bims-mitdyn 2020-12-06 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2020‒12‒06
twenty papers selected by
Edmond Chan
Queen’s University, School of Medicine

Dynamic Cardiolipin Synthesis Is Required for CD8+ T Cell Immunity.
Succinyl-CoA Ligase Deficiency in Pro-inflammatory and Tissue-Invasive T Cells.
Mitochondrial Damage and the Road to Exhaustion.
Telomeric injury by KML001 in human T cells induces mitochondrial dysfunction through the p53-PGC-1α pathway.
Drosophila MICOS knockdown impairs mitochondrial structure and function and promotes mitophagy in muscle tissue.
Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila.
Mitochondria Control mTORC1 Activity Linked Compartmentalization of eIF4E to Regulate Extracellular Export of microRNAs.
Blocking mitochondrial pyruvate import in brown adipocytes induces energy wasting via lipid cycling.
Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) rescues the cellular phenotype of MELAS by inducing homeostatic mechanisms.
Dual function of GTPBP6 in biogenesis and recycling of human mitochondrial ribosomes.
Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import.
DNA-PKcs promotes alcohol-related liver disease by activating Drp1-related mitochondrial fission and repressing FUNDC1-required mitophagy.
A Slc25a46-/- mouse model simulating motor deficit, imbalance of redox system and mitochondria dysfunction during aging.
Melatonin alleviates angiotensin-II-induced cardiac hypertrophy via activating MICU1 pathway.
Mitochondrial Lon-induced mtDNA leakage contributes to PD-L1-mediated immunoescape via STING-IFN signaling and extracellular vesicles.
Mapping the electrostatic profile of cellular membranes.
Human skeletal muscle mitochondrial dynamics in relation to oxidative capacity and insulin sensitivity.
Amyloid Β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer's Disease-Related Models.
Mucin-2 knockout is a model of intercellular junction defects, mitochondrial damage and ATP depletion in the intestinal epithelium.
Differences in relative capacities of oxidative phosphorylation pathways may explain sex- and tissue-specific susceptibility to vision defects due to mitochondrial dysfunction.

Cell Metab. 2020 Dec 01. pii: S1550-4131(20)30598-2. [Epub ahead of print]32(6): 981-995.e7

Dynamic Cardiolipin Synthesis Is Required for CD8+ T Cell Immunity.

Mauro Corrado, Joy Edwards-Hicks, Matteo Villa, Lea J Flachsmann, David E Sanin, Maaike Jacobs, Francesc Baixauli, Michal Stanczak, Eve Anderson, Mai Azuma, Andrea Quintana, Jonathan D Curtis, Thomas Clapes, Katarzyna M Grzes, Agnieszka M Kabat, Ryan Kyle, Annette E Patterson, Ramon Klein Geltink, Borko Amulic, Colin G Steward, Douglas Strathdee, Eirini Trompouki, David O'Sullivan, Edward J Pearce, Erika L Pearce.

  Mitochondria constantly adapt to the metabolic needs of a cell. This mitochondrial plasticity is critical to T cells, which modulate metabolism depending on antigen-driven signals and environment. We show here that de novo synthesis of the mitochondrial membrane-specific lipid cardiolipin maintains CD8+ T cell function. T cells deficient for the cardiolipin-synthesizing enzyme PTPMT1 had reduced cardiolipin and responded poorly to antigen because basal cardiolipin levels were required for activation. However, neither de novo cardiolipin synthesis, nor its Tafazzin-dependent remodeling, was needed for T cell activation. In contrast, PTPMT1-dependent cardiolipin synthesis was vital when mitochondrial fitness was required, most notably during memory T cell differentiation or nutrient stress. We also found CD8+ T cell defects in a small cohort of patients with Barth syndrome, where TAFAZZIN is mutated, and in a Tafazzin-deficient mouse model. Thus, the dynamic regulation of a single mitochondrial lipid is crucial for CD8+ T cell immunity.

Keywords:  Barth Syndrome; CD8 T cells; PTPMT1; Tafazzin; cardiolipin; immune memory; immunometabolism; mitochodria

DOI:  https://doi.org/10.1016/j.cmet.2020.11.003
Cell Metab. 2020 Dec 01. pii: S1550-4131(20)30594-5. [Epub ahead of print]32(6): 967-980.e5

Succinyl-CoA Ligase Deficiency in Pro-inflammatory and Tissue-Invasive T Cells.

Bowen Wu, Jingtao Qiu, Tuantuan V Zhao, Yanan Wang, Toshihisa Maeda, Isabel N Goronzy, Mitsuhiro Akiyama, Shozo Ohtsuki, Ke Jin, Lu Tian, Jörg J Goronzy, Cornelia M Weyand.

