bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2020‒08‒16
twenty-four papers selected by
Edmond Chan
Queen’s University, School of Medicine

  1. Nature. 2020 Aug 12.
    Muthusamy T, Cordes T, Handzlik MK, You L, Lim EW, Gengatharan J, Pinto AFM, Badur MG, Kolar MJ, Wallace M, Saghatelian A, Metallo CM.
      Serine, glycine and other nonessential amino acids are critical for tumour progression, and strategies to limit their availability are emerging as potential therapies for cancer1-3. However, the molecular mechanisms driving this response remain unclear and the effects on lipid metabolism are relatively unexplored. Serine palmitoyltransferase (SPT) catalyses the de novo biosynthesis of sphingolipids but also produces noncanonical 1-deoxysphingolipids when using alanine as a substrate4,5. Deoxysphingolipids accumulate in the context of mutations in SPTLC1 or SPTLC26,7-or in conditions of low serine availability8,9-to drive neuropathy, and deoxysphinganine has previously been investigated as an anti-cancer agent10. Here we exploit amino acid metabolism and the promiscuity of SPT to modulate the endogenous synthesis of toxic deoxysphingolipids and slow tumour progression. Anchorage-independent growth reprogrammes a metabolic network involving serine, alanine and pyruvate that drives the endogenous synthesis and accumulation of deoxysphingolipids. Targeting the mitochondrial pyruvate carrier promotes alanine oxidation to mitigate deoxysphingolipid synthesis and improve spheroid growth, similar to phenotypes observed with the direct inhibition of SPT or ceramide synthesis. Restriction of dietary serine and glycine potently induces the accumulation of deoxysphingolipids while decreasing tumour growth in xenograft models in mice. Pharmacological inhibition of SPT rescues xenograft growth in mice fed diets restricted in serine and glycine, and the reduction of circulating serine by inhibition of phosphoglycerate dehydrogenase (PHGDH) leads to the accumulation of deoxysphingolipids and mitigates tumour growth. The promiscuity of SPT therefore links serine and mitochondrial alanine metabolism to membrane lipid diversity, which further sensitizes tumours to metabolic stress.
  2. Science. 2020 Aug 14. 369(6505): 858-862
    Iwata R, Casimir P, Vanderhaeghen P.
      The conversion of neural stem cells into neurons is associated with the remodeling of organelles, but whether and how this is causally linked to fate change is poorly understood. We examined and manipulated mitochondrial dynamics during mouse and human cortical neurogenesis. We reveal that shortly after cortical stem cells have divided, daughter cells destined to self-renew undergo mitochondrial fusion, whereas those that retain high levels of mitochondria fission become neurons. Increased mitochondria fission promotes neuronal fate, whereas induction of mitochondria fusion after mitosis redirects daughter cells toward self-renewal. This occurs during a restricted time window that is doubled in human cells, in line with their increased self-renewal capacity. Our data reveal a postmitotic period of fate plasticity in which mitochondrial dynamics are linked with cell fate.
  3. Nat Chem Biol. 2020 Aug 10.
    Bazhin AA, Sinisi R, De Marchi U, Hermant A, Sambiagio N, Maric T, Budin G, Goun EA.
      Mitochondrial membrane potential (ΔΨm) is a universal selective indicator of mitochondrial function and is known to play a central role in many human pathologies, such as diabetes mellitus, cancer and Alzheimer's and Parkinson's diseases. Here, we report the design, synthesis and several applications of mitochondria-activatable luciferin (MAL), a bioluminescent probe sensitive to ΔΨm, and partially to plasma membrane potential (ΔΨp), for non-invasive, longitudinal monitoring of ΔΨm in vitro and in vivo. We applied this new technology to evaluate the aging-related change of ΔΨm in mice and showed that nicotinamide riboside (NR) reverts aging-related mitochondrial depolarization, revealing another important aspect of the mechanism of action of this potent biomolecule. In addition, we demonstrated application of the MAL probe for studies of brown adipose tissue (BAT) activation and non-invasive in vivo assessment of ΔΨm in animal cancer models, opening exciting opportunities for understanding the underlying mechanisms and for discovery of effective treatments for many human pathologies.
  4. Nat Immunol. 2020 Aug 10.
    Zhou H, Wang H, Yu M, Schugar RC, Qian W, Tang F, Liu W, Yang H, McDowell RE, Zhao J, Gao J, Dongre A, Carman JA, Yin M, Drazba JA, Dent R, Hine C, Chen YR, Smith JD, Fox PL, Brown JM, Li X.
