bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022–05–22
eleven papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Cryo-EM structures define ubiquinone-10 binding to mitochondrial complex I and conformational transitions accompanying Q-site occupancy.
  2. Identification of a modulator of the actin cytoskeleton, mitochondria, nutrient metabolism and lifespan in yeast.
  3. Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis.
  4. Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment.
  5. Lipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis.
  6. Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts.
  7. Mitochondrial TrxR2 regulates metabolism and protects from metabolic disease through enhanced TCA and ETC function.
  8. Spatiotemporal stop-and-go dynamics of the mitochondrial TOM core complex correlates with channel activity.
  9. SQSTM1 and its MAP1LC3B-binding domain induce forced mitophagy to degrade mitochondrial carryover during mitochondrial replacement therapy.
  10. TALEDs complete the toolkit for editing human mitochondrial DNA.
  11. Mitochondrial complex complexification.
  1. Nat Commun. 2022 May 19. 13(1): 2758
    Cryo-EM structures define ubiquinone-10 binding to mitochondrial complex I and conformational transitions accompanying Q-site occupancy.
    Injae Chung, John J Wright, Hannah R Bridges, Bozhidar S Ivanov, Olivier Biner, Caroline S Pereira, Guilherme M Arantes, Judy Hirst.
      Mitochondrial complex I is a central metabolic enzyme that uses the reducing potential of NADH to reduce ubiquinone-10 (Q10) and drive four protons across the inner mitochondrial membrane, powering oxidative phosphorylation. Although many complex I structures are now available, the mechanisms of Q10 reduction and energy transduction remain controversial. Here, we reconstitute mammalian complex I into phospholipid nanodiscs with exogenous Q10. Using cryo-EM, we reveal a Q10 molecule occupying the full length of the Q-binding site in the 'active' (ready-to-go) resting state together with a matching substrate-free structure, and apply molecular dynamics simulations to propose how the charge states of key residues influence the Q10 binding pose. By comparing ligand-bound and ligand-free forms of the 'deactive' resting state (that require reactivating to catalyse), we begin to define how substrate binding restructures the deactive Q-binding site, providing insights into its physiological and mechanistic relevance.
    DOI:  https://doi.org/10.1038/s41467-022-30506-1
  2. Nat Commun. 2022 May 16. 13(1): 2706
    Identification of a modulator of the actin cytoskeleton, mitochondria, nutrient metabolism and lifespan in yeast.
    Cierra N Sing, Enrique J Garcia, Thomas G Lipkin, Thomas M Huckaba, Catherine A Tsang, Arielle C Coughlin, Emily J Yang, Istvan R Boldogh, Ryo Higuchi-Sanabria, Liza A Pon.
      In yeast, actin cables are F-actin bundles that are essential for cell division through their function as tracks for cargo movement from mother to daughter cell. Actin cables also affect yeast lifespan by promoting transport and inheritance of higher-functioning mitochondria to daughter cells. Here, we report that actin cable stability declines with age. Our genome-wide screen for genes that affect actin cable stability identified the open reading frame YKL075C. Deletion of YKL075C results in increases in actin cable stability and abundance, mitochondrial fitness, and replicative lifespan. Transcriptome analysis revealed a role for YKL075C in regulating branched-chain amino acid (BCAA) metabolism. Consistent with this, modulation of BCAA metabolism or decreasing leucine levels promotes actin cable stability and function in mitochondrial quality control. Our studies support a role for actin stability in yeast lifespan, and demonstrate that this process is controlled by BCAA and a previously uncharacterized ORF YKL075C, which we refer to as actin, aging and nutrient modulator protein 1 (AAN1).
    DOI:  https://doi.org/10.1038/s41467-022-30045-9
  3. Nat Commun. 2022 May 16. 13(1): 2699
    Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis.