  Autoimmune T cells in rheumatoid arthritis (RA) have a defect in mitochondrial oxygen consumption and ATP production. Here, we identified suppression of the GDP-forming β subunit of succinate-CoA ligase (SUCLG2) as an underlying abnormality. SUCLG2-deficient T cells reverted the tricarboxylic acid (TCA) cycle from the oxidative to the reductive direction, accumulated α-ketoglutarate, citrate, and acetyl-CoA (AcCoA), and differentiated into pro-inflammatory effector cells. In AcCoAhi RA T cells, tubulin acetylation stabilized the microtubule cytoskeleton and positioned mitochondria in a perinuclear location, resulting in cellular polarization, uropod formation, T cell migration, and tissue invasion. In the tissue, SUCLG2-deficient T cells functioned as cytokine-producing effector cells and were hyperinflammatory, a defect correctable by replenishing the enzyme. Preventing T cell tubulin acetylation by tubulin acetyltransferase knockdown was sufficient to inhibit synovitis. These data link mitochondrial failure and AcCoA oversupply to autoimmune tissue inflammation.

Keywords:  T cell; acetyl-CoA; acetylation; alph-ketoglutarate; autoimmunity; citrate; microtubule; mitochondria; tissue invasion; uropod

DOI:  https://doi.org/10.1016/j.cmet.2020.10.025
Cell Metab. 2020 Dec 01. pii: S1550-4131(20)30599-4. [Epub ahead of print]32(6): 905-907

Mitochondrial Damage and the Road to Exhaustion.

Wenhui Li, Hongcheng Cheng, Guideng Li, Lianjun Zhang.

Two recent studies published in Nature Immunology map out the link between dysregulated mitochondrial metabolism and terminal exhaustion of tumor-infiltrating T lymphocytes. Yu et al. (2020) and Vardhana et al. (2020) show that defective mitophagy or impaired oxidative phosphorylation triggers mitochondrial reactive oxygen species production, which in turn promotes a T cell exhaustion program, limiting T cell proliferation and self-renewal.

DOI: https://doi.org/10.1016/j.cmet.2020.11.004
Cell Death Dis. 2020 Dec 02. 11(12): 1030

Telomeric injury by KML001 in human T cells induces mitochondrial dysfunction through the p53-PGC-1α pathway.

Madison Schank, Juan Zhao, Ling Wang, Zhengke Li, Dechao Cao, Lam Nhat Nguyen, Xindi Dang, Sushant Khanal, Lam Ngoc Thao Nguyen, Bal Krishna Chand Thakuri, Stella C Ogbu, Zeyuan Lu, Jinyu Zhang, Xiao Y Wu, Zheng D Morrison, Mohamed El Gazzar, Shunbin Ning, Jonathan P Moorman, Zhi Q Yao.

Telomere erosion and mitochondrial dysfunction are prominent features of aging cells with progressive declines of cellular functions. Whether telomere injury induces mitochondrial dysfunction in human T lymphocytes, the major component of adaptive host immunity against infection and malignancy, remains unclear. We have recently shown that disruption of telomere integrity by KML001, a telomere-targeting drug, induces T cell senescence and apoptosis via the telomeric DNA damage response (DDR). In this study, we used KML001 to further investigate the role and mechanism of telomere injury in mitochondrial dysregulation in aging T cells. We demonstrate that targeting telomeres by KML001 induces mitochondrial dysfunction, as evidenced by increased mitochondrial swelling and decreased mitochondrial membrane potential, oxidative phosphorylation, mitochondrial DNA content, mitochondrial respiration, oxygen consumption, glycolysis, and ATP energy production. Mechanistically, we found that the KML001-induced telomeric DDR activated p53 signaling, which in turn repressed the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and nuclear respiratory factor 1 (NRF-1), leading to T cell mitochondrial dysfunction. These results, forging a direct link between telomeric and mitochondrial biology, shed new light on the human T cell aging network, and demonstrate that the p53-PGC-1α-NRF-1 axis contributes to mitochondrial dysfunction in the setting of telomeric DDR. This study suggests that targeting this axis may offer an alternative, novel approach to prevent telomere damage-mediated mitochondrial and T cell dysfunctions to combat a wide range of immune aging-associated human diseases.

DOI: https://doi.org/10.1038/s41419-020-03238-7
Biol Open. 2020 Dec 02. pii: bio054262. [Epub ahead of print]9(12):

Drosophila MICOS knockdown impairs mitochondrial structure and function and promotes mitophagy in muscle tissue.

Li-Jie Wang, Tian Hsu, Hsiang-Ling Lin, Chi-Yu Fu.