      Chronic inflammation is a common feature of obesity, with elevated cytokines such as interleukin-1 (IL-1) in the circulation and tissues. Here, we report an unconventional IL-1R-MyD88-IRAK2-PHB/OPA1 signaling axis that reprograms mitochondrial metabolism in adipocytes to exacerbate obesity. IL-1 induced recruitment of IRAK2 Myddosome to mitochondria outer membranes via recognition by TOM20, followed by TIMM50-guided translocation of IRAK2 into mitochondria inner membranes, to suppress oxidative phosphorylation and fatty acid oxidation, thereby attenuating energy expenditure. Adipocyte-specific MyD88 or IRAK2 deficiency reduced high-fat-diet-induced weight gain, increased energy expenditure and ameliorated insulin resistance, associated with a smaller adipocyte size and increased cristae formation. IRAK2 kinase inactivation also reduced high-fat diet-induced metabolic diseases. Mechanistically, IRAK2 suppressed respiratory super-complex formation via interaction with PHB1 and OPA1 upon stimulation of IL-1. Taken together, our results suggest that the IRAK2 Myddosome functions as a critical link between inflammation and metabolism, representing a novel therapeutic target for patients with obesity.
  5. J Cell Sci. 2020 Aug 11. pii: jcs.248880. [Epub ahead of print]
    Zhou W, Hsu AY, Wang Y, Syahirah R, Wang T, Jeffries J, Wang X, Mohammad H, Seleem MN, Umulis D, Deng Q.
      Neutrophils rely on glycolysis for energy production. How mitochondria regulate neutrophil function is not fully understood. Here, we report that mitochondrial outer membrane protein Mitofusin 2 (Mfn2) regulates neutrophil homeostasis and chemotaxis in vivo. Mfn2-deficient neutrophils are released from the hematopoietic tissue, trapped in the vasculature in zebrafish embryos, and not capable of chemotaxis. Consistently, human neutrophil-like cells deficient with MFN2 fail to arrest on activated endothelium under sheer stress or perform chemotaxis on 2D surfaces. Deletion of Mfn2 results in a significant reduction of neutrophil infiltration to the inflamed peritoneal cavity in mice. Mechanistically, MFN2-deficient neutrophil-like cells display disrupted mitochondria-ER interaction, heightened intracellular calcium levels, and elevated Rac activation after chemokine stimulation. Restoring mitochondria-ER tether rescues the abnormal calcium levels, Rac hyperactivation, and chemotaxis defect resulted from MFN2 depletion. Finally, inhibition of Rac activation restores chemotaxis in MFN2-deficient neutrophils. Altogether, we identified that MFN2 regulates neutrophil migration via maintaining mitochondria-ER interaction to suppress Rac activation and uncovered a previously unrecognized role of MFN2 in regulating cell migration and the actin cytoskeleton.
    Keywords:  Actin; Chemotaxis; Leukocyte; Mitochondria; Rac; Zebrafish
  6. Nat Commun. 2020 Aug 13. 11(1): 4056
    Bosc C, Broin N, Fanjul M, Saland E, Farge T, Courdy C, Batut A, Masoud R, Larrue C, Skuli S, Espagnolle N, Pagès JC, Carrier A, Bost F, Bertrand-Michel J, Tamburini J, Récher C, Bertoli S, Mansat-De Mas V, Manenti S, Sarry JE, Joffre C.
      Autophagy has been associated with oncogenesis with one of its emerging key functions being its contribution to the metabolism of tumors. Therefore, deciphering the mechanisms of how autophagy supports tumor cell metabolism is essential. Here, we demonstrate that the inhibition of autophagy induces an accumulation of lipid droplets (LD) due to a decrease in fatty acid β-oxidation, that leads to a reduction of oxidative phosphorylation (OxPHOS) in acute myeloid leukemia (AML), but not in normal cells. Thus, the autophagic process participates in lipid catabolism that supports OxPHOS in AML cells. Interestingly, the inhibition of OxPHOS leads to LD accumulation with the concomitant inhibition of autophagy. Mechanistically, we show that the disruption of mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) phenocopies OxPHOS inhibition. Altogether, our data establish that mitochondria, through the regulation of MERCs, controls autophagy that, in turn finely tunes lipid degradation to fuel OxPHOS supporting proliferation and growth in leukemia.
