bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2020–11–08
24 papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Drp1 Tubulates the ER in a GTPase-Independent Manner.
  2. Metabolic determinants of cellular fitness dependent on mitochondrial reactive oxygen species.
  3. Daily mitochondrial dynamics in cone photoreceptors.
  4. Atg43 tethers isolation membranes to mitochondria to promote starvation-induced mitophagy in fission yeast.
  5. Insight into human Miro1/2 domain organization based on the structure of its N-terminal GTPase.
  6. BCAT1 affects mitochondrial metabolism independently of leucine transamination in activated human macrophages.
  7. Mitochondria Define Intestinal Stem Cell Differentiation Downstream of a FOXO/Notch Axis.
  8. Pyruvate Kinase Controls Signal Strength in the Insulin Secretory Pathway.
  9. Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health.
  10. Mitochondrial Dysfunction in Fragile-X Syndrome: Plugging the Leak May Save the Ship.
  11. OPA1 and MICOS Regulate mitochondrial crista dynamics and formation.
  12. Repeated hypoglycemia remodels neural inputs and disrupts mitochondrial function to blunt glucose-inhibited GHRH neuron responsiveness.
  13. Forces, Fluxes, and Fuels: Tracking mitochondrial metabolism by integrating measurements of membrane potential, respiration, and metabolites.
  14. Automated Quantification of Mitochondrial Fragmentation in an In Vitro Parkinson's Disease Model.
  15. Tumor start-up: mitochondrial fusion makes it happen.
  16. AMPKα1 in B Cells Dampens Primary Antibody Responses yet Promotes Mitochondrial Homeostasis and Persistence of B Cell Memory.
  17. Iron out, mitophagy in! A way to slow down hepatocellular carcinoma.
  18. Mitochondrial dysfunction in inflammatory bowel disease alters intestinal epithelial metabolism of hepatic acylcarnitines.
  19. Mitochondrial UQCC3 Modulates Hypoxia Adaptation by Orchestrating OXPHOS and Glycolysis in Hepatocellular Carcinoma.
  20. Targeting Metabolic Plasticity and Flexibility Dynamics for Cancer Therapy.
  21. Multi-kinase framework promotes proliferation and invasion of lung adenocarcinoma through activation of dynamin-related protein 1.
  22. Mito Hacker: a set of tools to enable high-throughput analysis of mitochondrial network morphology.
  23. Blackout in the powerhouse: clinical phenotypes associated with defects in the assembly of OXPHOS complexes and the mitoribosome.
  24. Regulation of Mitochondrial Ca2+ Uptake.
  1. Mol Cell. 2020 Oct 26. pii: S1097-2765(20)30720-6. [Epub ahead of print]
    Drp1 Tubulates the ER in a GTPase-Independent Manner.
    Yoshihiro Adachi, Takashi Kato, Tatsuya Yamada, Daisuke Murata, Kenta Arai, Robert V Stahelin, David C Chan, Miho Iijima, Hiromi Sesaki.
      Mitochondria are highly dynamic organelles that continuously grow, divide, and fuse. The division of mitochondria is crucial for human health. During mitochondrial division, the mechano-guanosine triphosphatase (GTPase) dynamin-related protein (Drp1) severs mitochondria at endoplasmic reticulum (ER)-mitochondria contact sites, where peripheral ER tubules interact with mitochondria. Here, we report that Drp1 directly shapes peripheral ER tubules in human and mouse cells. This ER-shaping activity is independent of GTP hydrolysis and located in a highly conserved peptide of 18 amino acids (termed D-octadecapeptide), which is predicted to form an amphipathic α helix. Synthetic D-octadecapeptide tubulates liposomes in vitro and the ER in cells. ER tubules formed by Drp1 promote mitochondrial division by facilitating ER-mitochondria interactions. Thus, Drp1 functions as a two-in-one protein during mitochondrial division, with ER tubulation and mechano-GTPase activities.
    Keywords:  Drp1; mitochondria; mitochondrial division; organelle contact sites; phosphaditic acid; the endoplasmic reticulum
    DOI:  https://doi.org/10.1016/j.molcel.2020.10.013
  2. Sci Adv. 2020 Nov;pii: eabb7272. [Epub ahead of print]6(45):
    Metabolic determinants of cellular fitness dependent on mitochondrial reactive oxygen species.
    Hyewon Kong, Colleen R Reczek, Gregory S McElroy, Elizabeth M Steinert, Tim Wang, David M Sabatini, Navdeep S Chandel.
