bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2022–09–04
twenty-two papers selected by
Catalina Vasilescu, University of Helsinki
  1. Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.
  2. The human mitochondrial genome contains a second light strand promoter.
  3. Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy.
  4. Impact of measuring heteroplasmy of a pathogenic mitochondrial DNA variant at the single-cell level in individuals with mitochondrial disease.
  5. Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics.
  6. Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy.
  7. A novel splice variant of Elp3/Kat9 regulates mitochondrial tRNA modification and function.
  8. Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects.
  9. Structural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA.
  10. A deafness-associated mitochondrial DNA mutation caused pleiotropic effects on DNA replication and tRNA metabolism.
  11. Kidney manifestations of mitochondrial disorders.
  12. Myocardial disturbances of intermediary metabolism in Barth syndrome.
  13. Bi-Allelic COQ4 Variants Cause Adult-Onset Ataxia-Spasticity Spectrum Disease.
  14. Maintenance of small molecule redox homeostasis in mitochondria.
  15. Identifying trajectories of fatigue in patients with primary mitochondrial disease due to the m.3243A > G variant.
  16. Functional characterization of two variants of mitochondrial topoisomerase TOP1MT that impact regulation of the mitochondrial genome.
  17. In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors.
  18. Mitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy.
  19. The mitochondrial seryl-tRNA synthetase SARS2 modifies onset in spastic paraplegia type 4.
  20. Operation of a TCA cycle subnetwork in the mammalian nucleus.
  21. ANT1 overexpression models: Some similarities with facioscapulohumeral muscular dystrophy.
  22. DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting.
  1. Am J Hum Genet. 2022 Sep 01. pii: S0002-9297(22)00311-1. [Epub ahead of print]109(9): 1692-1712
    Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.
    Rauan Kaiyrzhanov, Sami E M Mohammed, Reza Maroofian, Ralf A Husain, Alessia Catania, Alessandra Torraco, Ahmad Alahmad, Marina Dutra-Clarke, Sabine Grønborg, Annapurna Sudarsanam, Julie Vogt, Filippo Arrigoni, Julia Baptista, Shahzad Haider, René G Feichtinger, Paolo Bernardi, Alessandra Zulian, Mirjana Gusic, Stephanie Efthymiou, Renkui Bai, Farah Bibi, Alejandro Horga, Julian A Martinez-Agosto, Amanda Lam, Andreea Manole, Diego-Perez Rodriguez, Romina Durigon, Angela Pyle, Buthaina Albash, Carlo Dionisi-Vici, David Murphy, Diego Martinelli, Enrico Bugiardini, Katrina Allis, Costanza Lamperti, Siegfried Reipert, Lotte Risom, Lucia Laugwitz, Michela Di Nottia, Robert McFarland, Laura Vilarinho, Michael Hanna, Holger Prokisch, Johannes A Mayr, Enrico Silvio Bertini, Daniele Ghezzi, Elsebet Østergaard, Saskia B Wortmann, Rosalba Carrozzo, Tobias B Haack, Robert W Taylor, Antonella Spinazzola, Karin Nowikovsky, Henry Houlden.
      Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K+/H+ exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K+ efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial pathologies.
    Keywords:  LETM1; Wolf-Hirschhorn syndrome; genetics; mitochondria; mitochondrial diseases; neurodegeneration; neurology; oxidative phosphorylation; potassium transport; volume homeostasis
    DOI:  https://doi.org/10.1016/j.ajhg.2022.07.007
  2. Mol Cell. 2022 Aug 23. pii: S1097-2765(22)00764-X. [Epub ahead of print]
    The human mitochondrial genome contains a second light strand promoter.
    Benedict G Tan, Christian D Mutti, Yonghong Shi, Xie Xie, Xuefeng Zhu, Pedro Silva-Pinheiro, Katja E Menger, Héctor Díaz-Maldonado, Wei Wei, Thomas J Nicholls, Patrick F Chinnery, Michal Minczuk, Maria Falkenberg, Claes M Gustafsson.
      The human mitochondrial genome must be replicated and expressed in a timely manner to maintain energy metabolism and supply cells with adequate levels of adenosine triphosphate. Central to this process is the idea that replication primers and gene products both arise via transcription from a single light strand promoter (LSP) such that primer formation can influence gene expression, with no consensus as to how this is regulated. Here, we report the discovery of a second light strand promoter (LSP2) in humans, with features characteristic of a bona fide mitochondrial promoter. We propose that the position of LSP2 on the mitochondrial genome allows replication and gene expression to be orchestrated from two distinct sites, which expands our long-held understanding of mitochondrial gene expression in humans.
    Keywords:  DdCBE; LSP2; POLRMT; light strand promoter; mitochondria; mitochondrial DNA; mitochondrial gene expression; mitochondrial promoter; mtDNA; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.011
  3. Hum Mutat. 2022 Aug 28.
    Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy.
