bims-minimp 2022-03-13 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2022‒03‒13
fifteen papers selected by
Hanna Salmonowicz
International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

Mitochondrial respiration supports autophagy to provide stress resistance during quiescence.
Coordination of mitochondrial and lysosomal homeostasis mitigates inflammation and muscle atrophy during aging.
A non-canonical tricarboxylic acid cycle underlies cellular identity.
Box C/D small nucleolar ribonucleoproteins regulate mitochondrial surveillance and innate immunity.
Mito-FUNCAT-FACS reveals cellular heterogeneity in mitochondrial translation.
The Complicated Nature of Somatic mtDNA Mutations in Aging.
Effects of proton pumping on the structural rigidity of cristae in mitochondria.
Genes Involved in Maintaining Mitochondrial Membrane Potential Upon Electron Transport Chain Disruption.
Biological mechanisms of aging predict age-related disease co-occurrence in patients.
Iron Supplementation Delays Aging and Extends Cellular Lifespan through Potentiation of Mitochondrial Function.
Mitochondrial complex I as a therapeutic target for Alzheimer's disease.
Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy.
Extrusion of mitochondria: Garbage clearance or cell-cell communication signals?
How many molecules of mitochondrial complex I are in a cell?
Olive phenols preserve lamin B1 expression reducing cGAS/STING/NFκB-mediated SASP in ionizing radiation-induced senescence.

Autophagy. 2022 Mar 08. 1-18

Mitochondrial respiration supports autophagy to provide stress resistance during quiescence.

Silvia Magalhaes-Novais, Jan Blecha, Ravindra Naraine, Jana Mikesova, Pavel Abaffy, Alena Pecinova, Mirko Milosevic, Romana Bohuslavova, Jan Prochazka, Shawez Khan, Eliska Novotna, Radek Sindelka, Radek Machan, Mieke Dewerchin, Erik Vlcak, Joanna Kalucka, Sona Stemberkova Hubackova, Ales Benda, Jermaine Goveia, Tomas Mracek, Cyril Barinka, Peter Carmeliet, Jiri Neuzil, Katerina Rohlenova, Jakub Rohlena.

  Mitochondrial oxidative phosphorylation (OXPHOS) generates ATP, but OXPHOS also supports biosynthesis during proliferation. In contrast, the role of OXPHOS during quiescence, beyond ATP production, is not well understood. Using mouse models of inducible OXPHOS deficiency in all cell types or specifically in the vascular endothelium that negligibly relies on OXPHOS-derived ATP, we show that selectively during quiescence OXPHOS provides oxidative stress resistance by supporting macroautophagy/autophagy. Mechanistically, OXPHOS constitutively generates low levels of endogenous ROS that induce autophagy via attenuation of ATG4B activity, which provides protection from ROS insult. Physiologically, the OXPHOS-autophagy system (i) protects healthy tissue from toxicity of ROS-based anticancer therapy, and (ii) provides ROS resistance in the endothelium, ameliorating systemic LPS-induced inflammation as well as inflammatory bowel disease. Hence, cells acquired mitochondria during evolution to profit from oxidative metabolism, but also built in an autophagy-based ROS-induced protective mechanism to guard against oxidative stress associated with OXPHOS function during quiescence.Abbreviations: AMPK: AMP-activated protein kinase; AOX: alternative oxidase; Baf A: bafilomycin A1; CI, respiratory complexes I; DCF-DA: 2',7'-dichlordihydrofluorescein diacetate; DHE: dihydroethidium; DSS: dextran sodium sulfate; ΔΨmi: mitochondrial inner membrane potential; EdU: 5-ethynyl-2'-deoxyuridine; ETC: electron transport chain; FA: formaldehyde; HUVEC; human umbilical cord endothelial cells; IBD: inflammatory bowel disease; LC3B: microtubule associated protein 1 light chain 3 beta; LPS: lipopolysaccharide; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; mtDNA: mitochondrial DNA; NAC: N-acetyl cysteine; OXPHOS: oxidative phosphorylation; PCs: proliferating cells; PE: phosphatidylethanolamine; PEITC: phenethyl isothiocyanate; QCs: quiescent cells; ROS: reactive oxygen species; PLA2: phospholipase A2, WB: western blot.