  7. Nat Commun. 2020 Aug 12. 11(1): 4029
    Zaninello M, Palikaras K, Naon D, Iwata K, Herkenne S, Quintana-Cabrera R, Semenzato M, Grespi F, Ross-Cisneros FN, Carelli V, Sadun AA, Tavernarakis N, Scorrano L.
      In autosomal dominant optic atrophy (ADOA), caused by mutations in the mitochondrial cristae biogenesis and fusion protein optic atrophy 1 (Opa1), retinal ganglion cell (RGC) dysfunction and visual loss occur by unknown mechanisms. Here, we show a role for autophagy in ADOA pathogenesis. In RGCs expressing mutated Opa1, active 5' AMP-activated protein kinase (AMPK) and its autophagy effector ULK1 accumulate at axonal hillocks. This AMPK activation triggers localized hillock autophagosome accumulation and mitophagy, ultimately resulting in reduced axonal mitochondrial content that is restored by genetic inhibition of AMPK and autophagy. In C. elegans, deletion of AMPK or of key autophagy and mitophagy genes normalizes the axonal mitochondrial content that is reduced upon mitochondrial dysfunction. In conditional, RGC specific Opa1-deficient mice, depletion of the essential autophagy gene Atg7 normalizes the excess autophagy and corrects the visual defects caused by Opa1 ablation. Thus, our data identify AMPK and autophagy as targetable components of ADOA pathogenesis.
  8. Dev Cell. 2020 Aug 04. pii: S1534-5807(20)30588-8. [Epub ahead of print]
    Bertolini I, Ghosh JC, Kossenkov AV, Mulugu S, Krishn SR, Vaira V, Qin J, Plow EF, Languino LR, Altieri DC.
      The crosstalk between tumor cells and the adjacent normal epithelium contributes to cancer progression, but its regulators have remained elusive. Here, we show that breast cancer cells maintained in hypoxia release small extracellular vesicles (sEVs) that activate mitochondrial dynamics, stimulate mitochondrial movements, and promote organelle accumulation at the cortical cytoskeleton in normal mammary epithelial cells. This results in AKT serine/threonine kinase (Akt) activation, membrane focal adhesion turnover, and increased epithelial cell migration. RNA sequencing profiling identified integrin-linked kinase (ILK) as the most upregulated pathway in sEV-treated epithelial cells, and genetic or pharmacologic targeting of ILK reversed mitochondrial reprogramming and suppressed sEV-induced cell movements. In a three-dimensional (3D) model of mammary gland morphogenesis, sEV treatment induced hallmarks of malignant transformation, with deregulated cell death and/or cell proliferation, loss of apical-basal polarity, and appearance of epithelial-to-mesenchymal transition (EMT) markers. Therefore, sEVs released by hypoxic breast cancer cells reprogram mitochondrial dynamics and induce oncogenic changes in a normal mammary epithelium.
    Keywords:  breast cancer; extracellular vesicles; hypoxia; mitochondria; morphogenesis; normal mammary epithelium; transformation
  9. EMBO Rep. 2020 Aug 11. e48260
    Xu R, Jones W, Wilcz-Villega E, Costa AS, Rajeeve V, Bentham RB, Bryson K, Nagano A, Yaman B, Olendo Barasa S, Wang Y, Chelala C, Cutillas P, Szabadkai G, Frezza C, Bianchi K.
      IκB kinase ε (IKKε) is a key molecule at the crossroads of inflammation and cancer. Known to regulate cytokine secretion via NFκB and IRF3, the kinase is also a breast cancer oncogene, overexpressed in a variety of tumours. However, to what extent IKKε remodels cellular metabolism is currently unknown. Here, we used metabolic tracer analysis to show that IKKε orchestrates a complex metabolic reprogramming that affects mitochondrial metabolism and consequently serine biosynthesis independently of its canonical signalling role. We found that IKKε upregulates the serine biosynthesis pathway (SBP) indirectly, by limiting glucose-derived pyruvate utilisation in the TCA cycle, inhibiting oxidative phosphorylation. Inhibition of mitochondrial function induces activating transcription factor 4 (ATF4), which in turn drives upregulation of the expression of SBP genes. Importantly, pharmacological reversal of the IKKε-induced metabolic phenotype reduces proliferation of breast cancer cells. Finally, we show that in a highly proliferative set of ER negative, basal breast tumours, IKKε and PSAT1 are both overexpressed, corroborating the link between IKKε and the SBP in the clinical context.
