bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2022‒09‒25
25 papers selected by
Catalina Vasilescu
University of Helsinki
  1. Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy.
  2. Mitochondrial DNA variation in Alzheimer's disease reveals a unique microprotein called SHMOOSE.
  3. independent origin for M.3243A>G mitochondrial mutation in three venezuelan cases of melas syndrome.
  4. Ketogenic Diets and Mitochondrial Function: Benefits for Aging but not for Athletes.
  5. Effects of axon branching and asymmetry between the branches on transport, mean age, and age density distributions of mitochondria in neurons: a computational study.
  6. Mitochondrial quality control mechanisms as molecular targets in diabetic heart.
  7. Human Mutation special issue on Innovations in Genomic Diagnostics.
  8. The impact of diet upon mitochondrial physiology (Review).
  9. ORP5/8 and MIB/MICOS link ER-mitochondria and intra-mitochondrial contacts for non-vesicular transport of phosphatidylserine.
  10. RNA-based generation of iPSCs from a boy carrying the mutation m.9185 T>C in the mitochondrial gene MT-ATP6 and from his healthy mother.
  11. CLN3 is required for the clearance of glycerophosphodiesters from lysosomes.
  12. Protocol to detect in vitro and in cell ubiquitylation of mitochondrial DNA polymerase gamma by mitochondrial E3 ligase MITOL.
  13. The phenotypic spectrum of COX20-associated mitochondrial disorder.
  14. BiP inactivation due to loss of the deAMPylation function of FICD causes a motor neuron disease.
  15. A feed-forward pathway drives LRRK2 kinase membrane recruitment and activation.
  16. SAIGE-GENE+ improves the efficiency and accuracy of set-based rare variant association tests.
  17. Dual Mode of Mitochondrial ROS Action during Reprogramming to Pluripotency.
  18. The multiple facets of mitochondrial regulations controlling cellular thermogenesis.
  19. Small molecule SJ572946 activates BAK to initiate apoptosis.
  20. Coenzyme Q10 Supplementation in Statin Treated Patients: A Double-Blinded Randomized Placebo-Controlled Trial.
  21. Functional platelet-derived mitochondria induce the release of human neutrophil microvesicles.
  22. Clinical profile and outcome of cardiomyopathies in infants and children seen at a tertiary centre.
  23. Oxygen regulation of breathing is abolished in mitochondrial complex III-deficient arterial chemoreceptors.
  24. Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants.
  25. Targeted Proteomics for Monitoring One-Carbon Metabolism in Liver Diseases.
  1. Trials. 2022 Sep 20. 23(1): 789
    Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy.
    AIMM Trial Group:
      BACKGROUND: Mitochondrial disease is a heterogenous group of rare, complex neurometabolic disorders. Despite their individual rarity, collectively mitochondrial diseases represent the most common cause of inherited metabolic disorders in the UK; they affect 1 in every 4300 individuals, up to 15,000 adults (and a similar number of children) in the UK. Mitochondrial disease manifests multisystem and isolated organ involvement, commonly affecting those tissues with high energy demands, such as skeletal muscle. Myopathy manifesting as fatigue, muscle weakness and exercise intolerance is common and debilitating in patients with mitochondrial disease. Currently, there are no effective licensed treatments and consequently, there is an urgent clinical need to find an effective drug therapy.AIM: To investigate the efficacy of 12-week treatment with acipimox on the adenosine triphosphate (ATP) content of skeletal muscle in patients with mitochondrial disease and myopathy.
    METHODS: AIMM is a single-centre, double blind, placebo-controlled, adaptive designed trial, evaluating the efficacy of 12 weeks' administration of acipimox on skeletal muscle ATP content in patients with mitochondrial myopathy. Eligible patients will receive the trial investigational medicinal product (IMP), either acipimox or matched placebo. Participants will also be prescribed low dose aspirin as a non-investigational medical product (nIMP) in order to protect the blinding of the treatment assignment. Eighty to 120 participants will be recruited as required, with an interim analysis for sample size re-estimation and futility assessment being undertaken once the primary outcome for 50 participants has been obtained. Randomisation will be on a 1:1 basis, stratified by Fatigue Impact Scale (FIS) (dichotomised as < 40, ≥ 40). Participants will take part in the trial for up to 20 weeks, from screening visits through to follow-up at 16 weeks post randomisation. The primary outcome of change in ATP content in skeletal muscle and secondary outcomes relating to quality of life, perceived fatigue, disease burden, limb function, balance and walking, skeletal muscle analysis and symptom-limited cardiopulmonary fitness (optional) will be assessed between baseline and 12 weeks.
    DISCUSSION: The AIMM trial will investigate the effect of acipimox on modulating muscle ATP content and whether it can be repurposed as a new treatment for mitochondrial disease with myopathy.
    TRIAL REGISTRATION: EudraCT2018-002721-29 . Registered on 24 December 2018, ISRCTN 12895613. Registered on 03 January 2019, https://www.isrctn.com/search?q=aimm.
