bims-minimp 2022-04-17 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2022–04–17
twenty papers selected by
Hanna Salmonowicz, International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron depletion.
Metabolic Alterations in Cellular Senescence: The Role of Citrate in Ageing and Age-Related Disease.
Mitochondrial-to-nuclear communication in aging: an epigenetic perspective.
Caveolin-1 controls mitochondrial damage and ROS production by regulating fission - fusion dynamics and mitophagy.
Mitochondrial shape alteration by metabolites.
Theoretical analysis of reversible and irreversible mitochondrial swelling invivo.
A mitochondrial response to oxidative stress mediated by unscheduled RNA-DNA hybrids (R-loops).
Mitochondrial protease ClpP supplementation ameliorates diet-induced NASH in mice.
Mitochondrial Lipids: From Membrane Organization to Apoptotic Facilitation.
Contingency and selection in mitochondrial genome dynamics.
CARD19 Interacts with Mitochondrial Contact Site and Cristae Organizing System Constituent Proteins and Regulates Cristae Morphology.
The intra-mitochondrial O-GlcNAcylation system rapidly modulates OXPHOS function and ROS release in the heart.
cGAS modulates cytokine secretion and bacterial burdens by altering the release of mitochondrial DNA in Pseudomonas pulmonary infection.
Chlamydia trachomatis inhibits apoptosis in infected cells by targeting the pro-apoptotic proteins Bax and Bak.
Aggresome assembly at the centrosome is driven by CP110-CEP97-CEP290 and centriolar satellites.
A feedback loop engaging propionate catabolism intermediates controls mitochondrial morphology.
Mitolysosome exocytosis, a mitophagy-independent mitochondrial quality control in flunarizine-induced parkinsonism-like symptoms.
Dual Inhibition of H3K9me2 and H3K27me3 Promotes Tumor Cell Senescence without Triggering the Secretion of SASP.
Types and Functions of Mitoribosome-Specific Ribosomal Proteins across Eukaryotes.
Senescence Connects Autophagy Deficiency to Inflammation and Tumor Progression in the Liver.

EMBO J. 2022 Apr 12. e109390

DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron depletion.

Maeve Long, Alvaro Sanchez-Martinez, Marianna Longo, Fumi Suomi, Hans Stenlund, Annika I Johansson, Homa Ehsan, Veijo T Salo, Lambert Montava-Garriga, Seyedehshima Naddafi, Elina Ikonen, Ian G Ganley, Alexander J Whitworth, Thomas G McWilliams.

  Mitophagy removes defective mitochondria via lysosomal elimination. Increased mitophagy coincides with metabolic reprogramming, yet it remains unknown whether mitophagy is a cause or consequence of such state changes. The signalling pathways that integrate with mitophagy to sustain cell and tissue integrity also remain poorly defined. We performed temporal metabolomics on mammalian cells treated with deferiprone, a therapeutic iron chelator that stimulates PINK1/PARKIN-independent mitophagy. Iron depletion profoundly rewired the metabolome, hallmarked by remodelling of lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurred several hours before mitochondrial clearance, with lipid droplets bordering mitochondria upon iron chelation. We demonstrate that DGAT1 inhibition restricts mitophagy in vitro, with impaired lysosomal homeostasis and cell viability. Importantly, genetic depletion of DGAT1 in vivo significantly impaired neuronal mitophagy and locomotor function in Drosophila. Our data define iron depletion as a potent signal that rapidly reshapes metabolism and establishes an unexpected synergy between lipid homeostasis and mitophagy that safeguards cell and tissue integrity.

Keywords:  DGAT1; iron; lipid droplet; metabolism; mitophagy

DOI:  https://doi.org/10.15252/embj.2021109390
Int J Mol Sci. 2022 Mar 26. pii: 3652. [Epub ahead of print]23(7):

Metabolic Alterations in Cellular Senescence: The Role of Citrate in Ageing and Age-Related Disease.

Maria Elzbieta Mycielska, Emma Naomi James, Eric Kenneth Parkinson.

