bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2021‒01‒17
thirteen papers selected by
Edmond Chan
Queen’s University, School of Medicine


  1. iScience. 2021 Jan 22. 24(1): 101972
    Yeo AJ, Chong KL, Gatei M, Zou D, Stewart R, Withey S, Wolvetang E, Parton RG, Brown AD, Kastan MB, Coman D, Lavin MF.
      There is evidence that ATM mutated in ataxia-telangiectasia (A-T) plays a key role in protecting against mitochondrial dysfunction, the mechanism for which remains unresolved. We demonstrate here that ATM-deficient cells are exquisitely sensitive to nutrient deprivation, which can be explained by defective cross talk between the endoplasmic reticulum (ER) and the mitochondrion. Tethering between these two organelles in response to stress was reduced in cells lacking ATM, and consistent with this, Ca2+ release and transfer between ER and mitochondria was reduced dramatically when compared with control cells. The impact of this on mitochondrial function was evident from an increase in oxygen consumption rates and a defect in mitophagy in ATM-deficient cells. Our findings reveal that ER-mitochondrial connectivity through IP3R1-GRP75-VDAC1, to maintain Ca2+ homeostasis, as well as an abnormality in mitochondrial fusion defective in response to nutrient stress, can account for at least part of the mitochondrial dysfunction observed in A-T cells.
    Keywords:  Cell Biology; Functional Aspects of Cell Biology; Organizational Aspects of Cell Biology
    DOI:  https://doi.org/10.1016/j.isci.2020.101972
  2. Proc Natl Acad Sci U S A. 2021 Jan 05. pii: e2006476118. [Epub ahead of print]118(1):
    Apicco DJ, Shlevkov E, Nezich CL, Tran DT, Guilmette E, Nicholatos JW, Bantle CM, Chen Y, Glajch KE, Abraham NA, Dang LT, Kaynor GC, Tsai EA, Nguyen KH, Groot J, Liu Y, Weihofen A, Hurt JA, Runz H, Hirst WD.
      Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) is a ubiquitously expressed lipid kinase that inactivates IP3, a secondary messenger that stimulates calcium release from the endoplasmic reticulum (ER). Genome-wide association studies have identified common variants in the ITPKB gene locus associated with reduced risk of sporadic Parkinson's disease (PD). Here, we investigate whether ITPKB activity or expression level impacts PD phenotypes in cellular and animal models. In primary neurons, knockdown or pharmacological inhibition of ITPKB increased levels of phosphorylated, insoluble α-synuclein pathology following treatment with α-synuclein preformed fibrils (PFFs). Conversely, ITPKB overexpression reduced PFF-induced α-synuclein aggregation. We also demonstrate that ITPKB inhibition or knockdown increases intracellular calcium levels in neurons, leading to an accumulation of calcium in mitochondria that increases respiration and inhibits the initiation of autophagy, suggesting that ITPKB regulates α-synuclein pathology by inhibiting ER-to-mitochondria calcium transport. Furthermore, the effects of ITPKB on mitochondrial calcium and respiration were prevented by pretreatment with pharmacological inhibitors of the mitochondrial calcium uniporter complex, which was also sufficient to reduce α-synuclein pathology in PFF-treated neurons. Taken together, these results identify ITPKB as a negative regulator of α-synuclein aggregation and highlight modulation of ER-to-mitochondria calcium flux as a therapeutic strategy for the treatment of sporadic PD.
    Keywords:  Parkinson’s disease; calcium signaling; genetics; mitochondria; α-synuclein
    DOI:  https://doi.org/10.1073/pnas.2006476118
  3. Cell Rep. 2021 Jan 12. pii: S2211-1247(20)31613-2. [Epub ahead of print]34(2): 108624
    Schlein C, Fischer AW, Sass F, Worthmann A, Tödter K, Jaeckstein MY, Behrens J, Lynes MD, Kiebish MA, Narain NR, Bussberg V, Darkwah A, Jespersen NZ, Nielsen S, Scheele C, Schweizer M, Braren I, Bartelt A, Tseng YH, Heeren J, Scheja L.
