bims-mitdyn 2020-07-19 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2020–07–19
fourteen papers selected by
Edmond Chan, Queen’s University, School of Medicine

Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum-to-mitochondria Ca2+ transfer for survival.
Defective endoplasmic reticulum-mitochondria contacts and bioenergetics in SEPN1-related myopathy.
Mitochondria-Associated Degradation Pathway (MAD) Function beyond the Outer Membrane.
Mitochondrial dynamics during spermatogenesis.
Mitochondrial Metabolism as a Target for Cancer Therapy.
Aging shifts mitochondrial dynamics toward fission to promote germline stem cell loss.
Glucose-6-phosphate dehydrogenase is not essential for K-Ras-driven tumor growth or metastasis.
Assigning mitochondrial localization of dual localized proteins using a yeast Bi-Genomic Mitochondrial-Split-GFP.
Tafazzin deficiency impairs CoA-dependent oxidative metabolism in cardiac mitochondria.
Suppressing DRP1-mediated mitochondrial fission and mitophagy increases mitochondrial apoptosis of hepatocellular carcinoma cells in the setting of hypoxia.
Mitochondrial Fission Mediated Cigarette Smoke-induced Pulmonary Endothelial Injury.
Ageing-associated increase in SGLT2 disrupts mitochondrial/sarcoplasmic reticulum Ca2+ homeostasis and promotes cardiac dysfunction.
Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen.
Low expression of mitofusin 1 is associated with mitochondrial dysfunction and apoptosis in porcine somatic cell nuclear transfer embryos.

Sci Signal. 2020 Jul 14. pii: eaay1212. [Epub ahead of print]13(640):

Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum-to-mitochondria Ca2+ transfer for survival.

Cesar Cardenas, Alenka Lovy, Eduardo Silva-Pavez, Felix Urra, Craig Mizzoni, Ulises Ahumada-Castro, Galdo Bustos, Fabian Jaňa, Pablo Cruz, Paula Farias, Elizabeth Mendoza, Hernan Huerta, Paola Murgas, Martin Hunter, Melany Rios, Oscar Cerda, Irene Georgakoudi, Armen Zakarian, Jordi Molgó, J Kevin Foskett.

Spontaneous Ca2+ signaling from the InsP3R intracellular Ca2+ release channel to mitochondria is essential for optimal oxidative phosphorylation (OXPHOS) and ATP production. In cells with defective OXPHOS, reductive carboxylation replaces oxidative metabolism to maintain amounts of reducing equivalents and metabolic precursors. To investigate the role of mitochondrial Ca2+ uptake in regulating bioenergetics in these cells, we used OXPHOS-competent and OXPHOS-defective cells. Inhibition of InsP3R activity or mitochondrial Ca2+ uptake increased α-ketoglutarate (αKG) abundance and the NAD+/NADH ratio, indicating that constitutive endoplasmic reticulum (ER)-to-mitochondria Ca2+ transfer promoted optimal αKG dehydrogenase (αKGDH) activity. Reducing mitochondrial Ca2+ inhibited αKGDH activity and increased NAD+, which induced SIRT1-dependent autophagy in both OXPHOS-competent and OXPHOS-defective cells. Whereas autophagic flux in OXPHOS-competent cells promoted cell survival, it was impaired in OXPHOS-defective cells because of inhibition of autophagosome-lysosome fusion. Inhibition of αKGDH and impaired autophagic flux in OXPHOS-defective cells resulted in pronounced cell death in response to interruption of constitutive flux of Ca2+ from ER to mitochondria. These results demonstrate that mitochondria play a fundamental role in maintaining bioenergetic homeostasis of both OXPHOS-competent and OXPHOS-defective cells, with Ca2+ regulation of αKGDH activity playing a pivotal role. Inhibition of ER-to-mitochondria Ca2+ transfer may represent a general therapeutic strategy against cancer cells regardless of their OXPHOS status.

DOI: https://doi.org/10.1126/scisignal.aay1212
Cell Death Differ. 2020 Jul 13.

