bims-minimp 2022-06-12 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2022–06–12
nineteen papers selected by
Hanna Salmonowicz, International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

The retroviral restriction factor TRIM5/TRIM5α regulates mitochondrial quality control.
The "mitochondrial stress responses": the "Dr. Jekyll and Mr. Hyde" of neuronal disorders.
BAX regulates dendritic spine development via mitochondrial fusion.
Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease.
Temporal changes in mitochondrial function and reactive oxygen species generation during the development of replicative senescence in human fibroblasts.
Mining the mitochondrial proteome.
Protein disulfide isomerase PDI-6 regulates Wnt secretion to coordinate inter-tissue UPRmt activation and lifespan extension in C. elegans.
Towards a molecular mechanism underlying mitochondrial protein import through the TOM and TIM23 complexes.
Mechanism of mitoribosomal small subunit biogenesis and preinitiation.
A yeast suppressor screen links Coa4 to the mitochondrial copper delivery pathway for cytochrome c oxidase.
Mitochondrial respiration in B lymphocytes is essential for humoral immunity by controlling the flux of the TCA cycle.
Mitochondrial function and Aβ in Alzheimer's disease postmortem brain.
Lysosome lipid signalling from the periphery to neurons regulates longevity.
Fungal Patterns Induce Cytokine Expression through Fluxes of Metabolic Intermediates That Support Glycolysis and Oxidative Phosphorylation.
From infection to repair: Understanding the workings of our innate immune cells.
Endothelial cells give a boost to senescence surveillance.
Non-coding 7S RNA inhibits transcription via mitochondrial RNA polymerase dimerization.
Link between senescence and cell fate: Senescence-associated secretory phenotype (SASP) and its effects on stem cell fate transition.
De Novo Development of Mitochondria-Targeted Molecular Probes Targeting Pink1.

Autophagy. 2022 Jun 05. 1-2

The retroviral restriction factor TRIM5/TRIM5α regulates mitochondrial quality control.

Bhaskar Saha, Michael A Mandell.

  The protein TRIM5 is under intensive investigation related to its roles in antiviral defense, yet its underlying mechanisms of action remain elusive. In our study, we performed an unbiased identification of TRIM5-interacting partners and found proteins participating in a wide variety of cellular functions. We utilized this proteomics data set to uncover a role for TRIM5 in mitophagy, a mitochondrial quality control system that is impaired in multiple human diseases. Mitochondrial damage triggers the recruitment of TRIM5 to ER-mitochondria contact sites where TRIM5 colocalizes with markers of autophagosome biogenesis. Cells lacking TRIM5 are unable to carry out PRKN-dependent and PRKN-independent mitophagy pathways. TRIM5 knockout cells show reduced mitochondrial function and uncontrolled immune activation in response to mitochondrial damage; phenotypes consistent with a requirement for TRIM5 in mitophagy. Mechanistically, we found that TRIM5 is required for the recruitment of the autophagy initiation machinery to damaged mitochondria, where TRIM5 acts as a scaffold promoting interactions between protein markers of mitochondrial damage and the autophagy initiation machinery.

Keywords:  APEX2; HIV-1; TRIM5α; autophagy; inflammation; mitochondria; mitophagy; restriction factor; tripartite-motif

DOI:  https://doi.org/10.1080/15548627.2022.2084863
Neural Regen Res. 2022 Dec;17(12): 2563-2575

The "mitochondrial stress responses": the "Dr. Jekyll and Mr. Hyde" of neuronal disorders.

Simone Patergnani, Giampaolo Morciano, Marianna Carinci, Sara Leo, Paolo Pinton, Alessandro Rimessi.

