bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022‒03‒27
sixteen papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.
  2. Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue.
  3. Localized glucose import, glycolytic processing, and mitochondria generate a focused ATP burst to power basement-membrane invasion.
  4. Hexokinase 1 cellular localization regulates the metabolic fate of glucose.
  5. Sideroflexin 4 is a complex I assembly factor that interacts with the MCIA complex and is required for the assembly of the ND2 module.
  6. A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine.
  7. Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer.
  8. Macrophage mitochondrial bioenergetics and tissue invasion are boosted by an Atossa-Porthos axis in Drosophila.
  9. Prevention and regression of megamitochondria and steatosis by blocking mitochondrial fusion in the liver.
  10. Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice.
  11. Mitochondria transplantation between living cells.
  12. Live cell microscopy of mitochondria-lysosome contact site formation and tethering dynamics.
  13. DRP1 contributes to head and neck cancer progression and induces glycolysis through modulated FOXM1/MMP12 axis.
  14. Characterization of Mitochondrial Proteome and Function in Luminal A and Basal-like Breast Cancer Subtypes Reveals Alteration in Mitochondrial Dynamics and Bioenergetics Relevant to Their Diagnosis.
  15. The Interplay between Cell-Extracellular Matrix Interaction and Mitochondria Dynamics in Cancer.
  16. Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation.
  1. Nat Commun. 2022 Mar 24. 13(1): 1582
    Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.
    Huan Yang, Caroline Sibilla, Raymond Liu, Jina Yun, Bruce A Hay, Craig Blackstone, David C Chan, Robert J Harvey, Ming Guo.
      Mitochondrial fission is critically important for controlling mitochondrial morphology, function, quality and transport. Drp1 is the master regulator driving mitochondrial fission, but exactly how Drp1 is regulated remains unclear. Here, we identified Drosophila Clueless and its mammalian orthologue CLUH as key regulators of Drp1. As with loss of drp1, depletion of clueless or CLUH results in mitochondrial elongation, while as with drp1 overexpression, clueless or CLUH overexpression leads to mitochondrial fragmentation. Importantly, drp1 overexpression rescues adult lethality, tissue disintegration and mitochondrial defects of clueless null mutants in Drosophila. Mechanistically, Clueless and CLUH promote recruitment of Drp1 to mitochondria from the cytosol. This involves CLUH binding to mRNAs encoding Drp1 receptors MiD49 and Mff, and regulation of their translation. Our findings identify a crucial role of Clueless and CLUH in controlling mitochondrial fission through regulation of Drp1.
    DOI:  https://doi.org/10.1038/s41467-022-29071-4
  2. Cell Metab. 2022 Mar 15. pii: S1550-4131(22)00088-2. [Epub ahead of print]
    Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue.
    Marco Rosina, Veronica Ceci, Riccardo Turchi, Li Chuan, Nicholas Borcherding, Francesca Sciarretta, María Sánchez-Díaz, Flavia Tortolici, Keaton Karlinsey, Valerio Chiurchiù, Claudia Fuoco, Rocky Giwa, Rachael L Field, Matteo Audano, Simona Arena, Alessandro Palma, Federica Riccio, Farnaz Shamsi, Giovanni Renzone, Martina Verri, Anna Crescenzi, Salvatore Rizza, Fiorella Faienza, Giuseppe Filomeni, Sander Kooijman, Stefano Rufini, Antoine A F de Vries, Andrea Scaloni, Nico Mitro, Yu-Hua Tseng, Andrés Hidalgo, Beiyan Zhou, Jonathan R Brestoff, Katia Aquilano, Daniele Lettieri-Barbato.