  The mitochondrial contact site and cristae organizing system (MICOS) is a multi-protein interaction hub that helps define mitochondrial ultrastructure. While the functional importance of MICOS is mostly characterized in yeast and mammalian cells in culture, the contributions of MICOS to tissue homeostasis in vivo remain further elucidation. In this study, we examined how knocking down expression of Drosophila MICOS genes affects mitochondrial function and muscle tissue homeostasis. We found that CG5903/MIC26-MIC27 colocalizes and functions with Mitofilin/MIC60 and QIL1/MIC13 as a Drosophila MICOS component; knocking down expression of any of these three genes predictably altered mitochondrial morphology, causing loss of cristae junctions, and disruption of cristae packing. Furthermore, the knockdown flies exhibited low mitochondrial membrane potential, fusion/fission imbalances, increased mitophagy, and limited cell death. Reductions in climbing ability indicated deficits in muscle function. Knocking down MICOS genes also caused reduced mtDNA content and fragmented mitochondrial nucleoid structure in Drosophila Together, our data demonstrate an essential role of Drosophila MICOS in maintaining proper homeostasis of mitochondrial structure and function to promote the function of muscle tissue.

Keywords:  Drosophila; MICOS; Mitochondria

DOI:  https://doi.org/10.1242/bio.054262
PLoS Genet. 2020 Nov 30. 16(11): e1009083

Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila.

Ivana Bjedov, Helena M Cochemé, Andrea Foley, Daniela Wieser, Nathaniel S Woodling, Jorge Iván Castillo-Quan, Povilas Norvaisas, Celia Lujan, Jenny Regan, Janne M Toivonen, Michael P Murphy, Janet Thornton, Kerri J Kinghorn, Thomas P Neufeld, Filipe Cabreiro, Linda Partridge.

Increased cellular degradation by autophagy is a feature of many interventions that delay ageing. We report here that increased autophagy is necessary for reduced insulin-like signalling (IIS) to extend lifespan in Drosophila and is sufficient on its own to increase lifespan. We first established that the well-characterised lifespan extension associated with deletion of the insulin receptor substrate chico was completely abrogated by downregulation of the essential autophagy gene Atg5. We next directly induced autophagy by over-expressing the major autophagy kinase Atg1 and found that a mild increase in autophagy extended lifespan. Interestingly, strong Atg1 up-regulation was detrimental to lifespan. Transcriptomic and metabolomic approaches identified specific signatures mediated by varying levels of autophagy in flies. Transcriptional upregulation of mitochondrial-related genes was the signature most specifically associated with mild Atg1 upregulation and extended lifespan, whereas short-lived flies, possessing strong Atg1 overexpression, showed reduced mitochondrial metabolism and up-regulated immune system pathways. Increased proteasomal activity and reduced triacylglycerol levels were features shared by both moderate and high Atg1 overexpression conditions. These contrasting effects of autophagy on ageing and differential metabolic profiles highlight the importance of fine-tuning autophagy levels to achieve optimal healthspan and disease prevention.

DOI: https://doi.org/10.1371/journal.pgen.1009083
J Cell Sci. 2020 Dec 01. pii: jcs.250241. [Epub ahead of print]

Mitochondria Control mTORC1 Activity Linked Compartmentalization of eIF4E to Regulate Extracellular Export of microRNAs.

Susanta Chatterjee, Yogaditya Chakrabarty, Saikat Banerjee, Souvik Ghosh, Suvendra N Bhattacharyya.

  Defective intracellular trafficking and export of microRNAs have been observed in growth retarded mammalian cells having impaired mitochondrial potential and dynamics. Uncoupling Protein 2 mediated depolarization of mitochondrial membrane also results in progressive sequestration of microRNAs with polysomes and lowered their release via extracellular vesicles. Interestingly, impaired miRNA-trafficking process in growth retarded human cells could be reversed in presence of Genipin an inhibitor of Uncoupling Protein 2. Mitochondrial detethering of endoplasmic reticulum, observed in mitochondria depolarized cells, found to be responsible for defective compartmentalization of translation initiation factor eIF4E to endoplasmic reticulum attached polysomes. It causes retarded translation process accompanied by enhanced retention of miRNAs and target mRNAs with endoplasmic reticulum attached polysomes to restrict extracellular export of miRNAs. Reduced compartment specific activity of mTORC1 complex, the master regulator of protein synthesis, in mitochondria defective or ER- detethered cells, causes reduced phosphorylation of eIF4E-BP1 to prevent eIF-4E targeting to ER attached polysome and microRNA export. These data suggest how mitochondrial membrane potential and dynamics, by affecting mTORC1 activity and compartmentalization, determine sub-cellular localization and export of microRNAs.

Keywords:  EIF4E and mTORC1; Exosomes; Extracellular vesicles; MiRNA; Mitochondria; P-body; Polysome; Processing bodies

DOI:  https://doi.org/10.1242/jcs.250241
EMBO Rep. 2020 Dec 04. e49634

Blocking mitochondrial pyruvate import in brown adipocytes induces energy wasting via lipid cycling.

Michaela Veliova, Caroline M Ferreira, Ilan Y Benador, Anthony E Jones, Kiana Mahdaviani, Alexandra J Brownstein, Brandon R Desousa, Rebeca Acín-Pérez, Anton Petcherski, Essam A Assali, Linsey Stiles, Ajit S Divakaruni, Marc Prentki, Barbara E Corkey, Marc Liesa, Marcus F Oliveira, Orian S Shirihai.