  Neuronal disorders are associated with a profound loss of mitochondrial functions caused by various stress conditions, such as oxidative and metabolic stress, protein folding or import defects, and mitochondrial DNA alteration. Cells engage in different coordinated responses to safeguard mitochondrial homeostasis. In this review, we will explore the contribution of mitochondrial stress responses that are activated by the organelle to perceive these dangerous conditions, keep them under control and rescue the physiological condition of nervous cells. In the sections to come, particular attention will be dedicated to analyzing how compensatory mitochondrial hyperfusion, mitophagy, mitochondrial unfolding protein response, and apoptosis impact human neuronal diseases. Finally, we will discuss the relevance of the new concept: the "mito-inflammation", a mitochondria-mediated inflammatory response that is recently found to cover a relevant role in the pathogenesis of diverse inflammatory-related diseases, including neuronal disorders.

Keywords:  Alzheimer’s disease; Parkinson’s disease; UPR mt; apoptosis; mito-inflammation; mitochondrial dynamics; mitophagy; multiple sclerosis; neurodegeneration

DOI:  https://doi.org/10.4103/1673-5374.339473
Neurosci Res. 2022 Jun 07. pii: S0168-0102(22)00172-9. [Epub ahead of print]

BAX regulates dendritic spine development via mitochondrial fusion.

Qinhua Gu, Kaizheng Duan, Ronald S Petralia, Ya-Xian Wang, Zheng Li.

  BAX is a Bcl-2 family protein acting on apoptosis. It also promotes mitochondrial fusion by interacting with the mitochondrial fusion protein Mitofusin (Mfn1 and Mfn2). Neuronal mitochondria are important for the development and modification of dendritic spines, which are subcellular compartments accommodating excitatory synapses in postsynaptic neurons. The abundance of dendritic mitochondria influences dendritic spine development. Mitochondrial fusion is essential for mitochondrial homeostasis. Here, we show that in the hippocampal neuron of BAX knockout mice, mitochondrial fusion is impaired, leading to decreases in mitochondrial length and total mitochondrial mass in dendrites. Notably, BAX knockout mice also have fewer dendritic spines and less cellular Adenosine 5'triphosphate (ATP) in dendrites. The spine and ATP changes are abolished by restoring mitochondria fusion via overexpressing Mfn1 and Mfn2. These findings indicate that BAX-mediated mitochondrial fusion in neurons is crucial for the development of dendritic spines and the maintenance of cellular ATP levels.

Keywords:  ATP; Mfn; mitochondria; spine

DOI:  https://doi.org/10.1016/j.neures.2022.06.002
EMBO Mol Med. 2022 Jun 07. e15851

Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease.

Chunyue Liu, Zixing Fu, Shanshan Wu, Xiaosong Wang, Shengrong Zhang, Chu Chu, Yuan Hong, Wenbo Wu, Shengqi Chen, Yueqing Jiang, Yang Wu, Yongbo Song, Yan Liu, Xing Guo.

  Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington's disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell models, a YAC128 mouse model, and human striatal organoids derived from HD induced pluripotent stem cells (iPSCs). Overexpression of mitochondria-targeting HSF1 (mtHSF1) in the striatum causes neurodegeneration and HD-like behavior in mice. Mechanistically, mtHSF1 facilitates mitochondrial fission by activating dynamin-related protein 1 (Drp1) phosphorylation at S616. Moreover, mtHSF1 suppresses single-stranded DNA-binding protein 1 (SSBP1) oligomer formation, which results in mitochondrial DNA (mtDNA) deletion. The suppression of HSF1 mitochondrial localization by DH1, a unique peptide inhibitor, abolishes HSF1-induced mitochondrial abnormalities and ameliorates deficits in an HD animal model and human striatal organoids. Altogether, our findings describe an unsuspected role of HSF1 in contributing to mitochondrial dysfunction, which may provide a promising therapeutic target for HD.

Keywords:  Huntington's disease; heat shock transcription factor 1; human striatal organoids; mitochondrial DNA; single-stranded DNA-binding protein 1

DOI:  https://doi.org/10.15252/emmm.202215851
Exp Gerontol. 2022 Jun 06. pii: S0531-5565(22)00174-7. [Epub ahead of print]165 111866

Temporal changes in mitochondrial function and reactive oxygen species generation during the development of replicative senescence in human fibroblasts.