Keywords:  ATG4B; biosynthesis; cell death; electron transport chain; endothelial cells; mitochondria; oxidative phosphorylation; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1080/15548627.2022.2038898
Aging Cell. 2022 Mar 09. e13583

Coordination of mitochondrial and lysosomal homeostasis mitigates inflammation and muscle atrophy during aging.

Andrea Irazoki, Marta Martinez-Vicente, Pilar Aparicio, Cecilia Aris, Esmaeil Alibakhshi, Maria Rubio-Valera, Juan Castellanos, Luis Lores, Manuel Palacín, Anna Gumà, Antonio Zorzano, David Sebastián.

  Sarcopenia is one of the main factors contributing to the disability of aged people. Among the possible molecular determinants of sarcopenia, increasing evidences suggest that chronic inflammation contributes to its development. However, a key unresolved question is the nature of the factors that drive inflammation during aging and that participate in the development of sarcopenia. In this regard, mitochondrial dysfunction and alterations in mitophagy induce inflammatory responses in a wide range of cells and tissues. However, whether accumulation of damaged mitochondria (MIT) in muscle could trigger inflammation in the context of aging is still unknown. Here, we demonstrate that BCL2 interacting protein 3 (BNIP3) plays a key role in the control of mitochondrial and lysosomal homeostasis, and mitigates muscle inflammation and atrophy during aging. We show that muscle BNIP3 expression increases during aging in mice and in some humans. BNIP3 deficiency alters mitochondrial function, decreases mitophagic flux and, surprisingly, induces lysosomal dysfunction, leading to an upregulation of Toll-like receptor 9 (TLR9)-dependent inflammation and activation of the NLRP3 (nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain-containing protein 3) inflammasome in muscle cells and mouse muscle. Importantly, downregulation of muscle BNIP3 in aged mice exacerbates inflammation and muscle atrophy, and high BNIP3 expression in aged human subjects associates with a low inflammatory profile, suggesting a protective role for BNIP3 against age-induced muscle inflammation in mice and humans. Taken together, our data allow us to propose a new adaptive mechanism involving the mitophagy protein BNIP3, which links mitochondrial and lysosomal homeostasis with inflammation and is key to maintaining muscle health during aging.

Keywords:  aging; inflammation; lysosome; mitochondria; mitophagy; muscle

DOI:  https://doi.org/10.1111/acel.13583
Nature. 2022 Mar 09.

A non-canonical tricarboxylic acid cycle underlies cellular identity.

Paige K Arnold, Benjamin T Jackson, Katrina I Paras, Julia S Brunner, Madeleine L Hart, Oliver J Newsom, Sydney P Alibeckoff, Jennifer Endress, Esther Drill, Lucas B Sullivan, Lydia W S Finley.

The tricarboxylic acid (TCA) cycle is a central hub of cellular metabolism, oxidizing nutrients to generate reducing equivalents for energy production and critical metabolites for biosynthetic reactions. Despite the importance of the products of the TCA cycle for cell viability and proliferation, mammalian cells display diversity in TCA-cycle activity1,2. How this diversity is achieved, and whether it is critical for establishing cell fate, remains poorly understood. Here we identify a non-canonical TCA cycle that is required for changes in cell state. Genetic co-essentiality mapping revealed a cluster of genes that is sufficient to compose a biochemical alternative to the canonical TCA cycle, wherein mitochondrially derived citrate exported to the cytoplasm is metabolized by ATP citrate lyase, ultimately regenerating mitochondrial oxaloacetate to complete this non-canonical TCA cycle. Manipulating the expression of ATP citrate lyase or the canonical TCA-cycle enzyme aconitase 2 in mouse myoblasts and embryonic stem cells revealed that changes in the configuration of the TCA cycle accompany cell fate transitions. During exit from pluripotency, embryonic stem cells switch from canonical to non-canonical TCA-cycle metabolism. Accordingly, blocking the non-canonical TCA cycle prevents cells from exiting pluripotency. These results establish a context-dependent alternative to the traditional TCA cycle and reveal that appropriate TCA-cycle engagement is required for changes in cell state.