    Rocio Rius, Neal K Bennett, Kaustuv Bhattacharya, Lisa G Riley, Zafer Yüksel, Luke E Formosa, Alison G Compton, Russell C Dale, Mark J Cowley, Velimir Gayevskiy, Saeed Al Tala, Abdulrahman A Almehery, Michael T Ryan, David R Thorburn, Ken Nakamura, John Christodoulou.
      Primary mitochondrial diseases are a group of genetically and clinically heterogeneous disorders resulting from oxidative phosphorylation (OXPHOS) defects. COX11 encodes a copper chaperone that participates in the assembly of complex IV (CIV) and has not been previously linked to human disease. In a previous study, we identified that COX11 knockdown decreased cellular ATP derived from respiration, and that ATP levels could be restored with CoQ10 supplementation. This finding is surprising since COX11 has no known role in CoQ10 biosynthesis. Here, we report a novel gene-disease association by identifying biallelic pathogenic variants in COX11 associated with infantile-onset mitochondrial encephalopathies in two unrelated families using trio genome and exome sequencing. Functional studies showed that mutant COX11 fibroblasts had decreased ATP levels which could be rescued by CoQ10 . These results not only suggest that COX11 variants cause defects in energy production but reveal a potential metabolic therapeutic strategy for patients with COX11 variants. This article is protected by copyright. All rights reserved.
    Keywords:  COX11; Coenzyme Q; OXPHOS; mitochondrial disorders
    DOI:  https://doi.org/10.1002/humu.24453
  4. J Inherit Metab Dis. 2022 Aug 13.
    Impact of measuring heteroplasmy of a pathogenic mitochondrial DNA variant at the single-cell level in individuals with mitochondrial disease.
    Atsuko Imai-Okazaki, Kazuhiro R Nitta, Yukiko Yatsuka, Ayumu Sugiura, Masato Arao, Masaru Shimura, Tomohiro Ebihara, Takanori Onuki, Keiko Ichimoto, Akira Ohtake, Kei Murayama, Yasushi Okazaki.
      Pathogenic mitochondrial DNA heteroplasmy has mainly been assessed with bulk sequencing in individuals with mitochondrial disease. However, the distribution of heteroplasmy at the single-cell level in skin fibroblasts obtained from individuals, together with detailed clinical and biochemical information, remains to be investigated. We used the mitochondrial DNA single-cell assay for the transposase-accessible chromatin sequencing method. Skin fibroblasts were obtained from six individuals with mitochondrial disease and pathogenic m.3243A>G variants of differing severity. Different distributions of heteroplasmy at the single-cell level were identified in skin fibroblasts from all six individuals. Four individuals with different outcomes showed similar averaged heteroplasmy rates with normal mitochondrial respiratory chain enzyme activity, while the distribution of single-cell heteroplasmy patterns differed among the individuals. This study showed different heteroplasmy distribution patterns at the single-cell level in individuals with the m.3243A>G variant, who had a similar averaged heteroplasmy rates with normal mitochondrial respiratory chain enzyme activity. Whether such different heteroplasmy distribution patterns explain the different clinical outcomes should be assessed further in future studies. Measuring heteroplasmy of pathogenic mitochondrial DNA variants at the single-cell level could be important in individuals with mitochondrial disease.
    Keywords:  ATAC-seq; heteroplasmy; mitochondrial DNA; mitochondrial disease; single cell
    DOI:  https://doi.org/10.1002/jimd.12547
  5. J Cell Biol. 2022 Oct 03. pii: e202206140. [Epub ahead of print]221(10):
    Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics.
    Yvette C Wong, Soojin Kim, Jasmine Cisneros, Catherine G Molakal, Pingping Song, Steven J Lubbe, Dimitri Krainc.
      Lysosomes are highly dynamic organelles implicated in multiple diseases. Using live super-resolution microscopy, we found that lysosomal tethering events rarely undergo lysosomal fusion, but rather untether over time to reorganize the lysosomal network. Inter-lysosomal untethering events are driven by a mitochondrial Mid51/Fis1 complex that undergoes coupled oligomerization on the outer mitochondrial membrane. Importantly, Fis1 oligomerization mediates TBC1D15 (Rab7-GAP) mitochondrial recruitment to drive inter-lysosomal untethering via Rab7 GTP hydrolysis. Moreover, inhibiting Fis1 oligomerization by either mutant Fis1 or a Mid51 oligomerization mutant potentially associated with Parkinson's disease prevents lysosomal untethering events, resulting in misregulated lysosomal network dynamics. In contrast, dominant optic atrophy-linked mutant Mid51, which does not inhibit Mid51/Fis1 coupled oligomerization, does not disrupt downstream lysosomal dynamics. As Fis1 conversely also regulates Mid51 oligomerization, our work further highlights an oligomeric Mid51/Fis1 mitochondrial complex that mechanistically couples together both Drp1 and Rab7 GTP hydrolysis machinery at mitochondria-lysosome contact sites. These findings have significant implications for organelle networks in cellular homeostasis and human disease.