  Combined fatty acid esterification and lipolysis, termed lipid cycling, is an ATP-consuming process that contributes to energy expenditure. Therefore, interventions that stimulate energy expenditure through lipid cycling are of great interest. Here we find that pharmacological and genetic inhibition of the mitochondrial pyruvate carrier (MPC) in brown adipocytes activates lipid cycling and energy expenditure, even in the absence of adrenergic stimulation. We show that the resulting increase in ATP demand elevates mitochondrial respiration coupled to ATP synthesis and fueled by lipid oxidation. We identify that glutamine consumption and the Malate-Aspartate Shuttle are required for the increase in Energy Expenditure induced by MPC inhibition in Brown Adipocytes (MAShEEBA). We thus demonstrate that energy expenditure through enhanced lipid cycling can be activated in brown adipocytes by decreasing mitochondrial pyruvate availability. We present a new mechanism to increase energy expenditure and fat oxidation in brown adipocytes, which does not require adrenergic stimulation of mitochondrial uncoupling.

Keywords:  futile cycle; malate aspartate shuttle; metabolism; mitochondrial pyruvate carrier; thermogenesis

DOI:  https://doi.org/10.15252/embr.201949634
Proc Natl Acad Sci U S A. 2020 Nov 30. pii: 202005877. [Epub ahead of print]

Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) rescues the cellular phenotype of MELAS by inducing homeostatic mechanisms.

Siddhesh Aras, Neeraja Purandare, Stephanie Gladyck, Mallika Somayajulu-Nitu, Kezhong Zhang, Douglas C Wallace, Lawrence I Grossman.

  MNRR1 (CHCHD2) is a bi-organellar regulator of mitochondrial function that directly activates cytochrome c oxidase in the mitochondria and functions in the nucleus as a transcriptional activator for hundreds of genes. Since MNRR1 depletion contains features of a mitochondrial disease phenotype, we evaluated the effects of forced expression of MNRR1 on the mitochondrial disease MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome. MELAS is a multisystem encephalomyopathy disorder that can result from a heteroplasmic mutation in the mitochondrial DNA (mtDNA; m.3243A > G) at heteroplasmy levels of ∼50 to 90%. Since cybrid cell lines with 73% m.3243A > G heteroplasmy (DW7) display a significant reduction in MNRR1 levels compared to the wild type (0% heteroplasmy) (CL9), we evaluated the effects of MNRR1 levels on mitochondrial functioning. Overexpression of MNRR1 in DW7 cells induces the mitochondrial unfolded protein response (UPRmt), autophagy, and mitochondrial biogenesis, thereby rescuing the mitochondrial phenotype. It does so primarily as a transcription activator, revealing this function to be a potential therapeutic target. The role of MNRR1 in stimulating UPRmt, which is blunted in MELAS cells, was surprising and further investigation uncovered that under conditions of stress the import of MNRR1 into the mitochondria was blocked, allowing the protein to accumulate in the nucleus to enhance its transcription function. In the mammalian system, ATF5, has been identified as a mediator of UPRmt MNRR1 knockout cells display an ∼40% reduction in the protein levels of ATF5, suggesting that MNRR1 plays an important role upstream of this known mediator of UPRmt.

Keywords:  CHCHD2; cytochrome c oxidase; mitochondria; transcription; unfolded protein response

DOI:  https://doi.org/10.1073/pnas.2005877117
Nucleic Acids Res. 2020 Dec 02. pii: gkaa1132. [Epub ahead of print]

Dual function of GTPBP6 in biogenesis and recycling of human mitochondrial ribosomes.

Elena Lavdovskaia, Kärt Denks, Franziska Nadler, Emely Steube, Andreas Linden, Henning Urlaub, Marina V Rodnina, Ricarda Richter-Dennerlein.

Translation and ribosome biogenesis in mitochondria require auxiliary factors that ensure rapid and accurate synthesis of mitochondrial proteins. Defects in translation are associated with oxidative phosphorylation deficiency and cause severe human diseases, but the exact roles of mitochondrial translation-associated factors are not known. Here we identify the functions of GTPBP6, a homolog of the bacterial ribosome-recycling factor HflX, in human mitochondria. Similarly to HflX, GTPBP6 facilitates the dissociation of ribosomes in vitro and in vivo. In contrast to HflX, GTPBP6 is also required for the assembly of mitochondrial ribosomes. GTPBP6 ablation leads to accumulation of late assembly intermediate(s) of the large ribosomal subunit containing ribosome biogenesis factors MTERF4, NSUN4, MALSU1 and the GTPases GTPBP5, GTPBP7 and GTPBP10. Our data show that GTPBP6 has a dual function acting in ribosome recycling and biogenesis. These findings contribute to our understanding of large ribosomal subunit assembly as well as ribosome recycling pathway in mitochondria.