Yasunori Fujita, Masumi Iketani, Masafumi Ito, Ikuroh Ohsawa.

  Mitochondria are dysfunctional in post-senescent cells. Therefore, age-dependent impairment of mitochondrial energy production accompanied by excessive mitochondrial reactive oxygen species (ROS) is proposed to be a key driver of cellular senescence, which is a state of irreversible cell cycle arrest. However, it remains to be clarified whether mitochondrial dysfunction initiates or accelerates replicative senescence. In this study, we observed no increase in mitochondrial ROS or decrease in mitochondrial respiratory function in human TIG-1 fibroblasts in the transition phase, during which the population doubling rate gradually decreases due to the development of replicative senescence. The integrated stress response and expression of growth differentiation factor 15, which are triggered by respiratory chain deficiency, were also not induced in the transition phase. Mitochondria were elongated without aberrant cristae structures in the transition phase. Mitophagy-related protein levels started to decrease in the transition phase, but autophagic flux slightly increased during replicative senescence. These results suggest that mitochondrial dysfunction and excessive mitochondrial ROS generation do not occur predominately in the transition phase and may not play a role in the development of replicative senescence in normal diploid TIG-1 fibroblasts.

Keywords:  Aging; Mitochondrial dysfunction; Mitophagy; Reactive oxygen species; Replicative senescence

DOI:  https://doi.org/10.1016/j.exger.2022.111866
Nat Rev Mol Cell Biol. 2022 Jun 08.

Mining the mitochondrial proteome.

Paulina Strzyz.

DOI: https://doi.org/10.1038/s41580-022-00503-9
Cell Rep. 2022 Jun 07. pii: S2211-1247(22)00713-6. [Epub ahead of print]39(10): 110931

Protein disulfide isomerase PDI-6 regulates Wnt secretion to coordinate inter-tissue UPRmt activation and lifespan extension in C. elegans.

Xinyu Li, Jiasheng Li, Di Zhu, Ning Zhang, Xusheng Hao, Wenfeng Zhang, Qian Zhang, Yangli Liu, Xueying Wu, Ye Tian.

  Coordination of inter-tissue stress signaling is essential for organismal fitness. Neuronal mitochondrial perturbations activate the mitochondrial unfolded-protein response (UPRmt) in the intestine via the mitokine Wnt signaling in Caenorhabditis elegans. Here, we found that the protein disulfide isomerase PDI-6 coordinates inter-tissue UPRmt signaling via regulating the Wnt ligand EGL-20. PDI-6 is expressed in the endoplasmic reticulum (ER) and interacts with EGL-20 through disulfide bonds that are essential for EGL-20 stability and secretion. pdi-6 deficiency results in misfolded EGL-20, which leads to its degradation via ER-associated protein degradation (ERAD) machinery. Expression of PDI-6 declines drastically with aging, and animals with pdi-6 deficiency have decreased lifespan. Overexpression of PDI-6 is sufficient to maintain Wnt/EGL-20 protein levels during aging, activating the UPRmt, and significantly extending lifespan in a Wnt- and UPRmt-dependent manner. Our study reveals that protein disulfide isomerase facilitates Wnt secretion to coordinate the inter-tissue UPRmt signaling and organismal aging.

Keywords:  CP: Cell biology; PDI; PDI-6; UPR(mt); Wnt signaling; aging; cell-non-autonomous regulation; disulfide bond formation; mitochondrial unfolded-protein response; protein disulfide isomerase

DOI:  https://doi.org/10.1016/j.celrep.2022.110931
Elife. 2022 Jun 08. pii: e75426. [Epub ahead of print]11

Towards a molecular mechanism underlying mitochondrial protein import through the TOM and TIM23 complexes.