      Mitochondria-derived reactive oxygen species (mROS) are required for the survival, proliferation, and metastasis of cancer cells. The mechanism by which mitochondrial metabolism regulates mROS levels to support cancer cells is not fully understood. To address this, we conducted a metabolism-focused CRISPR-Cas9 genetic screen and uncovered that loss of genes encoding subunits of mitochondrial complex I was deleterious in the presence of the mitochondria-targeted antioxidant mito-vitamin E (MVE). Genetic or pharmacologic inhibition of mitochondrial complex I in combination with the mitochondria-targeted antioxidants, MVE or MitoTEMPO, induced a robust integrated stress response (ISR) and markedly diminished cell survival and proliferation in vitro. This was not observed following inhibition of mitochondrial complex III. Administration of MitoTEMPO in combination with the mitochondrial complex I inhibitor phenformin decreased the leukemic burden in a mouse model of T cell acute lymphoblastic leukemia. Thus, mitochondrial complex I is a dominant metabolic determinant of mROS-dependent cellular fitness.
    DOI:  https://doi.org/10.1126/sciadv.abb7272
  3. Proc Natl Acad Sci U S A. 2020 Nov 03. pii: 202007827. [Epub ahead of print]
    Daily mitochondrial dynamics in cone photoreceptors.
    Michelle M Giarmarco, Daniel C Brock, Brian M Robbings, Whitney M Cleghorn, Kristine A Tsantilas, Kellie C Kuch, William Ge, Kaitlyn M Rutter, Edward D Parker, James B Hurley, Susan E Brockerhoff.
      Cone photoreceptors in the retina are exposed to intense daylight and have higher energy demands in darkness. Cones produce energy using a large cluster of mitochondria. Mitochondria are susceptible to oxidative damage, and healthy mitochondrial populations are maintained by regular turnover. Daily cycles of light exposure and energy consumption suggest that mitochondrial turnover is important for cone health. We investigated the three-dimensional (3D) ultrastructure and metabolic function of zebrafish cone mitochondria throughout the day. At night retinas undergo a mitochondrial biogenesis event, corresponding to an increase in the number of smaller, simpler mitochondria and increased metabolic activity in cones. In the daytime, endoplasmic reticula (ER) and autophagosomes associate more with mitochondria, and mitochondrial size distribution across the cluster changes. We also report dense material shared between cone mitochondria that is extruded from the cell at night, sometimes forming extracellular structures. Our findings reveal an elaborate set of daily changes to cone mitochondrial structure and function.
    Keywords:  circadian; mitochondria; photoreceptors; retina; zebrafish
    DOI:  https://doi.org/10.1073/pnas.2007827117
  4. Elife. 2020 Nov 03. pii: e61245. [Epub ahead of print]9
    Atg43 tethers isolation membranes to mitochondria to promote starvation-induced mitophagy in fission yeast.
    Tomoyuki Fukuda, Yuki Ebi, Tetsu Saigusa, Kentaro Furukawa, Shun-Ichi Yamashita, Keiichi Inoue, Daiki Kobayashi, Yutaka Yoshida, Tomotake Kanki.
      Degradation of mitochondria through mitophagy contributes to the maintenance of mitochondrial function. In this study, we identified that Atg43, a mitochondrial outer membrane protein, serves as a mitophagy receptor in the model organism Schizosaccharomyces pombe to promote the selective degradation of mitochondria. Atg43 contains an Atg8-family-interacting motif essential for mitophagy. Forced recruitment of Atg8 to mitochondria restores mitophagy in Atg43-deficient cells, suggesting that Atg43 tethers expanding isolation membranes to mitochondria. We found that the mitochondrial import factors, including the Mim1-Mim2 complex and Tom70, are crucial for mitophagy. Artificial mitochondrial loading of Atg43 bypasses the requirement of the import factors, suggesting that they contribute to mitophagy through Atg43. Atg43 not only maintains growth ability during starvation but also facilitates vegetative growth through its mitophagy-independent function. Thus, Atg43 is a useful model to study the mechanism and physiological roles, as well as the origin and evolution, of mitophagy in eukaryotes.
    Keywords:  Atg43; MIM complex; S. pombe; autophagy; cell biology; mitochondria; mitophagy; receptor
    DOI:  https://doi.org/10.7554/eLife.61245
  5. J Struct Biol. 2020 Oct 24. pii: S1047-8477(20)30229-X. [Epub ahead of print]212(3): 107656
    Insight into human Miro1/2 domain organization based on the structure of its N-terminal GTPase.
    Kyle P Smith, Pamela J Focia, Srinivas Chakravarthy, Eric C Landahl, Julian L Klosowiak, Sarah E Rice, Douglas M Freymann.
      Dysfunction in mitochondrial dynamics is believed to contribute to a host of neurological disorders and has recently been implicated in cancer metastasis. The outer mitochondrial membrane adapter protein Miro functions in the regulation of mitochondrial mobility and degradation, however, the structural basis for its roles in mitochondrial regulation remain unknown. Here, we report a 1.7Å crystal structure of N-terminal GTPase domain (nGTPase) of human Miro1 bound unexpectedly to GTP, thereby revealing a non-catalytic configuration of the putative GTPase active site. We identify two conserved surfaces of the nGTPase, the "SELFYY" and "ITIP" motifs, that are potentially positioned to mediate dimerization or interaction with binding partners. Additionally, we report small angle X-ray scattering (SAXS) data obtained from the intact soluble HsMiro1 and its paralog HsMiro2. Taken together, the data allow modeling of a crescent-shaped assembly of the soluble domain of HsMiro1/2. PDB RSEFERENCE: Crystal structure of the human Miro1 N-terminal GTPase bound to GTP, 6D71.
