.

The bacterium Helicobacter pylori induces gastric inflammation and predisposes to cancer. H. pylori-infected epithelial cells secrete cytokines and chemokines and undergo DNA-damage. We show that the host cell's mitochondrial apoptosis system contributes to cytokine secretion and DNA-damage in the absence of cell death. H. pylori induced secretion of cytokines/chemokines from epithelial cells, dependent on the mitochondrial apoptosis machinery. A signalling step was identified in the release of mitochondrial Smac/DIABLO, which was required for alternative NF-κB-activation and contributed to chemokine secretion. The bacterial cag-pathogenicity island and bacterial muropeptide triggered mitochondrial host cell signals through the pattern recognition receptor NOD1. H. pylori-induced DNA-damage depended on mitochondrial apoptosis signals and the caspase-activated DNAse. In biopsies from H. pylori-positive patients, we observed a correlation of Smac-levels and inflammation. Non-apoptotic cells in these samples showed evidence of caspase-3-activation, correlating with phosphorylation of the DNA-damage response kinase ATM. Thus, H. pylori activates the mitochondrial apoptosis pathway to a sub-lethal level. During infection, Smac has a cytosolic, pro-inflammatory role in the absence of apoptosis. Further, DNA-damage through sub-lethal mitochondrial signals is likely to contribute to mutagenesis and cancer development.

DOI: https://doi.org/10.1038/s41418-022-01009-9
Sci Signal. 2022 May 03. 15(732): eabq7456

Letting go of damaged mitochondria.

Wei Wong.

Thermogenesis requires that macrophages digest damaged mitochondria released by brown adipocytes.

DOI: https://doi.org/10.1126/scisignal.abq7456
Bioessays. 2022 May 06. e2100287

The chaperone Clusterin in neurodegeneration-friend or foe?

Patricia Yuste-Checa, Andreas Bracher, F Ulrich Hartl.

  Fibrillar protein aggregates are the pathological hallmark of a group of age-dependent neurodegenerative conditions, including Alzheimer's and Parkinson's disease. Aggregates of the microtubule-associated protein Tau are observed in Alzheimer's disease and primary tauopathies. Tau pathology propagates from cell to cell in a prion-like process that is likely subject to modulation by extracellular chaperones such as Clusterin. We recently reported that Clusterin delayed Tau fibril formation but enhanced the activity of Tau oligomers to seed aggregation of endogenous Tau in a cellular model. In contrast, Clusterin inhibited the propagation of α-Synuclein aggregates associated with Parkinson's disease. These findings raise the possibility of a mechanistic link between Clusterin upregulation observed in Alzheimer's disease and the progression of Tau pathology. Here we review the diverse functions of Clusterin in the pathogenesis of neurodegenerative diseases, focusing on evidence that Clusterin may act either as a suppressor or enhancer of pathology.

Keywords:  Alzheimer's disease; Clusterin; extracellular chaperone; neurodegeneration; protein aggregation; tau; tauopathies

DOI:  https://doi.org/10.1002/bies.202100287
iScience. 2022 May 20. 25(5): 104199

Resilience integrates concepts in aging research.

Daniel Promislow, Rozalyn M Anderson, Marten Scheffer, Bernard Crespi, James DeGregori, Kelley Harris, Barbara Natterson Horowitz, Morgan E Levine, Maria A Riolo, David S Schneider, Sabrina L Spencer, Dario Riccardo Valenzano, Michael E Hochberg.

  Aging research is unparalleled in the breadth of disciplines it encompasses, from evolutionary studies examining the forces that shape aging to molecular studies uncovering the underlying mechanisms of age-related functional decline. Despite a common focus to advance our understanding of aging, these disciplines have proceeded along distinct paths with little cross-talk. We propose that the concept of resilience can bridge this gap. Resilience describes the ability of a system to respond to perturbations by returning to its original state. Although resilience has been applied in a few individual disciplines in aging research such as frailty and cognitive decline, it has not been explored as a unifying conceptual framework that is able to connect distinct research fields. We argue that because a resilience-based framework can cross broad physiological levels and time scales it can provide the missing links that connect these diverse disciplines. The resulting framework will facilitate predictive modeling and validation and influence targets and directions in research on the biology of aging.

Keywords:  Biological sciences; Cell biology; Evolutionary biology; Health sciences; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2022.104199
J Clin Invest. 2022 May 02. pii: e158449. [Epub ahead of print]132(9):

Mitochondria-derived peptides in aging and healthspan.

Brendan Miller, Su-Jeong Kim, Hiroshi Kumagai, Kelvin Yen, Pinchas Cohen.

The mechanisms that explain mitochondrial dysfunction in aging and healthspan continue to be studied, but one element has been unexplored: microproteins. Small open reading frames in circular mitochondria DNA can encode multiple microproteins, called mitochondria-derived peptides (MDPs). Currently, eight MDPs have been published: humanin, MOTS-c, and SHLPs 1-6. This Review describes recent advances in microprotein discovery with a focus on MDPs. It discusses what is currently known about MDPs in aging and how this new understanding could add to the way we understand age-related diseases including type 2 diabetes, cancer, and neurodegenerative diseases at the genomic, proteomic, and drug-development levels.

DOI: https://doi.org/10.1172/JCI158449
Commun Biol. 2022 May 06. 5(1): 423

The MFN1 and MFN2 mitofusins promote clustering between mitochondria and peroxisomes.

Yinbo Huo, Weiping Sun, Tiezhu Shi, Song Gao, Min Zhuang.

Mitochondria and peroxisomes are two types of functionally close-related organelles, and both play essential roles in lipid and ROS metabolism. However, how they physically interact with each other is not well understood. In this study, we apply the proximity labeling method with peroxisomal proteins and report that mitochondrial protein mitofusins (MFNs) are in proximity to peroxisomes. Overexpression of MFNs induces not only the mitochondria clustering but also the co-clustering of peroxisomes. We also report the enrichment of MFNs at the mitochondria-peroxisome interface. Induced mitofusin expression gives rise to more mitochondria-peroxisome contacting sites. Furthermore, the tethering of peroxisomes to mitochondria can be inhibited by the expression of a truncated MFN2, which lacks the transmembrane region. Collectively, our study suggests MFNs as regulators for mitochondria-peroxisome contacts. Our findings are essential for future studies of inter-organelle metabolism regulation and signaling, and may help understand the pathogenesis of mitofusin dysfunction-related disease.

DOI: https://doi.org/10.1038/s42003-022-03377-x