    Keywords:  ATF4; IKKε; breast cancer; mitochondrial metabolism; serine biosynthesis
  10. Nat Commun. 2020 Aug 12. 11(1): 4031
    Pittis AA, Goh V, Cebrian-Serrano A, Wettmarshausen J, Perocchi F, Gabaldón T.
      Calcium (Ca2+) influx into mitochondria occurs through a Ca2+-selective uniporter channel, which regulates essential cellular processes in eukaryotic organisms. Previous evolutionary analyses of its pore-forming subunits MCU and EMRE, and gatekeeper MICU1, pinpointed an evolutionary paradox: the presence of MCU homologs in fungal species devoid of any other uniporter components and of mt-Ca2+ uptake. Here, we trace the mt-Ca2+ uniporter evolution across 1,156 fully-sequenced eukaryotes and show that animal and fungal MCUs represent two distinct paralogous subfamilies originating from an ancestral duplication. Accordingly, we find EMRE orthologs outside Holoza and uncover the existence of an animal-like uniporter within chytrid fungi, which enables mt-Ca2+ uptake when reconstituted in vivo in the yeast Saccharomyces cerevisiae. Our study represents the most comprehensive phylogenomic analysis of the mt-Ca2+ uptake system and demonstrates that MCU, EMRE, and MICU formed the core of the ancestral opisthokont uniporter, with major implications for comparative structural and functional studies.
  11. Elife. 2020 Aug 14. pii: e52558. [Epub ahead of print]9
    Panic V, Pearson S, Banks J, Tippetts TS, Velasco-Silva JN, Lee S, Simcox J, Geoghegan G, Bensard CL, van Ry T, Holland WL, Summers SA, Cox J, Ducker GS, Rutter J, Villanueva CJ.
      Brown adipose tissue (BAT) is composed of thermogenic cells that convert chemical energy into heat to help maintain a constant body temperature and counteract metabolic disease in mammals. The metabolic adaptations required for thermogenesis are not fully understood. Here we explore how steady state levels of metabolic intermediates are altered in brown adipose tissue in response to cold exposure. Transcriptome and metabolome analysis revealed changes in pathways involved in amino acid, glucose, and TCA cycle metabolism. Using isotopic labeling experiments, we found that activated brown adipocytes increased labeling of pyruvate and TCA cycle intermediates from U13C-glucose. Although glucose oxidation has been implicated as being essential for thermogenesis, its requirement for efficient thermogenesis has not been directly tested. Here we show that mitochondrial pyruvate uptake is essential for optimal thermogenesis, as conditional deletion of Mpc1 in brown adipocytes leads to impaired cold adaptation. Isotopic labeling experiments using U13C-glucose showed that loss of MPC1 led to impaired labeling of TCA cycle intermediates, while labeling of glycolytic intermediates was unchanged. Loss of MPC1 in BAT increased 3-hydroxybutyrate levels in blood and BAT in response to the cold, suggesting that ketogenesis provides an alternative fuel source to compensate for impaired mitochondrial oxidation of cytosolic pyruvate. Collectively, these studies highlight that complete glucose oxidation is essential for optimal brown fat thermogenesis.
    Keywords:  biochemistry; chemical biology; mouse
  12. iScience. 2020 Jul 24. pii: S2589-0042(20)30600-3. [Epub ahead of print]23(8): 101410
    Shimizu T, Taguchi A, Higashijima Y, Takubo N, Kanki Y, Urade Y, Wada Y.
      Oxidative/nitrosative stress is a major trigger of cardiac dysfunction, involving the unfolded protein response and mitochondrial dysfunction. Activation of nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling by sildenafil improves cardiac mal-remodeling during pressure-overload-induced heart failure. Transcriptome analysis was conducted in failing hearts with or without sildenafil treatment. Protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) downstream signaling pathways, EIF2 and NRF2, were significantly altered. Although EIF2 signaling was suppressed, NRF2 signaling was upregulated, inhibiting the maturation of miR 24-3p through EGFR-mediated Ago2 phosphorylation. To study the effect of sildenafil on these pathways, we generated cardiac-specific PERK knockout mice. In these mice, sildenafil could not inhibit the maturations, the nuclear translocation of NRF2 was suppressed, and mitochondrial dysfunction advanced. Altogether, these results show that PERK-mediated suppression of miRNAs by sildenafil is vital for maintaining mitochondrial homeostasis through NRF2-mediated oxidative stress response.