      Recent findings have demonstrated that mitochondria can be transferred between cells to control metabolic homeostasis. Although the mitochondria of brown adipocytes comprise a large component of the cell volume and undergo reorganization to sustain thermogenesis, it remains unclear whether an intercellular mitochondrial transfer occurs in brown adipose tissue (BAT) and regulates adaptive thermogenesis. Herein, we demonstrated that thermogenically stressed brown adipocytes release extracellular vesicles (EVs) that contain oxidatively damaged mitochondrial parts to avoid failure of the thermogenic program. When re-uptaken by parental brown adipocytes, mitochondria-derived EVs reduced peroxisome proliferator-activated receptor-γ signaling and the levels of mitochondrial proteins, including UCP1. Their removal via the phagocytic activity of BAT-resident macrophages is instrumental in preserving BAT physiology. Depletion of macrophages in vivo causes the abnormal accumulation of extracellular mitochondrial vesicles in BAT, impairing the thermogenic response to cold exposure. These findings reveal a homeostatic role of tissue-resident macrophages in the mitochondrial quality control of BAT.
    Keywords:  adipose tissue; brown adipocytes; extracellular vesicles; homeostasis; immunometabolism; macrophages; mitochondria; mitochondrial quality control; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2022.02.016
  3. Dev Cell. 2022 Mar 14. pii: S1534-5807(22)00121-6. [Epub ahead of print]
    Localized glucose import, glycolytic processing, and mitochondria generate a focused ATP burst to power basement-membrane invasion.
    Aastha Garde, Isabel W Kenny, Laura C Kelley, Qiuyi Chi, Ayse Sena Mutlu, Meng C Wang, David R Sherwood.
      Invasive cells use transient, energy-consuming protrusions to breach basement membrane (BM) barriers. Using the ATP sensor PercevalHR during anchor cell (AC) invasion in Caenorhabditis elegans, we show that BM invasion is accompanied by an ATP burst from mitochondria at the invasive front. RNAi screening and visualization of a glucose biosensor identified two glucose transporters, FGT-1 and FGT-2, which bathe invasive front mitochondria with glucose and facilitate the ATP burst to form protrusions. FGT-1 localizes at high levels along the invasive membrane, while FGT-2 is adaptive, enriching most strongly during BM breaching and when FGT-1 is absent. Cytosolic glycolytic enzymes that process glucose for mitochondrial ATP production cluster with invasive front mitochondria and promote higher mitochondrial membrane potential and ATP levels. Finally, we show that UNC-6 (netrin), which polarizes invasive protrusions, also orients FGT-1. These studies reveal a robust and integrated energy acquisition, processing, and delivery network that powers BM breaching.
    Keywords:  ATP; basement membrane; biosensor; cell invasion; glucose transporters; glycolytic enzyme clustering; invasive protrusions; live imaging; mitochondria
    DOI:  https://doi.org/10.1016/j.devcel.2022.02.019
  4. Mol Cell. 2022 Mar 14. pii: S1097-2765(22)00166-6. [Epub ahead of print]
    Hexokinase 1 cellular localization regulates the metabolic fate of glucose.
    Adam De Jesus, Farnaz Keyhani-Nejad, Carolina M Pusec, Lauren Goodman, Justin A Geier, Joshua S Stoolman, Paulina J Stanczyk, Tivoli Nguyen, Kai Xu, Krishna V Suresh, Yihan Chen, Arianne E Rodriguez, Jason S Shapiro, Hsiang-Chun Chang, Chunlei Chen, Kriti P Shah, Issam Ben-Sahra, Brian T Layden, Navdeep S Chandel, Samuel E Weinberg, Hossein Ardehali.
      The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis or directed to alternative metabolic routes, such as the pentose phosphate pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal mitochondrial binding domain (MBD), but its physiologic significance remains unclear. To elucidate the effect of HK1 mitochondrial dissociation on cellular metabolism, we generated mice lacking the HK1 MBD (ΔE1HK1). These mice produced a hyper-inflammatory response when challenged with lipopolysaccharide. Additionally, there was decreased glucose flux below the level of GAPDH and increased upstream flux through the PPP. The glycolytic block below GAPDH is mediated by the binding of cytosolic HK1 with S100A8/A9, resulting in GAPDH nitrosylation through iNOS. Additionally, human and mouse macrophages from conditions of low-grade inflammation, such as aging and diabetes, displayed increased cytosolic HK1 and reduced GAPDH activity. Our data indicate that HK1 mitochondrial binding alters glucose metabolism through regulation of GAPDH.