Defective endoplasmic reticulum-mitochondria contacts and bioenergetics in SEPN1-related myopathy.

Anne Filipe, Alexander Chernorudskiy, Sandrine Arbogast, Ersilia Varone, Rocío-Nur Villar-Quiles, Diego Pozzer, Maryline Moulin, Stefano Fumagalli, Eva Cabet, Swati Dudhal, Maria-Grazia De Simoni, Raphaël Denis, Nathalie Vadrot, Corinne Dill, Matteo Giovarelli, Luke Szweda, Clara De Palma, Paolo Pinton, Carlotta Giorgi, Carlo Viscomi, Emilio Clementi, Sonia Missiroli, Simona Boncompagni, Ester Zito, Ana Ferreiro.

SEPN1-related myopathy (SEPN1-RM) is a muscle disorder due to mutations of the SEPN1 gene, which is characterized by muscle weakness and fatigue leading to scoliosis and life-threatening respiratory failure. Core lesions, focal areas of mitochondria depletion in skeletal muscle fibers, are the most common histopathological lesion. SEPN1-RM underlying mechanisms and the precise role of SEPN1 in muscle remained incompletely understood, hindering the development of biomarkers and therapies for this untreatable disease. To investigate the pathophysiological pathways in SEPN1-RM, we performed metabolic studies, calcium and ATP measurements, super-resolution and electron microscopy on in vivo and in vitro models of SEPN1 deficiency as well as muscle biopsies from SEPN1-RM patients. Mouse models of SEPN1 deficiency showed marked alterations in mitochondrial physiology and energy metabolism, suggesting that SEPN1 controls mitochondrial bioenergetics. Moreover, we found that SEPN1 was enriched at the mitochondria-associated membranes (MAM), and was needed for calcium transients between ER and mitochondria, as well as for the integrity of ER-mitochondria contacts. Consistently, loss of SEPN1 in patients was associated with alterations in body composition which correlated with the severity of muscle weakness, and with impaired ER-mitochondria contacts and low ATP levels. Our results indicate a role of SEPN1 as a novel MAM protein involved in mitochondrial bioenergetics. They also identify a systemic bioenergetic component in SEPN1-RM and establish mitochondria as a novel therapeutic target. This role of SEPN1 contributes to explain the fatigue and core lesions in skeletal muscle as well as the body composition abnormalities identified as part of the SEPN1-RM phenotype. Finally, these results point out to an unrecognized interplay between mitochondrial bioenergetics and ER homeostasis in skeletal muscle. They could therefore pave the way to the identification of biomarkers and therapeutic drugs for SEPN1-RM and for other disorders in which muscle ER-mitochondria cross-talk are impaired.

DOI: https://doi.org/10.1038/s41418-020-0587-z
Cell Rep. 2020 Jul 14. pii: S2211-1247(20)30883-4. [Epub ahead of print]32(2): 107902

Mitochondria-Associated Degradation Pathway (MAD) Function beyond the Outer Membrane.

Pin-Chao Liao, Dana M Alessi Wolken, Edith Serrano, Pallavi Srivastava, Liza A Pon.

  The mitochondria-associated degradation pathway (MAD) mediates ubiquitination and degradation of mitochondrial outer membrane (MOM) proteins by the proteasome. We find that the MAD, but not other quality-control pathways including macroautophagy, mitophagy, or mitochondrial chaperones and proteases, is critical for yeast cellular fitness under conditions of paraquat (PQ)-induced oxidative stress in mitochondria. Specifically, inhibition of the MAD increases PQ-induced defects in growth and mitochondrial quality and decreases chronological lifespan. We use mass spectrometry analysis to identify possible MAD substrates as mitochondrial proteins that exhibit increased ubiquitination in response to PQ treatment and inhibition of the MAD. We identify candidate substrates in the mitochondrial matrix and inner membrane and confirm that two matrix proteins are MAD substrates. Our studies reveal a broader function for the MAD in mitochondrial protein surveillance beyond the MOM and a major role for the MAD in cellular and mitochondrial fitness in response to chronic, low-level oxidative stress in mitochondria.