    DOI:  https://doi.org/10.1083/jcb.202206140
  6. Nat Commun. 2022 Sep 02. 13(1): 5164
    Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy.
    Jonas Benjamin Michaelis, Melinda Elaine Brunstein, Süleyman Bozkurt, Ludovico Alves, Martin Wegner, Manuel Kaulich, Christian Pohl, Christian Münch.
      Mitophagy is essential to maintain mitochondrial function and prevent diseases. It activates upon mitochondria depolarization, which causes PINK1 stabilization on the mitochondrial outer membrane. Strikingly, a number of conditions, including mitochondrial protein misfolding, can induce mitophagy without a loss in membrane potential. The underlying molecular details remain unclear. Here, we report that a loss of mitochondrial protein import, mediated by the pre-sequence translocase-associated motor complex PAM, is sufficient to induce mitophagy in polarized mitochondria. A genome-wide CRISPR/Cas9 screen for mitophagy inducers identifies components of the PAM complex. Protein import defects are able to induce mitophagy without a need for depolarization. Upon mitochondrial protein misfolding, PAM dissociates from the import machinery resulting in decreased protein import and mitophagy induction. Our findings extend the current mitophagy model to explain mitophagy induction upon conditions that do not affect membrane polarization, such as mitochondrial protein misfolding.
    DOI:  https://doi.org/10.1038/s41467-022-32564-x
  7. Sci Rep. 2022 Aug 31. 12(1): 14804
    A novel splice variant of Elp3/Kat9 regulates mitochondrial tRNA modification and function.
    Rachid Boutoual, Hyunsun Jo, Indra Heckenbach, Ritesh Tiwari, Herbert Kasler, Chad A Lerner, Samah Shah, Birgit Schilling, Vincenzo Calvanese, Matthew J Rardin, Morten Scheibye-Knudsen, Eric Verdin.
      Post-translational modifications, such as lysine acetylation, regulate the activity of diverse proteins across many cellular compartments. Protein deacetylation in mitochondria is catalyzed by the enzymatic activity of the NAD+-dependent deacetylase sirtuin 3 (SIRT3), however it remains unclear whether corresponding mitochondrial acetyltransferases exist. We used a bioinformatics approach to search for mitochondrial proteins with an acetyltransferase catalytic domain, and identified a novel splice variant of ELP3 (mt-ELP3) of the elongator complex, which localizes to the mitochondrial matrix in mammalian cells. Unexpectedly, mt-ELP3 does not mediate mitochondrial protein acetylation but instead induces a post-transcriptional modification of mitochondrial-transfer RNAs (mt-tRNAs). Overexpression of mt-ELP3 leads to the protection of mt-tRNAs against the tRNA-specific RNase angiogenin, increases mitochondrial translation, and furthermore increases expression of OXPHOS complexes. This study thus identifies mt-ELP3 as a non-canonical mt-tRNA modifying enzyme.
    DOI:  https://doi.org/10.1038/s41598-022-18114-x
  8. Front Mol Biosci. 2022 ;9 890653
    Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects.
    Madleen Zighan, David Arkadir, Liza Douiev, Guy Keller, Chaya Miller, Ann Saada.
      Omaveloxolone (RTA408) is a second-generation oleanane triterpenoid Nrf2 inducer with antioxidant and anti-inflammatory properties and was reported to improve mitochondrial bioenergetics. It is currently being tested in medical trials for Friedrich ataxia, a genetic, multi-organ disease involving mitochondrial dysfunction. Thus, omaveloxolone could potentially be beneficial for additional disorders involving mitochondrial dysfunction. To this end, we investigated its effect on primary fibroblasts derived from patients with mitochondrial complex I deficiency, mitochondrial cytochrome oxidase deficiency, and two recessive forms of Parkinson's disease. Patients and control cells were incubated in the presence or absence of 50 nM omaveloxolone for 72 h prior to measurements. Generally, growth on galactose medium and ATP production were unaltered. Mitochondrial membrane potential was slightly but significantly decreased, while reactive oxygen species (ROS) production was variably decreased. Mitochondrial mass and mitochondrial DNA (mtDNA) contents were significantly increased in the patient's cells. These results were partially confirmed by the results of oxygen consumption studies which disclosed increased maximal oxygen consumption rates in most cells and increased energy status in all treated cells. Further investigation is required to explore the precise effect of omaveloxolone on mitochondrial function in disease.