    Keywords:  Crystal structure; GTP-binding protein; Gem1p; Miro; Mitochondrial dynamics; RhoT
    DOI:  https://doi.org/10.1016/j.jsb.2020.107656
  6. J Cell Sci. 2020 Nov 04. pii: jcs.247957. [Epub ahead of print]
    BCAT1 affects mitochondrial metabolism independently of leucine transamination in activated human macrophages.
    Jeong-Hun Ko, Antoni Olona, Adonia E Papathanassiu, Norzawani Buang, Kwon-Sik Park, Ana S H Costa, Claudio Mauro, Christian Frezza, Jacques Behmoaras.
      In response to environmental stimuli, macrophages change their nutrient consumption and undergo an early metabolic adaptation that progressively shapes their polarization state. During the transient, early phase of pro-inflammatory macrophage activation, an increase in tricarboxylic acid (TCA) cycle activity has been reported but the relative contribution of branched chain amino acid (BCAA) leucine remain to be determined. Here we show that glucose but not glutamine is a major contributor of the increase in TCA cycle metabolites during early macrophage activation in humans. We then show that, although BCAA uptake is not altered, their transamination by BCAT1 is increased following 8h lipopolysaccharide (LPS) stimulation. Of note, leucine is not metabolized to integrate the TCA cycle in neither basal nor stimulated human macrophages. Surprisingly, the pharmacological inhibition of BCAT1 reduced glucose-derived itaconate, α-ketoglutarate, and 2-hydroxyglutarate levels, without affecting succinate and citrate levels, indicating a partial inhibition of TCA cycle. This indirect effect is associated with NRF2 activation and anti-oxidant responses. These results suggest a moonlighting role of BCAT1 through redox-mediated control of mitochondrial function during early macrophage activation.
    Keywords:  BCAT1; Immunometabolism; Macrophages; Mitochondria; Redox biology; TCA cycle
    DOI:  https://doi.org/10.1242/jcs.247957
  7. Cell Metab. 2020 Nov 03. pii: S1550-4131(20)30538-6. [Epub ahead of print]32(5): 889-900.e7
    Mitochondria Define Intestinal Stem Cell Differentiation Downstream of a FOXO/Notch Axis.
    Marlies C Ludikhuize, Maaike Meerlo, Marc Pages Gallego, Despina Xanthakis, Mar Burgaya Julià, Nguyen T B Nguyen, Eline C Brombacher, Nalan Liv, Madelon M Maurice, Ji-Hye Paik, Boudewijn M T Burgering, Maria J Rodriguez Colman.
      Differential WNT and Notch signaling regulates differentiation of Lgr5+ crypt-based columnar cells (CBCs) into intestinal cell lineages. Recently we showed that mitochondrial activity supports CBCs, while adjacent Paneth cells (PCs) show reduced mitochondrial activity. This implies that CBC differentiation into PCs involves a metabolic transition toward downregulation of mitochondrial dependency. Here we show that Forkhead box O (FoxO) transcription factors and Notch signaling interact in determining CBC fate. In agreement with the organoid data, Foxo1/3/4 deletion in mouse intestine induces secretory cell differentiation. Importantly, we show that FOXO and Notch signaling converge on regulation of mitochondrial fission, which in turn provokes stem cell differentiation into goblet cells and PCs. Finally, scRNA-seq-based reconstruction of CBC differentiation trajectories supports the role of FOXO, Notch, and mitochondria in secretory differentiation. Together, this points at a new signaling-metabolic axis in CBC differentiation and highlights the importance of mitochondria in determining stem cell fate.
    Keywords:  FOXO; Notch; differentiation; intestine; metabolism; mitochondria; stem cells
    DOI:  https://doi.org/10.1016/j.cmet.2020.10.005
  8. Cell Metab. 2020 Nov 03. pii: S1550-4131(20)30540-4. [Epub ahead of print]32(5): 736-750.e5
    Pyruvate Kinase Controls Signal Strength in the Insulin Secretory Pathway.
    Sophie L Lewandowski, Rebecca L Cardone, Hannah R Foster, Thuong Ho, Evgeniy Potapenko, Chetan Poudel, Halena R VanDeusen, Sophia M Sdao, Tiago C Alves, Xiaojian Zhao, Megan E Capozzi, Arnaldo H de Souza, Ishrat Jahan, Craig J Thomas, Craig S Nunemaker, Dawn Belt Davis, Jonathan E Campbell, Richard G Kibbey, Matthew J Merrins.