Holly C Ford, William J Allen, Gonçalo C Pereira, Xia Liu, Mark Simon Dillingham, Ian Collinson.

  Nearly all mitochondrial proteins need to be targeted for import from the cytosol. For the majority, the first port of call is the translocase of the outer membrane (TOM complex), followed by a procession of alternative molecular machines, conducting transport to their final destination. The pre-sequence translocase of the inner-membrane (TIM23-complex) imports proteins with cleavable pre-sequences. Progress in understanding these transport mechanisms has been hampered by the poor sensitivity and time-resolution of import assays. However, with the development of an assay based on split NanoLuc luciferase, we can now explore this process in greater detail. Here, we apply this new methodology to understand how ∆ψ and ATP hydrolysis, the two main driving forces for import into the matrix, contribute to the transport of pre-sequence-containing precursors (PCPs) with varying properties. Notably, we found that two major rate-limiting steps define PCP import time: passage of PCP across the outer membrane and initiation of inner membrane transport by the pre-sequence - the rates of which are influenced by PCP properties such as size and net charge. The apparent distinction between transport through the two membranes (passage through TOM is substantially complete before PCP-TIM engagement) is in contrast with the current view that import occurs through TOM and TIM in a single continuous step. Our results also indicate that PCPs spend very little time in the TIM23 channel - presumably rapid success or failure of import is critical for maintaining mitochondrial fitness.

Keywords:  S. cerevisiae; biochemistry; chemical biology

DOI:  https://doi.org/10.7554/eLife.75426
Nature. 2022 Jun 08.

Mechanism of mitoribosomal small subunit biogenesis and preinitiation.

Yuzuru Itoh, Anas Khawaja, Ivan Laptev, Miriam Cipullo, Ilian Atanassov, Petr Sergiev, Joanna Rorbach, Alexey Amunts.

Mitoribosomes are essential for the synthesis and maintenance of bioenergetic proteins. Here we use cryo-electron microscopy to determine a series of the small mitoribosomal subunit (SSU) intermediates in complex with auxiliary factors, revealing a sequential assembly mechanism. The methyltransferase TFB1M binds to partially unfolded rRNA h45 that is promoted by RBFA, while the mRNA channel is blocked. This enables binding of METTL15 that promotes further rRNA maturation and a large conformational change of RBFA. The new conformation allows initiation factor mtIF3 to already occupy the subunit interface during the assembly. Finally, the mitochondria-specific ribosomal protein mS37 (ref. 1) outcompetes RBFA to complete the assembly with the SSU-mS37-mtIF3 complex2 that proceeds towards mtIF2 binding and translation initiation. Our results explain how the action of step-specific factors modulate the dynamic assembly of the SSU, and adaptation of a unique protein, mS37, links the assembly to initiation to establish the catalytic human mitoribosome.

DOI: https://doi.org/10.1038/s41586-022-04795-x
Genetics. 2022 Jun 06. pii: iyac090. [Epub ahead of print]

A yeast suppressor screen links Coa4 to the mitochondrial copper delivery pathway for cytochrome c oxidase.

Abhinav B Swaminathan, Shivatheja Soma, Alison C Vicary, Mohammad Zulkifli, Harman Kaur, Vishal M Gohil.