    Keywords:  GAPDH; S-nitrosylation; hexokinase; inflammation; innate immunity; macrophage; metabolism; mitochondria; pentose phosphate pathway; subcellular localization
    DOI:  https://doi.org/10.1016/j.molcel.2022.02.028
  5. Proc Natl Acad Sci U S A. 2022 Mar 29. 119(13): e2115566119
    Sideroflexin 4 is a complex I assembly factor that interacts with the MCIA complex and is required for the assembly of the ND2 module.
    Thomas D Jackson, Jordan J Crameri, Linden Muellner-Wong, Ann E Frazier, Catherine S Palmer, Luke E Formosa, Daniella H Hock, Kenji M Fujihara, Tegan Stait, Alice J Sharpe, David R Thorburn, Michael T Ryan, David A Stroud, Diana Stojanovski.
      SignificanceMitochondria are double-membraned eukaryotic organelles that house the proteins required for generation of ATP, the energy currency of cells. ATP generation within mitochondria is performed by five multisubunit complexes (complexes I to V), the assembly of which is an intricate process. Mutations in subunits of these complexes, or the suite of proteins that help them assemble, lead to a severe multisystem condition called mitochondrial disease. We show that SFXN4, a protein that causes mitochondrial disease when mutated, assists with the assembly of complex I. This finding explains why mutations in SFXN4 cause mitochondrial disease and is surprising because SFXN4 belongs to a family of amino acid transporter proteins, suggesting that it has undergone a dramatic shift in function through evolution.
    Keywords:  complex assembly; mitochondria; respiratory chain; sideroflexins
    DOI:  https://doi.org/10.1073/pnas.2115566119
  6. Nat Commun. 2022 Mar 21. 13(1): 1503
    A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine.
    Carlos Sebastian, Christina Ferrer, Maria Serra, Jee-Eun Choi, Nadia Ducano, Alessia Mira, Manasvi S Shah, Sylwia A Stopka, Andrew J Perciaccante, Claudio Isella, Daniel Moya-Rull, Marianela Vara-Messler, Silvia Giordano, Elena Maldi, Niyati Desai, Diane E Capen, Enzo Medico, Murat Cetinbas, Ruslan I Sadreyev, Dennis Brown, Miguel N Rivera, Anna Sapino, David T Breault, Nathalie Y R Agar, Raul Mostoslavsky.
      Although reprogramming of cellular metabolism is a hallmark of cancer, little is known about how metabolic reprogramming contributes to early stages of transformation. Here, we show that the histone deacetylase SIRT6 regulates tumor initiation during intestinal cancer by controlling glucose metabolism. Loss of SIRT6 results in an increase in the number of intestinal stem cells (ISCs), which translates into enhanced tumor initiating potential in APCmin mice. By tracking down the connection between glucose metabolism and tumor initiation, we find a metabolic compartmentalization within the intestinal epithelium and adenomas, where a rare population of cells exhibit features of Warburg-like metabolism characterized by high pyruvate dehydrogenase kinase (PDK) activity. Our results show that these cells are quiescent cells expressing +4 ISCs and enteroendocrine markers. Active glycolysis in these cells suppresses ROS accumulation and enhances their stem cell and tumorigenic potential. Our studies reveal that aerobic glycolysis represents a heterogeneous feature of cancer, and indicate that this metabolic adaptation can occur in non-dividing cells, suggesting a role for the Warburg effect beyond biomass production in tumors.
    DOI:  https://doi.org/10.1038/s41467-022-29085-y
  7. Cell Death Differ. 2022 Mar 24.
    Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer.