    Keywords:  Omavleoxolone RTA408; Parkinson’s disease; ROS; fibroblasts; mitochondria; mitochondrial disease
    DOI:  https://doi.org/10.3389/fmolb.2022.890653
  9. Nat Commun. 2022 Aug 30. 13(1): 5100
    Structural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA.
    Bernhard Kuhle, Marscha Hirschi, Lili K Doerfel, Gabriel C Lander, Paul Schimmel.
      Human mitochondrial gene expression relies on the specific recognition and aminoacylation of mitochondrial tRNAs (mtRNAs) by nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs). Despite their essential role in cellular energy homeostasis, strong mutation pressure and genetic drift have led to an unparalleled sequence erosion of animal mtRNAs. The structural and functional consequences of this erosion are not understood. Here, we present cryo-EM structures of the human mitochondrial seryl-tRNA synthetase (mSerRS) in complex with mtRNASer(GCU). These structures reveal a unique mechanism of substrate recognition and aminoacylation. The mtRNASer(GCU) is highly degenerated, having lost the entire D-arm, tertiary core, and stable L-shaped fold that define canonical tRNAs. Instead, mtRNASer(GCU) evolved unique structural innovations, including a radically altered T-arm topology that serves as critical identity determinant in an unusual shape-selective readout mechanism by mSerRS. Our results provide a molecular framework to understand the principles of mito-nuclear co-evolution and specialized mechanisms of tRNA recognition in mammalian mitochondrial gene expression.
    DOI:  https://doi.org/10.1038/s41467-022-32544-1
  10. Nucleic Acids Res. 2022 Aug 30. pii: gkac720. [Epub ahead of print]
    A deafness-associated mitochondrial DNA mutation caused pleiotropic effects on DNA replication and tRNA metabolism.
    Feilong Meng, Zidong Jia, Jing Zheng, Yanchun Ji, Jing Wang, Yun Xiao, Yong Fu, Meng Wang, Feng Ling, Min-Xin Guan.
      In this report, we investigated the molecular mechanism underlying a deafness-associated m.5783C > T mutation that affects the canonical C50-G63 base-pairing of TΨC stem of tRNACys and immediately adjacent to 5' end of light-strand origin of mitochondrial DNA (mtDNA) replication (OriL). Two dimensional agarose gel electrophoresis revealed marked decreases in the replication intermediates including ascending arm of Y-fork arcs spanning OriL in the mutant cybrids bearing m.5783C > T mutation. mtDNA replication alterations were further evidenced by decreased levels of PolγA, Twinkle and SSBP1, newly synthesized mtDNA and mtDNA contents in the mutant cybrids. The m.5783C > T mutation altered tRNACys structure and function, including decreased melting temperature, conformational changes, instability and deficient aminoacylation of mutated tRNACys. The m.5783C > T mutation impaired the 5' end processing efficiency of tRNACys precursors and reduced the levels of tRNACys and downstream tRNATyr. The aberrant tRNA metabolism impaired mitochondrial translation, which was especially pronounced effects in the polypeptides harboring higher numbers of cysteine and tyrosine codons. These alterations led to deficient oxidative phosphorylation including instability and reduced activities of the respiratory chain enzyme complexes I, III, IV and intact supercomplexes overall. Our findings highlight the impact of mitochondrial dysfunction on deafness arising from defects in mitochondrial DNA replication and tRNA metabolism.
    DOI:  https://doi.org/10.1093/nar/gkac720
  11. Bratisl Lek Listy. 2022 ;123(9): 659-671
    Kidney manifestations of mitochondrial disorders.
    Katarina Gazdikova, Andrea Fojtova, Lucia Ticha.
      Mitochondria are intracellular organelles involved in a number of key biologic processes in the cell, including energy production, redox signaling, calcium homeostasis, inflammation, senescence, innate immune response, and mitophagy. Mitochondrial cytopathies include a heterogeneous group of diseases that are characterized by impaired oxidative phosphorylation, leading to multi-organ involvement and progressive clinical deterioration. Mitochondrial cytopathies can result from mitochondrial or nuclear DNA mutations. Mitochondrial defects play an important role in the pathogenesis of nephropathies as tubular syndromes, interstitial nephritis, focal and segmental glomerulosclerosis and diabetic nephropathy. The role of mitochondria in a pathogenesis of nephrotoxicity and kidney carcinogenesis is also discussed (Tab. 2, Fig. 7, Ref. 100). Keywords: mitochondrial nephropathy, interstitial nephritis, glomerulosclerosis, diabetic nephropathy, nephrotoxicity, mitochondrial cytopathies.
    DOI:  https://doi.org/10.4149/BLL_2022_106
  12. Front Cardiovasc Med. 2022 ;9 981972
    Myocardial disturbances of intermediary metabolism in Barth syndrome.
    Amanda A Greenwell, Seyed Amirhossein Tabatabaei Dakhili, John R Ussher.