Keywords:  Saccharomyces cerevisiae; chronological lifespan; mitochondrial quality control; mitophagy; oxidative stress; paraquat; proteasome; proteostasis; reactive oxygen species; ubiquitin

DOI:  https://doi.org/10.1016/j.celrep.2020.107902
J Cell Sci. 2020 Jul 16. pii: jcs235937. [Epub ahead of print]133(14):

Mitochondrial dynamics during spermatogenesis.

Grigor Varuzhanyan, David C Chan.

  Mitochondrial fusion and fission (mitochondrial dynamics) are homeostatic processes that safeguard normal cellular function. This relationship is especially strong in tissues with constitutively high energy demands, such as brain, heart and skeletal muscle. Less is known about the role of mitochondrial dynamics in developmental systems that involve changes in metabolic function. One such system is spermatogenesis. The first mitochondrial dynamics gene, Fuzzy onions (Fzo), was discovered in 1997 to mediate mitochondrial fusion during Drosophila spermatogenesis. In mammals, however, the role of mitochondrial fusion during spermatogenesis remained unknown for nearly two decades after discovery of Fzo Mammalian spermatogenesis is one of the most complex and lengthy differentiation processes in biology, transforming spermatogonial stem cells into highly specialized sperm cells over a 5-week period. This elaborate differentiation process requires several developmentally regulated mitochondrial and metabolic transitions, making it an attractive model system for studying mitochondrial dynamics in vivo We review the emerging role of mitochondrial biology, and especially its dynamics, during the development of the male germ line.

Keywords:  Membrane fission; Membrane fusion; Mitochondrial dynamics; Spermatogenesis

DOI:  https://doi.org/10.1242/jcs.235937
Cell Metab. 2020 Jul 08. pii: S1550-4131(20)30320-X. [Epub ahead of print]

Mitochondrial Metabolism as a Target for Cancer Therapy.

Karthik Vasan, Marie Werner, Navdeep S Chandel.

  Recent evidence in humans and mice supports the notion that mitochondrial metabolism is active and necessary for tumor growth. Mitochondrial metabolism supports tumor anabolism by providing key metabolites for macromolecule synthesis and generating oncometabolites to maintain the cancer phenotype. Moreover, there are multiple clinical trials testing the efficacy of inhibiting mitochondrial metabolism as a new cancer therapeutic treatment. In this review, we discuss the rationale of using these anti-cancer agents in clinical trials and highlight how to effectively utilize them in different tumor contexts.

Keywords:  metformin; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2020.06.019
Aging Cell. 2020 Jul 14. e13191

Aging shifts mitochondrial dynamics toward fission to promote germline stem cell loss.

Oyundari Amartuvshin, Chi-Hung Lin, Shao-Chun Hsu, Shih-Han Kao, Alvin Chen, Wei-Chun Tang, Han-Lin Chou, Dong-Lin Chang, Yen-Yang Hsu, Bai-Shiou Hsiao, Elham Rastegari, Kun-Yang Lin, Yu-Ting Wang, Chi-Kuang Yao, Guang-Chao Chen, Bi-Chang Chen, Hwei-Jan Hsu.

  Changes in mitochondrial dynamics (fusion and fission) are known to occur during stem cell differentiation; however, the role of this phenomenon in tissue aging remains unclear. Here, we report that mitochondrial dynamics are shifted toward fission during aging of Drosophila ovarian germline stem cells (GSCs), and this shift contributes to aging-related GSC loss. We found that as GSCs age, mitochondrial fragmentation and expression of the mitochondrial fission regulator, Dynamin-related protein (Drp1), are both increased, while mitochondrial membrane potential is reduced. Moreover, preventing mitochondrial fusion in GSCs results in highly fragmented depolarized mitochondria, decreased BMP stemness signaling, impaired fatty acid metabolism, and GSC loss. Conversely, forcing mitochondrial elongation promotes GSC attachment to the niche. Importantly, maintenance of aging GSCs can be enhanced by suppressing Drp1 expression to prevent mitochondrial fission or treating with rapamycin, which is known to promote autophagy via TOR inhibition. Overall, our results show that mitochondrial dynamics are altered during physiological aging, affecting stem cell homeostasis via coordinated changes in stemness signaling, niche contact, and cellular metabolism. Such effects may also be highly relevant to other stem cell types and aging-induced tissue degeneration.