DOI: https://doi.org/10.1093/nar/gkaa1132
Nat Commun. 2020 12 01. 11(1): 6145

Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import.

Enrico Girardi, Gennaro Agrimi, Ulrich Goldmann, Giuseppe Fiume, Sabrina Lindinger, Vitaly Sedlyarov, Ismet Srndic, Bettina Gürtl, Benedikt Agerer, Felix Kartnig, Pasquale Scarcia, Maria Antonietta Di Noia, Eva Liñeiro, Manuele Rebsamen, Tabea Wiedmer, Andreas Bergthaler, Luigi Palmieri, Giulio Superti-Furga.

About a thousand genes in the human genome encode for membrane transporters. Among these, several solute carrier proteins (SLCs), representing the largest group of transporters, are still orphan and lack functional characterization. We reasoned that assessing genetic interactions among SLCs may be an efficient way to obtain functional information allowing their deorphanization. Here we describe a network of strong genetic interactions indicating a contribution to mitochondrial respiration and redox metabolism for SLC25A51/MCART1, an uncharacterized member of the SLC25 family of transporters. Through a combination of metabolomics, genomics and genetics approaches, we demonstrate a role for SLC25A51 as enabler of mitochondrial import of NAD, showcasing the potential of genetic interaction-driven functional gene deorphanization.

DOI: https://doi.org/10.1038/s41467-020-19871-x
Signal Transduct Target Ther. 2019 Dec 06. 4(1): 56

DNA-PKcs promotes alcohol-related liver disease by activating Drp1-related mitochondrial fission and repressing FUNDC1-required mitophagy.

Hao Zhou, Pingjun Zhu, Jin Wang, Sam Toan, Jun Ren.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a novel housekeeper of hepatic mitochondrial homeostasis outside the DNA repair process. In this study, DNA-PKcs was upregulated in the livers of mice that were exposed to alcohol; the expression of DNA-PKcs positively correlated with hepatic steatosis, fibrosis, apoptosis, and mitochondrial damage. Functional studies revealed that liver-specific DNA-PKcs knockout (DNA-PKcsLKO) mice were protected from chronic ethanol-induced liver injury and mitochondrial damage. Mechanistic investigations established that DNA-PKcs promoted p53 activation, which elevated dynamin-related protein 1 (Drp1)-related mitochondrial fission but repressed FUN14 domain containing 1 (FUNDC1)-required mitophagy. Excessive fission and defective mitophagy triggered mtDNA damage, mitochondrial respiratory inhibition, mROS overproduction, cardiolipin oxidation, redox imbalance, calcium overload, and hepatic mitochondrial apoptosis. In contrast, the deletion of DNA-PKcs rescued these phenotypic alterations, which alleviated the susceptibility of hepatocytes to alcohol-induced cytotoxicity. Additionally, we also showed that orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) was the upstream signal for DNA-PKcs activation and that the genetic ablation of NR4A1 ameliorated the progression of alcohol-related liver disease (ARLD); these results were similar to those obtained in DNA-PKcs knockout mice. Collectively, our results identified the NR4A1/DNA-PKcs/p53 axis as a novel signaling pathway responsible for ARLD pathogenesis that acts by activating Drp1-related mitochondrial fission and restricting FUNDC1-required mitophagy. The findings have potential implications for new approaches for ARLD therapy.

DOI: https://doi.org/10.1038/s41392-019-0094-1
J Gerontol A Biol Sci Med Sci. 2020 Dec 04. pii: glaa306. [Epub ahead of print]

A Slc25a46-/- mouse model simulating motor deficit, imbalance of redox system and mitochondria dysfunction during aging.

Li Gao, Min Wang, Linfeng Liao, Na Gou, Piao Xu, Zhengyu Ren, Maojin Yao, Erdong Yuan, Xinquan Yang, Jiaoyan Ren.

  The mitochondrial theory of aging postulates that accumulation of mtDNA mutations and mitochondrial dysfunction are responsible for producing aging phenotypes. To more comprehensively explore the complex relationship between aging and mitochondria dysfunction, we have developed a mouse model with Slc25a46 knock out, a nuclear gene described as encoding mitochondrial carriers, by CRISPR/Cas9 gene editing to mimic some typical aging phenotypes in human. Slc25a46-/- mice present segmental premature aging phenotypes characterized by shortened lifespan of no more than two months, obviously defective motor ability, gastrocnemius muscle atrophy and imbalance of redox level in brain and liver. The underlying mechanism for multiple organ disorder may attribute to the mitochondrial dysfunction, which is mainly manifested on the damaged mitochondrial structure (e.g., vacuolar structure, irregular swelling and disorganized cristae) and an age-associated decrease in respiratory chain enzyme (mainly complex I and IV) activity. In summary, our study suggests that the Slc25a46-/- mouse is a valid animal model for segmental aging-related pathologies studies based on mitochondrial theory, generating a new platform to both understand mechanisms between aging and mitochondria dysfunction as well as to design mitochondria based therapeutic strategies to improve mitochondrial quality, and thereby the overall healthspan.