      Barth Syndrome (BTHS) is a rare X-linked mitochondrial disorder due to mutations in the gene TAFAZZIN, which leads to immature cardiolipin (CL) remodeling and is characterized by the development of cardiomyopathy. The immature CL remodeling in BTHS results in electron transport chain respiratory defects and destabilization of supercomplexes, thereby impairing ATP production. Thus, BTHS-related cardiomyopathy appears to share metabolic characteristics of the failing heart being an "engine out of fuel." As CL associates with numerous mitochondrial enzymes involved in ATP production, BTHS is also characterized by several defects in intermediary energy metabolism. Herein we will describe the primary disturbances in intermediary energy metabolism relating to the heart's major fuel sources, fatty acids, carbohydrates, ketones, and amino acids. In addition, we will interrogate whether these disturbances represent potential metabolic targets for alleviating BTHS-related cardiomyopathy.
    Keywords:  Barth syndrome (BTHS); cardiac energetics; cardiomyopathy; fatty acid oxidation; glucose oxidation; ketone oxidation
    DOI:  https://doi.org/10.3389/fcvm.2022.981972
  13. Mov Disord. 2022 Sep 01.
    Bi-Allelic COQ4 Variants Cause Adult-Onset Ataxia-Spasticity Spectrum Disease.
    Isabell Cordts, Luisa Semmler, Jannik Prasuhn, Annette Seibt, Diran Herebian, Tharsini Navaratnarajah, Joohyun Park, Natalie Deininger, Lucia Laugwitz, Sophia L Göricke, Paul Lingor, Norbert Brüggemann, Alexander Münchau, Matthis Synofzik, Dagmar Timmann, Johannes A Mayr, Tobias B Haack, Felix Distelmaier, Marcus Deschauer.
       BACKGROUND: COQ4 codes for a mitochondrial protein required for coenzyme Q10 (CoQ10 ) biosynthesis. Autosomal recessive COQ4-associated CoQ10 deficiency leads to an early-onset mitochondrial multi-organ disorder.
    METHODS: In-house exome and genome datasets (n = 14,303) were screened for patients with bi-allelic variants in COQ4. Work-up included clinical characterization and functional studies in patient-derived cell lines.
    RESULTS: Six different COQ4 variants, three of them novel, were identified in six adult patients from four different families. Three patients had a phenotype of hereditary spastic paraparesis, two sisters showed a predominant cerebellar ataxia, and one patient had mild signs of both. Studies in patient-derived fibroblast lines revealed significantly reduced amounts of COQ4 protein, decreased CoQ10 concentrations, and elevated levels of the metabolic intermediate 6-demethoxyubiquinone.
    CONCLUSION: We report bi-allelic variants in COQ4 causing an adult-onset ataxia-spasticity spectrum phenotype and a disease course much milder than previously reported. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  cerebellar ataxia; coenzyme Q10 deficiency; hereditary spastic paraplegia; mitochondriopathy
    DOI:  https://doi.org/10.1002/mds.29167
  14. FEBS Lett. 2022 Aug 27.
    Maintenance of small molecule redox homeostasis in mitochondria.
    Lianne Jhc Jacobs, Jan Riemer.
      Compartmentalization of eukaryotic cells enables fundamental otherwise often incompatible cellular processes. Establishment and maintenance of distinct compartments in the cell relies on proteins, lipids and metabolites but also on small redox molecules. In particular, small redox molecules such as glutathione, NAD(P)H, and hydrogen peroxide (H2 O2 ) cooperate with protein partners in dedicated machineries to establish specific subcellular redox compartments with conditions that enable oxidative protein folding and redox signalling. Dysregulated redox homeostasis has been directly linked with a number of diseases including cancer, neurological disorders, cardiovascular diseases, obesity, metabolic diseases, and aging. In this review, we will summarize mechanisms regulating establishment and maintenance of redox homeostasis in the mitochondrial subcompartments of mammalian cells.
    Keywords:  compartmentalization; glutathione; hydrogen peroxide; mitochondria
    DOI:  https://doi.org/10.1002/1873-3468.14485
  15. J Inherit Metab Dis. 2022 Aug 13.
    Identifying trajectories of fatigue in patients with primary mitochondrial disease due to the m.3243A > G variant.
    Inge-Lot Klein, Christianne M Verhaak, Jan A M Smeitink, Paul de Laat, Mirian C H Janssen, José A E Custers.
