bims-minimp 2021-12-26 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2021‒12‒26
ten papers selected by
Hanna Salmonowicz
International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

Peroxiredoxin 6 protects irradiated cells from oxidative stress and shapes their senescence-associated cytokine landscape.
Protein Quality Control at the Mitochondrial Surface.
ROS-Induced mtDNA Release: The Emerging Messenger for Communication between Neurons and Innate Immune Cells during Neurodegenerative Disorder Progression.
ATAD3A has a scaffolding role regulating mitochondria inner membrane structure and protein assembly.
BCL-2-family protein tBID can act as a BAX-like effector of apoptosis.
Inactivity of Peptidase ClpP Causes Primary Accumulation of Mitochondrial Disaggregase ClpX with Its Interacting Nucleoid Proteins, and of mtDNA.
Identification of Novel Therapeutic Targets for Polyglutamine Diseases That Target Mitochondrial Fragmentation.
Saccharomyces cerevisiae as a Tool for Studying Mutations in Nuclear Genes Involved in Diseases Caused by Mitochondrial DNA Instability.
Targeting Mitochondrial OXPHOS and Their Regulatory Signals in Prostate Cancers.
[Role of mitochondrial morphodynamics and contact sites in the antiviral response].

Redox Biol. 2021 Dec 11. pii: S2213-2317(21)00372-4. [Epub ahead of print]49 102212

Peroxiredoxin 6 protects irradiated cells from oxidative stress and shapes their senescence-associated cytokine landscape.

Barbora Salovska, Alexandra Kondelova, Kristyna Pimkova, Zuzana Liblova, Miroslav Pribyl, Ivo Fabrik, Jiri Bartek, Marie Vajrychova, Zdenek Hodny.

  Cellular senescence is a complex stress response defined as an essentially irreversible cell cycle arrest mediated by the inhibition of cell cycle-specific cyclin dependent kinases. The imbalance in redox homeostasis and oxidative stress have been repeatedly observed as one of the hallmarks of the senescent phenotype. However, a large-scale study investigating protein oxidation and redox signaling in senescent cells in vitro has been lacking. Here we applied a proteome-wide analysis using SILAC-iodoTMT workflow to quantitatively estimate the level of protein sulfhydryl oxidation and proteome level changes in ionizing radiation-induced senescence (IRIS) in hTERT-RPE-1 cells. We observed that senescent cells mobilized the antioxidant system to buffer the increased oxidation stress. Among the antioxidant proteins with increased relative abundance in IRIS, a unique 1-Cys peroxiredoxin family member, peroxiredoxin 6 (PRDX6), was identified as an important contributor to protection against oxidative stress. PRDX6 silencing increased ROS production in senescent cells, decreased their resistance to oxidative stress-induced cell death, and impaired their viability. Subsequent SILAC-iodoTMT and secretome analysis after PRDX6 silencing showed the downregulation of PRDX6 in IRIS affected protein secretory pathways, decreased expression of extracellular matrix proteins, and led to unexpected attenuation of senescence-associated secretory phenotype (SASP). The latter was exemplified by decreased secretion of pro-inflammatory cytokine IL-6 which was also confirmed after treatment with an inhibitor of PRDX6 iPLA2 activity, MJ33. In conclusion, by combining different methodological approaches we discovered a novel role of PRDX6 in senescent cell viability and SASP development. Our results suggest PRDX6 could have a potential as a drug target for senolytic or senomodulatory therapy.

Keywords:  Cellular senescence; Interleukin 6; Peroxiredoxin 6; Redox proteomics; SILAC-iodoTMT; Senescence-associated secretory phenotype

DOI:  https://doi.org/10.1016/j.redox.2021.102212
Front Cell Dev Biol. 2021 ;9 795685

Protein Quality Control at the Mitochondrial Surface.

Fabian den Brave, Arushi Gupta, Thomas Becker.

  Mitochondria contain two membranes, the outer and inner membrane. The outer membrane fulfills crucial functions for the communication of mitochondria with the cellular environment like exchange of lipids via organelle contact sites, the transport of metabolites and the formation of a signaling platform in apoptosis and innate immunity. The translocase of the outer membrane (TOM complex) forms the entry gate for the vast majority of precursor proteins that are produced on cytosolic ribosomes. Surveillance of the functionality of outer membrane proteins is critical for mitochondrial functions and biogenesis. Quality control mechanisms remove defective and mistargeted proteins from the outer membrane as well as precursor proteins that clog the TOM complex. Selective degradation of single proteins is also an important mode to regulate mitochondrial dynamics and initiation of mitophagy pathways. Whereas inner mitochondrial compartments are equipped with specific proteases, the ubiquitin-proteasome system is a central player in protein surveillance on the mitochondrial surface. In this review, we summarize our current knowledge about the molecular mechanisms that govern quality control of proteins at the outer mitochondrial membrane.