    Keywords:  Acipimox; Adenosine triphosphate; Mitochondria; Mitochondrial disease; Myopathy; Randomised controlled trial
    DOI:  https://doi.org/10.1186/s13063-022-06544-x
  2. Mol Psychiatry. 2022 Sep 21.
    Mitochondrial DNA variation in Alzheimer's disease reveals a unique microprotein called SHMOOSE.
    Brendan Miller, Su-Jeong Kim, Hemal H Mehta, Kevin Cao, Hiroshi Kumagai, Neehar Thumaty, Naphada Leelaprachakul, Henry Jiao, Joan Vaughan, Jolene Diedrich, Alan Saghatelian, Thalida E Arpawong, Eileen M Crimmins, Nilüfer Ertekin-Taner, Meral A Tubi, Evan T Hare, Meredith N Braskie, Léa Décarie-Spain, Scott E Kanoski, Francine Grodstein, David A Bennett, Lu Zhao, Arthur W Toga, Junxiang Wan, Kelvin Yen, Pinchas Cohen.
      Mitochondrial DNA variants have previously associated with disease, but the underlying mechanisms have been largely elusive. Here, we report that mitochondrial SNP rs2853499 associated with Alzheimer's disease (AD), neuroimaging, and transcriptomics. We mapped rs2853499 to a novel mitochondrial small open reading frame called SHMOOSE with microprotein encoding potential. Indeed, we detected two unique SHMOOSE-derived peptide fragments in mitochondria by using mass spectrometry-the first unique mass spectrometry-based detection of a mitochondrial-encoded microprotein to date. Furthermore, cerebrospinal fluid (CSF) SHMOOSE levels in humans correlated with age, CSF tau, and brain white matter volume. We followed up on these genetic and biochemical findings by carrying out a series of functional experiments. SHMOOSE acted on the brain following intracerebroventricular administration, differentiated mitochondrial gene expression in multiple models, localized to mitochondria, bound the inner mitochondrial membrane protein mitofilin, and boosted mitochondrial oxygen consumption. Altogether, SHMOOSE has vast implications for the fields of neurobiology, Alzheimer's disease, and microproteins.
    DOI:  https://doi.org/10.1038/s41380-022-01769-3
  3. Clin Biochem. 2022 Sep 18. pii: S0009-9120(22)00221-1. [Epub ahead of print]
    independent origin for M.3243A>G mitochondrial mutation in three venezuelan cases of melas syndrome.
    Ingrid Florez, Irune Pirrone, Liliana Casique, Carmen Luisa Domínguez, Antonieta Mahfoud, Tania Rodríguez, Daniel Rodríguez, Marisel De Lucca, José Luis Ramírez.
      Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a multisystem and progressive neurodegenerative mitochondrial disease, caused by point nucleotide changes in the mtDNA where 80% of cases have the mutation m.3243A>G in the MT-TL1 gene. In this work, we described the clinical, biochemical and molecular analysis of three Venezuelan patients affected with MELAS syndrome. All cases showed lactic acidosis, cortical cerebral atrophy on magnetic resonance imaging and muscular system deficit, and in two of the cases alteration of urine organic acid levels was also registered. A screening for the mutation m.3243A>G in different patients' body samples confirmed the presence of this mutation with variable degrees of heteroplasmy (blood=7-41%, buccal mucosa=14-53%, urine=58-94%). The mitochondrial haplogroups for the three patients were different (H, C1b, and A2), indicating an independent origin for the mutation.
    Keywords:  MELAS syndrome; MT-TL1 gene; Venezuelan patients; heteroplasmy; mitochondrial haplogroup; mtDNA
    DOI:  https://doi.org/10.1016/j.clinbiochem.2022.09.007
  4. Exerc Sport Sci Rev. 2022 Sep 16.
    Ketogenic Diets and Mitochondrial Function: Benefits for Aging but not for Athletes.
    Suraj J Pathak, Keith Baar.
      ABSTRACT: As humans age, we lose skeletal muscle mass, even in the absence of disease (sarcopenia), increasing the risk of death. Low mitochondrial mass and activity contributes to sarcopenia. It is our hypothesis that, a ketogenic diet improves skeletal muscle mitochondrial mass and function when they have declined due to aging or disease, but not in athletes where mitochondrial quality is high.
    DOI:  https://doi.org/10.1249/JES.0000000000000307
  5. Int J Numer Method Biomed Eng. 2022 Sep 20. e3648
    Effects of axon branching and asymmetry between the branches on transport, mean age, and age density distributions of mitochondria in neurons: a computational study.
    Ivan A Kuznetsov, Andrey V Kuznetsov.