DOI: https://doi.org/10.1038/s41586-022-04475-w
PLoS Genet. 2022 Mar 11. 18(3): e1010103

Box C/D small nucleolar ribonucleoproteins regulate mitochondrial surveillance and innate immunity.

Elissa Tjahjono, Alexey V Revtovich, Natalia V Kirienko.

Monitoring mitochondrial function is crucial for organismal survival. This task is performed by mitochondrial surveillance or quality control pathways, which are activated by signals originating from mitochondria and relayed to the nucleus (retrograde response) to start transcription of protective genes. In Caenorhabditis elegans, several systems are known to play this role, including the UPRmt, MAPKmt, and the ESRE pathways. These pathways are highly conserved and their loss compromises survival following mitochondrial stress. In this study, we found a novel interaction between the box C/D snoRNA core proteins (snoRNPs) and mitochondrial surveillance and innate immune pathways. We showed that box C/D, but not box H/ACA, snoRNPs are required for the full function of UPRmt and ESRE upon stress. The loss of box C/D snoRNPs reduced mitochondrial mass, mitochondrial membrane potential, and oxygen consumption rate, indicating overall degradation of mitochondrial function. Concomitantly, the loss of C/D snoRNPs increased immune response and reduced host intestinal colonization by infectious bacteria, improving host resistance to pathogenesis. Our data may indicate a model wherein box C/D snoRNP machinery regulates a "switch" of the cell's activity between mitochondrial surveillance and innate immune activation. Understanding this mechanism is likely to be important for understanding multifactorial processes, including responses to infection and aging.

DOI: https://doi.org/10.1371/journal.pgen.1010103
RNA. 2022 Mar 07. pii: rna.079097.122. [Epub ahead of print]

Mito-FUNCAT-FACS reveals cellular heterogeneity in mitochondrial translation.

Yusuke Kimura, Hironori Saito, Tatsuya Osaki, Yasuhiro Ikegami, Taisei Wakigawa, Yoshiho Ikeuchi, Shintaro Iwasaki.

  Mitochondria possess their own genome that encodes components of oxidative phosphorylation (OXPHOS) complexes, and mitochondrial ribosomes within the organelle translate the mRNAs expressed from the mitochondrial genome. Given the differential OXPHOS activity observed in diverse cell types, cell growth conditions, and other circumstances, cellular heterogeneity in mitochondrial translation can be expected. Although individual protein products translated in mitochondria have been monitored, the lack of techniques that address the variation in overall mitochondrial protein synthesis in cell populations poses analytic challenges. Here, we adapted mitochondrial-specific fluorescent noncanonical amino acid tagging (FUNCAT) for use with fluorescence-activated cell sorting (FACS) and developed mito-FUNCAT-FACS. The click chemistry-compatible methionine analog L-homopropargylglycine (HPG) enabled the metabolic labeling of newly synthesized proteins. In the presence of cytosolic translation inhibitors, HPG was selectively incorporated into mitochondrial nascent proteins and conjugated to fluorophores via the click reaction (mito-FUNCAT). The application of in situ mito-FUNCAT to flow cytometry allowed us to separate changes in net mitochondrial translation activity from those of the organelle mass and detect variations in mitochondrial translation in cancer cells. Our approach provides a useful methodology for examining mitochondrial protein synthesis in individual cells.

Keywords:  FACS; FUNCAT; HPG; Mitochondria; Translation

DOI:  https://doi.org/10.1261/rna.079097.122
Front Aging. 2022 ;pii: 805126. [Epub ahead of print]2

The Complicated Nature of Somatic mtDNA Mutations in Aging.

Monica Sanchez-Contreras, Scott R Kennedy.

  Mitochondria are the main source of energy used to maintain cellular homeostasis. This aspect of mitochondrial biology underlies their putative role in age-associated tissue dysfunction. Proper functioning of the electron transport chain (ETC), which is partially encoded by the extra-nuclear mitochondrial genome (mtDNA), is key to maintaining this energy production. The acquisition of de novo somatic mutations that interrupt the function of the ETC have long been associated with aging and common diseases of the elderly. Yet, despite over 30 years of study, the exact role(s) mtDNA mutations play in driving aging and its associated pathologies remains under considerable debate. Furthermore, even fundamental aspects of age-related mtDNA mutagenesis, such as when mutations arise during aging, where and how often they occur across tissues, and the specific mechanisms that give rise to them, remain poorly understood. In this review, we address the current understanding of the somatic mtDNA mutations, with an emphasis of when, where, and how these mutations arise during aging. Additionally, we highlight current limitations in our knowledge and critically evaluate the controversies stemming from these limitations. Lastly, we highlight new and emerging technologies that offer potential ways forward in increasing our understanding of somatic mtDNA mutagenesis in the aging process.