  Cytochrome c oxidase (CcO) is a multimeric copper-containing enzyme of the mitochondrial respiratory chain that powers cellular energy production. The two core subunits of CcO, Cox1 and Cox2, harbor the catalytic CuB and CuA sites, respectively. Biogenesis of each copper site occurs separately and requires multiple proteins that constitute the mitochondrial copper delivery pathway. Currently, the identity of all the members of the pathway is not known, though several evolutionarily conserved twin CX9C motif-containing proteins have been implicated in this process. Here, we performed a targeted yeast suppressor screen that placed Coa4, a twin CX9C motif-containing protein, in the copper delivery pathway to the Cox1 subunit. Specifically, we show that overexpression of Cox11, a copper metallochaperone required for the formation of CuB site, can restore Cox1 abundance, CcO assembly, and mitochondrial respiration in coa4Δ cells. This rescue is dependent on the copper-coordinating cysteines of Cox11. The abundance of Coa4 and Cox11 in mitochondria is reciprocally regulated, further linking Coa4 to the CuB site biogenesis. Additionally, we find that coa4Δ cells have reduced levels of copper and exogenous copper supplementation can partially ameliorate its respiratory-deficient phenotype, a finding that connects Coa4 to cellular copper homeostasis. Finally, we demonstrate that human COA4 can replace the function of yeast Coa4 indicating its evolutionarily conserved role. Our work provides genetic evidences for the role of Coa4 in the copper delivery pathway to the CuB site of CcO.

Keywords:  Coa4; Cox1; Cox11; copper; cytochrome c oxidase; mitochondria

DOI:  https://doi.org/10.1093/genetics/iyac090
Cell Rep. 2022 Jun 07. pii: S2211-1247(22)00689-1. [Epub ahead of print]39(10): 110912

Mitochondrial respiration in B lymphocytes is essential for humoral immunity by controlling the flux of the TCA cycle.

Sophia Urbanczyk, Olivier R Baris, Jörg Hofmann, R Verena Taudte, Naïg Guegen, Florian Golombek, Kathrin Castiglione, Xianyi Meng, Aline Bozec, Jana Thomas, Leonie Weckwerth, Dimitrios Mougiakakos, Sebastian R Schulz, Wolfgang Schuh, Ursula Schlötzer-Schrehardt, Tobit D Steinmetz, Susanne Brodesser, Rudolf J Wiesner, Dirk Mielenz.

  To elucidate the function of oxidative phosphorylation (OxPhos) during B cell differentiation, we employ CD23Cre-driven expression of the dominant-negative K320E mutant of the mitochondrial helicase Twinkle (DNT). DNT-expression depletes mitochondrial DNA during B cell maturation, reduces the abundance of respiratory chain protein subunits encoded by mitochondrial DNA, and, consequently, respiratory chain super-complexes in activated B cells. Whereas B cell development in DNT mice is normal, B cell proliferation, germinal centers, class switch to IgG, plasma cell maturation, and T cell-dependent as well as T cell-independent humoral immunity are diminished. DNT expression dampens OxPhos but increases glycolysis in lipopolysaccharide and B cell receptor-activated cells. Lipopolysaccharide-activated DNT-B cells exhibit altered metabolites of glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle and a lower amount of phosphatidic acid. Consequently, mTORC1 activity and BLIMP1 induction are curtailed, whereas HIF1α is stabilized. Hence, mitochondrial DNA controls the metabolism of activated B cells via OxPhos to foster humoral immunity.

Keywords:  B lymphocyte; CP: Immunology; HIF1; TCA cycle; class switch recombination; germinal center; hypoxia inducible factor 1; mTOR; mammalian target of Rapamycin; mitochondrial DNA; mitochondrial respiration; oxidative phosphorylation; phosphatidic acid; plasma cell

DOI:  https://doi.org/10.1016/j.celrep.2022.110912
Neurobiol Dis. 2022 Jun 03. pii: S0969-9961(22)00173-5. [Epub ahead of print] 105781

Mitochondrial function and Aβ in Alzheimer's disease postmortem brain.

Benjamin R Troutwine, Taylor A Strope, Edziu Franczak, Colton R Lysaker, Laylan Hamid, Clayton Mansel, Julia A Stopperan, Cynthia M Gouvion, Mohammad Haeri, Russell H Swerdlow, Heather M Wilkins.