      We report a computational study of mitochondria transport in a branched axon with two branches of different sizes. For comparison, we also investigate mitochondria transport in an axon with symmetric branches and in a straight (unbranched) axon. The interest in understanding mitochondria transport in branched axons is motivated by the large size of arbors of dopaminergic neurons, which die in Parkinson's disease. Since the failure of energy supply of multiple demand sites located in various axonal branches may be a possible reason for the death of these neurons, we were interested in investigating how branching affects mitochondria transport. Besides investigating mitochondria fluxes between the demand sites and mitochondria concentrations, we also studied how the mean age of mitochondria and mitochondria age densities depend on the distance from the soma. We established that if the axon splits into two branches of unequal length, the mean ages of mitochondria and age density distributions in the demand sites are affected by how the mitochondria flux splits at the branching junction (what portion of mitochondria enter the shorter branch and what portion enter the longer branch). However, if the axon splits into two branches of equal length, the mean ages and age densities of mitochondria are independent of how the mitochondria flux splits at the branching junction. This even holds for the case when all mitochondria enter one branch, which is equivalent to a straight axon. Because the mitochondrial membrane potential (which many researchers view as a proxy for mitochondrial health) decreases with mitochondria age, the independence of mitochondria age on whether the axon is symmetrically branched or straight (providing the two axons are of the same length), and on how the mitochondria flux splits at the branching junction, may explain how dopaminergic neurons can sustain very large arbors and still maintain mitochondrial health across branch extremities. This article is protected by copyright. All rights reserved.
    Keywords:  Parkinson's disease; axonal transport; large axonal arbors; mathematical modeling; mitochondrial health
    DOI:  https://doi.org/10.1002/cnm.3648
  6. Metabolism. 2022 Sep 17. pii: S0026-0495(22)00191-3. [Epub ahead of print] 155313
    Mitochondrial quality control mechanisms as molecular targets in diabetic heart.
    Xing Chang, Yukun Li, Chen Cai, Feng Wu, Jing He, Yaoyuan Zhang, Jiankai Zhong, Ying Tan, Ruxiu Liu, Hang Zhu, Hao Zhou.
      Mitochondrial dysfunction has been regarded as a hallmark of diabetic cardiomyopathy. In addition to their canonical metabolic actions, mitochondria influence various other aspects of cardiomyocyte function, including oxidative stress, iron regulation, metabolic reprogramming, intracellular signaling transduction and cell death. These effects depend on the mitochondrial quality control (MQC) system, which includes mitochondrial dynamics, mitophagy and mitochondrial biogenesis. Mitochondria are not static entities, but dynamic units that undergo fission and fusion cycles to maintain their structural integrity. Increased mitochondrial fission elevates the number of mitochondria within cardiomyocytes, a necessary step for cardiomyocyte metabolism. Enhanced mitochondrial fusion promotes communication and cooperation between pairs of mitochondria, thus facilitating mitochondrial genomic repair and maintenance. On the contrary, erroneous fission or reduced fusion promotes the formation of mitochondrial fragments that contain damaged mitochondrial DNA and exhibit impaired oxidative phosphorylation. Under normal/physiological conditions, injured mitochondria can undergo mitophagy, a degradative process that delivers poorly structured mitochondria to lysosomes. However, defective mitophagy promotes the accumulation of nonfunctional mitochondria, which may induce cardiomyocyte death. A decline in the mitochondrial population due to mitophagy can stimulate mitochondrial biogenesis), which generates new mitochondrial offspring to maintain an adequate mitochondrial number. Energy crises or ATP deficiency also increase mitochondrial biogenesis, because mitochondrial DNA encodes 13 subunits of the electron transport chain (ETC) complexes. Disrupted mitochondrial biogenesis diminishes the mitochondrial mass, accelerates mitochondrial senescence and promotes mitochondrial dysfunction. In this review, we describe the involvement of MQC in the pathogenesis of diabetic cardiomyopathy. Besides, the potential targeted therapies that could be applied to improve MQC during diabetic cardiomyopathy are also discussed and accelerate the development of cardioprotective drugs for diabetic patients.
    Keywords:  Diabetic cardiomyopathy; Mitochondrial biogenesis; Mitochondrial fission; Mitochondrial fusion; Mitochondrial quality control; Mitophagy
    DOI:  https://doi.org/10.1016/j.metabol.2022.155313
  7. Hum Mutat. 2022 Sep 18.
    Human Mutation special issue on Innovations in Genomic Diagnostics.
    Stuart A Scott, Kai Wang, Nancy B Spinner.
      This Special Issue of Human Mutation focuses on Innovations in Genomic Diagnostics. The increasing interest in genomic medicine, and the growing possibilities for treatment and management of genetic disease, make complete and accurate diagnosis mission critical. This issue describes leading edge technologies with emerging utility for genomic diagnostics. Genomic testing has dramatically evolved as a result of advances in technology, data analytics, and the continuing pace of disease gene discovery. Since 2011, clinical laboratories have increasingly employed next generation sequencing-based tests in addition to historical techniques to identify a spectrum of germline and somatic variants implicated in human disease. However, common testing platforms have known limitations, including failure to detect disease causing variants in certain regions, inability to identify all variant types, variant phasing, measuring epigenetic changes, and ongoing challenges with variant interpretation. Innovative solutions are emerging, including increasingly rapid genome sequencing, long-read sequencing, clinical RNA sequencing, epigenomic profiling, facial phenotyping, and an array of computational tools for variant identification and interpretation. This article is protected by copyright. All rights reserved.