Keywords:  Cdc48; TOM complex; mitochondria; protein quality control; protein sorting

DOI:  https://doi.org/10.3389/fcell.2021.795685
Antioxidants (Basel). 2021 Nov 29. pii: 1917. [Epub ahead of print]10(12):

ROS-Induced mtDNA Release: The Emerging Messenger for Communication between Neurons and Innate Immune Cells during Neurodegenerative Disorder Progression.

Yuanxin Zhao, Buhan Liu, Long Xu, Sihang Yu, Jiaying Fu, Jian Wang, Xiaoyu Yan, Jing Su.

  One of the most striking hallmarks shared by various neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, is microglia-mediated and astrocyte-mediated neuroinflammation. Although inhibitions of both harmful proteins and aggregation are major treatments for neurodegenerative diseases, whether the phenomenon of non-normal protein or peptide aggregation is causally related to neuronal loss and synaptic damage is still controversial. Currently, excessive production of reactive oxygen species (ROS), which induces mitochondrial dysfunction in neurons that may play a key role in the regulation of immune cells, is proposed as a regulator in neurological disorders. In this review, we propose that mitochondrial DNA (mtDNA) release due to ROS may act on microglia and astrocytes adjacent to neurons to induce inflammation through activation of innate immune responses (such as cGAS/STING). Elucidating the relationship between mtDNA and the formation of a pro-inflammatory microenvironment could contribute to a better understanding of the mechanism of crosstalk between neuronal and peripheral immune cells and lead to the development of novel therapeutic approaches to neurodegenerative diseases.

Keywords:  ROS; cGAS/STING; mtDNA; neurodegenerative diseases; neuroinflammation

DOI:  https://doi.org/10.3390/antiox10121917
Cell Rep. 2021 Dec 21. pii: S2211-1247(21)01635-1. [Epub ahead of print]37(12): 110139

ATAD3A has a scaffolding role regulating mitochondria inner membrane structure and protein assembly.

Tania Arguello, Susana Peralta, Hana Antonicka, Gabriel Gaidosh, Francisca Diaz, Ya-Ting Tu, Sofia Garcia, Ramin Shiekhattar, Antonio Barrientos, Carlos T Moraes.

  The ATPase Family AAA Domain Containing 3A (ATAD3A), is a mitochondrial inner membrane protein conserved in metazoans. ATAD3A has been associated with several mitochondrial functions, including nucleoid organization, cholesterol metabolism, and mitochondrial translation. To address its primary role, we generated a neuronal-specific conditional knockout (Atad3 nKO) mouse model, which developed a severe encephalopathy by 5 months of age. Pre-symptomatic mice showed aberrant mitochondrial cristae morphogenesis in the cortex as early as 2 months. Using a multi-omics approach in the CNS of 2-to-3-month-old mice, we found early alterations in the organelle membrane structure. We also show that human ATAD3A associates with different components of the inner membrane, including OXPHOS complex I, Letm1, and prohibitin complexes. Stochastic Optical Reconstruction Microscopy (STORM) shows that ATAD3A is regularly distributed along the inner mitochondrial membrane, suggesting a critical structural role in inner mitochondrial membrane and its organization, most likely in an ATPase-dependent manner.

Keywords:  ATAD3; cardiolipin; cristae; inner membrane; mitochondria

DOI:  https://doi.org/10.1016/j.celrep.2021.110139
EMBO J. 2021 Dec 21. e108690

BCL-2-family protein tBID can act as a BAX-like effector of apoptosis.

Hector Flores-Romero, Lisa Hohorst, Malina John, Marie-Christine Albert, Louise E King, Laura Beckmann, Tamas Szabo, Vanessa Hertlein, Xu Luo, Andreas Villunger, Lukas P Frenzel, Hamid Kashkar, Ana J Garcia-Saez.