    Keywords:  Biological Sciences; Cell Biology; Molecular Biology
  13. Cell. 2020 Aug 04. pii: S0092-8674(20)30873-4. [Epub ahead of print]
    Licznerski P, Park HA, Rolyan H, Chen R, Mnatsakanyan N, Miranda P, Graham M, Wu J, Cruz-Reyes N, Mehta N, Sohail S, Salcedo J, Song E, Effman C, Effman S, Brandao L, Xu GN, Braker A, Gribkoff VK, Levy RJ, Jonas EA.
      Loss of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) causes increased mRNA translation and aberrant synaptic development. We find neurons of the Fmr1-/y mouse have a mitochondrial inner membrane leak contributing to a "leak metabolism." In human Fragile X syndrome (FXS) fibroblasts and in Fmr1-/y mouse neurons, closure of the ATP synthase leak channel by mild depletion of its c-subunit or pharmacological inhibition normalizes stimulus-induced and constitutive mRNA translation rate, decreases lactate and key glycolytic and tricarboxylic acid (TCA) cycle enzyme levels, and triggers synapse maturation. FMRP regulates leak closure in wild-type (WT), but not FX synapses, by stimulus-dependent ATP synthase β subunit translation; this increases the ratio of ATP synthase enzyme to its c-subunit, enhancing ATP production efficiency and synaptic growth. In contrast, in FXS, inability to close developmental c-subunit leak prevents stimulus-dependent synaptic maturation. Therefore, ATP synthase c-subunit leak closure encourages development and attenuates autistic behaviors.
    Keywords:  Fragile X syndrome; autism; autism syndrome; glycolysis; mitochondria; oxidative phosphorylation; permeability transition pore; protein synthesis; repetitive mouse behavior; synaptic development; synaptic plasticity
  14. EMBO J. 2020 Aug 13. e104285
    Wu W, Shen Q, Zhang R, Qiu Z, Wang Y, Zheng J, Jia Z.
      The MICU1-MICU2 heterodimer regulates the mitochondrial calcium uniporter (MCU) and mitochondrial calcium uptake. Herein, we present two crystal structures of the MICU1-MICU2 heterodimer, in which Ca2+ -free and Ca2+ -bound EF-hands are observed in both proteins, revealing both electrostatic and hydrophobic interfaces. Furthermore, we show that MICU1 interacts with EMRE, another regulator of MCU, through a Ca2+ -dependent alkaline groove. Ca2+ binding strengthens the MICU1-EMRE interaction, which in turn facilitates Ca2+ uptake. Conversely, the MICU1-MCU interaction is favored in the absence of Ca2+ , thus inhibiting the channel activity. This Ca2+ -dependent switch illuminates how calcium signals are transmitted from regulatory subunits to the calcium channel and the transition between gatekeeping and activation channel functions. Furthermore, competition with an EMRE peptide alters the uniporter threshold in resting conditions and elevates Ca2+ accumulation in stimulated mitochondria, confirming the gatekeeper role of the MICU1-MICU2 heterodimer. Taken together, these structural and functional data provide new insights into the regulation of mitochondrial calcium uptake.
    Keywords:   EMRE ; MICU1-MICU2; mitochondria; uniporter
  15. Proc Natl Acad Sci U S A. 2020 Aug 11. pii: 202009364. [Epub ahead of print]
    Pape JK, Stephan T, Balzarotti F, Büchner R, Lange F, Riedel D, Jakobs S, Hell SW.