    Keywords:  Genome sequencing; RNA sequencing; cancer genomics; clinical bioinformatics.; clinical epigenomics; cytogenomics; long-read sequencing
    DOI:  https://doi.org/10.1002/humu.24474
  8. Int J Mol Med. 2022 Nov;pii: 135. [Epub ahead of print]50(5):
    The impact of diet upon mitochondrial physiology (Review).
    Ioannis D Kyriazis, Eleni Vassi, Maria Alvanou, Christos Angelakis, Zoi Skaperda, Fotios Tekos, Venkata Naga Srikanth Garikipati, Demetrios A Spandidos, Demetrios Kouretas.
      Mitochondria are considered the 'powerhouses' of cells, generating the essential energy in the form of adenosine triphosphate that they need for their energy demands. Nevertheless, their function is easily adaptable as regards the energy demands and the availability of chemical substrates. This allows cells to buffer sudden changes and reassure cellular metabolism, growth or survival. Currently, humans have different dietary habits, which provide several stimuli to the cell. According to the energy substrate availability due to the diet quality and diet temporality, mitochondrial physiology is greatly affected. The present review article aimed to collect all the available information that has been published to date concerning the impact of five different popular diets (high‑fat diet, ketogenic diet, fasting, caloric restriction diet and the Mediterranean diet) on specific mitochondrial physiological aspects, such as function, biogenesis, mitophagy and mitochondrial fission/fusion.
    Keywords:  biogenesis; caloric restriction; dynamics; fasting; high‑fat diet; ketogenic; mitochondria; mitophagy; physiology
    DOI:  https://doi.org/10.3892/ijmm.2022.5191
  9. Cell Rep. 2022 Sep 20. pii: S2211-1247(22)01196-2. [Epub ahead of print]40(12): 111364
    ORP5/8 and MIB/MICOS link ER-mitochondria and intra-mitochondrial contacts for non-vesicular transport of phosphatidylserine.
    Vera F Monteiro-Cardoso, Leila Rochin, Amita Arora, Audrey Houcine, Eeva Jääskeläinen, Annukka M Kivelä, Cécile Sauvanet, Romain Le Bars, Eyra Marien, Jonas Dehairs, Julie Neveu, Naima El Khallouki, Elena Santonico, Johannes V Swinnen, David Tareste, Vesa M Olkkonen, Francesca Giordano.
      Mitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the mitochondrial intermembrane space. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that the main physiological localization of the lipid transfer proteins ORP5 and ORP8 is at mitochondria-associated ER membrane (MAM) subdomains, physically linked to the mitochondrial intermembrane space bridging (MIB)/mitochondrial contact sites and cristae junction organizing system (MICOS) complexes that bridge the two mitochondrial membranes. We also show that ORP5/ORP8 mediate non-vesicular transport of phosphatidylserine (PS) lipids from the ER to mitochondria by cooperating with the MIB/MICOS complexes. Overall our study reveals a physical and functional link between ER-mitochondria contacts involved in lipid transfer and intra-mitochondrial membrane contacts maintained by the MIB/MICOS complexes.
    Keywords:  CP: Cell biology; MAM; MICOS; Mic60; ORP; SAM50; cristae junctions; membrane contact sites; mitochondria; phosphatidylserine
    DOI:  https://doi.org/10.1016/j.celrep.2022.111364
  10. Stem Cell Res. 2022 Sep 15. pii: S1873-5061(22)00269-0. [Epub ahead of print]64 102920
    RNA-based generation of iPSCs from a boy carrying the mutation m.9185 T>C in the mitochondrial gene MT-ATP6 and from his healthy mother.
    Tabea Steiner, Annika Zink, Marie-Therese Henke, Giulia Cecchetto, Miriam Buenning, Andrea Rossi, Markus Schuelke, Alessandro Prigione.
      We used a non-integrative self-replicating RNA vector to establish four iPSC lines: two iPSC lines from a young male carrying the mutation m.9185 T>C in the mitochondrial gene MT-ATP6 (present at virtual homoplasmic level), and two iPSC lines from his healthy mother (carrying the mutation in only about 4 % of mtDNA copies). All iPSC lines exhibited pluripotency characteristics, were capable to give rise to cells of the three germ layers in vitro, and presented a normal karyotype. The derived iPSC lines retained the MT-ATP6 mutation at levels similar to those observed in the parental fibroblasts.
    DOI:  https://doi.org/10.1016/j.scr.2022.102920
  11. Nature. 2022 Sep 21.
    CLN3 is required for the clearance of glycerophosphodiesters from lysosomes.
    Nouf N Laqtom, Wentao Dong, Uche N Medoh, Andrew L Cangelosi, Vimisha Dharamdasani, Sze Ham Chan, Tenzin Kunchok, Caroline A Lewis, Ivonne Heinze, Rachel Tang, Christian Grimm, An N Dang Do, Forbes D Porter, Alessandro Ori, David M Sabatini, Monther Abu-Remaileh.