      Pancreatic β cells couple nutrient metabolism with appropriate insulin secretion. Here, we show that pyruvate kinase (PK), which converts ADP and phosphoenolpyruvate (PEP) into ATP and pyruvate, underlies β cell sensing of both glycolytic and mitochondrial fuels. Plasma membrane-localized PK is sufficient to close KATP channels and initiate calcium influx. Small-molecule PK activators increase the frequency of ATP/ADP and calcium oscillations and potently amplify insulin secretion. PK restricts respiration by cyclically depriving mitochondria of ADP, which accelerates PEP cycling until membrane depolarization restores ADP and oxidative phosphorylation. Our findings support a compartmentalized model of β cell metabolism in which PK locally generates the ATP/ADP required for insulin secretion. Oscillatory PK activity allows mitochondria to perform synthetic and oxidative functions without any net impact on glucose oxidation. These findings suggest a potential therapeutic route for diabetes based on PK activation that would not be predicted by the current consensus single-state model of β cell function.
    Keywords:  K(ATP) channel; anaplerosis; biosensor imaging; insulin secretion; metabolic flux; metabolic oscillations; oxidative phosphorylation; phosphoenolpyruvate cycle; pyruvate kinase; β cell metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2020.10.007
  9. Cell Metab. 2020 Nov 03. pii: S1550-4131(20)30539-8. [Epub ahead of print]32(5): 751-766.e11
    Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health.
    Abudukadier Abulizi, Rebecca L Cardone, Romana Stark, Sophie L Lewandowski, Xiaojian Zhao, Joelle Hillion, Lingjun Ma, Raghav Sehgal, Tiago C Alves, Craig Thomas, Charles Kung, Bei Wang, Stephan Siebel, Zane B Andrews, Graeme F Mason, Jesse Rinehart, Matthew J Merrins, Richard G Kibbey.
      The mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle couples mitochondrial PEPCK (PCK2) to pyruvate kinase (PK) in the liver and pancreatic islets to regulate glucose homeostasis. Here, small molecule PK activators accelerated the PEP cycle to improve islet function, as well as metabolic homeostasis, in preclinical rodent models of diabetes. In contrast, treatment with a PK activator did not improve insulin secretion in pck2-/- mice. Unlike other clinical secretagogues, PK activation enhanced insulin secretion but also had higher insulin content and markers of differentiation. In addition to improving insulin secretion, acute PK activation short-circuited gluconeogenesis to reduce endogenous glucose production while accelerating red blood cell glucose turnover. Four-week delivery of a PK activator in vivo remodeled PK phosphorylation, reduced liver fat, and improved hepatic and peripheral insulin sensitivity in HFD-fed rats. These data provide a preclinical rationale for PK activation to accelerate the PEP cycle to improve metabolic homeostasis and insulin sensitivity.
    Keywords:  anaplerosis; cataplerosis; fatty liver; human islets; insulin resistance; insulin secretion; mitochondrial GTP; mitochondrial PEPCK; phosphoenolpyruvate cycle; pyruvate kinase
    DOI:  https://doi.org/10.1016/j.cmet.2020.10.006
  10. Mol Cell. 2020 Nov 05. pii: S1097-2765(20)30685-7. [Epub ahead of print]80(3): 381-383
    Mitochondrial Dysfunction in Fragile-X Syndrome: Plugging the Leak May Save the Ship.
    Divakar S Mithal, Navdeep S Chandel.
      Recent work by Licznerski et al. suggests that mutant FMRP linked to Fragile-X syndrome elevates the inner mitochondrial membrane proton leak, leading to increased metabolism and changes in protein synthesis that trigger impaired synaptic maturation and autistic behaviors.
    DOI:  https://doi.org/10.1016/j.molcel.2020.10.002
  11. Cell Death Dis. 2020 Oct 31. 11(10): 940
    OPA1 and MICOS Regulate mitochondrial crista dynamics and formation.
    Chao Hu, Li Shu, Xiaoshuai Huang, Jianglong Yu, Liuju Li, Longlong Gong, Meigui Yang, Zhida Wu, Zhi Gao, Yungang Zhao, Liangyi Chen, Zhiyin Song.