      Thermoneutral conditions typical for standard human living environments result in brown adipose tissue (BAT) involution, characterized by decreased mitochondrial mass and increased lipid deposition. Low BAT activity is associated with poor metabolic health, and BAT reactivation may confer therapeutic potential. However, the molecular drivers of this BAT adaptive process in response to thermoneutrality remain enigmatic. Using metabolic and lipidomic approaches, we show that endogenous fatty acid synthesis, regulated by carbohydrate-response element-binding protein (ChREBP), is the central regulator of BAT involution. By transcriptional control of lipogenesis-related enzymes, ChREBP determines the abundance and composition of both storage and membrane lipids known to regulate organelle turnover and function. Notably, ChREBP deficiency and pharmacological inhibition of lipogenesis during thermoneutral adaptation preserved mitochondrial mass and thermogenic capacity of BAT independently of mitochondrial biogenesis. In conclusion, we establish lipogenesis as a potential therapeutic target to prevent loss of BAT thermogenic capacity as seen in adult humans.
    Keywords:  ChREBP; brown adipose tissue; cardiolipins; de novo lipogenesis; energy expenditure; fatty acid synthesis; fatty acids; lipidome; mitochondria; mitophagy; non-shivering thermogenesis; phospholipids; thermoneutrality; triacylglycerols; whitening
    DOI:  https://doi.org/10.1016/j.celrep.2020.108624
  4. Nat Commun. 2021 01 11. 12(1): 265
    Shin CS, Meng S, Garbis SD, Moradian A, Taylor RW, Sweredoski MJ, Lomenick B, Chan DC.
      Most mitochondrial precursor polypeptides are imported from the cytosol into the mitochondrion, where they must efficiently undergo folding. Mitochondrial precursors are imported as unfolded polypeptides. For proteins of the mitochondrial matrix and inner membrane, two separate chaperone systems, HSP60 and mitochondrial HSP70 (mtHSP70), facilitate protein folding. We show that LONP1, an AAA+ protease of the mitochondrial matrix, works with the mtHSP70 chaperone system to promote mitochondrial protein folding. Inhibition of LONP1 results in aggregation of a protein subset similar to that caused by knockdown of DNAJA3, a co-chaperone of mtHSP70. LONP1 is required for DNAJA3 and mtHSP70 solubility, and its ATPase, but not its protease activity, is required for this function. In vitro, LONP1 shows an intrinsic chaperone-like activity and collaborates with mtHSP70 to stabilize a folding intermediate of OXA1L. Our results identify LONP1 as a critical factor in the mtHSP70 folding pathway and demonstrate its proposed chaperone activity.
    DOI:  https://doi.org/10.1038/s41467-020-20597-z
  5. Mol Cell Proteomics. 2020 Jan;pii: S1535-9476(20)30006-2. [Epub ahead of print]19(1): 65-77
    Dibley MG, Formosa LE, Lyu B, Reljic B, McGann D, Muellner-Wong L, Kraus F, Sharpe AJ, Stroud DA, Ryan MT.
      NDUFAB1 is the mitochondrial acyl carrier protein (ACP) essential for cell viability. Through its pantetheine-4'-phosphate post-translational modification, NDUFAB1 interacts with members of the leucine-tyrosine-arginine motif (LYRM) protein family. Although several LYRM proteins have been described to participate in a variety of defined processes, the functions of others remain either partially or entirely unknown. We profiled the interaction network of NDUFAB1 to reveal associations with 9 known LYRM proteins as well as more than 20 other proteins involved in mitochondrial respiratory chain complex and mitochondrial ribosome assembly. Subsequent knockout and interaction network studies in human cells revealed the LYRM member AltMiD51 to be important for optimal assembly of the large mitoribosome subunit, consistent with recent structural studies. In addition, we used proteomics coupled with topographical heat-mapping to reveal that knockout of LYRM2 impairs assembly of the NADH-dehydrogenase module of complex I, leading to defects in cellular respiration. Together, this work adds to the catalogue of functions executed by LYRM family of proteins in building mitochondrial complexes and emphasizes the common and essential role of NDUFAB1 as a protagonist in mitochondrial metabolism.
    Keywords:  Mitochondria function or biology; acyl-carrier protein; affinity proteomics; blue native polyacrylamide gel electrophoresis; complex I; protein complex analysis; protein structure; protein-protein interactions
    DOI:  https://doi.org/10.1074/mcp.RA119.001784
  6. Elife. 2021 Jan 13. pii: e63102. [Epub ahead of print]10
    Sercel AJ, Patananan AN, Man T, Wu TH, Yu AK, Guyot GW, Rabizadeh S, Niazi KR, Chiou PY, Teitell MA.