      Lysosomes have many roles, including degrading macromolecules and signalling to the nucleus1. Lysosomal dysfunction occurs in various human conditions, such as common neurodegenerative diseases and monogenic lysosomal storage disorders (LSDs)2-4. For most LSDs, the causal genes have been identified but, in some, the function of the implicated gene is unknown, in part because lysosomes occupy a small fraction of the cellular volume so that changes in lysosomal contents are difficult to detect. Here we develop the LysoTag mouse for the tissue-specific isolation of intact lysosomes that are compatible with the multimodal profiling of their contents. We used the LysoTag mouse to study CLN3, a lysosomal transmembrane protein with an unknown function. In children, the loss of CLN3 causes juvenile neuronal ceroid lipofuscinosis (Batten disease), a lethal neurodegenerative LSD. Untargeted metabolite profiling of lysosomes from the brains of mice lacking CLN3 revealed a massive accumulation of glycerophosphodiesters (GPDs)-the end products of glycerophospholipid catabolism. GPDs also accumulate in the lysosomes of CLN3-deficient cultured cells and we show that CLN3 is required for their lysosomal egress. Loss of CLN3 also disrupts glycerophospholipid catabolism in the lysosome. Finally, we found elevated levels of glycerophosphoinositol in the cerebrospinal fluid of patients with Batten disease, suggesting the potential use of glycerophosphoinositol as a disease biomarker. Our results show that CLN3 is required for the lysosomal clearance of GPDs and reveal Batten disease as a neurodegenerative LSD with a defect in glycerophospholipid metabolism.
    DOI:  https://doi.org/10.1038/s41586-022-05221-y
  12. STAR Protoc. 2022 Sep 21. pii: S2666-1667(22)00590-1. [Epub ahead of print]3(4): 101710
    Protocol to detect in vitro and in cell ubiquitylation of mitochondrial DNA polymerase gamma by mitochondrial E3 ligase MITOL.
    Mansoor Hussain, Shabnam Saifi, Aftab Mohammed, Sagar Sengupta.
      Mitochondrial polymerase gamma (PolγA) is the only replicative polymerase in mitochondria. To determine PolγA ubiquitylation in cells, Flag-PolγA and MITOL are overexpressed, and subsequently the immunoprecipitated Flag-PolγA is checked for ubiquitylation. Alternately, in vitro synthesized PolγA and MITOL are used to determine whether PolγA is ubiquitylated. Either anti-ubiquitin or anti-Flag antibody is used to detect the ubiquitylated product. Thus, we provide a detailed, reliable, highly reproducible protocol for detecting ubiquitylation of PolγA by MITOL, both in cells and in vitro. For complete details on the use and execution of this protocol, please refer to Hussain et al. (2021).
    Keywords:  Cell biology; Genetics; Molecular biology; Protein biochemistry; Protein expression and purification
    DOI:  https://doi.org/10.1016/j.xpro.2022.101710
  13. Brain. 2022 Sep 22. pii: awac344. [Epub ahead of print]
    The phenotypic spectrum of COX20-associated mitochondrial disorder.
    Rui Ban, Robert Kopajtich, Junlan Lv, Sarah L Stenton, Masaru Shimura, Zhaoxia Wang, Yun Yuan, Junling Wang, Xiaodi Han, Zhimei Liu, Qiang Shi, Chuanqiang Pu, Holger Prokisch, Fang Fang, Matthias Elstner.
      
    DOI:  https://doi.org/10.1093/brain/awac344
  14. Genet Med. 2022 Sep 22. pii: S1098-3600(22)00910-8. [Epub ahead of print]
    BiP inactivation due to loss of the deAMPylation function of FICD causes a motor neuron disease.
    Adriana P Rebelo, Ariel Ruiz, Maike F Dohrn, Melanie Wayand, Amjad Farooq, Matt C Danzi, Danique Beijer, Brooke Aaron, Jana Vandrovcova, Henry Houlden, Leslie Matalonga, Lisa Abreu, Guy Rouleau, Mehrdad A Estiar, Liedewei Van de Vondel, Ziv Gan-Or, Jonathan Baets, Rebecca Schüle, Stephan Zuchner.
      PURPOSE: The chaperone protein BiP is the master regulator of the unfolded protein response in the endoplasmic reticulum. BiP chaperone activity is regulated by the post-translational modification AMPylation, exclusively provided by FICD. We investigated whether FICD variants identified in patients with motor neuron disease could interfere with BiP activity regulation.METHODS: Exome sequencing was performed to identify causative pathogenic variants associated with motor neuron diseases. Functional studies were conducted on fibroblasts from patients to explore the molecular mechanism of the disease.