      The mitochondrial contact site and cristae organizing system (MICOS) is a multisubunit protein complex that is essential for the proper architecture of the mitochondrial inner membrane. MICOS plays a key role in establishing and maintaining crista junctions, tubular or slit-like structures that connect the cristae membrane with the inner boundary membrane, thereby ensuring a contiguous inner membrane. MICOS is enriched at crista junctions, but the detailed distribution of its subunits around crista junctions is unclear because such small length scales are inaccessible with established fluorescence microscopy. By targeting individually activated fluorophores with an excitation beam featuring a central zero-intensity point, the nanoscopy method called MINFLUX delivers single-digit nanometer-scale three-dimensional (3D) resolution and localization precision. We employed MINFLUX nanoscopy to investigate the submitochondrial localization of the core MICOS subunit Mic60 in relation to two other MICOS proteins, Mic10 and Mic19. We demonstrate that dual-color 3D MINFLUX nanoscopy is applicable to the imaging of organellar substructures, yielding a 3D localization precision of ∼5 nm in human mitochondria. This isotropic precision facilitated the development of an analysis framework that assigns localization clouds to individual molecules, thus eliminating a source of bias when drawing quantitative conclusions from single-molecule localization microscopy data. MINFLUX recordings of Mic60 indicate ringlike arrangements of multiple molecules with a diameter of 40 to 50 nm, suggesting that Mic60 surrounds individual crista junctions. Statistical analysis of dual-color MINFLUX images demonstrates that Mic19 is generally in close proximity to Mic60, whereas the spatial coordination of Mic10 with Mic60 is less regular, suggesting structural heterogeneity of MICOS.
    Keywords:  MICOS; MINFLUX; cluster analysis; mitochondria; superresolution microscopy
  16. Front Neurosci. 2020 ;14 599
    Liu J, Li L, Yang Y, Hong B, Chen X, Xie Q, Han H.
      Together, mitochondria and the endoplasmic reticulum (ER) occupy more than 20% of a cell's volume, and morphological abnormality may lead to cellular function disorders. With the rapid development of large-scale electron microscopy (EM), manual contouring and three-dimensional (3D) reconstruction of these organelles has previously been accomplished in biological studies. However, manual segmentation of mitochondria and ER from EM images is time consuming and thus unable to meet the demands of large data analysis. Here, we propose an automated pipeline for mitochondrial and ER reconstruction, including the mitochondrial and ER contact sites (MAMs). We propose a novel recurrent neural network to detect and segment mitochondria and a fully residual convolutional network to reconstruct the ER. Based on the sparse distribution of synapses, we use mitochondrial context information to rectify the local misleading results and obtain 3D mitochondrial reconstructions. The experimental results demonstrate that the proposed method achieves state-of-the-art performance.
    Keywords:  3D reconstruction; electron microscopes; endoplasmic reticulum; mitochondria; segmentation
  17. Mitochondrion. 2020 Aug 09. pii: S1567-7249(20)30170-7. [Epub ahead of print]
    Purushottam Dharaskar S, Paithankar K, Kanugovi Vijayavittal A, Shabbir Kara H, Amere Subbarao S.
      Mitochondria play a central role in regulating cellular energy metabolism. However, the present understanding of mitochondria has changed from its unipotent functions to pluripotent and insists on understanding the role of mitochondria not only in regulating the life and death of cells, but in pathological conditions such as cancer. Unlike other cellular organelles, subtle alterations in mitochondrial organization may significantly influence the balance between metabolic networks and cellular behavior. Therefore, the delicate balance between the fusion and fission dynamics of mitochondrion can indicate cell fate. Here, we present mitochondrial chaperone TRAP1 influence on mitochondrial architecture and its correlation with tumor growth and metastasis. We show that TRAP1 overexpression (TRAP1 OE) promotes mitochondrial fission, whereas, TRAP1 knockdown (TRAP1 KD) promotes mitochondrial fusion. Interestingly, TRAP1 OE or KD had a negligible effect on mitochondrial integrity. However, TRAP1 OE cells exhibited enhanced proliferative potential, while TRAP1 KD cells showing increased doubling time. Further, TRAP1 dependent mitochondrial dynamic alterations appeared to be unique since mitochondrial localization of TRAP1 is a mandate for dynamic changes. The expression patterns of fusion and fission genes have failed to correlate with TRAP1 expression, indicating a possibility that the dynamic changes can be independent of these genes. In agreement with enhanced proliferative potential, TRAP1 OE cells also exhibited enhanced migration in vitro and tumor metastasis in vivo. Further, TRAP1 OE cells showed altered homing properties, which may challenge site-specific anticancer treatments. Our findings unravel the TRAP1 role in tumor metastasis, which is in addition to altered energy metabolism.
  18. Cell Death Differ. 2020 Aug 07.
    Yang Z, Zhao X, Shang W, Liu Y, Ji JF, Liu JP, Tong C.