    Xiaopeng Xiong, Sumati Hasani, Lyndsay E A Young, Dylan R Rivas, Ashley T Skaggs, Rebecca Martinez, Chi Wang, Heidi L Weiss, Matthew S Gentry, Ramon C Sun, Tianyan Gao.
      Cancer cells are known for their ability to adapt variable metabolic programs depending on the availability of specific nutrients. Our previous studies have shown that uptake of fatty acids alters cellular metabolic pathways in colon cancer cells to favor fatty acid oxidation. Here, we show that fatty acids activate Drp1 to promote metabolic plasticity in cancer cells. Uptake of fatty acids (FAs) induces mitochondrial fragmentation by promoting ERK-dependent phosphorylation of Drp1 at the S616 site. This increased phosphorylation of Drp1 enhances its dimerization and interaction with Mitochondrial Fission Factor (MFF) at the mitochondria. Consequently, knockdown of Drp1 or MFF attenuates fatty acid-induced mitochondrial fission. In addition, uptake of fatty acids triggers mitophagy via a Drp1- and p62-dependent mechanism to protect mitochondrial integrity. Moreover, results from metabolic profiling analysis reveal that silencing Drp1 disrupts cellular metabolism and blocks fatty acid-induced metabolic reprograming by inhibiting fatty acid utilization. Functionally, knockdown of Drp1 decreases Wnt/β-catenin signaling by preventing fatty acid oxidation-dependent acetylation of β-catenin. As a result, Drp1 depletion inhibits the formation of tumor organoids in vitro and xenograft tumor growth in vivo. Taken together, our study identifies Drp1 as a key mediator that connects mitochondrial dynamics with fatty acid metabolism and cancer cell signaling.
    DOI:  https://doi.org/10.1038/s41418-022-00974-5
  8. EMBO J. 2022 Mar 23. e109049
    Macrophage mitochondrial bioenergetics and tissue invasion are boosted by an Atossa-Porthos axis in Drosophila.
    Shamsi Emtenani, Elliot T Martin, Attila Gyoergy, Julia Bicher, Jakob-Wendelin Genger, Thomas Köcher, Maria Akhmanova, Mariana Guarda, Marko Roblek, Andreas Bergthaler, Thomas R Hurd, Prashanth Rangan, Daria E Siekhaus.
      Cellular metabolism must adapt to changing demands to enable homeostasis. During immune responses or cancer metastasis, cells leading migration into challenging environments require an energy boost, but what controls this capacity is unclear. Here, we study a previously uncharacterized nuclear protein, Atossa (encoded by CG9005), which supports macrophage invasion into the germband of Drosophila by controlling cellular metabolism. First, nuclear Atossa increases mRNA levels of Porthos, a DEAD-box protein, and of two metabolic enzymes, lysine-α-ketoglutarate reductase (LKR/SDH) and NADPH glyoxylate reductase (GR/HPR), thus enhancing mitochondrial bioenergetics. Then Porthos supports ribosome assembly and thereby raises the translational efficiency of a subset of mRNAs, including those affecting mitochondrial functions, the electron transport chain, and metabolism. Mitochondrial respiration measurements, metabolomics, and live imaging indicate that Atossa and Porthos power up OxPhos and energy production to promote the forging of a path into tissues by leading macrophages. Since many crucial physiological responses require increases in mitochondrial energy output, this previously undescribed genetic program may modulate a wide range of cellular behaviors.
    Keywords:  immune cell infiltration; mitochondrial bioenergetics; oxidative phosphorylation; protein translation; transcription factor
    DOI:  https://doi.org/10.15252/embj.2021109049
  9. iScience. 2022 Apr 15. 25(4): 103996
    Prevention and regression of megamitochondria and steatosis by blocking mitochondrial fusion in the liver.