  Recent mouse model experiments support an instrumental role for senescent cells in age-related diseases and senescent cells may be causal to certain age-related pathologies. A strongly supported hypothesis is that extranuclear chromatin is recognized by the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, which in turn leads to the induction of several inflammatory cytokines as part of the senescence-associated secretory phenotype. This sterile inflammation increases with chronological age and age-associated disease. More recently, several intracellular and extracellular metabolic changes have been described in senescent cells but it is not clear whether any of them have functional significance. In this review, we highlight the potential effect of dietary and age-related metabolites in the modulation of the senescent phenotype in addition to discussing how experimental conditions may influence senescent cell metabolism, especially that of energy regulation. Finally, as extracellular citrate accumulates following certain types of senescence, we focus on the recently reported role of extracellular citrate in aging and age-related pathologies. We propose that citrate may be an active component of the senescence-associated secretory phenotype and via its intake through the diet may even contribute to the cause of age-related disease.

Keywords:  ageing; cancer; citrate; energy; metabolism; senescence; telomere; transport

DOI:  https://doi.org/10.3390/ijms23073652
Trends Biochem Sci. 2022 Apr 06. pii: S0968-0004(22)00067-6. [Epub ahead of print]

Mitochondrial-to-nuclear communication in aging: an epigenetic perspective.

Di Zhu, Xinyu Li, Ye Tian.

  Age-associated changes in mitochondria are closely involved in aging. Apart from the established roles in bioenergetics and biosynthesis, mitochondria are signaling organelles that communicate their fitness to the nucleus, triggering transcriptional programs to adapt homeostasis stress that is essential for organismal health and aging. Emerging studies revealed that mitochondrial-to-nuclear (mito-nuclear) communication via altered levels of mitochondrial metabolites or stress signals causes various epigenetic changes, facilitating efforts to maintain homeostasis and affect aging. Here, we summarize recent studies on the mechanisms by which mito-nuclear communication modulates epigenomes and their effects on regulating the aging process. Insights into understanding how mitochondrial metabolites serve as prolongevity signals and how aging affects this communication will help us develop interventions to promote longevity and health.

Keywords:  UPR(mt); aging; epigenetic regulation; longevity; mitochondrial metabolites; mitochondrial–nuclear communication

DOI:  https://doi.org/10.1016/j.tibs.2022.03.008
Redox Biol. 2022 Apr 06. pii: S2213-2317(22)00076-3. [Epub ahead of print]52 102304

Caveolin-1 controls mitochondrial damage and ROS production by regulating fission - fusion dynamics and mitophagy.

Ying Jiang, Sarah Krantz, Xiang Qin, Shun Li, Hirushi Gunasekara, Young-Mee Kim, Adriana Zimnicka, Misuk Bae, Ke Ma, Peter T Toth, Ying Hu, Ayesha N Shajahan-Haq, Hemal H Patel, Saverio Gentile, Marcelo G Bonini, Jalees Rehman, Yiyao Liu, Richard D Minshall.

  As essential regulators of mitochondrial quality control, mitochondrial dynamics and mitophagy play key roles in maintenance of metabolic health and cellular homeostasis. Here we show that knockdown of the membrane-inserted scaffolding and structural protein caveolin-1 (Cav-1) and expression of tyrosine 14 phospho-defective Cav-1 mutant (Y14F), as opposed to phospho-mimicking Y14D, altered mitochondrial morphology, and increased mitochondrial matrix mixing, mitochondrial fusion and fission dynamics as well as mitophagy in MDA-MB-231 triple negative breast cancer cells. Further, we found that interaction of Cav-1 with mitochondrial fusion/fission machinery Mitofusin 2 (Mfn2) and Dynamin related protein 1 (Drp1) was enhanced by Y14D mutant indicating Cav-1 Y14 phosphorylation prevented Mfn2 and Drp1 translocation to mitochondria. Moreover, limiting mitochondrial recruitment of Mfn2 diminished formation of the PINK1/Mfn2/Parkin complex required for initiation of mitophagy resulting in accumulation of damaged mitochondria and ROS (mtROS). Thus, these studies indicate that phospho-Cav-1 may be an important switch mechanism in cancer cell survival which could lead to novel strategies for complementing cancer therapies.

Keywords:  Cav-1; Dynamin-related protein 1; Mitochondrial dynamics; Mitofusin 2; Mitophagy; mtROS

DOI:  https://doi.org/10.1016/j.redox.2022.102304
Nat Cell Biol. 2022 Apr 13.

Mitochondrial shape alteration by metabolites.