  During apoptosis, the BCL-2-family protein tBID promotes mitochondrial permeabilization by activating BAX and BAK and by blocking anti-apoptotic BCL-2 members. Here, we report that tBID can also mediate mitochondrial permeabilization by itself, resulting in release of cytochrome c and mitochondrial DNA, caspase activation and apoptosis even in absence of BAX and BAK. This previously unrecognized activity of tBID depends on helix 6, homologous to the pore-forming regions of BAX and BAK, and can be blocked by pro-survival BCL-2 proteins. Importantly, tBID-mediated mitochondrial permeabilization independent of BAX and BAK is physiologically relevant for SMAC release in the immune response against Shigella infection. Furthermore, it can be exploited to kill leukaemia cells with acquired venetoclax resistance due to lack of active BAX and BAK. Our findings define tBID as an effector of mitochondrial permeabilization in apoptosis and provide a new paradigm for BCL-2 proteins, with implications for anti-bacterial immunity and cancer therapy.

Keywords:  BCL-2 proteins; apoptosis; mitochondrial permeabilization; pore formation

DOI:  https://doi.org/10.15252/embj.2021108690
Cells. 2021 Nov 29. pii: 3354. [Epub ahead of print]10(12):

Inactivity of Peptidase ClpP Causes Primary Accumulation of Mitochondrial Disaggregase ClpX with Its Interacting Nucleoid Proteins, and of mtDNA.

Jana Key, Sylvia Torres-Odio, Nina C Bach, Suzana Gispert, Gabriele Koepf, Marina Reichlmeir, A Phillip West, Holger Prokisch, Peter Freisinger, William G Newman, Stavit Shalev, Stephan A Sieber, Ilka Wittig, Georg Auburger.

  Biallelic pathogenic variants in CLPP, encoding mitochondrial matrix peptidase ClpP, cause a rare autosomal recessive condition, Perrault syndrome type 3 (PRLTS3). It is characterized by primary ovarian insufficiency and early sensorineural hearing loss, often associated with progressive neurological deficits. Mouse models showed that accumulations of (i) its main protein interactor, the substrate-selecting AAA+ ATPase ClpX, (ii) mitoribosomes, and (iii) mtDNA nucleoids are the main cellular consequences of ClpP absence. However, the sequence of these events and their validity in human remain unclear. Here, we studied global proteome profiles to define ClpP substrates among mitochondrial ClpX interactors, which accumulated consistently in ClpP-null mouse embryonal fibroblasts and brains. Validation work included novel ClpP-mutant patient fibroblast proteomics. ClpX co-accumulated in mitochondria with the nucleoid component POLDIP2, the mitochondrial poly(A) mRNA granule element LRPPRC, and tRNA processing factor GFM1 (in mouse, also GRSF1). Only in mouse did accumulated ClpX, GFM1, and GRSF1 appear in nuclear fractions. Mitoribosomal accumulation was minor. Consistent accumulations in murine and human fibroblasts also affected multimerizing factors not known as ClpX interactors, namely, OAT, ASS1, ACADVL, STOM, PRDX3, PC, MUT, ALDH2, PMPCB, UQCRC2, and ACADSB, but the impact on downstream metabolites was marginal. Our data demonstrate the primary impact of ClpXP on the assembly of proteins with nucleic acids and show nucleoid enlargement in human as a key consequence.

Keywords:  ClpB; ERAL1; HARS2; LARS2; Parkinson’s disease; TWNK; ataxia; leukodystrophy

DOI:  https://doi.org/10.3390/cells10123354
Int J Mol Sci. 2021 Dec 14. pii: 13447. [Epub ahead of print]22(24):

Identification of Novel Therapeutic Targets for Polyglutamine Diseases That Target Mitochondrial Fragmentation.

Annika Traa, Emily Machiela, Paige D Rudich, Sonja K Soo, Megan M Senchuk, Jeremy M Van Raamsdonk.

  Huntington's disease (HD) is one of at least nine polyglutamine diseases caused by a trinucleotide CAG repeat expansion, all of which lead to age-onset neurodegeneration. Mitochondrial dynamics and function are disrupted in HD and other polyglutamine diseases. While multiple studies have found beneficial effects from decreasing mitochondrial fragmentation in HD models by disrupting the mitochondrial fission protein DRP1, disrupting DRP1 can also have detrimental consequences in wild-type animals and HD models. In this work, we examine the effect of decreasing mitochondrial fragmentation in a neuronal C. elegans model of polyglutamine toxicity called Neur-67Q. We find that Neur-67Q worms exhibit mitochondrial fragmentation in GABAergic neurons and decreased mitochondrial function. Disruption of drp-1 eliminates differences in mitochondrial morphology and rescues deficits in both movement and longevity in Neur-67Q worms. In testing twenty-four RNA interference (RNAi) clones that decrease mitochondrial fragmentation, we identified eleven clones-each targeting a different gene-that increase movement and extend lifespan in Neur-67Q worms. Overall, we show that decreasing mitochondrial fragmentation may be an effective approach to treating polyglutamine diseases and we identify multiple novel genetic targets that circumvent the potential negative side effects of disrupting the primary mitochondrial fission gene drp-1.