    Nicole Kiweler, Catherine Delbrouck, Vitaly I Pozdeev, Laura Neises, Leticia Soriano-Baguet, Kim Eiden, Feng Xian, Mohaned Benzarti, Lara Haase, Eric Koncina, Maryse Schmoetten, Christian Jaeger, Muhammad Zaeem Noman, Alexei Vazquez, Bassam Janji, Gunnar Dittmar, Dirk Brenner, Elisabeth Letellier, Johannes Meiser.
      Metastasis is the most common cause of death in cancer patients. Canonical drugs target mainly the proliferative capacity of cancer cells, which leaves slow-proliferating, persistent cancer cells unaffected. Metabolic determinants that contribute to growth-independent functions are still poorly understood. Here we show that antifolate treatment results in an uncoupled and autarkic mitochondrial one-carbon (1C) metabolism during cytosolic 1C metabolism impairment. Interestingly, antifolate dependent growth-arrest does not correlate with decreased migration capacity. Therefore, using methotrexate as a tool compound allows us to disentangle proliferation and migration to profile the metabolic phenotype of migrating cells. We observe that increased serine de novo synthesis (SSP) supports mitochondrial serine catabolism and inhibition of SSP using the competitive PHGDH-inhibitor BI-4916 reduces cancer cell migration. Furthermore, we show that sole inhibition of mitochondrial serine catabolism does not affect primary breast tumor growth but strongly inhibits pulmonary metastasis. We conclude that mitochondrial 1C metabolism, despite being dispensable for proliferative capacities, confers an advantage to cancer cells by supporting their motility potential.
    DOI:  https://doi.org/10.1038/s41467-022-30363-y
  4. Nat Commun. 2022 May 19. 13(1): 2769
    Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment.
    Enrique Balderas, David R Eberhardt, Sandra Lee, John M Pleinis, Salah Sommakia, Anthony M Balynas, Xue Yin, Mitchell C Parker, Colin T Maguire, Scott Cho, Marta W Szulik, Anna Bakhtina, Ryan D Bia, Marisa W Friederich, Timothy M Locke, Johan L K Van Hove, Stavros G Drakos, Yasemin Sancak, Martin Tristani-Firouzi, Sarah Franklin, Aylin R Rodan, Dipayan Chaudhuri.
      Calcium entering mitochondria potently stimulates ATP synthesis. Increases in calcium preserve energy synthesis in cardiomyopathies caused by mitochondrial dysfunction, and occur due to enhanced activity of the mitochondrial calcium uniporter channel. The signaling mechanism that mediates this compensatory increase remains unknown. Here, we find that increases in the uniporter are due to impairment in Complex I of the electron transport chain. In normal physiology, Complex I promotes uniporter degradation via an interaction with the uniporter pore-forming subunit, a process we term Complex I-induced protein turnover. When Complex I dysfunction ensues, contact with the uniporter is inhibited, preventing degradation, and leading to a build-up in functional channels. Preventing uniporter activity leads to early demise in Complex I-deficient animals. Conversely, enhancing uniporter stability rescues survival and function in Complex I deficiency. Taken together, our data identify a fundamental pathway producing compensatory increases in calcium influx during Complex I impairment.
    DOI:  https://doi.org/10.1038/s41467-022-30236-4
  5. Nat Commun. 2022 May 19. 13(1): 2760
    Lipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis.
    Odeta Meçe, Diede Houbaert, Maria-Livia Sassano, Tania Durré, Hannelore Maes, Marco Schaaf, Sanket More, Maarten Ganne, Melissa García-Caballero, Mila Borri, Jelle Verhoeven, Madhur Agrawal, Kathryn Jacobs, Gabriele Bergers, Silvia Blacher, Bart Ghesquière, Mieke Dewerchin, Johan V Swinnen, Stefan Vinckier, María S Soengas, Peter Carmeliet, Agnès Noël, Patrizia Agostinis.