Keywords:  BMP; Drp1; GSC; Marf; mitochondrial fission; mitochondrial fusion

DOI:  https://doi.org/10.1111/acel.13191
Cancer Res. 2020 Jul 13. pii: canres.2486.2019. [Epub ahead of print]

Glucose-6-phosphate dehydrogenase is not essential for K-Ras-driven tumor growth or metastasis.

Jonathan M Ghergurovich, Mark Esposito, Zihong Chen, Joshua Z Wang, Vrushank Bhatt, Taijin Lan, Eileen White, Yibin Kang, Jessie Yanxiang Guo, Joshua D Rabinowitz.

The enzyme glucose-6-phosphate dehydrogenase (G6PD) is a major contributor to NADPH production and redox homeostasis and its expression is upregulated and correlated with negative patient outcomes in multiple human cancer types. Despite these associations, whether G6PD is essential for tumor initiation, growth, or metastasis remains unclear. Here we employ modern genetic tools to evaluate the role of G6PD in lung, breast, and colon cancer driven by oncogenic K-Ras. Human HCT116 colorectal cancer cells lacking G6PD exhibited metabolic indicators of oxidative stress but developed into subcutaneous xenografts with growth comparable to that of wild-type controls. In a genetically engineered mouse model of non-small-cell lung cancer driven by K-Ras G12D and p53-deficiency, G6PD knockout did not block formation or proliferation of primary lung tumors. In MDA-MB 231-derived human triple-negative breast cancer cells implanted as orthotopic xenografts, loss of G6PD modestly decreased primary site growth without ablating spontaneous metastasis to the lung and moderately impaired the ability of breast cancer cells to colonize the lung when delivered via tail vein injection. Thus, in the studied K-Ras tumor models, G6PD is not strictly essential for tumorigenesis and at most modestly promotes disease progression.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-2486
Elife. 2020 Jul 13. pii: e56649. [Epub ahead of print]9

Assigning mitochondrial localization of dual localized proteins using a yeast Bi-Genomic Mitochondrial-Split-GFP.

Gaétan Bader, Ludovic Enkler, Yuhei Araiso, Marine Hemmerle, Krystyna Binko, Emilia Baranowska, Johan-Owen De Craene, Julie Ruer-Laventie, Jean Pieters, Déborah Tribouillard-Tanvier, Bruno Senger, Jean-Paul di Rago, Sylvie Friant, Roza Kucharczyk, Hubert Dominique Becker.

  A single nuclear gene can be translated into a dual localized protein that distributes between the cytosol and mitochondria. Accumulating evidences show that mitoproteomes contain lots of these dual localized proteins termed echoforms. Unraveling the existence of mitochondrial echoforms using current GFP (Green Fluorescent Protein) fusion microscopy approaches is extremely difficult because the GFP signal of the cytosolic echoform will almost inevitably mask that of the mitochondrial echoform. We therefore engineered a yeast strain expressing a new type of Split-GFP that we termed Bi-Genomic Mitochondrial-Split-GFP (BiG Mito-Split-GFP). Because one moiety of the GFP is translated from the mitochondrial machinery while the other is fused to the nuclear-encoded protein of interest translated in the cytosol, the self-reassembly of this Bi-Genomic-encoded Split-GFP is confined to mitochondria. We could authenticate the mitochondrial importability of any protein or echoform from yeast, but also from other organisms such as the human Argonaute 2 mitochondrial echoform.

Keywords:  S. cerevisiae; Split-GFP; aminoacyl-tRNA synthetase; argonaute 2 protein; cell biology; dual localized protein; import; mitochondria

DOI:  https://doi.org/10.7554/eLife.56649
J Biol Chem. 2020 Jul 14. pii: jbc.RA119.011229. [Epub ahead of print]

Tafazzin deficiency impairs CoA-dependent oxidative metabolism in cardiac mitochondria.