Keywords:  C. elegans; DRP1; Huntington’s disease; genetics; mitochondria; mitochondrial dynamics; polyglutamine diseases

DOI:  https://doi.org/10.3390/ijms222413447
Genes (Basel). 2021 Nov 24. pii: 1866. [Epub ahead of print]12(12):

Saccharomyces cerevisiae as a Tool for Studying Mutations in Nuclear Genes Involved in Diseases Caused by Mitochondrial DNA Instability.

Alexandru Ionut Gilea, Camilla Ceccatelli Berti, Martina Magistrati, Giulia di Punzio, Paola Goffrini, Enrico Baruffini, Cristina Dallabona.

  Mitochondrial DNA (mtDNA) maintenance is critical for oxidative phosphorylation (OXPHOS) since some subunits of the respiratory chain complexes are mitochondrially encoded. Pathological mutations in nuclear genes involved in the mtDNA metabolism may result in a quantitative decrease in mtDNA levels, referred to as mtDNA depletion, or in qualitative defects in mtDNA, especially in multiple deletions. Since, in the last decade, most of the novel mutations have been identified through whole-exome sequencing, it is crucial to confirm the pathogenicity by functional analysis in the appropriate model systems. Among these, the yeast Saccharomyces cerevisiae has proved to be a good model for studying mutations associated with mtDNA instability. This review focuses on the use of yeast for evaluating the pathogenicity of mutations in six genes, MPV17/SYM1, MRM2/MRM2, OPA1/MGM1, POLG/MIP1, RRM2B/RNR2, and SLC25A4/AAC2, all associated with mtDNA depletion or multiple deletions. We highlight the techniques used to construct a specific model and to measure the mtDNA instability as well as the main results obtained. We then report the contribution that yeast has given in understanding the pathogenic mechanisms of the mutant variants, in finding the genetic suppressors of the mitochondrial defects and in the discovery of molecules able to improve the mtDNA stability.

Keywords:  MPV17/SYM1; MRM2/MRM2; OPA1/MGM1; POLG/MIP1; RRM2B/RNR2; SLC25A4 (ANT1)/AAC2; diseases associated with mtDNA deletions; drug repurposing; mtDNA depletion syndromes; yeast model

DOI:  https://doi.org/10.3390/genes12121866
Int J Mol Sci. 2021 Dec 14. pii: 13435. [Epub ahead of print]22(24):

Targeting Mitochondrial OXPHOS and Their Regulatory Signals in Prostate Cancers.

Chia-Lin Chen, Ching-Yu Lin, Hsing-Jien Kung.

  Increasing evidence suggests that tumor development requires not only oncogene/tumor suppressor mutations to drive the growth, survival, and metastasis but also metabolic adaptations to meet the increasing energy demand for rapid cellular expansion and to cope with the often nutritional and oxygen-deprived microenvironment. One well-recognized strategy is to shift the metabolic flow from oxidative phosphorylation (OXPHOS) or respiration in mitochondria to glycolysis or fermentation in cytosol, known as Warburg effects. However, not all cancer cells follow this paradigm. In the development of prostate cancer, OXPHOS actually increases as compared to normal prostate tissue. This is because normal prostate epithelial cells divert citrate in mitochondria for the TCA cycle to the cytosol for secretion into seminal fluid. The sustained level of OXPHOS in primary tumors persists in progression to an advanced stage. As such, targeting OXPHOS and mitochondrial activities in general present therapeutic opportunities. In this review, we summarize the recent findings of the key regulators of the OXPHOS pathway in prostate cancer, ranging from transcriptional regulation, metabolic regulation to genetic regulation. Moreover, we provided a comprehensive update of the current status of OXPHOS inhibitors for prostate cancer therapy. A challenge of developing OXPHOS inhibitors is to selectively target cancer mitochondria and spare normal counterparts, which is also discussed.

Keywords:  OXPHOS; cancer therapy; mitochondria

DOI:  https://doi.org/10.3390/ijms222413435
Med Sci (Paris). 2021 Dec;37(12): 1166-1168

[Role of mitochondrial morphodynamics and contact sites in the antiviral response].

Benoit de Chassey, Etienne Morel.

DOI: https://doi.org/10.1051/medsci/2021171