bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023–03–05
thirteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Transgenic NADH dehydrogenase restores oxygen regulation of breathing in mitochondrial complex I-deficient mice.
  2. mcPGK1-dependent mitochondrial import of PGK1 promotes metabolic reprogramming and self-renewal of liver TICs.
  3. An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets.
  4. Mitochondria-localized cGAS suppresses ferroptosis to promote cancer progression.
  5. Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells.
  6. Limiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming in prolonged dietary stress.
  7. Nitration-mediated activation of the small GTPase RhoA stimulates cellular glycolysis through enhanced mitochondrial fission.
  8. ANKLE1 cleaves mitochondrial DNA and contributes to cancer risk by promoting apoptosis resistance and metabolic dysregulation.
  9. The multifaceted mitochondrial OXA insertase.
  10. Analyzing mitochondrial respiration of human induced pluripotent stem cell-derived myeloid progenitors using Seahorse technology.
  11. Evaluating mitochondrial length, volume, and cristae ultrastructure in rare mouse adult stem cell populations.
  12. Optimized protocol for quantification of mitochondrial non-heme and heme iron content in mouse tissues and cultured cells.
  13. Protocol for mitochondrial isolation and sub-cellular localization assay for mitochondrial proteins.
  1. Nat Commun. 2023 Mar 01. 14(1): 1172
    Transgenic NADH dehydrogenase restores oxygen regulation of breathing in mitochondrial complex I-deficient mice.
    Blanca Jiménez-Gómez, Patricia Ortega-Sáenz, Lin Gao, Patricia González-Rodríguez, Paula García-Flores, Navdeep Chandel, José López-Barneo.
      The hypoxic ventilatory response (HVR) is a life-saving reflex, triggered by the activation of chemoreceptor glomus cells in the carotid body (CB) connected with the brainstem respiratory center. The molecular mechanisms underlying glomus cell acute oxygen (O2) sensing are unclear. Genetic disruption of mitochondrial complex I (MCI) selectively abolishes the HVR and glomus cell responsiveness to hypoxia. However, it is unknown what functions of MCI (metabolic, proton transport, or signaling) are essential for O2 sensing. Here we show that transgenic mitochondrial expression of NDI1, a single-molecule yeast NADH/quinone oxidoreductase that does not directly contribute to proton pumping, fully recovers the HVR and glomus cell sensitivity to hypoxia in MCI-deficient mice. Therefore, maintenance of mitochondrial NADH dehydrogenase activity and the electron transport chain are absolutely necessary for O2-dependent regulation of breathing. NDI1 expression also rescues other systemic defects caused by MCI deficiency. These data explain the role of MCI in acute O2 sensing by arterial chemoreceptors and demonstrate the optimal recovery of complex organismal functions by gene therapy.
    DOI:  https://doi.org/10.1038/s41467-023-36894-2
  2. Nat Commun. 2023 Feb 27. 14(1): 1121
    mcPGK1-dependent mitochondrial import of PGK1 promotes metabolic reprogramming and self-renewal of liver TICs.
    Zhenzhen Chen, Qiankun He, Tiankun Lu, Jiayi Wu, Gaoli Shi, Luyun He, Hong Zong, Benyu Liu, Pingping Zhu.
      Liver tumour-initiating cells (TICs) contribute to tumour initiation, metastasis, progression and drug resistance. Metabolic reprogramming is a cancer hallmark and plays vital roles in liver tumorigenesis. However, the role of metabolic reprogramming in TICs remains poorly explored. Here, we identify a mitochondria-encoded circular RNA, termed mcPGK1 (mitochondrial circRNA for translocating phosphoglycerate kinase 1), which is highly expressed in liver TICs. mcPGK1 knockdown impairs liver TIC self-renewal, whereas its overexpression drives liver TIC self-renewal. Mechanistically, mcPGK1 regulates metabolic reprogramming by inhibiting mitochondrial oxidative phosphorylation (OXPHOS) and promoting glycolysis. This alters the intracellular levels of α-ketoglutarate and lactate, which are modulators in Wnt/β-catenin activation and liver TIC self-renewal. In addition, mcPGK1 promotes PGK1 mitochondrial import via TOM40 interactions, reprogramming metabolism from oxidative phosphorylation to glycolysis through PGK1-PDK1-PDH axis. Our work suggests that mitochondria-encoded circRNAs represent an additional regulatory layer controlling mitochondrial function, metabolic reprogramming and liver TIC self-renewal.