      Autophagy has vasculoprotective roles, but whether and how it regulates lymphatic endothelial cells (LEC) homeostasis and lymphangiogenesis is unknown. Here, we show that genetic deficiency of autophagy in LEC impairs responses to VEGF-C and injury-driven corneal lymphangiogenesis. Autophagy loss in LEC compromises the expression of main effectors of LEC identity, like VEGFR3, affects mitochondrial dynamics and causes an accumulation of lipid droplets (LDs) in vitro and in vivo. When lipophagy is impaired, mitochondrial ATP production, fatty acid oxidation, acetyl-CoA/CoA ratio and expression of lymphangiogenic PROX1 target genes are dwindled. Enforcing mitochondria fusion by silencing dynamin-related-protein 1 (DRP1) in autophagy-deficient LEC fails to restore LDs turnover and lymphatic gene expression, whereas supplementing the fatty acid precursor acetate rescues VEGFR3 levels and signaling, and lymphangiogenesis in LEC-Atg5-/- mice. Our findings reveal that lipophagy in LEC by supporting FAO, preserves a mitochondrial-PROX1 gene expression circuit that safeguards LEC responsiveness to lymphangiogenic mediators and lymphangiogenesis.
    DOI:  https://doi.org/10.1038/s41467-022-30490-6
  6. J Clin Invest. 2022 May 16. pii: e155333. [Epub ahead of print]132(10):
    Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts.
    Bo Zhou, Arianne Caudal, Xiaoting Tang, Juan D Chavez, Timothy S McMillen, Andrew Keller, Outi Villet, Mingyue Zhao, Yaxin Liu, Julia Ritterhoff, Pei Wang, Stephen C Kolwicz, Wang Wang, James E Bruce, Rong Tian.
      In hypertrophied and failing hearts, fuel metabolism is reprogrammed to increase glucose metabolism, especially glycolysis. This metabolic shift favors biosynthetic function at the expense of ATP production. Mechanisms responsible for the switch are poorly understood. We found that inhibitory factor 1 of the mitochondrial FoF1-ATP synthase (ATPIF1), a protein known to inhibit ATP hydrolysis by the reverse function of ATP synthase during ischemia, was significantly upregulated in pathological cardiac hypertrophy induced by pressure overload, myocardial infarction, or α-adrenergic stimulation. Chemical cross-linking mass spectrometry analysis of hearts hypertrophied by pressure overload suggested that increased expression of ATPIF1 promoted the formation of FoF1-ATP synthase nonproductive tetramer. Using ATPIF1 gain- and loss-of-function cell models, we demonstrated that stalled electron flow due to impaired ATP synthase activity triggered mitochondrial ROS generation, which stabilized HIF1α, leading to transcriptional activation of glycolysis. Cardiac-specific deletion of ATPIF1 in mice prevented the metabolic switch and protected against the pathological remodeling during chronic stress. These results uncover a function of ATPIF1 in nonischemic hearts, which gives FoF1-ATP synthase a critical role in metabolic rewiring during the pathological remodeling of the heart.
    Keywords:  Cardiology; Heart failure; Metabolism; Mitochondria; Structural biology
    DOI:  https://doi.org/10.1172/JCI155333
  7. Commun Biol. 2022 May 16. 5(1): 467
    Mitochondrial TrxR2 regulates metabolism and protects from metabolic disease through enhanced TCA and ETC function.
    E Sandra Chocron, Kennedy Mdaki, Nisi Jiang, Jodie Cropper, Andrew M Pickering.
      Mitochondrial dysfunction is a key driver of diabetes and other metabolic diseases. Mitochondrial redox state is highly impactful to metabolic function but the mechanism driving this is unclear. We generated a transgenic mouse which overexpressed the redox enzyme Thioredoxin Reductase 2 (TrxR2), the rate limiting enzyme in the mitochondrial thioredoxin system. We found augmentation of TrxR2 to enhance metabolism in mice under a normal diet and to increase resistance to high-fat diet induced metabolic dysfunction by both increasing glucose tolerance and decreasing fat deposition. We show this to be caused by increased mitochondrial function which is driven at least in part by enhancements to the tricarboxylic acid cycle and electron transport chain function. Our findings demonstrate a role for TrxR2 and mitochondrial thioredoxin as metabolic regulators and show a critical role for redox enzymes in controlling functionality of key mitochondrial metabolic systems.