    RESULTS: We identified biallelic variants in FICD causing a neurodegenerative disease of upper and lower motor neurons. Affected individuals harbor a specific missense variant, Arg374His, positioned in the catalytic motif of the enzyme and important for adenosine triphosphate binding. The mutated residue abolishes intramolecular interaction with the regulatory residue Glu234, essential to inhibit AMPylation and to promote de-AMPylation by FICD. Consequently, fibroblasts from patients with FICD variants have abnormally increased levels of AMPylated and thus inactivated BiP.
    CONCLUSION: Loss of BiP chaperone activity in patients likely results in a chronic impairment of the protein quality control system in the endoplasmic reticulum. These findings will guide the development of therapeutic strategies for motoneuron and related diseases linked to proteotoxic stress.
    Keywords:  Motor neuron disease; Neurodegeneration; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.gim.2022.08.019
  15. Elife. 2022 Sep 23. pii: e79771. [Epub ahead of print]11
    A feed-forward pathway drives LRRK2 kinase membrane recruitment and activation.
    Edmundo G Vides, Ayan Adhikari, Claire Y Chiang, Pawel Lis, Elena Purlyte, Charles Limouse, Justin L Shumate, Elena Spinola-Lasso, Herschel S Dhekne, Dario R Alessi, Suzanne R Pfeffer.
      Activating mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) cause Parkinson's disease and previously we showed that activated LRRK2 phosphorylates a subset of Rab GTPases (Steger et al., 2017). Moreover, Golgi-associated Rab29 can recruit LRRK2 to the surface of the Golgi and activate it there for both auto- and Rab substrate phosphorylation. Here we define the precise Rab29 binding region of the LRRK2 Armadillo domain between residues 360-450 and show that this domain, termed 'Site #1', can also bind additional LRRK2 substrates, Rab8A and Rab10. Moreover, we identify a distinct, N-terminal, higher affinity interaction interface between LRRK2 phosphorylated Rab8 and Rab10 termed 'Site #2', that can retain LRRK2 on membranes in cells to catalyze multiple, subsequent phosphorylation events. Kinase inhibitor washout experiments demonstrate that rapid recovery of kinase activity in cells depends on the ability of LRRK2 to associate with phosphorylated Rab proteins, and phosphorylated Rab8A stimulates LRRK2 phosphorylation of Rab10 in vitro. Reconstitution of purified LRRK2 recruitment onto planar lipid bilayers decorated with Rab10 protein demonstrates cooperative association of only active LRRK2 with phospho-Rab10-containing membrane surfaces. These experiments reveal a feed-forward pathway that provides spatial control and membrane activation of LRRK2 kinase activity.
    Keywords:  biochemistry; cell biology; chemical biology; human
    DOI:  https://doi.org/10.7554/eLife.79771
  16. Nat Genet. 2022 Sep 22.
    SAIGE-GENE+ improves the efficiency and accuracy of set-based rare variant association tests.
    Wei Zhou, Wenjian Bi, Zhangchen Zhao, Kushal K Dey, Karthik A Jagadeesh, Konrad J Karczewski, Mark J Daly, Benjamin M Neale, Seunggeun Lee.
      Several biobanks, including UK Biobank (UKBB), are generating large-scale sequencing data. An existing method, SAIGE-GENE, performs well when testing variants with minor allele frequency (MAF) ≤ 1%, but inflation is observed in variance component set-based tests when restricting to variants with MAF ≤ 0.1% or 0.01%. Here, we propose SAIGE-GENE+ with greatly improved type I error control and computational efficiency to facilitate rare variant tests in large-scale data. We further show that incorporating multiple MAF cutoffs and functional annotations can improve power and thus uncover new gene-phenotype associations. In the analysis of UKBB whole exome sequencing data for 30 quantitative and 141 binary traits, SAIGE-GENE+ identified 551 gene-phenotype associations.
    DOI:  https://doi.org/10.1038/s41588-022-01178-w
  17. Int J Mol Sci. 2022 Sep 18. pii: 10924. [Epub ahead of print]23(18):
    Dual Mode of Mitochondrial ROS Action during Reprogramming to Pluripotency.
    Elena V Skvortsova, Igor B Nazarov, Alexey N Tomilin, Sergey A Sinenko.
      Essential changes in cell metabolism and redox signaling occur during the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). In this paper, using genetic and pharmacological approaches, we have investigated the role of electron transport chain (ETC) complex-I (CI) of mitochondria in the process of cell reprogramming to pluripotency. Knockdown of NADH-ubiquinone oxidoreductase core subunits S1 (Ndufs1) or subunit B10 (Ndufb10) of the CI or inhibition of this complex with rotenone during mouse embryonic fibroblast (MEF) reprogramming resulted in a significantly decreased number of induced pluripotent stem cells (iPSCs). We have found that mitochondria and ROS levels due course of the reprogramming tightly correlate with each other, both reaching peak by day 3 and significantly declining by day 10 of the process. The transient augmentation of mitochondrial reactive oxygen species (ROS) could be attenuated by antioxidant treatment, which ameliorated overall reprogramming. However, ROS scavenging after day 3 or during the entire course of reprogramming was suppressive for iPSC formation. The ROS scavenging within the CI-deficient iPSC-precursors did not improve, but further suppressed the reprogramming. Our data therefore point to distinct modes of mitochondrial ROS action during the early versus mid and late stages of reprogramming. The data further substantiate the paradigm that balanced levels of oxidative phosphorylation have to be maintained on the route to pluripotency.