      Mitochondrial cristae are the main site for oxidative phosphorylation, which is critical for cellular energy production. Upon different physiological or pathological stresses, mitochondrial cristae undergo remodeling to reprogram mitochondrial function. However, how mitochondrial cristae are formed, maintained, and remolded is still largely unknown due to the technical challenges of tracking mitochondrial crista dynamics in living cells. Here, using live-cell Hessian structured illumination microscopy combined with transmission electron microscopy, focused ion beam/scanning electron microscopy, and three-dimensional tomographic reconstruction, we show, in living cells, that mitochondrial cristae are highly dynamic and undergo morphological changes, including elongation, shortening, fusion, division, and detachment from the mitochondrial inner boundary membrane (IBM). In addition, we find that OPA1, Yme1L, MICOS, and Sam50, along with the newly identified crista regulator ATAD3A, control mitochondrial crista dynamics. Furthermore, we discover two new types of mitochondrial crista in dysfunctional mitochondria, "cut-through crista" and "spherical crista", which are formed due to incomplete mitochondrial fusion and dysfunction of the MICOS complex. Interestingly, cut-through crista can convert to "lamellar crista". Overall, we provide a direct link between mitochondrial crista formation and mitochondrial crista dynamics.
    DOI:  https://doi.org/10.1038/s41419-020-03152-y
  12. JCI Insight. 2020 Nov 05. pii: 133488. [Epub ahead of print]5(21):
    Repeated hypoglycemia remodels neural inputs and disrupts mitochondrial function to blunt glucose-inhibited GHRH neuron responsiveness.
    Mitchell Bayne, Alexandra Alvarsson, Kavya Devarakonda, Rosemary Li, Maria Jimenez-Gonzalez, Darline Garibay, Kaetlyn Conner, Merina Varghese, Madhavika N Serasinghe, Jerry E Chipuk, Patrick R Hof, Sarah A Stanley.
      Hypoglycemia is a frequent complication of diabetes, limiting therapy and increasing morbidity and mortality. With recurrent hypoglycemia, the counterregulatory response (CRR) to decreased blood glucose is blunted, resulting in hypoglycemia-associated autonomic failure (HAAF). The mechanisms leading to these blunted effects are only poorly understood. Here, we report, with ISH, IHC, and the tissue-clearing capability of iDISCO+, that growth hormone releasing hormone (GHRH) neurons represent a unique population of arcuate nucleus neurons activated by glucose deprivation in vivo. Repeated glucose deprivation reduces GHRH neuron activation and remodels excitatory and inhibitory inputs to GHRH neurons. We show that low glucose sensing is coupled to GHRH neuron depolarization, decreased ATP production, and mitochondrial fusion. Repeated hypoglycemia attenuates these responses during low glucose. By maintaining mitochondrial length with the small molecule mitochondrial division inhibitor-1, we preserved hypoglycemia sensitivity in vitro and in vivo. Our findings present possible mechanisms for the blunting of the CRR, significantly broaden our understanding of the structure of GHRH neurons, and reveal that mitochondrial dynamics play an important role in HAAF. We conclude that interventions targeting mitochondrial fission in GHRH neurons may offer a new pathway to prevent HAAF in patients with diabetes.
    Keywords:  Diabetes; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.133488
  13. Am J Physiol Cell Physiol. 2020 Nov 04.
    Forces, Fluxes, and Fuels: Tracking mitochondrial metabolism by integrating measurements of membrane potential, respiration, and metabolites.
    Anthony E Jones, Li Sheng, Aracely Acevedo, Michaela Veliova, Orian S Shirihai, Linsey Stiles, Ajit S Divakaruni.
      Assessing mitochondrial function in cell-based systems is a central component of metabolism research. However, the selection of an initial measurement technique may be complicated given the range of parameters that can be studied as well as the need to define the mitochondrial (dys)function of interest. This methods-focused review compares and contrasts the use of mitochondrial membrane potential measurements, plate-based respirometry, and metabolomics and stable isotope tracing. We demonstrate how measurements of (i) cellular substrate preference, (ii) respiratory chain activity, (iii) cell activation, and (iv) mitochondrial biogenesis are enriched by integrating information from multiple methods. This manuscript is meant to serve as a perspective to help choose which technique might be an appropriate initial method to answer a given question, as well as provide a broad 'roadmap' for designing follow-up assays to enrich datasets or resolve ambiguous results.
    Keywords:  bioenergetics; membrane potential; metabolomics; mitochondria; oxygen consumption
    DOI:  https://doi.org/10.1152/ajpcell.00235.2020
  14. Curr Protoc Neurosci. 2020 Dec;94(1): e105
    Automated Quantification of Mitochondrial Fragmentation in an In Vitro Parkinson's Disease Model.
    Daniel J Rees, Luke Roberts, M Carla Carisi, Alwena H Morgan, M Rowan Brown, Jeffrey S Davies.
      Neuronal mitochondrial fragmentation is a phenotype exhibited in models of neurodegeneration such as Parkinson's disease. Delineating the dysfunction in mitochondrial dynamics found in diseased states can aid our understanding of underlying mechanisms of disease progression and possibly identify novel therapeutic approaches. Advances in microscopy and the availability of intuitive open-access software have accelerated the rate of image acquisition and analysis, respectively. These developments allow routine biology researchers to rapidly turn hypotheses into results. In this protocol, we describe the utilization of cell culture techniques, high-content imaging (HCI), and the subsequent open-source image analysis pipeline for the quantification of mitochondrial fragmentation in the context of a rotenone-based in vitro Parkinson's disease model. © 2020 The Authors. Basic Protocol 1: SN4741 neuron culture and treatment in a rotenone-based model of Parkinson's disease Basic Protocol 2: Identification of cell nuclei, measurement of mitochondrial membrane potential, and measurement of mitochondrial fragmentation in mouse-derived midbrain dopaminergic neurons.