Till Klecker, Benedikt Westermann.

DOI: https://doi.org/10.1038/s41556-022-00889-w
Biosystems. 2022 Apr 09. pii: S0303-2647(22)00069-7. [Epub ahead of print] 104679

Theoretical analysis of reversible and irreversible mitochondrial swelling invivo.

Igor Khmelinskii, Vladimir Makarov.

  Theoretical biophysical model is reported for mitochondrial swelling (MS) dynamics in vivo. This newly developed model is based on the detailed biophysical model of MS dynamics in vitro, where mechanical properties of the inner mitochondrial membrane (IMM) were taken into account. The present model of MS dynamics in vivo is capable of analyzing MS dynamic transition from the reversible (physiological) to the irreversible (pathological) mode. This model was used to describe myocytes, assuming 1000 mitochondria distributed homogeneously over the sarcoplasm. Solute transport through the myocyte membrane was described by simplified phenomenological mechanisms of solute uptake and release. Biophysical processes occurring in mitochondria within cells were similar to those included in the earlier reported in vitro biophysical model of MS dynamics. Additionally, in vivo MS dynamics was simulated in different initial conditions, with results different from those of the in vitro model. Note that the presently reported model is the first attempt to develop a detailed biophysical model for the analysis of MS dynamics in vivo, capable of reproducing the transition between reversible and irreversible MS dynamics.

Keywords:  Biophysical model in vivo; Irreversible mitochondrial swelling; Matrix solute dynamics; Mitochondrial swelling; Reversible mitochondrial swelling; Solute dynamics

DOI:  https://doi.org/10.1016/j.biosystems.2022.104679
Mol Cell Oncol. 2021 ;8(6): 2007028

A mitochondrial response to oxidative stress mediated by unscheduled RNA-DNA hybrids (R-loops).

Xavier Renaudin, Ashok R Venkitaraman.

  How oxidative stress promotes aging-related human diseases like cancer and neurodegeneration remains unclear. Here, we discuss the origins and implications of an oxidative-stress response recently reported to destabilize the mitochondrial (mt) genome via unscheduled RNA/DNA hybrid (R-loop) accumulation, by impairing the recruitment of RNAseH1 to the regulatory regions of mtDNA.

Keywords:  BRCA2; Oxidative stress; PRPF8; R-loops; RNA-DNA hybrid; SETX; cancer; genomic instability; mitochondria; mtDNA replication; neurodegeneration

DOI:  https://doi.org/10.1080/23723556.2021.2007028
J Hepatol. 2022 Apr 11. pii: S0168-8278(22)00226-4. [Epub ahead of print]

Mitochondrial protease ClpP supplementation ameliorates diet-induced NASH in mice.

Sung-E Choi, Yoonjung Hwang, Soo-Jin Lee, Hyunkyung Jung, Tae Hwan Shin, Youngho Son, Seokho Park, Seung Jin Han, Hae Jin Kim, Kwan Woo Lee, Gwang Lee, Jongsook Kim Kemper, Hyun Kyu Song, Yup Kang.

   BACKGROUND & AIMS: Mitochondrial dysfunction is considered a pathogenic linker in the development of non-alcoholic steatohepatitis (NASH). Inappropriate mitochondrial protein-quality control, possibly induced due to insufficiency of the mitochondrial matrix caseinolytic protease P (ClpP), can potentially cause mitochondrial dysfunction. Herein, we aimed to investigate hepatic ClpP levels in a diet-induced model of NASH and determine whether supplementation of ClpP can ameliorate the diet-induced NASH.
METHODS: NASH was induced by a high fat/high fructose (HF/HFr) diet in C57BL/6J mice. Stress/inflammatory signals were induced in mouse primary hepatocytes (MPHs) by treatment with palmitate/oleate (PA/OA). ClpP levels in hepatocytes were reduced using the RNAi-mediated gene knockdown technique but increased through the viral transduction of ClpP. ClpP activation was induced by administering a chemical activator of ClpP.
RESULTS: Hepatic ClpP protein levels in C57BL/6J mice fed a HF/HFr diet were lower than the levels in those fed a normal chow diet. PA/OA treatment also decreased the ClpP protein levels in MPHs. Overexpression or activation of ClpP reversed the PA/OA-induced mitochondrial dysfunction and stress/inflammatory signal activation in MPHs, whereas ClpP knockdown induced mitochondrial dysfunction and stress/inflammatory signals in these cells. On the other hand, ClpP overexpression or activation improved HF/HFr-induced NASH characteristics such as hepatic steatosis, inflammation, fibrosis, and injury in the C57BL/6J mice, whereas ClpP knockdown further augmented steatohepatitis in mice fed a HF/HFr diet.
CONCLUSIONS: Reduced ClpP expression and subsequent mitochondrial dysfunction are key to the development of diet-induced NASH. ClpP supplementation through viral transduction or chemical activation represents potential therapeutic strategies for preventing diet-induced NASH.