    Keywords:  Ndufb10; Ndufs1; complex I (CI) of electron transport chain (ETC); hydrogen peroxide; induced pluripotent stem cells (iPSCs); reactive oxygen species (ROS); rotenone; superoxide anion
    DOI:  https://doi.org/10.3390/ijms231810924
  18. Cell Mol Life Sci. 2022 Sep 20. 79(10): 525
    The multiple facets of mitochondrial regulations controlling cellular thermogenesis.
    Florian Beignon, Naig Gueguen, Hélène Tricoire-Leignel, César Mattei, Guy Lenaers.
      Understanding temperature production and regulation in endotherm organisms becomes a crucial challenge facing the increased frequency and intensity of heat strokes related to global warming. Mitochondria, located at the crossroad of metabolism, respiration, Ca2+ homeostasis, and apoptosis, were recently proposed to further act as cellular radiators, with an estimated inner temperature reaching 50 °C in common cell lines. This inner thermogenesis might be further exacerbated in organs devoted to produce consistent efforts as muscles, or heat as brown adipose tissue, in response to acute solicitations. Consequently, pathways promoting respiratory chain uncoupling and mitochondrial activity, such as Ca2+ fluxes, uncoupling proteins, futile cycling, and substrate supplies, provide the main processes controlling heat production and cell temperature. The mitochondrial thermogenesis might be further amplified by cytoplasmic mechanisms promoting the over-consumption of ATP pools. Considering these new thermic paradigms, we discuss here all conventional wisdoms linking mitochondrial functions to cellular thermogenesis in different physiological conditions.
    Keywords:  Energy balance; Mitochondria; Temperature; Thermogenesis; Uncoupling
    DOI:  https://doi.org/10.1007/s00018-022-04523-8
  19. iScience. 2022 Oct 21. 25(10): 105064
    Small molecule SJ572946 activates BAK to initiate apoptosis.
    Giridhar Sekar, Geetika Singh, Xingping Qin, Cristina D Guibao, Brittany Schwam, Zintis Inde, Christy R Grace, Weixing Zhang, P Jake Slavish, Wenwei Lin, Taosheng Chen, Richard E Lee, Zoran Rankovic, Kristopher Sarosiek, Tudor Moldoveanu.
      Poration of the outer mitochondrial membrane by the effector BCL-2 proteins BAK and BAX initiates apoptosis. BH3-only initiators BID and BIM trigger conformational changes in BAK and BAX transforming them from globular dormant proteins to oligomers of the apoptotic pores. Small molecules that can directly activate effectors are being sought for applications in cancer treatment. Here, we describe the small molecule SJ572946, discovered in a fragment-based screen that binds to the activation groove of BAK and selectively triggers BAK activation over that of BAX in liposome and mitochondrial permeabilization assays. SJ572946 independently kills BAK-expressing BCL2allKO HCT116 cells revealing on target cellular activity. In combination with apoptotic inducers and BH3 mimetics, SJ572946 kills experimental cancer cell lines. SJ572946 also cooperates with the endogenous BAK activator BID in activating a misfolded BAK mutant substantially impaired in activation. SJ572946 is a proof-of-concept tool for probing BAK-mediated apoptosis in preclinical cancer research.
    Keywords:  Biochemistry; Cell biology; Small molecule; Structural biology
    DOI:  https://doi.org/10.1016/j.isci.2022.105064
  20. Antioxidants (Basel). 2022 Aug 29. pii: 1698. [Epub ahead of print]11(9):
    Coenzyme Q10 Supplementation in Statin Treated Patients: A Double-Blinded Randomized Placebo-Controlled Trial.
    Tine L Dohlmann, Anja B Kuhlman, Thomas Morville, Maria Dahl, Magnus Asping, Patrick Orlando, Sonia Silvestri, Luca Tiano, Jørn W Helge, Flemming Dela, Steen Larsen.
      Myalgia and new-onset of type 2 diabetes have been associated with statin treatment, which both could be linked to reduced coenzyme Q10 (CoQ10) in skeletal muscle and impaired mitochondrial function. Supplementation with CoQ10 focusing on levels of CoQ10 in skeletal muscle and mitochondrial function has not been investigated in patients treated with statins. To investigate whether concomitant administration of CoQ10 with statins increases the muscle CoQ10 levels and improves the mitochondrial function, and if changes in muscle CoQ10 levels correlate with changes in the intensity of myalgia. 37 men and women in simvastatin therapy with and without myalgia were randomized to receive 400 mg CoQ10 daily or matched placebo tablets for eight weeks. Muscle CoQ10 levels, mitochondrial respiratory capacity, mitochondrial content (using citrate synthase activity as a biomarker), and production of reactive oxygen species were measured before and after CoQ10 supplementation, and intensity of myalgia was determined using the 10 cm visual analogue scale. Muscle CoQ10 content and mitochondrial function were unaltered by CoQ10 supplementation. Individual changes in muscle CoQ10 levels were not correlated with changes in intensity of myalgia. CoQ10 supplementation had no effect on muscle CoQ10 levels or mitochondrial function and did not affect symptoms of myalgia.