Keywords:  Age-related pathology; Animal model; Oxidation/Oxidative stress; Respiratory chain

DOI:  https://doi.org/10.1093/gerona/glaa306
Aging (Albany NY). 2020 Nov 26. 12

Melatonin alleviates angiotensin-II-induced cardiac hypertrophy via activating MICU1 pathway.

Yi Yang, Jin Du, Rui Xu, Yang Shen, Dachun Yang, De Li, Houxiang Hu, Haifeng Pei, Yongjian Yang.

  Mitochondrial calcium uptake 1 (MICU1) is a pivotal molecule in maintaining mitochondrial homeostasis under stress conditions. However, it is unclear whether MICU1 attenuates mitochondrial stress in angiotensin II (Ang-II)-induced cardiac hypertrophy or if it has a role in the function of melatonin. Here, small-interfering RNAs against MICU1 or adenovirus-based plasmids encoding MICU1 were delivered into left ventricles of mice or incubated with neonatal murine ventricular myocytes (NMVMs) for 48 h. MICU1 expression was depressed in hypertrophic myocardia and MICU1 knockdown aggravated Ang-II-induced cardiac hypertrophy in vivo and in vitro. In contrast, MICU1 upregulation decreased cardiomyocyte susceptibility to hypertrophic stress. Ang-II administration, particularly in NMVMs with MICU1 knockdown, led to significantly increased reactive oxygen species (ROS) overload, altered mitochondrial morphology, and suppressed mitochondrial function, all of which were reversed by MICU1 supplementation. Moreover, peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α)/MICU1 expression in hypertrophic myocardia increased with melatonin. Melatonin ameliorated excessive ROS generation, promoted mitochondrial function, and attenuated cardiac hypertrophy in control but not MICU1 knockdown NMVMs or mice. Collectively, our results demonstrate that MICU1 attenuates Ang-II-induced cardiac hypertrophy by inhibiting mitochondria-derived oxidative stress. MICU1 activation may be the mechanism underlying melatonin-induced protection against myocardial hypertrophy.

Keywords:  MICU1; PGC-1α; ROS; cardiac hypertrophy; melatonin

DOI:  https://doi.org/10.18632/aging.202159
J Immunother Cancer. 2020 Dec;pii: e001372. [Epub ahead of print]8(2):

Mitochondrial Lon-induced mtDNA leakage contributes to PD-L1-mediated immunoescape via STING-IFN signaling and extracellular vesicles.

An Ning Cheng, Li-Chun Cheng, Cheng-Liang Kuo, Yu Kang Lo, Han-Yu Chou, Chung-Hsing Chen, Yi-Hao Wang, Tsung-Hsien Chuang, Shih-Jung Cheng, Alan Yueh-Luen Lee.

  BACKGROUND: Mitochondrial Lon is a chaperone and DNA-binding protein that functions in protein quality control and stress response pathways. The level of Lon regulates mitochondrial DNA (mtDNA) metabolism and the production of mitochondrial reactive oxygen species (ROS). However, there is little information in detail on how mitochondrial Lon regulates ROS-dependent cancer immunoescape through mtDNA metabolism in the tumor microenvironment (TME).METHODS: We explored the understanding of the intricate interplay between mitochondria and the innate immune response in the inflammatory TME.
RESULTS: We found that oxidized mtDNA is released into the cytosol when Lon is overexpressed and then it induces interferon (IFN) signaling via cGAS-STING-TBK1, which upregulates PD-L1 and IDO-1 expression to inhibit T-cell activation. Unexpectedly, upregulation of Lon also induces the secretion of extracellular vehicles (EVs), which carry mtDNA and PD-L1. Lon-induced EVs further induce the production of IFN and IL-6 from macrophages, which attenuates T-cell immunity in the TME.
CONCLUSIONS: The levels of mtDNA and PD-L1 in EVs in patients with oral cancer function as a potential diagnostic biomarker for anti-PD-L1 immunotherapy. Our studies provide an insight into the immunosuppression on mitochondrial stress and suggest a therapeutic synergy between anti-inflammation therapy and immunotherapy in cancer.

Keywords:  inflammation; interferon inducers; tumor biomarkers; tumor escape; tumor microenvironment

DOI:  https://doi.org/10.1136/jitc-2020-001372
Mol Biol Cell. 2020 Dec 02. mbcE19080436

Mapping the electrostatic profile of cellular membranes.

Sharon Eisenberg, Ehud Haimov, Glenn F W Walpole, Jonathan Plumb, Michael M Kozlov, Sergio Grinstein.