      Generating mammalian cells with specific mtDNA-nDNA combinations is desirable but difficult to achieve and would be enabling for studies of mitochondrial-nuclear communication and coordination in controlling cell fates and functions. We developed 'MitoPunch', a pressure-driven mitochondrial transfer device, to deliver isolated mitochondria into numerous target mammalian cells simultaneously. MitoPunch and MitoCeption, a previously described force-based mitochondrial transfer approach, both yield stable isolated mitochondrial recipient (SIMR) cells that permanently retain exogenous mtDNA, whereas coincubation of mitochondria with cells does not yield SIMR cells. Although a typical MitoPunch or MitoCeption delivery results in dozens of immortalized SIMR clones with restored oxidative phosphorylation, only MitoPunch can produce replication-limited, non-immortal human SIMR clones. The MitoPunch device is versatile, inexpensive to assemble, and easy to use for engineering mtDNA-nDNA combinations to enable fundamental studies and potential translational applications.
    Keywords:  cell biology; human
    DOI:  https://doi.org/10.7554/eLife.63102
  7. Biosens Bioelectron. 2021 Jan 01. pii: S0956-5663(20)30871-X. [Epub ahead of print]176 112886
    Liu W, Qiao Q, Zheng J, Chen J, Zhou W, Xu N, Li J, Miao L, Xu Z.
      Super-resolution fluorescence microscopy has emerged as a powerful tool for studying mitochondrial dynamics in living cells. However, the lack of photostable and chemstable probe makes long-term super-resolution imaging of mitochondria still a challenging work. Herein, we reported a 4-azetidinyl-naphthliamide derived SNAP-tag probe AN-BG exhibiting excellent fluorogenicity and photostability for long-term super-resolution imaging of mitochondrial dynamics. The azetidinyl group and naphthalimide fluorophore are in a flat conformation which can effectively suppress twisted intramolecular charge transfer and then effectively improve the brightness and photostability. This planarized molecular structure is conducive to the formation of fluorescence-quenched J-aggregates, and the protein labeling process will depolymerize the probes and restore fluorescence. Fluorescent labeling mitochondrial inner membrane proteins via SNAP tags overcomes the shortcomings that variations in mitochondrial inner membrane potential will release probes attached to mitochondria by electrostatic interactions. Therefore, AN-BG realized the stable labeling of mitochondria and the long-term imaging of mitochondrial dynamics under super-resolution microscopy.
    Keywords:  Fluorogenic; Mitochondrial dynamic; SNAP-tag; Super-resolution imaging
    DOI:  https://doi.org/10.1016/j.bios.2020.112886
  8. Trends Cell Biol. 2021 Jan 11. pii: S0962-8924(20)30251-8. [Epub ahead of print]
    Tábara LC, Morris JL, Prudent J.
      Mitochondria are dynamic organelles that undergo cycles of fission and fusion events depending on cellular requirements. During mitochondrial division, the GTPase dynamin-related protein-1 is recruited to endoplasmic reticulum (ER)-induced mitochondrial constriction sites where it drives fission. However, the events required to complete scission of mitochondrial membranes are not well understood. Here, we emphasize the recently described roles for Golgi-derived phosphatidylinositol 4-phosphate (PI4P)-containing vesicles in the last steps of mitochondrial division. We then propose how trans-Golgi network vesicles at mitochondria-ER contact sites and PI4P generation could mechanistically execute mitochondrial division, by recruiting PI4P effectors and/or the actin nucleation machinery. Finally, we speculate on mechanisms to explain why such a complex dance of different organelles is required to facilitate the remodelling of mitochondrial membranes.
    Keywords:  Drp1; PI4P; TGN vesicles; membrane contact sites; mitochondrial division
    DOI:  https://doi.org/10.1016/j.tcb.2020.12.005
  9. Free Radic Biol Med. 2021 Jan 12. pii: S0891-5849(21)00001-0. [Epub ahead of print]
    Wu D, Dasgupta A, Read AD, Bentley RET, Motamed M, Chen KH, Al-Qazazi R, Mewburn JD, Dunham-Snary KJ, Alizadeh E, Tian L, Archer SL.