    Tatsuya Yamada, Daisuke Murata, David E Kleiner, Robert Anders, Avi Z Rosenberg, Jeffrey Kaplan, James P Hamilton, Mariam Aghajan, Moshe Levi, Nae-Yuh Wang, Ted M Dawson, Toru Yanagawa, Andrew F Powers, Miho Iijima, Hiromi Sesaki.
      Non-alcoholic steatohepatitis (NASH) is a most common chronic liver disease that is manifested by steatosis, inflammation, fibrosis, and tissue damage. Hepatocytes produce giant mitochondria termed megamitochondria in patients with NASH. It has been shown that gene knockout of OPA1, a mitochondrial dynamin-related GTPase that mediates mitochondrial fusion, prevents megamitochondria formation and liver damage in a NASH mouse model induced by a methionine-choline-deficient (MCD) diet. However, it is unknown whether blocking mitochondrial fusion mitigates NASH pathologies. Here, we acutely depleted OPA1 using antisense oligonucleotides in the NASH mouse model before or after megamitochondria formation. When OPA1 ASOs were applied at the disease onset, they effectively prevented megamitochondria formation and liver pathologies in the MCD model. Notably, even when applied after mice robustly developed NASH pathologies, OPA1 targeting effectively regressed megamitochondria and the disease phenotypes. Thus, our data show the efficacy of mitochondrial dynamics as a unique therapy for megamitochondria-associated liver disease.
    Keywords:  Cell biology; Hepatology
    DOI:  https://doi.org/10.1016/j.isci.2022.103996
  10. Sci Rep. 2022 Mar 25. 12(1): 5196
    Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice.
    Gregory S McElroy, Ram P Chakrabarty, Karis B D'Alessandro, Karthik Vasan, Jerica Tan, Joshua S Stoolman, Samuel E Weinberg, Elizabeth M Steinert, Paul A Reyfman, Benjamin D Singer, Warren C Ladiges, Lin Gao, José Lopéz-Barneo, G R Scott Budinger, Navdeep S Chandel.
      Aging in mammals leads to reduction in genes encoding the 45-subunit mitochondrial electron transport chain complex I. It has been hypothesized that normal aging and age-related diseases such as Parkinson's disease are in part due to modest decrease in expression of mitochondrial complex I subunits. By contrast, diminishing expression of mitochondrial complex I genes in lower organisms increases lifespan. Furthermore, metformin, a putative complex I inhibitor, increases healthspan in mice and humans. In the present study, we investigated whether loss of one allele of Ndufs2, the catalytic subunit of mitochondrial complex I, impacts healthspan and lifespan in mice. Our results indicate that Ndufs2 hemizygous mice (Ndufs2+/-) show no overt impairment in aging-related motor function, learning, tissue histology, organismal metabolism, or sensitivity to metformin in a C57BL6/J background. Despite a significant reduction of Ndufs2 mRNA, the mice do not demonstrate a significant decrease in complex I function. However, there are detectable transcriptomic changes in individual cell types and tissues due to loss of one allele of Ndufs2. Our data indicate that a 50% decline in mRNA of the core mitochondrial complex I subunit Ndufs2 is neither beneficial nor detrimental to healthspan.
    DOI:  https://doi.org/10.1038/s41598-022-09074-3
  11. PLoS Biol. 2022 Mar;20(3): e3001576
    Mitochondria transplantation between living cells.
    Christoph G Gäbelein, Qian Feng, Edin Sarajlic, Tomaso Zambelli, Orane Guillaume-Gentil, Benoît Kornmann, Julia A Vorholt.