    DOI:  https://doi.org/10.1038/s42003-022-03405-w
  8. Commun Biol. 2022 May 17. 5(1): 471
    Spatiotemporal stop-and-go dynamics of the mitochondrial TOM core complex correlates with channel activity.
    Shuo Wang, Lukas Findeisen, Sebastian Leptihn, Mark I Wallace, Marcel Hörning, Stephan Nussberger.
      Single-molecule studies can reveal phenomena that remain hidden in ensemble measurements. Here we show the correlation between lateral protein diffusion and channel activity of the general protein import pore of mitochondria (TOM-CC) in membranes resting on ultrathin hydrogel films. Using electrode-free optical recordings of ion flux, we find that TOM-CC switches reversibly between three states of ion permeability associated with protein diffusion. While freely diffusing TOM-CC molecules are predominantly in a high permeability state, non-mobile molecules are mostly in an intermediate or low permeability state. We explain this behavior by the mechanical binding of the two protruding Tom22 subunits to the hydrogel and a concomitant combinatorial opening and closing of the two β-barrel pores of TOM-CC. TOM-CC could thus represent a β-barrel membrane protein complex to exhibit membrane state-dependent mechanosensitive properties, mediated by its two Tom22 subunits.
    DOI:  https://doi.org/10.1038/s42003-022-03419-4
  9. Autophagy. 2022 May 19. 1-2
    SQSTM1 and its MAP1LC3B-binding domain induce forced mitophagy to degrade mitochondrial carryover during mitochondrial replacement therapy.
    Xiao-Yan Fan, Shen Yin, Shi-Ming Luo.
      Mitophagy is a process that selectively degrades mitochondria in cells, and it involves a series of signaling events. Our recent paper shows that the ectopic expression of SQSTM1 and its MAP1LC3B-binding domain (Binding) at the mitochondrial outer membrane, can directly cause mitophagy. To distinguish this mitophagy from others, we called it forced mitophagy. Further results show that the forced mitophagy can degrade half of the mitochondria and their DNA in HeLa cells and mouse embryos. Meanwhile, there are no apparent effects on mitochondrial membrane potential (MMP), reactive oxygen species (ROS), mitosis and embryo development. Thus, the forced mitophagy was examined to selectively degrade mitochondrial carryover in the nuclear donor embryos' mitochondria by pre-labeling with Binding before mitochondrial replacement therapy (MRT). The results show that the forced mitophagy can reduce mitochondrial carryover from an average of 4% to 0.09% compared to the controls in mouse embryos and tissues. In addition, the offspring from MRT mice show negligible effects on growth, reproduction, exercise and behavior. Furthermore, results from human tri-pronuclear embryos show that the forced mitophagy results in undetectable mitochondrial carryover in 77% of embryos following MRT. Therefore, forced mitophagy is efficient and safe for degrading mitochondrial carryover in MRT.
    Keywords:  Forced mitophagy; NIX; SQSTM1; mitochondrial carryover; mitochondrial replacement therapy
    DOI:  https://doi.org/10.1080/15548627.2022.2077552
  10. Nat Struct Mol Biol. 2022 May;29(5): 415
    TALEDs complete the toolkit for editing human mitochondrial DNA.
    Carolina N Perdigoto.
      
    DOI:  https://doi.org/10.1038/s41594-022-00781-z
  11. Science. 2022 May 20. 376(6595): 794-795
    Mitochondrial complex complexification.
    Martijn A Huynen, Dei M Elurbe.
      Variation in complex composition provides clues about the function of individual subunits.
    DOI:  https://doi.org/10.1126/science.abq0368
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