Keywords:  aging; mitochondria; mtDNA; mutagenesis; sequencing; somatic mutations

DOI:  https://doi.org/10.3389/fragi.2021.805126
Arch Biochem Biophys. 2022 Mar 08. pii: S0003-9861(22)00057-1. [Epub ahead of print] 109172

Effects of proton pumping on the structural rigidity of cristae in mitochondria.

Mayu Yoneda, Jannatul Aklima, Ikuroh Ohsawa, Yoshihiro Ohta.

  Mitochondria change their morphology and inner membrane structure depending on their activity. Since mitochondrial activity also depends on their structure, it is important to elucidate the interrelationship between the activity and structure of mitochondria. However, the mechanism by which mitochondrial activity affects the structure of cristae, the folded structure of the inner membrane, is not well understood. In this study, the effect of the mitochondrial activity on the cristae structure was investigated by examining the structural rigidity of cristae. Taking advantage of the fact that unfolding of cristae induces mitochondrial swelling, we investigated the relationship between mitochondrial activity and the susceptibility to swelling. The swelling of individual isolated mitochondria exposed to a hypotonic solution was observed with an optical microscope. The presence of respiratory substrates (malate and glutamate) increased the percentage of mitochondria that underwent swelling, and the further addition of rotenone or KCN (inhibitors of proton pumps) reversed the increase. In the absence of respiratory substrates, acidification of the buffer surrounding the mitochondria also increased the percentage of swollen mitochondria. These observations suggest that acidification of the outer surface of inner membranes, especially intracristal space, by proton translocation from the matrix to the intracristal space, decreases the structural rigidity of the cristae. This interpretation was verified by the observation that ADP or CCCP, which induces proton re-entry to the matrix, suppressed the mitochondrial swelling in the presence of respiratory substrates. The addition of CCCP to the cells induced a morphological change in mitochondria from an initial elongated structure to a largely curved structure at pH 7.4, but there were no morphological changes when the pH of the cytosol dropped to 6.2. These results suggest that a low pH in the intracristal space may be helpful in maintaining the elongated structure of mitochondria. The present study shows that proton pumping by the electron transfer chain is the mechanism underlying mitochondrial morphology and the flexibility of cristae structure.

Keywords:  Inner mitochondrial membrane; Intracristal space; Proton pumps; mitochondria; mitochondrial cristae; mitochondrial swelling

DOI:  https://doi.org/10.1016/j.abb.2022.109172
Front Cell Dev Biol. 2022 ;10 781558

Genes Involved in Maintaining Mitochondrial Membrane Potential Upon Electron Transport Chain Disruption.

Karthik Vasan, Matt Clutter, Sara Fernandez Dunne, Mariam D George, Chi-Hao Luan, Navdeep S Chandel, Inmaculada Martínez-Reyes.

  Mitochondria are biosynthetic, bioenergetic, and signaling organelles with a critical role in cellular physiology. Dysfunctional mitochondria are associated with aging and underlie the cause of a wide range of diseases, from neurodegeneration to cancer. Through signaling, mitochondria regulate diverse biological outcomes. The maintenance of the mitochondrial membrane potential, for instance, is essential for proliferation, the release of mitochondrial reactive oxygen species, and oxygen sensing. The loss of mitochondrial membrane potential triggers pathways to clear damaged mitochondria and often results in cell death. In this study, we conducted a genome-wide positive selection CRISPR screen using a combination of mitochondrial inhibitors to uncover genes involved in sustaining a mitochondrial membrane potential, and therefore avoid cell death when the electron transport chain is impaired. Our screen identified genes involved in mitochondrial protein translation and ATP synthesis as essential for the induction of cell death when cells lose their mitochondrial membrane potential. This report intends to provide potential targets for the treatment of diseases associated with mitochondrial dysfunction.