    DOI:  https://doi.org/10.1038/s41467-023-36651-5
  3. PLoS Biol. 2023 Mar;21(3): e3001977
    An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets.
    Natalia Moskal, Naomi P Visanji, Olena Gorbenko, Vijay Narasimhan, Hannah Tyrrell, Jess Nash, Peter N Lewis, G Angus McQuibban.
      Failures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. Using an artificial intelligence platform, we employed a natural language processing approach to evaluate the semantic similarity of candidate molecules to a set of well-established mitophagy enhancers. Top candidates were screened in a cell-based mitochondrial clearance assay. Probucol, a lipid-lowering drug, was validated across several orthogonal mitophagy assays. In vivo, probucol improved survival, locomotor function, and dopaminergic neuron loss in zebrafish and fly models of mitochondrial damage. Probucol functioned independently of PINK1/Parkin, but its effects on mitophagy and in vivo depended on ABCA1, which negatively regulated mitophagy following mitochondrial damage. Autophagosome and lysosomal markers were elevated by probucol treatment in addition to increased contact between lipid droplets (LDs) and mitochondria. Conversely, LD expansion, which occurs following mitochondrial damage, was suppressed by probucol and probucol-mediated mitophagy enhancement required LDs. Probucol-mediated LD dynamics changes may prime the cell for a more efficient mitophagic response to mitochondrial damage.
    DOI:  https://doi.org/10.1371/journal.pbio.3001977
  4. Cell Res. 2023 Mar 02.
    Mitochondria-localized cGAS suppresses ferroptosis to promote cancer progression.
    Shiqiao Qiu, Xiuying Zhong, Xiang Meng, Shiting Li, Xiaoyu Qian, Hui Lu, Jin Cai, Yi Zhang, Mingjie Wang, Zijian Ye, Huafeng Zhang, Ping Gao.
      A well-established role of cyclic GMP-AMP synthase (cGAS) is the recognition of cytosolic DNA, which is linked to the activation of host defense programs against pathogens via stimulator of interferon genes (STING)-dependent innate immune response. Recent advance has also revealed that cGAS may be involved in several noninfectious contexts by localizing to subcellular compartments other than the cytosol. However, the subcellular localization and function of cGAS in different biological conditions is unclear; in particular, its role in cancer progression remains poorly understood. Here we show that cGAS is localized to mitochondria and protects hepatocellular carcinoma cells from ferroptosis in vitro and in vivo. cGAS anchors to the outer mitochondrial membrane where it associates with dynamin-related protein 1 (DRP1) to facilitate its oligomerization. In the absence of cGAS or DRP1 oligomerization, mitochondrial ROS accumulation and ferroptosis increase, inhibiting tumor growth. Collectively, this previously unrecognized role for cGAS in orchestrating mitochondrial function and cancer progression suggests that cGAS interactions in mitochondria can serve as potential targets for new cancer interventions.
    DOI:  https://doi.org/10.1038/s41422-023-00788-1
  5. Sci Adv. 2023 Mar;9(9): eadd5220
    Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells.
    Francesco Petrelli, Valentina Scandella, Sylvie Montessuit, Nicola Zamboni, Jean-Claude Martinou, Marlen Knobloch.
      Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully understood. We here show that the mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part in this process. MPC transports pyruvate into mitochondria, linking cytosolic glycolysis to mitochondrial tricarboxylic acid cycle and oxidative phosphorylation. Despite its metabolic key function, the role of MPC in NSPCs has not been addressed. We show that quiescent NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological MPC inhibition increases aspartate and triggers NSPC activation. Furthermore, genetic Mpc1 ablation in vitro and in vivo also activates NSPCs, which differentiate into mature neurons, leading to overall increased hippocampal neurogenesis in adult and aged mice. These findings highlight the importance of metabolism for NSPC regulation and identify an important pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation.
    DOI:  https://doi.org/10.1126/sciadv.add5220
  6. Cell Rep. 2023 Feb 27. pii: S2211-1247(23)00166-3. [Epub ahead of print]42(3): 112155
    Limiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming in prolonged dietary stress.
    Travis R Madaris, Manigandan Venkatesan, Soumya Maity, Miriam C Stein, Neelanjan Vishnu, Mridula K Venkateswaran, James G Davis, Karthik Ramachandran, Sukanthathulse Uthayabalan, Cristel Allen, Ayodeji Osidele, Kristen Stanley, Nicholas P Bigham, Terry M Bakewell, Melanie Narkunan, Amy Le, Varsha Karanam, Kang Li, Aum Mhapankar, Luke Norton, Jean Ross, M Imran Aslam, W Brian Reeves, Brij B Singh, Jeffrey Caplan, Justin J Wilson, Peter B Stathopulos, Joseph A Baur, Muniswamy Madesh.
      The most abundant cellular divalent cations, Mg2+ (mM) and Ca2+ (nM-μM), antagonistically regulate divergent metabolic pathways with several orders of magnitude affinity preference, but the physiological significance of this competition remains elusive. In mice consuming a Western diet, genetic ablation of the mitochondrial Mg2+ channel Mrs2 prevents weight gain, enhances mitochondrial activity, decreases fat accumulation in the liver, and causes prominent browning of white adipose. Mrs2 deficiency restrains citrate efflux from the mitochondria, making it unavailable to support de novo lipogenesis. As citrate is an endogenous Mg2+ chelator, this may represent an adaptive response to a perceived deficit of the cation. Transcriptional profiling of liver and white adipose reveals higher expression of genes involved in glycolysis, β-oxidation, thermogenesis, and HIF-1α-targets, in Mrs2-/- mice that are further enhanced under Western-diet-associated metabolic stress. Thus, lowering mMg2+ promotes metabolism and dampens diet-induced obesity and metabolic syndrome.
    Keywords:  CP: Metabolism; HCC; HIF1; MCU; Mrs2; NAFLD; Western diet; adipose expansion; adipose tissue; calcium channel; cardiometabolic disease; diabetes; energy imbalance; hepatocytes; liver; magnesium channel; metabolic disease; metabolic syndrome; mitochondrial dysfunction; obesity; whole-body metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2023.112155
  7. J Biol Chem. 2023 Feb 23. pii: S0021-9258(23)00199-0. [Epub ahead of print] 103067
    Nitration-mediated activation of the small GTPase RhoA stimulates cellular glycolysis through enhanced mitochondrial fission.
    Qing Lu, Xutong Sun, Manivannan Yegambran, Wojciech Ornatowski, Xiaomin Wu, Hui Wang, Alejandro Garcia-Flores, Victoria Da Silva, EvgenyA Zemskov, Haiyang Tang, JeffreyR Fineman, Kim Tieu, Ting Wang, StephenM Black.