Keywords:  inflammation; mitochondrial dysfunction; proteostasis; steatohepatitis

DOI:  https://doi.org/10.1016/j.jhep.2022.03.034
Int J Mol Sci. 2022 Mar 29. pii: 3738. [Epub ahead of print]23(7):

Mitochondrial Lipids: From Membrane Organization to Apoptotic Facilitation.

Aikaterini Poulaki, Stavroula Giannouli.

  Mitochondria are the most complex intracellular organelles, their function combining energy production for survival and apoptosis facilitation for death. Such a multivariate physiology is structurally and functionally reflected upon their membrane configuration and lipid composition. Mitochondrial double membrane lipids, with cardiolipin as the protagonist, show an impressive level of complexity that is mandatory for maintenance of mitochondrial health and protection from apoptosis. Given that lipidomics is an emerging field in cancer research and that mitochondria are the organelles with the most important role in malignant maintenance knowledge of the mitochondrial membrane, lipid physiology in health is mandatory. In this review, we will thus describe the delicate nature of the healthy mitochondrial double membrane and its role in apoptosis. Emphasis will be given on mitochondrial membrane lipids and the changes that they undergo during apoptosis induction and progression.

Keywords:  apoptosis; cardiolipin; ceramide; cytochrome C; double membrane; mitochondria; mitochondrial lipids

DOI:  https://doi.org/10.3390/ijms23073738
Elife. 2022 Apr 11. pii: e76557. [Epub ahead of print]11

Contingency and selection in mitochondrial genome dynamics.

Christopher J Nunn, Sidhartha Goyal.

  High frequencies of mutant mitochondrial DNA (mtDNA) in human cells lead to cellular defects that are associated with aging and disease. Yet much remains to be understood about the dynamics of the generation of mutant mtDNAs and their relative replicative fitness that informs their fate within cells and tissues. To address this, we utilize long-read single-molecule sequencing to track mutational trajectories of mtDNA in the model organism Saccharomyces cerevisiae. This model has numerous advantages over mammalian systems due to its much larger mtDNA and ease of artificially competing mutant and wild-type mtDNA copies in cells. We show a previously unseen pattern that constrains subsequent excision events in mtDNA fragmentation in yeast. We also provide evidence for the generation of rare and contentious non-periodic mtDNA structures that lead to persistent diversity within individual cells. Finally, we show that measurements of relative fitness of mtDNA fit a phenomenological model that highlights important biophysical parameters governing mtDNA fitness. Altogether, our study provides techniques and insights into the dynamics of large structural changes in genomes that we show are applicable to more complex organisms like humans.

Keywords:  S. cerevisiae; computational biology; genetics; genomics; systems biology

DOI:  https://doi.org/10.7554/eLife.76557
Cells. 2022 Mar 31. pii: 1175. [Epub ahead of print]11(7):

CARD19 Interacts with Mitochondrial Contact Site and Cristae Organizing System Constituent Proteins and Regulates Cristae Morphology.

Kariana E Rios, Ming Zhou, Nathaniel M Lott, Chelsi R Beauregard, Dennis P McDaniel, Thomas P Conrads, Brian C Schaefer.