Keywords:  ATP synthase; CRISPR screen; cell death; mitochondria; mitochondrial membrane potential; mitochondrial protein translation

DOI:  https://doi.org/10.3389/fcell.2022.781558
Aging Cell. 2022 Mar 08. e13524

Biological mechanisms of aging predict age-related disease co-occurrence in patients.

Helen C Fraser, Valerie Kuan, Ronja Johnen, Magdalena Zwierzyna, Aroon D Hingorani, Andreas Beyer, Linda Partridge.

  Genetic, environmental, and pharmacological interventions into the aging process can confer resistance to multiple age-related diseases in laboratory animals, including rhesus monkeys. These findings imply that individual mechanisms of aging might contribute to the co-occurrence of age-related diseases in humans and could be targeted to prevent these conditions simultaneously. To address this question, we text mined 917,645 literature abstracts followed by manual curation and found strong, non-random associations between age-related diseases and aging mechanisms in humans, confirmed by gene set enrichment analysis of GWAS data. Integration of these associations with clinical data from 3.01 million patients showed that age-related diseases associated with each of five aging mechanisms were more likely than chance to be present together in patients. Genetic evidence revealed that innate and adaptive immunity, the intrinsic apoptotic signaling pathway and activity of the ERK1/2 pathway were associated with multiple aging mechanisms and diverse age-related diseases. Mechanisms of aging hence contribute both together and individually to age-related disease co-occurrence in humans and could potentially be targeted accordingly to prevent multimorbidity.

Keywords:  age-related disease; aging; aging hallmarks; genetics; multimorbidity

DOI:  https://doi.org/10.1111/acel.13524
Cells. 2022 Mar 02. pii: 862. [Epub ahead of print]11(5):

Iron Supplementation Delays Aging and Extends Cellular Lifespan through Potentiation of Mitochondrial Function.

Jovian Lin Jing, Trishia Cheng Yi Ning, Federica Natali, Frank Eisenhaber, Mohammad Alfatah.

  Aging is the greatest challenge to humankind worldwide. Aging is associated with a progressive loss of physiological integrity due to a decline in cellular metabolism and functions. Such metabolic changes lead to age-related diseases, thereby compromising human health for the remaining life. Thus, there is an urgent need to identify geroprotectors that regulate metabolic functions to target the aging biological processes. Nutrients are the major regulator of metabolic activities to coordinate cell growth and development. Iron is an important nutrient involved in several biological functions, including metabolism. In this study using yeast as an aging model organism, we show that iron supplementation delays aging and increases the cellular lifespan. To determine how iron supplementation increases lifespan, we performed a gene expression analysis of mitochondria, the main cellular hub of iron utilization. Quantitative analysis of gene expression data reveals that iron supplementation upregulates the expression of the mitochondrial tricarboxylic acid (TCA) cycle and electron transport chain (ETC) genes. Furthermore, in agreement with the expression profiles of mitochondrial genes, ATP level is elevated by iron supplementation, which is required for increasing the cellular lifespan. To confirm, we tested the role of iron supplementation in the AMPK knockout mutant. AMPK is a highly conserved controller of mitochondrial metabolism and energy homeostasis. Remarkably, iron supplementation rescued the short lifespan of the AMPK knockout mutant and confirmed its anti-aging role through the enhancement of mitochondrial functions. Thus, our results suggest a potential therapeutic use of iron supplementation to delay aging and prolong healthspan.

Keywords:  AMPK; Saccharomyces cerevisiae; cellular lifespan extension; chronological aging; iron; mitochondria

DOI:  https://doi.org/10.3390/cells11050862
Acta Pharm Sin B. 2022 Feb;12(2): 483-495

Mitochondrial complex I as a therapeutic target for Alzheimer's disease.

Eugenia Trushina, Sergey Trushin, Md Fayad Hasan.