   INTRODUCTION: Mitochondrial dysfunction is observed in Alzheimer's disease (AD). However, the relationship between functional mitochondrial deficits and AD pathologies is not well established in human subjects.
METHODS: Post-mortem human brain tissue from 11 non-demented (ND) and 12 AD subjects was used to examine mitochondrial electron transport chain (ETC) function. Data were analyzed by neuropathology diagnosis and Apolipoprotein E (APOE) genotype. Relationships between AD pathology and mitochondrial function were determined.
RESULTS: AD subjects had reductions in brain cytochrome oxidase (COX) function and complex II Vmax. APOE ε4 carriers had COX, complex II and III deficits. AD subjects had reduced expression of Complex I-III ETC proteins, no changes were observed in APOE ε4 carriers. No correlation between p-Tau Thr 181 and mitochondrial outcomes was observed, although brains from non-demented subjects demonstrated positive correlations between Aβ concentration and COX Vmax.
DISCUSSION: These data support a dysregulated relationship between brain mitochondrial function and Aβ pathology in AD.

Keywords:  Alzheimer's disease; Aβ; Brain; Cytochrome oxidase; Mitochondria

DOI:  https://doi.org/10.1016/j.nbd.2022.105781
Nat Cell Biol. 2022 Jun 09.

Lysosome lipid signalling from the periphery to neurons regulates longevity.

Marzia Savini, Andrew Folick, Yi-Tang Lee, Feng Jin, André Cuevas, Matthew C Tillman, Jonathon D Duffy, Qian Zhao, Isaiah A Neve, Pei-Wen Hu, Yong Yu, Qinghao Zhang, Youqiong Ye, William B Mair, Jin Wang, Leng Han, Eric A Ortlund, Meng C Wang.

Lysosomes are key cellular organelles that metabolize extra- and intracellular substrates. Alterations in lysosomal metabolism are implicated in ageing-associated metabolic and neurodegenerative diseases. However, how lysosomal metabolism actively coordinates the metabolic and nervous systems to regulate ageing remains unclear. Here we report a fat-to-neuron lipid signalling pathway induced by lysosomal metabolism and its longevity-promoting role in Caenorhabditis elegans. We discovered that induced lysosomal lipolysis in peripheral fat storage tissue upregulates the neuropeptide signalling pathway in the nervous system to promote longevity. This cell-non-autonomous regulation is mediated by a specific polyunsaturated fatty acid, dihomo-γ-linolenic acid, and LBP-3 lipid chaperone protein transported from the fat storage tissue to neurons. LBP-3 binds to dihomo-γ-linolenic acid, and acts through NHR-49 nuclear receptor and NLP-11 neuropeptide in neurons to extend lifespan. These results reveal lysosomes as a signalling hub to coordinate metabolism and ageing, and lysosomal signalling mediated inter-tissue communication in promoting longevity.

DOI: https://doi.org/10.1038/s41556-022-00926-8
J Immunol. 2022 Jun 10. pii: ji2100666. [Epub ahead of print]

Fungal Patterns Induce Cytokine Expression through Fluxes of Metabolic Intermediates That Support Glycolysis and Oxidative Phosphorylation.

Cristina Mancebo, José Javier Fernández, Carmen Herrero-Sánchez, Yolanda Alvarez, Sara Alonso, Tito A Sandoval, Juan R Cubillos-Ruiz, Olimpio Montero, Nieves Fernández, Mariano Sánchez Crespo.