Catherine H Le, Lindsay G Benage, Kalyn S Specht, Lance C Li Puma, Christopher M Mulligan, Adam L Heuberger, Jessica E Prenni, Steven M Claypool, Kathryn C Chatfield, Genevieve C Sparagna, Adam J Chicco.

  Barth syndrome (BTHS) is a mitochondrial myopathy resulting from mutations in the tafazzin (TAZ) gene encoding a phospholipid transacylase required for cardiolipin remodeling. Cardiolipin is phospholipid of the inner mitochondrial membrane essential for the function of numerous mitochondrial proteins and processes. However, it is unclear how tafazzin deficiency impacts cardiac mitochondrial metabolism. To address this question while avoiding confounding effects of cardiomyopathy on mitochondrial phenotype, we utilized Taz-shRNA "knockdown" (TazKD ) mice, which exhibit defective cardiolipin remodeling and respiratory supercomplex instability characteristic of human BTHS, but normal cardiac function into adulthood. Consistent with previous reports from other models, mitochondrial H2O2 emission and oxidative damage were greater in TazKD than in wild-type (WT) hearts, but there were no differences in oxidative phosphorylation coupling efficiency or membrane potential. Fatty acid and pyruvate oxidation capacities were 40-60% lower in TazKD mitochondria, but an upregulation of glutamate oxidation supported respiration rates approximating those with pyruvate and palmitoylcarnitine in WT. Deficiencies in mitochondrial CoA and shifts in the cardiac acyl-CoA profile paralleled changes in fatty acid oxidation enzymes and acyl-CoA thioesterases suggesting limitations of CoA availability or "trapping" in TazKD mitochondrial metabolism. Incubation of TazKD mitochondria with exogenous CoA partially rescued pyruvate and palmitoylcarnitine oxidation capacities, implicating dysregulation of CoA-dependent intermediary metabolism rather than respiratory chain defects in the bioenergetic impacts of tafazzin-deficiency. These findings support links among cardiolipin abnormalities, respiratory supercomplex instability and mitochondrial oxidant production, and shed new light on the distinct metabolic consequences of tafazzin-deficiency in the mammalian heart.

Keywords:  Barth Syndrome (BTHS); X-linked mitochondrial disorder; bioenergetics; cardiolipin; cardioskeletal myopathy; lipid metabolism; mitochondrial disease; mitochondrial metabolism; phospholipid transacylase; tafazzin (TAZ)

DOI:  https://doi.org/10.1074/jbc.RA119.011229
Oncogenesis. 2020 Jul 13. 9(7): 67

Suppressing DRP1-mediated mitochondrial fission and mitophagy increases mitochondrial apoptosis of hepatocellular carcinoma cells in the setting of hypoxia.

Xia-Hui Lin, Bai-Quan Qiu, Min Ma, Rui Zhang, Shu-Jung Hsu, Hua-Hua Liu, Jun Chen, Dong-Mei Gao, Jie-Feng Cui, Zheng-Gang Ren, Rong-Xin Chen.

Transarterial embolization/transarterial chemoembolization (TAE/TACE) is the acceptable palliative treatment for hepatocellular carcinoma (HCC), mainly through ischemic necrosis induced by arterial embolization. However, how HCC cells survive under such ischemic hypoxic condition remains unclear, which can be exploited to potentiate TAE/TACE treatment. We hypothesized that targeting mitophagy can increase HCC cell apoptosis during hypoxia. HCC cells were subjected to hypoxia and then mitophagy was quantified. The role of dynamin-related protein 1 (DRP1) in hypoxia-induced HCC mitophagy was determined. Moreover, the synergistic effect of hypoxia and DRP1 inhibitor on HCC apoptosis was assessed in vitro and in vivo. Clinical association between DRP1 expression and outcome for HCC patients was validated. HCC cells that survived hypoxia showed significantly increased DRP1-mediated mitochondrial fission and mitophagy compared with cells in normoxia. Hypoxia induced mitophagy in surviving HCC cells by enhancing DRP1 expression and its translocation into the mitochondria and excessive mitochondrial fission into fragments. Blocking the DRP1 heightened the possibility of hypoxic cytotoxicity to HCC cells due to impaired mitophagy and increased the mitochondrial apoptosis, which involved decreased in mitochondrial membrane potential and mitochondrial release of apoptosis-inducing factor and cytochrome c. Additionally, DRP1 inhibitor Mdivi-1 suppressed the in vivo growth of hypoxia-exposed HCC cells. High expression of DRP1 was significantly associated with shorter survival in HCC patients. In conclusion, our results demonstrate that blocking DRP1-mediated mitochondrial fission and mitophagy increases the incidence of mitochondrial apoptosis of HCC cells during hypoxia, suggesting the new approach of targeting mitophagy to potentiate TAE/TACE.