      The homeostatic oxygen sensing system (HOSS) optimizes systemic oxygen delivery. Specialized tissues utilize a conserved mitochondrial sensor, often involving NDUFS2 in complex I of the mitochondrial electron transport chain, as a site of pO2-responsive production of reactive oxygen species (ROS). These ROS are converted to a diffusible signaling molecule, hydrogen peroxide (H2O2), by superoxide dismutase (SOD2). H2O2 exits the mitochondria and regulates ion channels and enzymes, altering plasma membrane potential, intracellular Ca2+ and Ca2+-sensitization and controlling acute, adaptive, responses to hypoxia that involve changes in ventilation, vascular tone and neurotransmitter release. Subversion of this O2-sensing pathway creates a pseudohypoxic state that promotes disease progression in pulmonary arterial hypertension (PAH) and cancer. Pseudohypoxia is a state in which biochemical changes, normally associated with hypoxia, occur despite normal pO2. Epigenetic silencing of SOD2 by DNA methylation alters H2O2 production, activating hypoxia-inducible factor 1α, thereby disrupting mitochondrial metabolism and dynamics, accelerating cell proliferation and inhibiting apoptosis. Other epigenetic mechanisms, including dysregulation of microRNAs (miR), increase pyruvate dehydrogenase kinase and pyruvate kinase muscle isoform 2 expression in both diseases, favoring uncoupled aerobic glycolysis. This Warburg metabolic shift also accelerates cell proliferation and impairs apoptosis. Disordered mitochondrial dynamics, usually increased mitotic fission and impaired fusion, promotes disease progression in PAH and cancer. Epigenetic upregulation of dynamin-related protein 1 (Drp1) and its binding partners, MiD49 and MiD51, contributes to the pathogenesis of PAH and cancer. Finally, dysregulation of intramitochondrial Ca2+, resulting from impaired mitochondrial calcium uniporter complex (MCUC) function, links abnormal mitochondrial metabolism and dynamics. MiR-mediated decreases in MCUC function reduce intramitochondrial Ca2+, promoting Warburg metabolism, whilst increasing cytosolic Ca2+, promoting fission. Epigenetically disordered mitochondrial O2-sensing, metabolism, dynamics, and Ca2+ homeostasis offer new therapeutic targets for PAH and cancer. Promoting glucose oxidation, restoring the fission/fusion balance, and restoring mitochondrial calcium regulation are promising experimental therapeutic strategies.
    Keywords:  ABT-199 (Venetoclax); ABT-263 (Navitoclax); B-cell lymphoma 2 (BCL-2); DNA methylation; DNA methyltransferase (DNMT); Sugen5416; dynamin-related protein 1 (Drp1); group 1 pulmonary hypertension; hypoxia-inducible factor 1α (HIF-1α); hypoxia-inducible factor 2α (HIF-2α); hypoxic pulmonary vasoconstriction; mammalian target of rapamycin (mTOR); miR-138; miR-25; microRNA (miRNA); mitochondrial calcium uniporter (MCU); mitochondrial dynamics protein of 49 kDa (MiD49); mitochondrial dynamics protein of 51 kDa (MiD51); mitofusin 2 (Mfn2); mitophagy; monocrotaline; oxygen sensing; peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α); pyruvate dehydrogenase (PDH); pyruvate dehydrogenase kinase (PDK); pyruvate kinase muscle isoform 2 (PKM2); reactive oxygen species (ROS); survivin; von Hippel-Lindau protein (VHL)
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2020.12.452
  10. EMBO J. 2021 Jan 13. e104705
    Onishi M, Yamano K, Sato M, Matsuda N, Okamoto K.
      Degradation of mitochondria via a selective form of autophagy, named mitophagy, is a fundamental mechanism conserved from yeast to humans that regulates mitochondrial quality and quantity control. Mitophagy is promoted via specific mitochondrial outer membrane receptors, or ubiquitin molecules conjugated to proteins on the mitochondrial surface leading to the formation of autophagosomes surrounding mitochondria. Mitophagy-mediated elimination of mitochondria plays an important role in many processes including early embryonic development, cell differentiation, inflammation, and apoptosis. Recent advances in analyzing mitophagy in vivo also reveal high rates of steady-state mitochondrial turnover in diverse cell types, highlighting the intracellular housekeeping role of mitophagy. Defects in mitophagy are associated with various pathological conditions such as neurodegeneration, heart failure, cancer, and aging, further underscoring the biological relevance. Here, we review our current molecular understanding of mitophagy, and its physiological implications, and discuss how multiple mitophagy pathways coordinately modulate mitochondrial fitness and populations.