Cytokine expression is fine-tuned by metabolic intermediates, which makes research on immunometabolism suitable to yield drugs with a wider prospect of application than the biological therapies that block proinflammatory cytokines. Switch from oxidative phosphorylation (OXPHOS) to glycolysis has been considered a characteristic feature of activated immune cells. However, some stimuli might enhance both routes concomitantly. The connection between the tricarboxylic acid cycle and cytokine expression was scrutinized in human monocyte-derived dendritic cells stimulated with the fungal surrogate zymosan. Results showed that nucleocytosolic citrate and ATP-citrate lyase activity drove IL1B, IL10, and IL23A expression by yielding acetyl-CoA and oxaloacetate, with the latter one supporting glycolysis and OXPHOS by maintaining cytosolic NAD+ and mitochondrial NADH levels through mitochondrial shuttles. Succinate dehydrogenase showed a subunit-specific ability to modulate IL23A and IL10 expression. Succinate dehydrogenase A subunit activity supported cytokine expression through the control of the 2-oxoglutarate/succinate ratio, whereas C and D subunits underpinned cytokine expression by conveying electron flux from complex II to complex III of the electron transport chain. Fatty acids may also fuel the tricarboxylic acid cycle and influence cytokine expression. Overall, these results show that fungal patterns support cytokine expression through a strong boost of glycolysis and OXPHOS supported by the use of pyruvate, citrate, and succinate, along with the compartmentalized NAD(H) redox state maintained by mitochondrial shuttles.

DOI: https://doi.org/10.4049/jimmunol.2100666
WIREs Mech Dis. 2022 Jun 08. e1567

From infection to repair: Understanding the workings of our innate immune cells.

Martin Mawhinney, Amelia Kulle, Ajitha Thanabalasuriar.

  In a world filled with microbes, some posing a threat to our body, our immune system is key to living a healthy life. The innate immune system is made of various cell types that act to guard our bodies. Unlike the adaptive immune system that has a specific response, our innate immune system encompasses cells that elicit unspecific immune responses, triggered whenever the right signals are detected. Our understanding of immunity started with the concept of our immune system only responding to "nonself" like the pathogens that invade our body. However, over the past few decades, we have learned that the immune system is more than an on/off switch that recognizes nonself. The innate immune system regularly patrols our bodies for pathogens and tissue damage. Our innate immune system not only seeks to resolve infection but also repair tissue injury, through phagocytosing debris and initiating the release of growth factors. Recently, we are starting to see that it is not just recognizing danger, our innate immune system plays a crucial role in repair. Innate immune cells phenotypically change during repair. In the context of severe injury or trauma, our innate immune system is modified quite drastically to help repair, resulting in reduced infection control. Moreover, these changes in immune cell function can be modified by sex as a biological variable. From past to present, in this overview, we provide a summary of the innate immune cells and pathways in infection and tissue repair. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology.

Keywords:  immunology; innate immune cells; sterile injury

DOI:  https://doi.org/10.1002/wsbm.1567
Genes Dev. 2022 May 01. 36(9-10): 511-513

Endothelial cells give a boost to senescence surveillance.

Daniel Sampaio Gonçalves, William M Keyes.

  Senescence is a specialized form of cell cycle arrest induced in response to damage and stress. In certain settings, senescent cells can promote their own removal by recruitment of the immune system, a process that is thought to decline in efficiency with age. In this issue of Genes & Development, Yin et al. (pp. 533-549) discover a surprising cross-talk where senescent cells instruct endothelial cells to help organize the clearance of the senescent population. This uncovers yet another layer of complexity in senescent cell biology, with implications for cancer treatment and aging.

Keywords:   liver; NF-κB; SASP; endothelium; immune surveillance; senescence

DOI:  https://doi.org/10.1101/gad.349767.122
Cell. 2022 May 30. pii: S0092-8674(22)00590-6. [Epub ahead of print]

Non-coding 7S RNA inhibits transcription via mitochondrial RNA polymerase dimerization.

Xuefeng Zhu, Xie Xie, Hrishikesh Das, Benedict G Tan, Yonghong Shi, Ali Al-Behadili, Bradley Peter, Elisa Motori, Sebastian Valenzuela, Viktor Posse, Claes M Gustafsson, B Martin Hällberg, Maria Falkenberg.