  CARD19 is a mitochondrial protein of unknown function. While CARD19 was originally reported to regulate TCR-dependent NF-κB activation via interaction with BCL10, this function is not recapitulated ex vivo in primary murine CD8+ T cells. Here, we employ a combination of SIM, TEM, and confocal microscopy, along with proteinase K protection assays and proteomics approaches, to identify interacting partners of CARD19 in macrophages. Our data show that CARD19 is specifically localized to the outer mitochondrial membrane. Through deletion of functional domains, we demonstrate that both the distal C-terminus and transmembrane domain are required for mitochondrial targeting, whereas the CARD is not. Importantly, mass spectrometry analysis of 3×Myc-CARD19 immunoprecipitates reveals that CARD19 interacts with the components of the mitochondrial intermembrane bridge (MIB), consisting of mitochondrial contact site and cristae organizing system (MICOS) components MIC19, MIC25, and MIC60, and MICOS-interacting proteins SAMM50 and MTX2. These CARD19 interactions are in part dependent on a properly folded CARD. Consistent with previously reported phenotypes upon siRNA silencing of MICOS subunits, absence of CARD19 correlates with irregular cristae morphology. Based on these data, we propose that CARD19 is a previously unknown interacting partner of the MIB and the MIC19-MIC25-MIC60 MICOS subcomplex that regulates cristae morphology.

Keywords:  BinCARD; CARD proteins; CARD19; MIB; MICOS; cristae

DOI:  https://doi.org/10.3390/cells11071175
Commun Biol. 2022 Apr 12. 5(1): 349

The intra-mitochondrial O-GlcNAcylation system rapidly modulates OXPHOS function and ROS release in the heart.

Justine Dontaine, Asma Bouali, Frederic Daussin, Laurent Bultot, Didier Vertommen, Manon Martin, Raahulan Rathagirishnan, Alexanne Cuillerier, Sandrine Horman, Christophe Beauloye, Laurent Gatto, Benjamin Lauzier, Luc Bertrand, Yan Burelle.

Protein O-GlcNAcylation is increasingly recognized as an important cellular regulatory mechanism, in multiple organs including the heart. However, the mechanisms leading to O-GlcNAcylation in mitochondria and the consequences on their function remain poorly understood. In this study, we use an in vitro reconstitution assay to characterize the intra-mitochondrial O-GlcNAc system without potential cytoplasmic confounding effects. We compare the O-GlcNAcylome of isolated cardiac mitochondria with that of mitochondria acutely exposed to NButGT, a specific inhibitor of glycoside hydrolase. Amongst the 409 O-GlcNAcylated mitochondrial proteins identified, 191 display increased O-GlcNAcylation in response to NButGT. This is associated with enhanced Complex I (CI) activity, increased maximal respiration in presence of pyruvate-malate, and a striking reduction of mitochondrial ROS release, which could be related to O-GlcNAcylation of specific subunits of ETC complexes (CI, CIII) and TCA cycle enzymes. In conclusion, our work underlines the existence of a dynamic mitochondrial O-GlcNAcylation system capable of rapidly modifying mitochondrial function.

DOI: https://doi.org/10.1038/s42003-022-03282-3
Immunology. 2022 Apr 14.

cGAS modulates cytokine secretion and bacterial burdens by altering the release of mitochondrial DNA in Pseudomonas pulmonary infection.

Biao Wang, Chuanmin Zhou, Qun Wu, Ping Lin, Qinqin Pu, Shugang Qin, Pan Gao, Zhihan Wang, Yingying Liu, Jacob Arel, Yanjiong Chen, Teng Chen, Min Wu.

  Cyclic GMP-AMP synthase (cGAS) is essential for fighting against viruses and bacteria, but how cGAS is involved in host immune response remains largely elusive. Here, we uncover the crucial role of cGAS in host immunity based on a Pseudomonas aeruginosa pulmonary infection model. cGAS-/- mice showed more heavy bacterial burdens and serious lung injury accompanied with exorbitant proinflammatory cytokines than wild-type mice. cGAS deficiency caused an accumulation of mitochondrial DNA in cytoplasm, which in turn induced excessive secretion of proinflammatory factors by activating inflammasome and TLR9 signaling. Mechanistically, cGAS deficiency inhibited the recruitment of LC3 by reducing the binding capacity of TBK-1 to p62, leading to impaired mitophagy and augmented release of mitochondrial DNA. Importantly, cytoplasmic mitochondrial DNA also acted as a feedback signal that induced the activation of cGAS. Altogether, these findings identify protective and homeostasis functions of cGAS against Pseudomonas aeruginosa infection, adding significant insight into the pathogenesis of bacterial infectious diseases.