      Severe fatigue is a common complaint in patients with primary mitochondrial disease. However, less is known about the course of fatigue over time. This longitudinal observational cohort study of patients with the mitochondrial DNA 3243 A>G variant explored trajectories of fatigue over 2 years, and characteristics of patients within these fatigue trajectories. Fifty-three adult patients treated at the Radboud University Medical Center Nijmegen were included. The majority of the patients reported consistent, severe fatigue (41%), followed by patients with a mixed pattern of severe and mild fatigue (36%). Then, 23% of patients reported stable mild fatigue levels. Patients with a stable high fatigue trajectory were characterized by higher disease manifestations scores, more clinically relevant mental health symptoms, and lower psychosocial functioning and quality of life compared to patients reporting stable low fatigue levels. Fatigue at baseline and disease manifestation scores predicted fatigue severity at the 2-year assessment (57% explained variance). This study demonstrates that severe fatigue is a common and stable complaint in the majority of patients. Clinicians should be aware of severe fatigue in patients with moderate to severe disease manifestation scores on the Newcastle Mitochondrial Disease Scale, the high prevalence of clinically relevant mental health symptoms and overall impact on quality of life in these patients. Screening of fatigue and psychosocial variables will guide suitable individualized treatment to improve the quality of life.
    Keywords:  fatigue; longitudinal; mental health; mitochondrial disease; mtDNA 3243A>G variant; quality of life
    DOI:  https://doi.org/10.1002/jimd.12546
  16. J Biol Chem. 2022 Aug 24. pii: S0021-9258(22)00863-8. [Epub ahead of print] 102420
    Functional characterization of two variants of mitochondrial topoisomerase TOP1MT that impact regulation of the mitochondrial genome.
    Iman Al Khatib, Jingti Deng, Andrew Symes, Marina Kerr, Hongliang Zhang, Sharyin Huang, Yves Pommier, Aneal Khan, Timothy E Shutt.
      TOP1MT encodes a mitochondrial topoisomerase that is important for mtDNA regulation, and is involved in mitochondrial replication, transcription, and translation. Two variants predicted to affect TOP1MT function (V1 - R198C and V2 - V338L) were identified by exome sequencing of a newborn with hypertrophic cardiomyopathy. As no pathogenic TOP1MT variants had been confirmed previously, we characterized these variants for their ability to rescue several TOP1MT functions in knockout cells. Consistent with these TOP1MT variants contributing to the patient phenotype, our comprehensive characterization suggests that both variants had impaired activity. Critically, we determined neither variant was able to restore steady state levels of mitochondrial-encoded proteins, nor to rescue oxidative phosphorylation when re-expressed in TOP1MT knockout cells. However, we found the two variants behaved differently in some respects; while the V1 variant was more efficient in restoring transcript levels, the V2 variant showed better rescue of mtDNA copy number and replication. These findings suggest that the different TOP1MT variants affect distinct TOP1MT functions. Altogether, these findings begin to provide insight into the many roles that TOP1MT plays in the maintenance and expression of the mitochondrial genome, and how impairments in this important protein may lead to human pathology.
    Keywords:  TOP1MT; mitochondria; mtDNA; replication; transcription; translation
    DOI:  https://doi.org/10.1016/j.jbc.2022.102420
  17. Sci Adv. 2022 Sep 02. 8(35): eabn9550
    In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors.
    Panayotis Pachnis, Zheng Wu, Brandon Faubert, Alpaslan Tasdogan, Wen Gu, Spencer Shelton, Ashley Solmonson, Aparna D Rao, Akash K Kaushik, Thomas J Rogers, Jessalyn M Ubellacker, Collette A LaVigne, Chendong Yang, Bookyung Ko, Vijayashree Ramesh, Jessica Sudderth, Lauren G Zacharias, Misty S Martin-Sandoval, Duyen Do, Thomas P Mathews, Zhiyu Zhao, Prashant Mishra, Sean J Morrison, Ralph J DeBerardinis.
      In mice and humans with cancer, intravenous 13C-glucose infusion results in 13C labeling of tumor tricarboxylic acid (TCA) cycle intermediates, indicating that pyruvate oxidation in the TCA cycle occurs in tumors. The TCA cycle is usually coupled to the electron transport chain (ETC) because NADH generated by the cycle is reoxidized to NAD+ by the ETC. However, 13C labeling does not directly report ETC activity, and other pathways can oxidize NADH, so the ETC's role in these labeling patterns is unverified. We examined the impact of the ETC complex I inhibitor IACS-010759 on tumor 13C labeling. IACS-010759 suppresses TCA cycle labeling from glucose or lactate and increases labeling from glutamine. Cancer cells expressing yeast NADH dehydrogenase-1, which recycles NADH to NAD+ independently of complex I, display normalized labeling when complex I is inhibited, indicating that cancer cell ETC activity regulates TCA cycle metabolism and 13C labeling from multiple nutrients.
    DOI:  https://doi.org/10.1126/sciadv.abn9550
  18. Proc Natl Acad Sci U S A. 2022 Sep 06. 119(36): e2117396119
    Mitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy.
    Na Ta, Chuanren Qu, Hao Wu, Di Zhang, Tiantian Sun, Yanjun Li, Jun Wang, Xiaohui Wang, Tieshan Tang, Quan Chen, Lei Liu.