      Mitochondrial fission and a Warburg phenotype of increased cellular glycolysis are involved in the pathogenesis of pulmonary hypertension (PH). The purpose of this study was to determine whether increases in mitochondrial fission are involved in a glycolytic switch in pulmonary arterial endothelial cells (PAEC). Mitochondrial fission is increased in PAEC isolated from a sheep model of PH induced by pulmonary over-circulation (Shunt PAEC). In Shunt PAEC we identified increases in the S616 phosphorylation responsible for dynamin-related protein 1 (Drp1) activation, the mitochondrial redistribution of Drp1, and increased cellular glycolysis. Reducing mitochondrial fission attenuated cellular glycolysis in Shunt PAEC. Additionally, we observed nitration-mediated activation of the small GTPase RhoA in Shunt PAEC, and utilizing a nitration-shielding peptide, NipR1 attenuated RhoA nitration and reversed the Warburg phenotype. Thus, our data identify a novel link between RhoA, mitochondrial fission, and cellular glycolysis and suggest that targeting RhoA nitration could have therapeutic benefits for treating PH.
    Keywords:  Mitochondrial fission; ROS; endothelial cell; mitochondrial bioenergetics; pulmonary hypertension
    DOI:  https://doi.org/10.1016/j.jbc.2023.103067
  8. Commun Biol. 2023 Mar 01. 6(1): 231
    ANKLE1 cleaves mitochondrial DNA and contributes to cancer risk by promoting apoptosis resistance and metabolic dysregulation.
    Piotr Przanowski, Róża K Przanowska, Michael J Guertin.
      Alleles within the chr19p13.1 locus are associated with increased risk of both ovarian and breast cancer and increased expression of the ANKLE1 gene. ANKLE1 is molecularly characterized as an endonuclease that efficiently cuts branched DNA and shuttles between the nucleus and cytoplasm. However, the role of ANKLE1 in mammalian development and homeostasis remains unknown. In normal development ANKLE1 expression is limited to the erythroblast lineage and we found that ANKLE1's role is to cleave the mitochondrial genome during erythropoiesis. We show that ectopic expression of ANKLE1 in breast epithelial-derived cells leads to genome instability and mitochondrial DNA (mtDNA) cleavage. mtDNA degradation then leads to mitophagy and causes a shift from oxidative phosphorylation to glycolysis (Warburg effect). Moreover, mtDNA degradation activates STAT1 and expression of epithelial-mesenchymal transition (EMT) genes. Reduction in mitochondrial content contributes to apoptosis resistance, which may allow precancerous cells to avoid apoptotic checkpoints and proliferate. These findings provide evidence that ANKLE1 is the causal cancer susceptibility gene in the chr19p13.1 locus and describe mechanisms by which higher ANKLE1 expression promotes cancer risk.
    DOI:  https://doi.org/10.1038/s42003-023-04611-w
  9. Trends Cell Biol. 2023 Feb 28. pii: S0962-8924(23)00020-X. [Epub ahead of print]
    The multifaceted mitochondrial OXA insertase.
    Bettina Homberg, Peter Rehling, Luis Daniel Cruz-Zaragoza.
      Most mitochondrial proteins are synthesized in the cytosol and transported into mitochondria by protein translocases. Yet, mitochondria contain their own genome and gene expression system, which generates proteins that are inserted in the inner membrane by the oxidase assembly (OXA) insertase. OXA contributes to targeting proteins from both genetic origins. Recent data provides insights into how OXA cooperates with the mitochondrial ribosome during synthesis of mitochondrial-encoded proteins. A picture of OXA emerges in which it coordinates insertion of OXPHOS core subunits and their assembly into protein complexes but also participates in the biogenesis of select imported proteins. These functions position the OXA as a multifunctional protein insertase that facilitates protein transport, assembly, and stability at the inner membrane.
    Keywords:  mitochondria; oxidase assembly; oxidative phosphorylation; protein translocation; ribosomes
    DOI:  https://doi.org/10.1016/j.tcb.2023.02.001
  10. STAR Protoc. 2023 Jan 28. pii: S2666-1667(23)00031-X. [Epub ahead of print]4(1): 102073
    Analyzing mitochondrial respiration of human induced pluripotent stem cell-derived myeloid progenitors using Seahorse technology.