    Keywords:  Parkinson's disease; fragmentation; image analysis; mitochondria
    DOI:  https://doi.org/10.1002/cpns.105
  15. EMBO J. 2020 Oct 31. e106927
    Tumor start-up: mitochondrial fusion makes it happen.
    Ana R Rebelo, Marcia Garcez, Catarina Cf Homem.
      Whether changes in cellular metabolism precede tumor formation and trigger malignant properties or simply serve as a bioenergetic adaptation of cancer during disease progression remains debated. Bonnay et al (2020) now show that a metabolic reprogramming toward increased oxidative phosphorylation is required for irreversible cell immortalization and subsequent tumor formation.
    DOI:  https://doi.org/10.15252/embj.2020106927
  16. J Immunol. 2020 Nov 04. pii: ji1901474. [Epub ahead of print]
    AMPKα1 in B Cells Dampens Primary Antibody Responses yet Promotes Mitochondrial Homeostasis and Persistence of B Cell Memory.
    Shawna K Brookens, Sung Hoon Cho, Paulo J Basso, Mark R Boothby.
      Emerging evidence indicates that metabolic programs regulate B cell activation and Ab responses. However, the metabolic mediators that support the durability of the memory B cell and long-lived plasma cell populations are not fully elucidated. Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionary conserved serine/threonine kinase that integrates cellular energy status and nutrient availability to intracellular signaling and metabolic pathways. In this study, we use genetic mouse models to show that loss of ΑMPKα1 in B cells led to a weakened recall Ab response associated with a decline in the population of memory-phenotype B cells. AMPKα1-deficient memory B lymphocytes exhibited aberrant mitochondrial activity, decreased mitophagy, and increased lipid peroxidation. Moreover, loss of AMPKα1 in B lymphoblasts was associated with decreased mitochondrial spare respiratory capacity. Of note, AMPKα1 in B cells was dispensable for stability of the bone marrow-resident, long-lived plasma cell population, yet absence of this kinase led to increased rates of Ig production and elevated serum Ab concentrations elicited by primary immunization. Collectively, our findings fit a model in which AMPKα1 in B cells supports recall function of the memory B cell compartment by promoting mitochondrial homeostasis and longevity but restrains rates of Ig production.
    DOI:  https://doi.org/10.4049/jimmunol.1901474
  17. EMBO Rep. 2020 Nov 05. 21(11): e51652
    Iron out, mitophagy in! A way to slow down hepatocellular carcinoma.
    Yahyah Aman, Shuqin Cao, Evandro F Fang.
      Mitochondrial homeostasis is necessary for the maintenance of cellular function and neuronal survival. Mitochondrial quality is tightly regulated by mitophagy, in which defective/superfluous mitochondria are degraded and recycled. Here, Hara et al demonstrate that induction of mitophagy via iron depletion suppresses the development of hepatocellular carcinoma (HCC). This work suggests turning up mitophagy as a potential therapeutic strategy against liver cancer.
    DOI:  https://doi.org/10.15252/embr.202051652
  18. J Clin Invest. 2020 Nov 03. pii: 133371. [Epub ahead of print]
    Mitochondrial dysfunction in inflammatory bowel disease alters intestinal epithelial metabolism of hepatic acylcarnitines.
    Sarah A Smith, Sayaka A Ogawa, Lillian Chau, Kelly A Whelan, Kathryn E Hamilton, Jie Chen, Lu Tan, Eric Z Chen, Sue Keilbaugh, Franz Fogt, Meenakshi Bewtra, Jonathan Braun, Ramnik J Xavier, Clary B Clish, Barry Slaff, Aalim M Weljie, Frederic D Bushman, James D Lewis, Hongzhe Li, Stephen R Master, Michael J Bennett, Hiroshi Nakagawa, Gary D Wu.
      As the interface between the gut microbiota and the mucosal immune system, there has been great interest in the maintenance of colonic epithelial integrity through mitochondrial oxidation of butyrate, a short-chain fatty acid produced by the gut microbiota. Herein, we showed that the intestinal epithelium can also oxidize long-chain fatty acids, and that luminally-delivered acylcarnitines in bile can be consumed via apical absorption by the intestinal epithelium resulting in mitochondrial oxidation. Finally, intestinal inflammation led to mitochondrial dysfunction in the apical domain of the surface epithelium that may reduce the consumption of fatty acids, contributing to higher concentrations of fecal acylcarnitines in murine Citrobacter rodentium-induced colitis and human inflammatory bowel disease. These results emphasized the importance of both the gut microbiota and the liver in the delivery of energy substrates for mitochondrial metabolism by the intestinal epithelium.