      Ferroptosis is an iron-dependent programmed necrosis characterized by glutathione (GSH) depletion and lipid peroxidation (LPO). Armed with both the pro- and antiferroptosis machineries, mitochondria play a central role in ferroptosis. However, how mitochondria sense the stress to activate ferroptosis under (patho-)physiological settings remains incompletely understood. Here, we show that FUN14 domain-containing 2, also known as HCBP6 (FUNDC2), a highly conserved and ubiquitously expressed mitochondrial outer membrane protein, regulates ferroptosis and contributes to doxorubicin (DOX)-induced cardiomyopathy. We showed that knockout of FUNDC2 protected mice from DOX-induced cardiac injury by preventing ferroptosis. Mechanistic studies reveal that FUNDC2 interacts with SLC25A11, the mitochondrial glutathione transporter, to regulate mitoGSH levels. Specifically, knockdown of SLC25A11 in FUNDC2-knockout (KO) cells reduced mitoGSH and augmented erasin-induced ferroptosis. FUNDC2 also affected the stability of both SLC25A11 and glutathione peroxidase 4 (GPX4), key regulators for ferroptosis. Our results demonstrate that FUNDC2 modulates ferroptotic stress via regulating mitoGSH and further support a therapeutic strategy of cardioprotection by preventing mitoGSH depletion and ferroptosis.
    Keywords:  FUNDC2; SLC25A11; ferroptosis; mitoGSH; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2117396119
  19. Genet Med. 2022 Sep 03. pii: S1098-3600(22)00875-9. [Epub ahead of print]
    The mitochondrial seryl-tRNA synthetase SARS2 modifies onset in spastic paraplegia type 4.
    Livia Parodi, Mathieu Barbier, Maxime Jacoupy, Claire Pujol, François-Xavier Lejeune, Pauline Lallemant-Dudek, Typhaine Esteves, Maartje Pennings, Erik-Jan Kamsteeg, Marine Guillaud-Bataille, Guillaume Banneau, Giulia Coarelli, Badreddine Mohand Oumoussa, Matthew J Fraidakis, Giovanni Stevanin, Christel Depienne, Bart van de Warrenburg, Alexis Brice, Alexandra Durr.
       PURPOSE: Hereditary spastic paraplegia type 4 is extremely variable in age at onset; the same variant can cause onset at birth or in the eighth decade. We recently discovered that missense variants in SPAST, which influences microtubule dynamics, are associated with earlier onset and more severe disease than truncating variants, but even within the early and late-onset groups there remained significant differences in onset. Given the rarity of the condition, we adapted an extreme phenotype approach to identify genetic modifiers of onset.
    METHODS: We performed a genome-wide association study on 134 patients bearing truncating pathogenic variants in SPAST, divided into early- and late-onset groups (aged ≤15 and ≥45 years, respectively). A replication cohort of 419 included patients carrying either truncating or missense variants. Finally, age at onset was analyzed in the merged cohort (N = 553).
    RESULTS: We found 1 signal associated with earlier age at onset (rs10775533, P = 8.73E-6) in 2 independent cohorts and in the merged cohort (N = 553, Mantel-Cox test, P < .0001). Western blotting in lymphocytes of 20 patients showed that this locus tends to upregulate SARS2 expression in earlier-onset patients.
    CONCLUSION: SARS2 overexpression lowers the age of onset in hereditary spastic paraplegia type 4. Lowering SARS2 or improving mitochondrial function could thus present viable approaches to therapy.
    Keywords:  Genetic modifier; Hereditary spastic paraplegia; Mitochondria; SARS2; Spastin
    DOI:  https://doi.org/10.1016/j.gim.2022.07.023
  20. Sci Adv. 2022 Sep 02. 8(35): eabq5206
    Operation of a TCA cycle subnetwork in the mammalian nucleus.
    Eleni Kafkia, Amparo Andres-Pons, Kerstin Ganter, Markus Seiler, Tom S Smith, Anna Andrejeva, Paula Jouhten, Filipa Pereira, Catarina Franco, Anna Kuroshchenkova, Sergio Leone, Ritwick Sawarkar, Rebecca Boston, James Thaventhiran, Judith B Zaugg, Kathryn S Lilley, Christophe Lancrin, Martin Beck, Kiran Raosaheb Patil.