      Mitochondria and the complex endomembrane system are hallmarks of eukaryotic cells. To date, it has been difficult to manipulate organelle structures within single live cells. We developed a FluidFM-based approach to extract, inject, and transplant organelles from and into living cells with subcellular spatial resolution. The technology combines atomic force microscopy, optical microscopy, and nanofluidics to achieve force and volume control with real-time inspection. We developed dedicated probes that allow minimally invasive entry into cells and optimized fluid flow to extract specific organelles. When extracting single or a defined number of mitochondria, their morphology transforms into a pearls-on-a-string phenotype due to locally applied fluidic forces. We show that the induced transition is calcium independent and results in isolated, intact mitochondria. Upon cell-to-cell transplantation, the transferred mitochondria fuse to the host cells mitochondrial network. Transplantation of healthy and drug-impaired mitochondria into primary keratinocytes allowed monitoring of mitochondrial subpopulation rescue. Fusion with the mitochondrial network of recipient cells occurred 20 minutes after transplantation and continued for over 16 hours. After transfer of mitochondria and cell propagation over generations, donor mitochondrial DNA (mtDNA) was replicated in recipient cells without the need for selection pressure. The approach opens new prospects for the study of organelle physiology and homeostasis, but also for therapy, mechanobiology, and synthetic biology.
    DOI:  https://doi.org/10.1371/journal.pbio.3001576
  12. STAR Protoc. 2022 Jun 17. 3(2): 101262
    Live cell microscopy of mitochondria-lysosome contact site formation and tethering dynamics.
    Tayler B Belton, Eric D Leisten, Jasmine Cisneros, Yvette C Wong.
      Mitochondria-lysosome contact sites are critical for maintaining cellular homeostasis by regulating mitochondrial and lysosomal network dynamics and mediating metabolite exchange. Here, we present a protocol to quantitatively analyze the formation and tethering duration of mitochondria-lysosome contact sites by using time-lapse live confocal microscopy of LAMP1 and TOMM20. Although this protocol focuses on mammalian HeLa cells, it can be applied to other cell types for further studies on mitochondria-lysosome contact regulation and function, and elucidation of their role in human disorders. For complete details on the use and execution of this protocol, please refer to Wong et al. (2018) and Wong et al. (2019b).
    Keywords:  Cell Biology; Cell culture; Microscopy
    DOI:  https://doi.org/10.1016/j.xpro.2022.101262
  13. Mol Oncol. 2022 Mar 21.
    DRP1 contributes to head and neck cancer progression and induces glycolysis through modulated FOXM1/MMP12 axis.
    Tai-Lin Huang, Chuang-Rung Chang, Chih-Yen Chien, Gong-Kai Huang, Yi-Fan Chen, Li-Jen Su, Hsin-Ting Tsai, Yu-Sheng Lin, Fu-Min Fang, Chang-Han Chen.
      Abnormal DRP1 expression has been identified in a variety of human cancers., However, the prognostic potential and mechanistic role of DRP1 in head and neck cancer (HNC) are currently poorly understood. Here, we demonstrated a significant upregulation of DRP1 in HNC tissues, and that DRP1 expression correlates with poor survival of HNC patients. Diminished DRP1 expression suppressed tumor growth and metastasis in both in vitro and in vivo models. DRP1 expression positively correlated with FOXM1 and MMP12 expression in HNC patient samples, suggesting pathological relevance in the context of HNC development. Moreover, DRP1 depletion affected aerobic glycolysis through the downregulation of glycolytic genes, and overexpression of MMP12 in DRP1-depleted cells could help restore glucose consumption and lactate production. Using ChIP-qPCR we showed that DRP1 suppresses FOXM1 expression, which can enhance MMP12 transcription by binding to its promoter. We also showed that miR-575 could target 3'UTR of DRP1 mRNA and attenuated DRP1 expression. Collectively, our study provides mechanistic insights into the role of DRP1 in HNC and highlights the potential of targeting the miR-575/DRP1/FOXM1/MMP12 axis as a novel therapy for the prevention of HNC progression.
    Keywords:  DRP1; FOXM1; MMP12; glycolysis; head and neck cancer; miR-575
    DOI:  https://doi.org/10.1002/1878-0261.13212
  14. Biomolecules. 2022 Feb 28. pii: 379. [Epub ahead of print]12(3):
    Characterization of Mitochondrial Proteome and Function in Luminal A and Basal-like Breast Cancer Subtypes Reveals Alteration in Mitochondrial Dynamics and Bioenergetics Relevant to Their Diagnosis.