  Alzheimer's disease (AD), the most prominent form of dementia in the elderly, has no cure. Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials. Novel therapeutic targets and strategies are urgently needed. Emerging data suggest that in response to environmental stress, mitochondria initiate an integrated stress response (ISR) shown to be beneficial for healthy aging and neuroprotection. Here, we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR. Specifically, partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions, including AD, with several small molecules being tested in clinical trials. We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach. Since this strategy has also been shown to enhance health and life span, the development of safe and efficacious complex I inhibitors could promote healthy aging, delaying the onset of age-related neurodegenerative diseases.

Keywords:  AD, Alzheimer's disease; ADP, adenosine diphosphate; AIDS, acquired immunodeficiency syndrome; AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; APP/PS1, amyloid precursor protein/presenilin 1; ATP, adenosine triphosphate; Alzheimer's disease; Aβ, amyloid beta; BBB, blood‒brain barrier; BDNF, brain-derived neurotrophic factor; CP2, tricyclic pyrone compound two; Complex I inhibitors; ER, endoplasmic reticulum; ETC, electron transport chain; FADH2, flavin adenine dinucleotide; FDG-PET, fluorodeoxyglucose-positron emission tomography; GWAS, genome-wide association study; HD, Huntington's disease; HIF-1α, hypoxia induced factor 1 α; Healthy aging; ISR, integrated stress response; Integrated stress response; LTP, long term potentiation; MCI, mild cognitive impairment; MPTP, 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine; Mitochondria; Mitochondria signaling; Mitochondria targeted therapeutics; NAD+ and NADH, nicotinamide adenine dinucleotide; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NRF2, nuclear factor E2-related factor 2; Neuroprotection; OXPHOS, oxidative phosphorylation; PD, Parkinson's disease; PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; PMF, proton-motive force; RNAi, RNA interference; ROS, reactive oxygen species; T2DM, type II diabetes mellitus; TCA, the tricarboxylic acid cycle; mtDNA, mitochondrial DNA; mtUPR, mitochondrial unfolded protein response; pTau, hyper-phosphorylated Tau protein; ΔpH, proton gradient; Δψm, mitochondrial membrane potential

DOI:  https://doi.org/10.1016/j.apsb.2021.11.003
Cell Rep. 2022 Mar 08. pii: S2211-1247(22)00208-X. [Epub ahead of print]38(10): 110475

Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy.

Nicole M Sayles, Nneka Southwell, Kevin McAvoy, Kihwan Kim, Alba Pesini, Corey J Anderson, Catarina Quinzii, Suzanne Cloonan, Hibiki Kawamata, Giovanni Manfredi.

  Mitochondrial cardiomyopathies are fatal diseases, with no effective treatment. Alterations of heart mitochondrial function activate the mitochondrial integrated stress response (ISRmt), a transcriptional program affecting cell metabolism, mitochondrial biogenesis, and proteostasis. In humans, mutations in CHCHD10, a mitochondrial protein with unknown function, were recently associated with dominant multi-system mitochondrial diseases, whose pathogenic mechanisms remain to be elucidated. Here, in CHCHD10 knockin mutant mice, we identify an extensive cardiac metabolic rewiring triggered by proteotoxic ISRmt. The stress response arises early on, before the onset of bioenergetic impairments, triggering a switch from oxidative to glycolytic metabolism, enhancement of transsulfuration and one carbon (1C) metabolism, and widespread metabolic imbalance. In parallel, increased NADPH oxidases elicit antioxidant responses, leading to heme depletion. As the disease progresses, the adaptive metabolic stress response fails, resulting in fatal cardiomyopathy. Our findings suggest that early interventions to counteract metabolic imbalance could ameliorate mitochondrial cardiomyopathy associated with proteotoxic ISRmt.

Keywords:  1C metabolism; CHCHD10; coiled-coil-helix-coiled-coil-helix domain containing 10; heart, cardiomyopathy; heme; integrated stress response; metabolic rewiring; mitochondria

DOI:  https://doi.org/10.1016/j.celrep.2022.110475
J Cell Physiol. 2022 Mar 06.

Extrusion of mitochondria: Garbage clearance or cell-cell communication signals?

Konstantin G Lyamzaev, Roman A Zinovkin, Boris V Chernyak.