      Pyrroline-5-carboxylate synthase (P5CS) catalyzes the synthesis of pyrroline-5-carboxylate (P5C), a key precursor for the synthesis of proline and ornithine. P5CS malfunction leads to multiple human diseases; however, the molecular mechanism underlying these diseases is unknown. We found that P5CS localizes in mitochondria in rod- and ring-like patterns but diffuses inside the mitochondria upon cellular starvation or exposure to oxidizing agents. Some of the human disease-related mutant forms of P5CS also exhibit diffused distribution. Multimerization (but not the catalytic activity) of P5CS regulates its localization. P5CS mutant cells have a reduced proliferation rate and are sensitive to cellular stresses. Flies lacking P5CS have reduced eclosion rates. Lipid droplets accumulate in the eyes of the newly eclosed P5CS mutant flies, which degenerate with aging. The loss of P5CS in cells leads to abnormal purine metabolism and lipid-droplet accumulation. The reduced lipid-droplet consumption is likely due to decreased expression of the fatty acid transporter, CPT1, and few β-oxidation-related genes following P5CS knockdown. Surprisingly, we found that P5CS is required for mitochondrial respiratory complex organization and that the respiration defects in P5CS knockout cells likely contribute to the metabolic defects in purine synthesis and lipid consumption. This study links amino acid synthesis with mitochondrial respiration and other key metabolic processes, whose imbalance might contribute to P5CS-related disease conditions.
  19. Physiology (Bethesda). 2020 Sep 01. 35(5): 302-327
    Kunji ERS, King MS, Ruprecht JJ, Thangaratnarajah C.
      Members of the mitochondrial carrier family (SLC25) transport a variety of compounds across the inner membrane of mitochondria. These transport steps provide building blocks for the cell and link the pathways of the mitochondrial matrix and cytosol. An increasing number of diseases and pathologies has been associated with their dysfunction. In this review, the molecular basis of these diseases is explained based on our current understanding of their transport mechanism.
    Keywords:  bioenergetics; impaired transport mechanism; mitochondrial disease; mitochondrial physiology; pathological mutations
  20. Front Mol Biosci. 2020 ;7 151
    Hillen AEJ, Heine VM.
      Glutamate homeostasis is an important determinant of health of the central nervous system (CNS). Mitochondria play crucial roles in glutamate metabolism, especially in processes with a high energy demand such as action potential generation. Mitochondrial glutamate carriers (GCs) and aspartate-GCs (AGCs) regulate the transport of glutamate from the cytoplasm across the mitochondrial membrane, which is needed to control energy demand, lipid metabolism, and metabolic activity including oxidative phosphorylation and glycolysis. Dysfunction in these carriers are associated with seizures, spasticity, and/or myelin deficits, all of which are associated with inherited metabolic disorders. Since solute carrier functioning and associated processes are cell type- and context-specific, selective vulnerability to glutamate excitotoxicity and mitochondrial dysfunctioning is expected. Understanding this could offer important insights into the pathomechanisms of associated disorders. This perspective aims to explore the link between functions of both AGCs and GCs and their role in metabolic disorders, with a focus on a subclass of lysosomal storage disorders called leukodystrophies (LDs).
    Keywords:  aspartate-glutamate carriers; cell metabolism; cell type specificity; excitotoxicity; glutamate carriers; leukodystrophy; mitochondria; white matter
  21. Aging Cell. 2020 Aug 11. e13211
    Gao F, Zhang Y, Hou X, Tao Z, Ren H, Wang G.
      Accumulation of PINK1 on the outer mitochondrial membrane (OMM) is necessary for PINK-mediated mitophagy. The proton ionophores, like carbonyl cyanide m-chlorophenylhydrazone (CCCP) and carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP), inhibit PINK1 import into mitochondrial matrix and induce PINK1 OMM accumulation. Here, we show that the CHCHD4/GFER disulfide relay system in the mitochondrial intermembrane space (IMS) is required for PINK1 stabilization when mitochondrial membrane potential is lost. Activation of CHCHD4/GFER system by mitochondrial oxidative stress or inhibition of CHCHD4/GFER system with antioxidants can promote or suppress PINK1 accumulation, respectively. Thus data suggest a pivotal role of CHCHD4/GFER system in PINK1 accumulation. The amyotrophic lateral sclerosis-related superoxide dismutase 1 mutants dysregulated redox state and CHCHD4/GFER system in the IMS, leading to inhibitions of PINK1 accumulation and mitophagy. Thus, the redox system in the IMS is involved in PINK1 accumulation and damaged mitochondrial clearance, which may play roles in mitochondrial dysfunction-related neurodegenerative diseases.