Keywords:  bacterial burdens; cGAS; cytokine secretion; mitochondrial DNA; pulmonary infection

DOI:  https://doi.org/10.1111/imm.13482
Cell Death Differ. 2022 Apr 09.

Chlamydia trachomatis inhibits apoptosis in infected cells by targeting the pro-apoptotic proteins Bax and Bak.

Collins Waguia Kontchou, Ian E Gentle, Arnim Weber, Axel Schoeniger, Frank Edlich, Georg Häcker.

Apoptosis acts in defense against microbial infection, and many infectious agents have developed strategies to inhibit host cell apoptosis. The human pathogen Chlamydia trachomatis (Ctr) is an obligate intracellular bacterium that strongly inhibits mitochondrial apoptosis of its human host cell but there is no agreement how the bacteria achieve this. We here provide a molecular analysis of chlamydial apoptosis-inhibition in infected human cells and demonstrate that the block of apoptosis occurs during the activation of the effectors of mitochondrial apoptosis, Bak and Bax. We use small-molecule Bcl-2-family inhibitors and gene targeting to show that previous models cannot explain the anti-apoptotic effect of chlamydial infection. Although the anti-apoptotic Bcl-2-family protein Mcl-1 was strongly upregulated upon infection, Mcl-1-deficient cells and cells where Mcl-1 was pharmacologically inactivated were still protected. Ctr-infection could inhibit both Bax- and Bak-induced apoptosis. Apoptotic Bax-oligomerization and association with the outer mitochondrial membrane was reduced upon chlamydial infection. Infection further inhibited apoptosis induced conformational changes of Bak, as evidenced by changes to protease sensitivity, oligomerization and release from the mitochondrial porin VDAC2. Mitochondria isolated from Ctr-infected cells were protected against the pro-apoptotic Bcl-2-family proteins Bim and tBid but this protection was lost upon protease digestion. However, the protective effect of Ctr-infection was reduced in cells lacking the Bax/Bak-regulator VDAC2. We further found that OmpA, a porin of the outer membrane of Ctr, associated upon experimental expression with mitochondria and inhibited apoptosis, phenocopying the effect of the infection. These results identify a novel way of apoptosis inhibition, involving only the most downstream modulator of mitochondrial apoptosis and suggest that Chlamydia has a protein dedicated to the inhibition of apoptosis to secure its survival in human cells.

DOI: https://doi.org/10.1038/s41418-022-00995-0
Nat Cell Biol. 2022 Apr 11.

Aggresome assembly at the centrosome is driven by CP110-CEP97-CEP290 and centriolar satellites.

Suzanna L Prosser, Johnny Tkach, Ladan Gheiratmand, Jaeyoun Kim, Brian Raught, Ciaran G Morrison, Laurence Pelletier.

Protein degradation is critical to maintaining cellular homeostasis, and perturbation of the ubiquitin proteasome system leads to the accumulation of protein aggregates. These aggregates are either directed towards autophagy for destruction or sequestered into an inclusion, termed the aggresome, at the centrosome. Utilizing high-resolution quantitative analysis, here, we define aggresome assembly at the centrosome in human cells. Centriolar satellites are proteinaceous granules implicated in the trafficking of proteins to the centrosome. During aggresome assembly, satellites were required for the growth of the aggresomal structure from an initial ring of phosphorylated HSP27 deposited around the centrioles. The seeding of this phosphorylated HSP27 ring depended on the centrosomal proteins CP110, CEP97 and CEP290. Owing to limiting amounts of CP110, senescent cells, which are characterized by the accumulation of protein aggregates, were defective in aggresome formation. Furthermore, satellites and CP110-CEP97-CEP290 were required for the aggregation of mutant huntingtin. Together, these data reveal roles for CP110-CEP97-CEP290 and satellites in the control of cellular proteostasis and the aggregation of disease-relevant proteins.

DOI: https://doi.org/10.1038/s41556-022-00869-0
Nat Cell Biol. 2022 Apr 13.

A feedback loop engaging propionate catabolism intermediates controls mitochondrial morphology.

Junxiang Zhou, Mei Duan, Xin Wang, Fengxia Zhang, Hejiang Zhou, Tengfei Ma, Qiuyuan Yin, Jie Zhang, Fei Tian, Guodong Wang, Chonglin Yang.