    Keywords:  Fatty acid oxidation; Gastroenterology; Inflammation; Inflammatory bowel disease; Mitochondria
    DOI:  https://doi.org/10.1172/JCI133371
  19. Cell Rep. 2020 Nov 03. pii: S2211-1247(20)31329-2. [Epub ahead of print]33(5): 108340
    Mitochondrial UQCC3 Modulates Hypoxia Adaptation by Orchestrating OXPHOS and Glycolysis in Hepatocellular Carcinoma.
    Yun Yang, Guimin Zhang, Fengzhu Guo, Qiqi Li, Hui Luo, Yang Shu, Yuge Shen, Jia Gan, Lin Xu, Hanshuo Yang.
      Bioenergetic reprogramming during hypoxia adaption is critical to promote hepatocellular carcinoma (HCC) growth and progression. However, the mechanism underlying the orchestration of mitochondrial OXPHOS (oxidative phosphorylation) and glycolysis in hypoxia is not fully understood. Here, we report that mitochondrial UQCC3 (C11orf83) expression increases in hypoxia and correlates with the poor prognosis of HCC patients. Loss of UQCC3 impairs HCC cell proliferation in hypoxia in vitro and in vivo. Mechanistically, UQCC3 forms a positive feedback loop with mitochondrial reactive oxygen species (ROS) to sustain UQCC3 expression and ROS generation in hypoxic HCC cells and subsequently maintains mitochondrial structure and function and stabilizes HIF-1α expression to enhance glycolysis under hypoxia. Thus, UQCC3 plays an indispensable role for bioenergetic reprogramming of HCC cells during hypoxia adaption by simultaneously regulating OXPHOS and glycolysis. The positive feedback between UQCC3 and ROS indicates a self-modulating model within mitochondria that initiates the adaptation of HCC to hypoxic stress.
    Keywords:  ATP; HCC; HIF-1α; OXPHOS; ROS; UQCC3 (C11orf83); bioenergenesis; glycolysis; hypoxia; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2020.108340
  20. Cancer Discov. 2020 Nov 02.
    Targeting Metabolic Plasticity and Flexibility Dynamics for Cancer Therapy.
    Sarah-Maria Fendt, Christian Frezza, Ayelet Erez.
      Cancer cells continuously rewire their metabolism to fulfill their need for rapid growth and survival while subject to changes in environmental cues. Thus, a vital component of a cancer cell lies in its metabolic adaptability. The constant demand for metabolic alterations requires flexibility, that is, the ability to utilize different metabolic substrates; as well as plasticity, that is, the ability to process metabolic substrates in different ways. In this review, we discuss how dynamic changes in cancer metabolism affect tumor progression and the consequential implications for cancer therapy. SIGNIFICANCE: Recognizing cancer dynamic metabolic adaptability as an entity can lead to targeted therapy that is expected to decrease drug resistance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-0844
  21. Mol Oncol. 2020 Nov 05.
    Multi-kinase framework promotes proliferation and invasion of lung adenocarcinoma through activation of dynamin-related protein 1.
    Kuei-Pin Chung, Yen-Lin Huang, Yi-Jung Chen, Yi-Hsiu Juan, Chia-Lang Hsu, Kiichi Nakahira, Yen-Tsung Huang, Mong-Wei Lin, Shang-Gin Wu, Jin-Yuan Shih, Yih-Leong Chang, Chong-Jen Yu.
      Recent studies revealed the role of dynamin-related protein 1 (DRP1), encoded by the DNM1L gene, in regulating the growth of cancer cells of various origins. However, the regulation, function and clinical significance of DRP1 remain undetermined in lung adenocarcinoma. Our study shows that the expression and activation of DRP1 are significantly correlated with proliferation and disease extent, as well as an increased risk of post-operative recurrence in stage I to IIIA lung adenocarcinoma. Loss of DRP1 in lung adenocarcinoma cell lines leads to an altered mitochondrial morphology, fewer copies of mitochondrial DNA, decreased respiratory complexes, and impaired oxidative phosphorylation. Additionally, proliferation and invasion are both suppressed in DRP1-depleted lung adenocarcinoma cell lines. Our data further revealed that DRP1 activation through serine 616 phosphorylation is regulated by ERK/AKT and CDK2 in lung adenocarcinoma cell lines. Collectively, we propose the multi-kinase framework in activating DRP1 in lung adenocarcinoma to promote the malignant properties. Biomarkers related to mitochondrial reprogramming, such as DRP1, can be used to evaluate the risk of post-operative recurrence in early-stage lung adenocarcinoma.