      Nucleic acid and histone modifications critically depend on the tricarboxylic acid (TCA) cycle for substrates and cofactors. Although a few TCA cycle enzymes have been reported in the nucleus, the corresponding pathways are considered to operate in mitochondria. Here, we show that a part of the TCA cycle is operational also in the nucleus. Using 13C-tracer analysis, we identified activity of glutamine-to-fumarate, citrate-to-succinate, and glutamine-to-aspartate routes in the nuclei of HeLa cells. Proximity labeling mass spectrometry revealed a spatial vicinity of the involved enzymes with core nuclear proteins. We further show nuclear localization of aconitase 2 and 2-oxoglutarate dehydrogenase in mouse embryonic stem cells. Nuclear localization of the latter enzyme, which produces succinyl-CoA, changed from pluripotency to a differentiated state with accompanying changes in the nuclear protein succinylation. Together, our results demonstrate operation of an extended metabolic pathway in the nucleus, warranting a revision of the canonical view on metabolic compartmentalization.
    DOI:  https://doi.org/10.1126/sciadv.abq5206
  21. Redox Biol. 2022 Aug 22. pii: S2213-2317(22)00222-1. [Epub ahead of print]56 102450
    ANT1 overexpression models: Some similarities with facioscapulohumeral muscular dystrophy.
    Sandrine Arbogast, Heinrich Kotzur, Corinna Frank, Nathalie Compagnone, Thibault Sutra, Fabien Pillard, Sylvia Pietri, Nisrine Hmada, Daouda Moustapha Abba Moussa, Jamie Bride, Sarah Françonnet, Jacques Mercier, Jean-Paul Cristol, Marie-Christine Dabauvalle, Dalila Laoudj-Chenivesse.
      Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder characterized by progressive muscle weakness. Adenine nucleotide translocator 1 (ANT1), the only 4q35 gene involved in mitochondrial function, is strongly expressed in FSHD skeletal muscle biopsies. However, its role in FSHD is unclear. In this study, we evaluated ANT1 overexpression effects in primary myoblasts from healthy controls and during Xenopus laevis organogenesis. We also compared ANT1 overexpression effects with the phenotype of FSHD muscle cells and biopsies. Here, we report that the ANT1 overexpression-induced phenotype presents some similarities with FSHD muscle cells and biopsies. ANT1-overexpressing muscle cells showed disorganized morphology, altered cytoskeletal arrangement, enhanced mitochondrial respiration/glycolysis, ROS production, oxidative stress, mitochondrial fragmentation and ultrastructure alteration, as observed in FSHD muscle cells. ANT1 overexpression in Xenopus laevis embryos affected skeletal muscle development, impaired skeletal muscle, altered mitochondrial ultrastructure and led to oxidative stress as observed in FSHD muscle biopsies. Moreover, ANT1 overexpression in X. laevis embryos affected heart structure and mitochondrial ultrastructure leading to cardiac arrhythmia, as described in some patients with FSHD. Overall our data suggest that ANT1 could contribute to mitochondria dysfunction and oxidative stress in FSHD muscle cells by modifying their bioenergetic profile associated with ROS production. Such interplay between energy metabolism and ROS production in FSHD will be of significant interest for future prospects.
    Keywords:  Adenine nucleotide translocase type 1 (ANT1); Facioscapulohumeral muscular dystrophy (FSHD); Metabolism; Muscle morphological abnormalities; Oxidative stress; Primary muscle cells; Xenopus laevis, Mitochondrial function
    DOI:  https://doi.org/10.1016/j.redox.2022.102450
  22. Cell Rep. 2022 Aug 30. pii: S2211-1247(22)01098-1. [Epub ahead of print]40(9): 111278
    DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting.
    Christopher J Yuskaitis, Jinita B Modasia, Sandra Schrötter, Leigh-Ana Rossitto, Karenna J Groff, Christopher Morici, Divakar S Mithal, Ram P Chakrabarty, Navdeep S Chandel, Brendan D Manning, Mustafa Sahin.
      Caloric restriction and acute fasting are known to reduce seizures but through unclear mechanisms. mTOR signaling has been suggested as a potential mechanism for seizure protection from fasting. We demonstrate that brain mTORC1 signaling is reduced after acute fasting of mice and that neuronal mTORC1 integrates GATOR1 complex-mediated amino acid and tuberous sclerosis complex (TSC)-mediated growth factor signaling. Neuronal mTORC1 is most sensitive to withdrawal of leucine, arginine, and glutamine, which are dependent on DEPDC5, a component of the GATOR1 complex. Metabolomic analysis reveals that Depdc5 neuronal-specific knockout mice are resistant to sensing significant fluctuations in brain amino acid levels after fasting. Depdc5 neuronal-specific knockout mice are resistant to the protective effects of fasting on seizures or seizure-induced death. These results establish that acute fasting reduces seizure susceptibility in a DEPDC5-dependent manner. Modulation of nutrients upstream of GATOR1 and mTORC1 could offer a rational therapeutic strategy for epilepsy treatment.
    Keywords:  CP: Metabolism; CP: Neuroscience; GATOR1; SUDEP; TSC; amino acids; cell signaling; epilepsy; fasting; mTOR; metabolomics; seizures
    DOI:  https://doi.org/10.1016/j.celrep.2022.111278
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