D-2-Hydroxyglutarate (D-2HG) is an α-ketoglutarate-derived mitochondrial metabolite that causes D-2-hydroxyglutaric aciduria, a devastating developmental disorder. How D-2HG adversely affects mitochondria is largely unknown. Here, we report that in Caenorhabditis elegans, loss of the D-2HG dehydrogenase DHGD-1 causes D-2HG accumulation and mitochondrial damage. The excess D-2HG leads to a build-up of 3-hydroxypropionate (3-HP), a toxic metabolite in mitochondrial propionate oxidation, by inhibiting the 3-HP dehydrogenase HPHD-1. We demonstrate that 3-HP binds the MICOS subunit MIC60 (encoded by immt-1) and inhibits its membrane-binding and membrane-shaping activities. We further reveal that dietary and gut bacteria affect mitochondrial health by modulating the host production of 3-HP. These findings identify a feedback loop that links the toxic effects of D-2HG and 3-HP on mitochondria, thus providing important mechanistic insights into human diseases related to D-2HG and 3-HP.

DOI: https://doi.org/10.1038/s41556-022-00883-2
Sci Adv. 2022 Apr 15. 8(15): eabk2376

Mitolysosome exocytosis, a mitophagy-independent mitochondrial quality control in flunarizine-induced parkinsonism-like symptoms.

Feixiang Bao, Lingyan Zhou, Rui Zhou, Qiaoying Huang, Junguo Chen, Sheng Zeng, Yi Wu, Liang Yang, Shufang Qian, Mengfei Wang, Xueying He, Shan Liang, Juntao Qi, Ge Xiang, Qi Long, Jingyi Guo, Zhongfu Ying, Yanshuang Zhou, Qiuge Zhao, Jiwei Zhang, Di Zhang, Wei Sun, Mi Gao, Hao Wu, Yifan Zhao, Jinfu Nie, Min Li, Quan Chen, Jiekai Chen, Xiao Zhang, Guangjin Pan, Hong Zhang, Mingtao Li, Mei Tian, Xingguo Liu.

Mitochondrial quality control plays an important role in maintaining mitochondrial homeostasis and function. Disruption of mitochondrial quality control degrades brain function. We found that flunarizine (FNZ), a drug whose chronic use causes parkinsonism, led to a parkinsonism-like motor dysfunction in mice. FNZ induced mitochondrial dysfunction and decreased mitochondrial mass specifically in the brain. FNZ decreased mitochondrial content in both neurons and astrocytes, without affecting the number of nigral dopaminergic neurons. In human neural progenitor cells, FNZ also induced mitochondrial depletion. Mechanistically, independent of ATG5- or RAB9-mediated mitophagy, mitochondria were engulfed by lysosomes, followed by a vesicle-associated membrane protein 2- and syntaxin-4-dependent extracellular secretion. A genome-wide CRISPR knockout screen identified genes required for FNZ-induced mitochondrial elimination. These results reveal not only a previously unidentified lysosome-associated exocytosis process of mitochondrial quality control that may participate in the FNZ-induced parkinsonism but also a drug-based method for generating mitochondria-depleted mammal cells.

DOI: https://doi.org/10.1126/sciadv.abk2376
Int J Mol Sci. 2022 Apr 01. pii: 3911. [Epub ahead of print]23(7):

Dual Inhibition of H3K9me2 and H3K27me3 Promotes Tumor Cell Senescence without Triggering the Secretion of SASP.

Na Zhang, Mengjie Shang, Hongxin Li, Lan Wu, Meichen Dong, Baiqu Huang, Jun Lu, Yu Zhang.

  Chemotherapy remains the most common cancer treatment. Although chemotherapeutic drugs induce tumor cell senescence, they are often associated with post-therapy tumor recurrence by inducing the senescence-associated secretory phenotype (SASP). Therefore, it is important to identify effective strategies to induce tumor cell senescence without triggering SASP. In this study, we used the small molecule inhibitors, UNC0642 (G9a inhibitor) and UNC1999 (EZH2 inhibitor) alone or in combination, to inhibit H3K9 and H3K27 methylation in different cancer cells. Dual inhibition of H3K9me2 and H3K27me3 in highly metastatic tumor cells had a stronger pro-senescence effect than either inhibitor alone and did not trigger SASP in tumor cells. Dual inhibition of H3K9me2 and H3K27me3 suppressed the formation of cytosolic chromatin fragments, which inhibited the cGAS-STING-SASP pathway. Collectively, these data suggested that dual inhibition of H3K9 and H3K27 methylation induced senescence of highly metastatic tumor cells without triggering SASP by inhibiting the cGAS-STING-SASP pathway, providing a new mechanism for the epigenetics-based therapy targeting H3K9 and H3K27 methylation.