    Keywords:  PINK1; autophagy; mitochondrion; mitophagy; neurodegenerative diseases
  22. Nat Commun. 2020 Aug 13. 11(1): 4046
    Bailey PSJ, Ortmann BM, Martinelli AW, Houghton JW, Costa ASH, Burr SP, Antrobus R, Frezza C, Nathan JA.
      2-oxoglutarate (2-OG or α-ketoglutarate) relates mitochondrial metabolism to cell function by modulating the activity of 2-OG dependent dioxygenases involved in the hypoxia response and DNA/histone modifications. However, metabolic pathways that regulate these oxygen and 2-OG sensitive enzymes remain poorly understood. Here, using CRISPR Cas9 genome-wide mutagenesis to screen for genetic determinants of 2-OG levels, we uncover a redox sensitive mitochondrial lipoylation pathway, dependent on the mitochondrial hydrolase ABHD11, that signals changes in mitochondrial 2-OG metabolism to 2-OG dependent dioxygenase function. ABHD11 loss or inhibition drives a rapid increase in 2-OG levels by impairing lipoylation of the 2-OG dehydrogenase complex (OGDHc)-the rate limiting step for mitochondrial 2-OG metabolism. Rather than facilitating lipoate conjugation, ABHD11 associates with the OGDHc and maintains catalytic activity of lipoyl domain by preventing the formation of lipoyl adducts, highlighting ABHD11 as a regulator of functional lipoylation and 2-OG metabolism.
  23. Mol Pain. 2020 Jan-Dec;16:16 1744806920946889
    Yousuf MS, Maguire AD, Simmen T, Kerr BJ.
      Chronic pain is a debilitating condition that affects roughly a third to a half of the world's population. Despite its substantial effect on society, treatment for chronic pain is modest, at best, notwithstanding its side effects. Hence, novel therapeutics are direly needed. Emerging evidence suggests that calcium plays an integral role in mediating neuronal plasticity that underlies sensitization observed in chronic pain states. The endoplasmic reticulum and the mitochondria are the largest calcium repositories in a cell. Here, we review how stressors, like accumulation of misfolded proteins and oxidative stress, influence endoplasmic reticulum and mitochondria function and contribute to chronic pain. We further examine the shuttling of calcium across the mitochondrial-associated membrane as a mechanism of cross-talk between the endoplasmic reticulum and the mitochondria. In addition, we discuss how endoplasmic reticulum stress, mitochondrial impairment, and calcium dyshomeostasis are implicated in various models of neuropathic pain. We propose a novel framework of endoplasmic reticulum-mitochondria signaling in mediating pain hypersensitivity. These observations require further investigation in order to develop novel therapies for chronic pain.
    Keywords:  Endoplasmic reticulum stress; calcium; mitochondria; mitochondrial-associated membrane; pain
  24. Elife. 2020 Aug 14. pii: e58573. [Epub ahead of print]9
    Kulkarni CA, Nadtochiy SM, Kennedy L, Zhang J, Chhim S, Alwaseem H, Murphy E, Fu D, Brookes PS.
      Alkb homolog 7 (ALKBH7) is a mitochondrial α-ketoglutarate dioxygenase required for DNA alkylation induced necrosis, but its function and substrates remain unclear. Herein we show ALKBH7 regulates dialdehyde metabolism, which impacts the cardiac response to ischemia-reperfusion (IR) injury. Using a multi-omics approach, we find no evidence ALKBH7 functions as a prolyl-hydroxylase, but we do find Alkbh7-/- mice have elevated glyoxalase I (GLO-1), a dialdehyde detoxifying enzyme. Metabolic pathways related to the glycolytic by-product methylglyoxal (MGO) are rewired in Alkbh7-/- mice, along with elevated levels of MGO protein adducts. Despite greater glycative stress, hearts from Alkbh7-/- mice are protected against IR injury, in a manner blocked by GLO-1 inhibition. Integrating these observations, we propose ALKBH7 regulates glyoxal metabolism, and that protection against necrosis and cardiac IR injury bought on by ALKBH7 deficiency originates from the signaling response to elevated MGO stress.
    Keywords:  cell biology; mouse