    Keywords:  autophagy; mitochondria; phosphorylation; quality and quantity control; ubiquitin
    DOI:  https://doi.org/10.15252/embj.2020104705
  11. Trends Cell Biol. 2021 Jan 06. pii: S0962-8924(20)30255-5. [Epub ahead of print]
    Sercel AJ, Carlson NM, Patananan AN, Teitell MA.
      Mammalian cells, with the exception of erythrocytes, harbor mitochondria, which are organelles that provide energy, intermediate metabolites, and additional activities to sustain cell viability, replication, and function. Mitochondria contain multiple copies of a circular genome called mitochondrial DNA (mtDNA), whose individual sequences are rarely identical (homoplasmy) because of inherited or sporadic mutations that result in multiple mtDNA genotypes (heteroplasmy). Here, we examine potential mechanisms for maintenance or shifts in heteroplasmy that occur in induced pluripotent stem cells (iPSCs) generated by cellular reprogramming, and further discuss manipulations that can alter heteroplasmy to impact stem and differentiated cell performance. This additional insight will assist in developing more robust iPSC-based models of disease and differentiated cell therapies.
    Keywords:  heteroplasmy; induced pluripotent stem cell; mitochondrial DNA; pluripotency; reprogramming
    DOI:  https://doi.org/10.1016/j.tcb.2020.12.009
  12. Annu Rev Biochem. 2021 Jan 13.
    Wen Y, Vogt VM, Feigenson GW.
      Located at the inner leaflet of the plasma membrane, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] comprises only 1-2 mol% of total PM lipids. With its synthesis and turnover both spatially and temporally regulated, PI(4,5)P2 recruits and interacts with hundreds of cellular proteins to support a broad spectrum of cellular functions. Several factors contribute to the versatile and dynamic distribution of PI(4,5)P2 in membranes. Physiological multivalent cations such as Ca2+ and Mg2+ can bridge between PI(4,5)P2 headgroups, forming nanoscopic PI(4,5)P2-cation clusters. The distinct lipid environment surrounding PI(4,5)P2 affects the degree of PI(4,5)P2 clustering. In addition, diverse cellular proteins interacting with PI(4,5)P2 can further regulate PI(4,5)P2 lateral distribution and accessibility. This review summarizes the current understanding of PI(4,5)P2 behavior in both cells and model membranes, with emphasis on both multivalent cation- and protein-induced PI(4,5)P2 clustering. Understanding the nature of spatially separated pools of PI(4,5)P2 is fundamental to cell biology. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-biochem-070920-094827
  13. Metabolism. 2021 Jan 11. pii: S0026-0495(21)00008-1. [Epub ahead of print] 154708
    Longo M, Meroni M, Paolini E, Macchi C, Dongiovanni P.
      Nonalcoholic fatty liver disease (NAFLD) includes a broad spectrum of liver dysfunctions and it is predicted to become the primary cause of liver failure and hepatocellular carcinoma. Mitochondria are highly dynamic organelles involved in multiple metabolic/bioenergetic pathways in the liver. Emerging evidence outlined that hepatic mitochondria adapt in number and functionality in response to external cues, as high caloric intake and obesity, by modulating mitochondrial biogenesis, and maladaptive mitochondrial response has been described from the early stages of NAFLD. Indeed, mitochondrial plasticity is lost in progressive NAFLD and these organelles may assume an aberrant phenotype to drive or contribute to hepatocarcinogenesis. Severe alimentary regimen and physical exercise represent the cornerstone for NAFLD care, although the low patients' compliance is urging towards the discovery of novel pharmacological treatments. Mitochondrial-targeted drugs aimed to recover mitochondrial lifecycle and to modulate oxidative stress are becoming attractive molecules to be potentially introduced for NAFLD management. Although the path guiding the switch from bench to bedside remains tortuous, the study of mitochondrial dynamics is providing intriguing perspectives for future NAFLD healthcare.
    Keywords:  Genetics; HCC; Mitochondrial dysfunction; Mitochondrial-based strategy; NAFLD
    DOI:  https://doi.org/10.1016/j.metabol.2021.154708