  The mitochondrial genome encodes 13 components of the oxidative phosphorylation system, and altered mitochondrial transcription drives various human pathologies. A polyadenylated, non-coding RNA molecule known as 7S RNA is transcribed from a region immediately downstream of the light strand promoter in mammalian cells, and its levels change rapidly in response to physiological conditions. Here, we report that 7S RNA has a regulatory function, as it controls levels of mitochondrial transcription both in vitro and in cultured human cells. Using cryo-EM, we show that POLRMT dimerization is induced by interactions with 7S RNA. The resulting POLRMT dimer interface sequesters domains necessary for promoter recognition and unwinding, thereby preventing transcription initiation. We propose that the non-coding 7S RNA molecule is a component of a negative feedback loop that regulates mitochondrial transcription in mammalian cells.

Keywords:  7S RNA; POLRMT; SUV3; cryo-EM; dimer; mitochondria; mtDNA; mtEXO; non-coding RNA; transcription

DOI:  https://doi.org/10.1016/j.cell.2022.05.006
Rejuvenation Res. 2022 Jun 04.

Link between senescence and cell fate: Senescence-associated secretory phenotype (SASP) and its effects on stem cell fate transition.

Yu Pan, Zhenzhen Gu, Yansi Lyu, Yi Yang, Manhon Chung, Xiaohua Pan, Sa Cai.

Senescence is a form of durable cell cycle arrest elicited in response to a wide range of stimuli. Senescent cells remain metabolically active and secrete a variety of factors collectively termed senescence-associated secretory phenotype (SASP). SASP is highly pleiotropic and can impact numerous biological processes in which it has both beneficial and deleterious roles. The underlying mechanisms by which SASP exerts its pleiotropic influence remain largely unknown. SASP serves as an environmental factor, which regulates stem cell differentiation and alters its routine. The latter can potentially be accomplished through dedifferentiation, transdifferentiation, or reprogramming. Behavioral changes that cells undergo when exposed to SASP are involved in several senescence-associated physiological and pathological phenomena. These findings provide clues for identifying possible interventions to reduce the deleterious effects without interfering in the beneficial outcomes. Here, we discuss the multifaced effects of SASP and the changes occurring in cellular states upon exposure to SASP factors.

DOI: https://doi.org/10.1089/rej.2022.0021
Int J Mol Sci. 2022 May 28. pii: 6076. [Epub ahead of print]23(11):

De Novo Development of Mitochondria-Targeted Molecular Probes Targeting Pink1.

Shulamit Fluss Ben-Uliel, Faten Habrat Zoabi, Moriya Slavin, Hadas Sibony-Benyamini, Nir Kalisman, Nir Qvit.

  Mitochondria play central roles in maintaining cellular metabolic homeostasis, cell survival and cell death, and generate most of the cell's energy. Mitochondria maintain their homeostasis by dynamic (fission and fusion) and quality control mechanisms, including mitophagy, the removal of damaged mitochondria that is mediated mainly by the Pink1/Parkin pathway. Pink1 is a serine/threonine kinase which regulates mitochondrial function, hitherto many molecular mechanisms underlying Pink1 activity in mitochondrial homeostasis and cell fate remain unknown. Peptides are vital biological mediators that demonstrate remarkable potency, selectivity, and low toxicity, yet they have two major limitations, low oral bioavailability and poor stability. Herein, we rationally designed a linear peptide that targets Pink1 and, using straightforward chemistry, we developed molecular probes with drug-like properties to further characterize Pink1. Initially, we conjugated a cell-penetrating peptide and a cross-linker to map Pink1's 3D structure and its interaction sites. Next, we conjugated a fluorescent dye for cell-imaging. Finally, we developed cyclic peptides with improved stability and binding affinity. Overall, we present a facile approach to converting a non-permeable linear peptide into a research tool possessing important properties for therapeutics. This is a general approach using straightforward chemistry that can be tailored for various applications by numerous laboratories.

Keywords:  Pink1; backbone cyclization; bioactive peptides; mitochondria; mitophagy; molecular probes; peptidomimetics; protein-peptide interactions; protein-protein interactions; therapeutic peptides

DOI:  https://doi.org/10.3390/ijms23116076