DOI: https://doi.org/10.1038/s41389-020-00251-5
Am J Respir Cell Mol Biol. 2020 Jul 16.

Mitochondrial Fission Mediated Cigarette Smoke-induced Pulmonary Endothelial Injury.

Zhengke Wang, Alexis White, Xing Wang, Junsuk Ko, Gaurav Choudhary, Thilo Lange, Sharon Rounds, Qing Lu.

  Cigarette smoke (CS) exposure increases the risk for acute respiratory distress syndrome (ARDS) in humans and promotes alveolar-capillary barrier permeability and acute lung injury in animal models. However, the underlying mechanism(s) is not well understood. Mitochondrial fusion and fission are essential for mitochondrial homeostasis in health and disease. In this study, we hypothesized that CS caused endothelial injury via imbalance of mitochondrial fusion and fission and resultant mitochondrial oxidative stress and dysfunction. We noted that CS altered mitochondrial morphology by shortening mitochondrial networks and causing perinuclear accumulation of damaged mitochondria in primary rat lung microvascular endothelial cells (LMVEC). We also found that CS increased mitochondrial fission likely by decreasing Drp1-S637 and increasing FIS1, Drp1-S616 phosphorylation, mitochondrial translocation and tetramerization and reduced mitochondrial fusion likely by decreasing Mfn2 in LMVEC and mouse lungs. CS also caused aberrant mitophagy, increased mitochondrial oxidative stress and reduced mitochondrial respiration. An inhibitor of mitochondrial fission and a mitochondria-specific anti-oxidant prevented CS-induced increased endothelial barrier dysfunction and apoptosis. Our data suggest that excessive mitochondrial fission and resultant oxidative stress are essential mediators of CS-induced endothelial injury and that inhibition of mitochondrial fission and mitochondria-specific antioxidants may be useful therapeutic strategies for CS-induced endothelial injury and associated pulmonary diseases.

Keywords:  Apoptosis; Cigarette smoke; Endothelial permeability; Mitochondrial fission/fusion; Mitophagy

DOI:  https://doi.org/10.1165/rcmb.2020-0008OC
J Cell Mol Med. 2020 Jul 11.

Ageing-associated increase in SGLT2 disrupts mitochondrial/sarcoplasmic reticulum Ca2+ homeostasis and promotes cardiac dysfunction.

Yusuf Olgar, Erkan Tuncay, Sinan Degirmenci, Deniz Billur, Rimpy Dhingra, Lorrie Kirshenbaum, Belma Turan.