    Ariadna Jazmín Ortega-Lozano, Leopoldo Gómez-Caudillo, Alfredo Briones-Herrera, Omar Emiliano Aparicio-Trejo, José Pedraza-Chaverri.
      Breast cancer (BC) is the most prevalent cancer and the one with the highest mortality among women worldwide. Although the molecular classification of BC has been a helpful tool for diagnosing and predicting the treatment of BC, developments are still being made to improve the diagnosis and find new therapeutic targets. Mitochondrial dysfunction is a crucial feature of cancer, which can be associated with cancer aggressiveness. Although the importance of mitochondrial dynamics in cancer is well recognized, its involvement in the mitochondrial function and bioenergetics context in BC molecular subtypes has been scantly explored. In this study, we combined mitochondrial function and bioenergetics experiments in MCF7 and MDA-MB-231 cell lines with statistical and bioinformatics analyses of the mitochondrial proteome of luminal A and basal-like tumors. We demonstrate that basal-like tumors exhibit a vicious cycle between mitochondrial fusion and fission; impaired but not completely inactive mitochondrial function; and the Warburg effect, associated with decreased oxidative phosphorylation (OXPHOS) complexes I and III. Together with the results obtained in the cell lines and the mitochondrial proteome analysis, two mitochondrial signatures were proposed: one signature reflecting alterations in mitochondrial functions and a second signature exclusively of OXPHOS, which allow us to distinguish between luminal A and basal-like tumors.
    Keywords:  MCF7 cell line; MDA-MB-231 cell line; basal-like breast cancer; luminal A breast cancer; mitochondria dynamics; mitochondrial biogenesis; mitochondrial proteome; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.3390/biom12030379
  15. Cancers (Basel). 2022 Mar 10. pii: 1433. [Epub ahead of print]14(6):
    The Interplay between Cell-Extracellular Matrix Interaction and Mitochondria Dynamics in Cancer.
    Bian Yanes, Elena Rainero.
      The tumor microenvironment, in particular the extracellular matrix (ECM), plays a pivotal role in controlling tumor initiation and progression. In particular, the interaction between cancer cells and the ECM promotes cancer cell growth and invasion, leading to the formation of distant metastasis. Alterations in cancer cell metabolism is a key hallmark of cancer, which is often associated with alterations in mitochondrial dynamics. Recent research highlighted that, changes in mitochondrial dynamics are associated with cancer migration and metastasis-these has been extensively reviewed elsewhere. However, less is known about the interplay between the extracellular matrix and mitochondria functions. In this review, we will highlight how ECM remodeling associated with tumorigenesis contribute to the regulation of mitochondrial function, ultimately promoting cancer cell metabolic plasticity, able to fuel cancer invasion and metastasis.
    Keywords:  extracellular matrix; mitochondria dynamics; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers14061433
  16. Cells. 2022 Mar 21. pii: 1053. [Epub ahead of print]11(6):
    Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation.
    Xiawei Dang, Emily K Walton, Barbara Zablocka, Robert H Baloh, Michael E Shy, Gerald W Dorn.
      Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot-Marie-Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect CMT2A patient fibroblasts (MFN2 T105M, R274W, H361Y, R364W) from glycolytic metabolism to mitochondrial oxidative phosphorylation, which provoked characteristic mitochondrial fragmentation and depolarization and induced a distinct transcriptional signature. Pharmacological MFN activation of metabolically reprogrammed fibroblasts partially reversed the mitochondrial abnormalities in CMT2A and CMT1 and a subset of Parkinson's and Alzheimer's disease patients, implicating addressable mitochondrial dysdynamism in these illnesses.
    Keywords:  mitochondrial dynamics; mitofusin; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/cells11061053
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