    Yanxin Fan, Yoko Mizoguchi, Megumi Tatematsu, Monika I Linder, Stephanie Frenz, Jongsu Choi, Christoph Klein.
      Mitochondrial metabolism is critical in hematopoietic stem cell maintenance and differentiation. Here, we present a step-by-step protocol to efficiently differentiate human induced pluripotent stem cells into myeloid progenitors by a robust feeder- and serum-free system. Furthermore, we provide a protocol to subsequently assess mitochondrial function in iPSC-derived myeloid progenitors. We comprehensively describe a protocol to analyze and to quantify key parameters of mitochondrial respiration of iPSC-derived myeloid progenitors by the Seahorse XFe96 Analyzer. Additionally, our protocol includes extensive troubleshooting suggestions. For complete details on the use and execution of this protocol, please refer to Fan et al. (2022).1.
    Keywords:  Cell Biology; Cell Differentiation; Immunology; Metabolism; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2023.102073
  11. STAR Protoc. 2023 Feb 09. pii: S2666-1667(23)00065-5. [Epub ahead of print]4(1): 102107
    Evaluating mitochondrial length, volume, and cristae ultrastructure in rare mouse adult stem cell populations.
    Matthew Triolo, Steven Wade, Nicole Baker, Mireille Khacho.
      Since changes in mitochondrial morphology regulate key functions of stem cells, it is important to assess their structure under physiological and pathophysiological conditions. Here, we present techniques optimized in rare adult muscle stem cells (MuSCs). For evaluating mitochondrial length and volume within a compact cytoplasmic area in MuSCs on intact myofibers, we describe steps for mitochondrial staining, imaging, and quantification. For evaluating mitochondrial ultrastructure in small cell numbers, we describe steps for agarose embedding and quantification by TEM. For complete details on generation and use of this protocol, please refer to Baker et al. (2022).1.
    Keywords:  Cell Biology; Metabolism; Microscopy; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2023.102107
  12. STAR Protoc. 2023 Jan 24. pii: S2666-1667(23)00022-9. [Epub ahead of print]4(1): 102064
    Optimized protocol for quantification of mitochondrial non-heme and heme iron content in mouse tissues and cultured cells.
    Tatsuya Sato, Hsiang-Chun Chang, Konrad T Sawicki, Hossein Ardehali.
      Impaired mitochondrial iron metabolism is associated with aging and a variety of diseases, and there is a growing need to accurately quantify mitochondrial iron levels. This protocol provides an optimized method for evaluating non-heme and heme iron in mitochondrial and cytosolic fractions of tissues and cultured cells. Our protocol consists of three steps: sample fractionation, non-heme iron measurement, and heme iron measurement. For complete details on the use and execution of this protocol, please refer to Sato et al. (2022).1.
    Keywords:  Cell Biology; Cell Separation/Fractionation; Metabolism; Molecular Biology
    DOI:  https://doi.org/10.1016/j.xpro.2023.102064
  13. STAR Protoc. 2023 Feb 03. pii: S2666-1667(23)00046-1. [Epub ahead of print]4(1): 102088
    Protocol for mitochondrial isolation and sub-cellular localization assay for mitochondrial proteins.
    Danyi Zhou, Sheng Zhong, Xinyu Han, Dandan Liu, Hezhi Fang, Ya Wang.
      Here, we provide a protocol to isolate mitochondria from cultured cells and extract differently located mitochondrial proteins. We detail steps to separate both integral and peripheral membrane proteins from soluble proteins using sonication. We describe the separation of integral membrane proteins from the peripheral membrane and soluble proteins using sodium carbonate extraction. Furthermore, we detail the use of proteinase K and Triton X-100 to distinguish outer membrane proteins from mitochondrial proteins.
    Keywords:  Cell Membrane; Cell culture; Cell separation/fractionation; Protein Biochemistry
    DOI:  https://doi.org/10.1016/j.xpro.2023.102088
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