  The prevalence of death from cardiovascular disease is significantly higher in elderly populations; the underlying factors that contribute to the age-associated decline in cardiac performance are poorly understood. Herein, we identify the involvement of sodium/glucose co-transporter gene (SGLT2) in disrupted cellular Ca2+ -homeostasis, and mitochondrial dysfunction in age-associated cardiac dysfunction. In contrast to younger rats (6-month of age), older rats (24-month of age) exhibited severe cardiac ultrastructural defects, including deformed, fragmented mitochondria with high electron densities. Cardiomyocytes isolated from aged rats demonstrated increased reactive oxygen species (ROS), loss of mitochondrial membrane potential and altered mitochondrial dynamics, compared with younger controls. Moreover, mitochondrial defects were accompanied by mitochondrial and cytosolic Ca2+ ([Ca2+ ]i ) overload, indicative of disrupted cellular Ca2+ -homeostasis. Interestingly, increased [Ca2+ ]i coincided with decreased phosphorylation of phospholamban (PLB) and contractility. Aged-cardiomyocytes also displayed high Na+ /Ca2+ -exchanger (NCX) activity and blood glucose levels compared with young-controls. Interestingly, the protein level of SGLT2 was dramatically increased in the aged cardiomyocytes. Moreover, SGLT2 inhibition was sufficient to restore age-associated defects in [Ca2+ ]i -homeostasis, PLB phosphorylation, NCX activity and mitochondrial Ca2+ -loading. Hence, the present data suggest that deregulated SGLT2 during ageing disrupts mitochondrial function and cardiac contractility through a mechanism that impinges upon [Ca2+ ]i -homeostasis. Our studies support the notion that interventions that modulate SGLT2-activity can provide benefits in maintaining [Ca2+ ]i and cardiac function with advanced age.

Keywords:  Ca2+ homeostasis; ageing-heart; cardiovascular function; mitochondria; reactive oxygen species; sarcoplasmic reticulum; sodium/glucose cotransporter 2

DOI:  https://doi.org/10.1111/jcmm.15483
Nat Immunol. 2020 Jul 13.

Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen.

Santosha A Vardhana, Madeline A Hwee, Mirela Berisa, Daniel K Wells, Kathryn E Yost, Bryan King, Melody Smith, Pamela S Herrera, Howard Y Chang, Ansuman T Satpathy, Marcel R M van den Brink, Justin R Cross, Craig B Thompson.

The majority of tumor-infiltrating T cells exhibit a terminally exhausted phenotype, marked by a loss of self-renewal capacity. How repetitive antigenic stimulation impairs T cell self-renewal remains poorly defined. Here, we show that persistent antigenic stimulation impaired ADP-coupled oxidative phosphorylation. The resultant bioenergetic compromise blocked proliferation by limiting nucleotide triphosphate synthesis. Inhibition of mitochondrial oxidative phosphorylation in activated T cells was sufficient to suppress proliferation and upregulate genes linked to T cell exhaustion. Conversely, prevention of mitochondrial oxidative stress during chronic T cell stimulation allowed sustained T cell proliferation and induced genes associated with stem-like progenitor T cells. As a result, antioxidant treatment enhanced the anti-tumor efficacy of chronically stimulated T cells. These data reveal that loss of ATP production through oxidative phosphorylation limits T cell proliferation and effector function during chronic antigenic stimulation. Furthermore, treatments that maintain redox balance promote T cell self-renewal and enhance anti-tumor immunity.

DOI: https://doi.org/10.1038/s41590-020-0725-2
Anim Sci J. 2020 Jan;91(1): e13430

Low expression of mitofusin 1 is associated with mitochondrial dysfunction and apoptosis in porcine somatic cell nuclear transfer embryos.

Mi-Ryung Park, In-Sul Hwang, Tae-Uk Kwak, Ji-Hyun Lim, Seongsoo Hwang, Seong-Keun Cho.

  Mitochondria are necessary for the transition from oocyte to embryo and for early embryonic development. Mitofusin 1 is the main mediator of mitochondrial fusion and homeostasis. We investigated Mitofusin 1 expression levels in porcine somatic cell nuclear transfer (SCNT) embryos. The rate of blastocyst formation in SCNT embryos was reduced significantly compared with that of parthenogenetic activation embryos. SCNT embryos showed significantly decreased Mitofusin 1 expression and mitochondrial membrane potential, while exhibiting increased reactive oxygen species and apoptosis. Mitochondrial functional changes were observed in the SCNT embryos and may be correlated with low levels of Mitofusin 1 to negatively affect development.

Keywords:  SCNT; mitochondria; mitofusin 1; porcine

DOI:  https://doi.org/10.1111/asj.13430