    Keywords:  cyclin-dependent kinase 2; dynamin-related protein 1; glycolytic serine synthesis; lung adenocarcinoma; mitochondria; prognosis
    DOI:  https://doi.org/10.1002/1878-0261.12843
  22. Sci Rep. 2020 Nov 03. 10(1): 18941
    Mito Hacker: a set of tools to enable high-throughput analysis of mitochondrial network morphology.
    Ali Rohani, Jennifer A Kashatus, Dane T Sessions, Salma Sharmin, David F Kashatus.
      Mitochondria are highly dynamic organelles that can exhibit a wide range of morphologies. Mitochondrial morphology can differ significantly across cell types, reflecting different physiological needs, but can also change rapidly in response to stress or the activation of signaling pathways. Understanding both the cause and consequences of these morphological changes is critical to fully understanding how mitochondrial function contributes to both normal and pathological physiology. However, while robust and quantitative analysis of mitochondrial morphology has become increasingly accessible, there is a need for new tools to generate and analyze large data sets of mitochondrial images in high throughput. The generation of such datasets is critical to fully benefit from rapidly evolving methods in data science, such as neural networks, that have shown tremendous value in extracting novel biological insights and generating new hypotheses. Here we describe a set of three computational tools, Cell Catcher, Mito Catcher and MiA, that we have developed to extract extensive mitochondrial network data on a single-cell level from multi-cell fluorescence images. Cell Catcher automatically separates and isolates individual cells from multi-cell images; Mito Catcher uses the statistical distribution of pixel intensities across the mitochondrial network to detect and remove background noise from the cell and segment the mitochondrial network; MiA uses the binarized mitochondrial network to perform more than 100 mitochondria-level and cell-level morphometric measurements. To validate the utility of this set of tools, we generated a database of morphological features for 630 individual cells that encode 0, 1 or 2 alleles of the mitochondrial fission GTPase Drp1 and demonstrate that these mitochondrial data could be used to predict Drp1 genotype with 87% accuracy. Together, this suite of tools enables the high-throughput and automated collection of detailed and quantitative mitochondrial structural information at a single-cell level. Furthermore, the data generated with these tools, when combined with advanced data science approaches, can be used to generate novel biological insights.
    DOI:  https://doi.org/10.1038/s41598-020-75899-5
  23. Biochem J. 2020 Nov 13. 477(21): 4085-4132
    Blackout in the powerhouse: clinical phenotypes associated with defects in the assembly of OXPHOS complexes and the mitoribosome.
    Daniella H Hock, David R L Robinson, David A Stroud.
      Mitochondria produce the bulk of the energy used by almost all eukaryotic cells through oxidative phosphorylation (OXPHOS) which occurs on the four complexes of the respiratory chain and the F1-F0 ATPase. Mitochondrial diseases are a heterogenous group of conditions affecting OXPHOS, either directly through mutation of genes encoding subunits of OXPHOS complexes, or indirectly through mutations in genes encoding proteins supporting this process. These include proteins that promote assembly of the OXPHOS complexes, the post-translational modification of subunits, insertion of cofactors or indeed subunit synthesis. The latter is important for all 13 of the proteins encoded by human mitochondrial DNA, which are synthesised on mitochondrial ribosomes. Together the five OXPHOS complexes and the mitochondrial ribosome are comprised of more than 160 subunits and many more proteins support their biogenesis. Mutations in both nuclear and mitochondrial genes encoding these proteins have been reported to cause mitochondrial disease, many leading to defective complex assembly with the severity of the assembly defect reflecting the severity of the disease. This review aims to act as an interface between the clinical and basic research underpinning our knowledge of OXPHOS complex and ribosome assembly, and the dysfunction of this process in mitochondrial disease.
    Keywords:  mitochondria; mitochondrial dysfunction; mitochondrial respiration; mutation; oxidative phosphorylation; ribosomes
    DOI:  https://doi.org/10.1042/BCJ20190767
  24. Annu Rev Physiol. 2020 Nov 03.
    Regulation of Mitochondrial Ca2+ Uptake.
    Elizabeth Murphy, Charles Steenbergen.
      Mitochondria are responsible for ATP production but are also known as regulators of cell death, and mitochondrial matrix Ca2+ is a key modulator of both ATP production and cell death. Although mitochondrial Ca2+ uptake and efflux have been studied for over 50 years, it is only in the past decade that the proteins responsible for mitochondrial Ca2+ uptake and efflux have been identified. The identification of the mitochondrial Ca2+ uniporter (MCU) led to an explosion of studies identifying regulators of the MCU. The levels of these regulators vary in a tissue- and disease-specific manner, providing new insight into how mitochondrial Ca2+ is regulated. This review focuses on the proteins responsible for mitochondrial transport and what we have learned from mouse studies with genetic alterations in these proteins. Expected final online publication date for the Annual Review of Physiology, Volume 83 is February 10, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-physiol-031920-092419
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