Keywords:  CCF; H3K27me3; H3K9me2; SASP; tumor cell senescence

DOI:  https://doi.org/10.3390/ijms23073911
Int J Mol Sci. 2022 Mar 23. pii: 3474. [Epub ahead of print]23(7):

Types and Functions of Mitoribosome-Specific Ribosomal Proteins across Eukaryotes.

Vassilis Scaltsoyiannes, Nicolas Corre, Florent Waltz, Philippe Giegé.

  Mitochondria are key organelles that combine features inherited from their bacterial endosymbiotic ancestor with traits that arose during eukaryote evolution. These energy producing organelles have retained a genome and fully functional gene expression machineries including specific ribosomes. Recent advances in cryo-electron microscopy have enabled the characterization of a fast-growing number of the low abundant membrane-bound mitochondrial ribosomes. Surprisingly, mitoribosomes were found to be extremely diverse both in terms of structure and composition. Still, all of them drastically increased their number of ribosomal proteins. Interestingly, among the more than 130 novel ribosomal proteins identified to date in mitochondria, most of them are composed of a-helices. Many of them belong to the nuclear encoded super family of helical repeat proteins. Here we review the diversity of functions and the mode of action held by the novel mitoribosome proteins and discuss why these proteins that share similar helical folds were independently recruited by mitoribosomes during evolution in independent eukaryote clades.

Keywords:  helical repeat proteins; mitochondrial gene expression; pentatricopeptide repeat proteins; ribosomes; single particle cryo-EM; translation

DOI:  https://doi.org/10.3390/ijms23073474
Cell Mol Gastroenterol Hepatol. 2022 Apr 07. pii: S2352-345X(22)00068-6. [Epub ahead of print]

Senescence Connects Autophagy Deficiency to Inflammation and Tumor Progression in the Liver.

Nazmul Huda, Bilon Khambu, Gang Liu, Hirokazu Nakatsumi, Shengmin Yan, Xiaoyun Chen, Michelle Ma, Zheng Dong, Keiichi I Nakayama, Xiao-Ming Yin.

   BACKGROUND & AIMS: Cellular senescence is frequently present in injured livers. The induction mechanism and the pathological role are not always clear. We aimed to understand the dynamics of senescence induction and progression, and the mechanism responsible for the pathology using a mouse model that disables the essential process of autophagy.
METHODS: Mice deficient in key autophagy genes, Atg7 or Atg5, in the livers were used. Senescence was measured using established cellular and molecular signatures. The mechanistic roles of NRF2, FOXK1 and CCR2 were assessed using mouse genetic models. Liver functions, pathology and tumor development were measured using biochemical and histological approaches.
RESULTS: Inducible deletion of Atg7 rapidly upregulated cyclin dependent kinase inhibitors (CDKi) independently of injury and induced senescence-associated β-galactosidase activities and senescence associated secretory phenotype (SASP). Sustained activation of NRF2 was the major factor causing senescence by mediating oxidative DNA damage and upregulating CCL2, a key component of autophagy-related SASP, via the NRF2-FOXK1 axis. Senescence was responsible for hepatic inflammation through CCR2-mediated recruitment of CD11b+ monocytes and CD3+ T cells. CCR2-mediated process in turn enhanced senescence and SASP by upregulating CDKi and chemokines. Thus, senescence and inflammation can mutually augment each other, forming an amplification loop for both events. CCR2-mediated process also modulated liver injury and tumor progression at the later stage of autophagy deficiency related pathology.
CONCLUSIONS: These results provide the insight that hepatic senescence can occur early in the disease process, triggers inflammation and is enhanced by inflammation, and has long-term effects on liver injury and tumor progression.

Keywords:  CCR2; CD11b; CDK inhibitors; chemokines; liver injury

DOI:  https://doi.org/10.1016/j.jcmgh.2022.04.003