Anionic phospholipids can confer a net negative charge to biological membranes. This surface charge generates an electrical field that serves to recruit extrinsic cationic proteins, can alter the disposition of transmembrane proteins and causes the local accumulation of soluble counterions, altering the local pH and the concentration of physiologically important ions like calcium. Because the phospholipid composition of the different organellar membranes varies, their surface charge is similarly expected to diverge. Yet, despite the important functional implications, remarkably little is known about the electrostatic properties of the individual organellar membranes. We therefore designed and implemented approaches to estimate the surface charge of the cytosolic membrane of various organelles in situ in intact cells. Our data indicate that the inner leaflet of the plasma membrane is most negative, with a surface potential of approximately -35 mV, followed by the Golgi complex > lysosomes > mitochondria ≈ peroxisomes > the endoplasmic reticulum, in decreasing order.

DOI: https://doi.org/10.1091/mbc.E19-08-0436
Diabetologia. 2020 Nov 30.

Human skeletal muscle mitochondrial dynamics in relation to oxidative capacity and insulin sensitivity.

Alexandre Houzelle, Johanna A Jörgensen, Gert Schaart, Sabine Daemen, Nynke van Polanen, Ciarán E Fealy, Matthijs K C Hesselink, Patrick Schrauwen, Joris Hoeks.

  AIMS/HYPOTHESIS: Mitochondria operate in networks, adapting to external stresses and changes in cellular metabolic demand and are subject to various quality control mechanisms. On the basis of these traits, we here hypothesise that the regulation of mitochondrial networks in skeletal muscle is hampered in humans with compromised oxidative capacity and insulin sensitivity.METHODS: In a cross-sectional design, we compared four groups of participants (selected from previous studies) ranging in aerobic capacity and insulin sensitivity, i.e. participants with type 2 diabetes (n = 11), obese participants without diabetes (n = 12), lean individuals (n = 10) and endurance-trained athletes (n = 12); basal, overnight fasted muscle biopsies were newly analysed for the current study and we compared the levels of essential mitochondrial dynamics and quality control regulatory proteins in skeletal muscle tissue.
RESULTS: Type 2 diabetes patients and obese participants were older than lean participants and athletes (58.6 ± 4.0 and 56.7 ± 7.2 vs 21.8 ± 2.5 and 25.1 ± 4.3 years, p < 0.001, respectively) and displayed a higher BMI (32.4 ± 3.7 and 31.0 ± 3.7 vs 22.1 ± 1.8 and 21.0 ± 1.5 kg/m2, p < 0.001, respectively) than lean individuals and endurance-trained athletes. Fission protein 1 (FIS1) and optic atrophy protein 1 (OPA1) protein content was highest in muscle from athletes and lowest in participants with type 2 diabetes and obesity, respectively (FIS1: 1.86 ± 0.79 vs 0.79 ± 0.51 AU, p = 0.002; and OPA1: 1.55 ± 0.64 vs 0.76 ± 0.52 AU, p = 0.014), which coincided with mitochondrial network fragmentation in individuals with type 2 diabetes, as assessed by confocal microscopy in a subset of type 2 diabetes patients vs endurance-trained athletes (n = 6). Furthermore, lean individuals and athletes displayed a mitonuclear protein balance that was different from obese participants and those with type 2 diabetes. Mitonuclear protein balance also associated with heat shock protein 60 (HSP60) protein levels, which were higher in athletes when compared with participants with obesity (p = 0.048) and type 2 diabetes (p = 0.002), indicative for activation of the mitochondrial unfolded protein response. Finally, OPA1, FIS1 and HSP60 correlated positively with aerobic capacity (r = 0.48, p = 0.0001; r = 0.55, p < 0.001 and r = 0.61, p < 0.0001, respectively) and insulin sensitivity (r = 0.40, p = 0.008; r = 0.44, p = 0.003 and r = 0.48, p = 0.001, respectively).
CONCLUSIONS/INTERPRETATION: Collectively, our data suggest that mitochondrial dynamics and quality control in skeletal muscle are linked to oxidative capacity in humans, which may play a role in the maintenance of muscle insulin sensitivity. CLINICAL TRIAL REGISTRY: numbers NCT00943059, NCT01298375 and NL1888 Graphical abstract.

Keywords:  Fission, FIS1; Fusion; HSP60; Insulin sensitivity; Mitochondria; OPA1; Oxidative phosphorylation; Skeletal muscle

DOI:  https://doi.org/10.1007/s00125-020-05335-w
Cells. 2020 Nov 28. pii: E2552. [Epub ahead of print]9(12):

Amyloid Β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer's Disease-Related Models.

Nuno Santos Leal, Giacomo Dentoni, Bernadette Schreiner, Luana Naia, Antonio Piras, Caroline Graff, Antonio Cattaneo, Giovanni Meli, Maho Hamasaki, Per Nilsson, Maria Ankarcrona.

  Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria-ER contact sites (MERCS) are altered in Alzheimer's disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as well as regulation of mitochondrial function. Here, the interplay between MERCS, mitochondria ultrastructure and function and autophagy were evaluated in different AD animal models with increased levels of Aβ as well as in primary neurons derived from these animals. We start by showing that the levels of Mitofusin 1, Mitofusin 2 and mitochondrial import receptor subunit TOM70 are decreased in post-mortem brain tissue derived from familial AD. We also show that Aβ increases the juxtaposition between ER and mitochondria both in adult brain of different AD mouse models as well as in primary cultures derived from these animals. In addition, the connectivity between ER and mitochondria are also increased in wild-type neurons exposed to Aβ. This alteration in MERCS affects autophagosome formation, mitochondrial function and ATP formation during starvation. Interestingly, the increment in ER-mitochondria connectivity occurs simultaneously with an increase in mitochondrial activity and is followed by upregulation of autophagosome formation in a clear chronological sequence of events. In summary, we report that Aβ can affect cell homeostasis by modulating MERCS and, consequently, altering mitochondrial activity and autophagosome formation. Our data suggests that MERCS is a potential target for drug discovery in AD.

Keywords:  Alzheimer’s disease; Mitochondria-ER contact sites; amyloid β-peptide; autophagy; mitochondria

DOI:  https://doi.org/10.3390/cells9122552
Sci Rep. 2020 Dec 03. 10(1): 21135

Mucin-2 knockout is a model of intercellular junction defects, mitochondrial damage and ATP depletion in the intestinal epithelium.

Mariya A Borisova, Kseniya M Achasova, Ksenia N Morozova, Evgeniya N Andreyeva, Ekaterina A Litvinova, Anna A Ogienko, Maryana V Morozova, Mariya B Berkaeva, Elena Kiseleva, Elena N Kozhevnikova.

The disruption of the protective intestinal barrier-the 'leaky gut'-is a common complication of the inflammatory bowel disease. There is limited data on the mechanisms of the intestinal barrier disruption upon low-grade inflammation characteristic of patients with inflammatory bowel disease in clinical remission. Thus, animal models that recapitulate the complexity of chronic intestinal inflammation in vivo are of particular interest. In this study, we used Mucin-2 (Muc2) knockout mice predisposed to colitis to study intestinal barrier upon chronic inflammation. We used 4-kDa FITC-Dextran assay and transmission electron microscopy to demonstrate the increased intestinal permeability and morphological defects in intercellular junctions in Muc2 knockout mice. Confocal microscopy revealed the disruption of the apical F-actin cytoskeleton and delocalization of tight junction protein Claudin-3 from the membrane. We further demonstrate mitochondrial damage, impaired oxygen consumption and the reduction of the intestinal ATP content in Muc2 knockout mice. Finally, we show that chemically induced mitochondrial uncoupling in the wild type mice mimics the intestinal barrier disruption in vivo and causes partial loss of F-actin and membrane localization of Claudin-3. We propose that mitochondrial damage and metabolic shifts during chronic inflammation contribute to the leaky gut syndrome in Muc2 knockout animal model of colitis.

DOI: https://doi.org/10.1038/s41598-020-78141-4
Mitochondrion. 2020 Nov 30. pii: S1567-7249(20)30220-8. [Epub ahead of print]

Differences in relative capacities of oxidative phosphorylation pathways may explain sex- and tissue-specific susceptibility to vision defects due to mitochondrial dysfunction.

Claudia Holody, Anaïs Anfray, Heather Mast, Martin Lessard, Woo Hyun Han, Rowan Carpenter, Stephane Bourque, Yves Sauvé, Hélène Lemieux.

  Mitochondrial dysfunction is a major cause and/or contributor to the development and progression of vision defects in many ophthalmologic and mitochondrial diseases. Despite their mechanistic commonality, these diseases exhibit an impressive variety in sex- and tissue-specific penetrance, incidence, and severity. Currently, there is no functional explanation for these differences. We measured the function, relative capacities, and patterns of control of various oxidative phosphorylation pathways in the retina, the eyecup, the extraocular muscles, the optic nerve, and the sciatic nerve of adult male and female rats. We show that the control of mitochondrial respiratory pathways in the visual system is sex- and tissue-specific and that this may be an important factor in determining susceptibility to mitochondrial dysfunction between these groups. The optic nerve showed a low relative capacity of the NADH pathway, depending on complex I, compared to other tissues relying mainly on mitochondria for energy production. Furthermore, NADH pathway capacity is higher in females compared to males, and this sexual dimorphism occurs only in the optic nerve. Our results propose an explanation for Leber's hereditary optic neuropathy, a mitochondrial disease more prevalent in males where the principal tissue affected is the optic nerve. To our knowledge, this is the first study to identify and provide functional explanations for differences in the occurrence and severity of visual defects between tissues and between sexes. Our results highlight the importance of considering sex- and tissue-specific mitochondrial function in elucidating pathophysiological mechanisms of visual defects.

Keywords:  Leber’s hereditary optic neuropathy; mitochondria; optic nerve; oxidative phosphorylation; visual system

DOI:  https://doi.org/10.1016/j.mito.2020.11.013