  Mitochondria are dynamic organelles that regulate various intracellular signaling pathways, including the mechanisms of programmed cell death, differentiation, inflammation, and so on. Mitochondria may be extruded as membrane enveloped or as free organelles during developmental processes, inflammatory activation, and in the process of "garbage clearance" of damaged mitochondria in postmitotic cells. Extracellular mitochondria can be engulfed by immune and nonimmune cells and trigger intracellular signaling leading to an inflammatory response. At the same time, it was reported that the release of extracellular vesicles containing mitochondria from mesenchymal stem cells contributes to their therapeutic anti-inflammatory effects. Numerous studies claim that engulfed mitochondria improve cellular bioenergetics, but this assumption requires further investigation. This review aims at a critical discussion of the mechanisms of mitochondrial extrusion in mammals, the reception of mitochondrial components, and the responses of recipient cells to extracellular mitochondria.

Keywords:  extracellular mitochondria; extracellular vesicles; mitochondria; mitophagy; quality control

DOI:  https://doi.org/10.1002/jcp.30711
Anal Biochem. 2022 Mar 05. pii: S0003-2697(22)00102-6. [Epub ahead of print] 114646

How many molecules of mitochondrial complex I are in a cell?

Fariha Ansari, Belem Yoval, Zoya Niatsetskaya, Vadim Ten, Ilka Wittig, Alexander Galkin.

  Mitochondrial complex I is the only enzyme responsible for oxidation of matrix NADH and regeneration of NAD+ for catabolism. Nuclear and mtDNA mutations, assembly impairments, and enzyme damage are implicated in inherited diseases, ischemia-reperfusion injury, neurodegeneration, and tumorogenesis. Here we introduce a novel method to measure the absolute content of complex I. The method is based on flavin fluorescence scanning of a polyacrylamide gel after separation of complexes by Clear Native electrophoresis. Using mouse primary astrocytes as an example, we calculated an average value of 2.2 × 105 complex I molecules/cell. Our method can be used for accurate quantification of complex I content.

Keywords:  Astrocytes; Flavin mononucleotide; Fluorescence; Mitochondrial complex I; Respiratory chain

DOI:  https://doi.org/10.1016/j.ab.2022.114646
J Cell Mol Med. 2022 Mar 12.

Olive phenols preserve lamin B1 expression reducing cGAS/STING/NFκB-mediated SASP in ionizing radiation-induced senescence.

Elena Frediani, Francesca Scavone, Anna Laurenzana, Anastasia Chillà, Katia Tortora, Ilaria Cimmino, Manuela Leri, Monica Bucciantini, Monica Mangoni, Gabriella Fibbi, Mario Del Rosso, Alessandra Mocali, Lisa Giovannelli, Francesca Margheri.

  Senescence occurs upon critical telomere shortening, or following DNA damage, oncogenic activation, hypoxia and oxidative stress, overall referred to stress-induced premature senescence (SIPS). In response to DNA damage, senescent cells release cytoplasmic chromatin fragments (CCFs), and express an altered secretome, the senescence-associated secretory phenotype (SASP), which contributes to generate a pro-inflammatory and pro-tumoral extracellular milieu. Polyphenols have gained significant attention owing to their anti-inflammatory and anti-tumour activities. Here, we studied the effect of oleuropein aglycone (OLE) and hydroxytyrosol (HT) on DNA damage, CCF appearance and SASP in a model of irradiation-induced senescence. Neonatal human dermal fibroblasts (NHDFs) were γ-irradiated and incubated with OLE, 5 µM and HT, 1 µM. Cell growth and senescence-associated (SA)-β-Gal-staining were used as senescence markers. DNA damage was evaluated by Comet assay, lamin B1 expression, release of CCFs, cyclic GMP-AMP Synthase (cGAS) activation. IL-6, IL-8, MCP-1 and RANTES were measured by ELISA assay. Our results showed that OLE and HT exerted a protective effect on 8 Gy irradiation-induced senescence, preserving lamin B1 expression and reducing cGAS/STING/NFκB-mediated SASP. The ability of OLE and HT to mitigate DNA damage, senescence status and the related SASP in normal cells can be exploited to improve the efficacy and safety of cancer radiotherapy.

Keywords:  DNA damage; SASP; human fibroblasts; polyphenols; radiation-induced senescence

DOI:  https://doi.org/10.1111/jcmm.17255