    Keywords:  HMG-CoA reductase inhibitor; antioxidant; diet supplementation; mitochondria; myopathy; reactive oxygen species; skeletal muscle
    DOI:  https://doi.org/10.3390/antiox11091698
  21. EMBO Rep. 2022 Sep 20. e54910
    Functional platelet-derived mitochondria induce the release of human neutrophil microvesicles.
    Jacob L Léger, Marie-France N Soucy, Vanessa Veilleux, Robert D Foulem, Gilles A Robichaud, Marc E Surette, Eric P Allain, Luc H Boudreau.
      Inflammation is an essential process of host defense against infections, illness, or tissue damage. Polymorphonuclear neutrophils (PMN) are among the first immune cells involved in acute inflammatory responses and are on the front line in the fight against bacterial infections. In the presence of bacterial fragments, PMN release inflammatory mediators, enzymes, and microvesicles in the extracellular milieu to recruit additional immune cells required to eliminate the pathogens. Recent evidence shows that platelets (PLTs), initially described for their role in coagulation, are involved in inflammatory responses. Furthermore, upon activation, PLT also release functional mitochondria (freeMitos) within their extracellular milieu. Mitochondria share characteristics with bacterial and mitochondrial damage-associated molecular patterns, which are important contributors in sterile inflammation processes. Deep sequencing transcriptome analysis demonstrates that freeMitos increase the mitochondrial gene expression in PMN. However, freeMitos do not affect the mitochondrial-dependent increase in oxygen consumption in PMN. Interestingly, freeMitos significantly induce the release of PMN-derived microvesicles. This study provides new insight into the role of freeMitos in the context of sterile inflammation.
    Keywords:  extracellular vesicles; freeMitos; sterile inflammation
    DOI:  https://doi.org/10.15252/embr.202254910
  22. Int J Cardiol. 2022 Sep 18. pii: S0167-5273(22)01384-5. [Epub ahead of print]
    Clinical profile and outcome of cardiomyopathies in infants and children seen at a tertiary centre.
    M Pagano, C Fumagalli, F Girolami, S Passantino, A Gozzini, A Brambilla, V Spinelli, A Morrone, E Procopio, F Pochiero, M A Donati, I Olivotto, S Favilli.
      INTRODUCTION: Due to their rare prevalence and marked heterogeneity, pediatric cardiomyopathies (CMPs) are little known and scarcely reported. We report the etiology, clinical profile and outcome of a consecutive cohort of children diagnosed with CMP and followed at Meyer Children's Hospital over a decade.PATIENTS AND METHODS: We retrospectively reviewed patients consecutively referred from May 2008 to May 2019 for pediatric onset CMP (<18 years). Heart disease caused by arrhythmic disorders, toxic agents, rheumatic conditions and maternal disease were excluded.
    RESULTS: We enrolled 110 patients (65 males), diagnosed at a median age of 27 [4-134] months; 35% had an infant onset (<1 year of age). A positive family history was more often associated with childhood-onset (38.8%). Hypertrophic cardiomyopathy (HCM; 48 patients) was the most frequent phenotype, followed by dilated cardiomyopathy (DCM; 35 patients). While metabolic and idiopathic etiologies were preponderant in infants, metabolic and sarcomeric diseases were most frequent in the childhood-onset group. Major adverse cardiac events (MACE) occurred in 31.8% of patients, including hospitalization for acute heart failure in 25.5% of patients, most commonly due to DCM. Overall, the most severe outcomes were documented in patients with metabolic diseases.
    CONCLUSIONS: In a consecutive cohort of pediatric patients with CMP, those with infantile onset and with a metabolic etiology had the worst prognosis. Overall, MACE occurred in 41% of the entire population, most commonly associated with DCM, inborn errors of metabolism and genetic syndromes. Systematic NGS genetic testing was critical for etiological diagnosis and management.
    Keywords:  Cardiomyopathies; Childhood-onset; Genetics; Infant-onset; MACE; Pediatrics
    DOI:  https://doi.org/10.1016/j.ijcard.2022.09.034
  23. Proc Natl Acad Sci U S A. 2022 Sep 27. 119(39): e2202178119
    Oxygen regulation of breathing is abolished in mitochondrial complex III-deficient arterial chemoreceptors.
    Daniel Cabello-Rivera, Patricia Ortega-Sáenz, Lin Gao, Ana M Muñoz-Cabello, Victoria Bonilla-Henao, Paul T Schumacker, José López-Barneo.
      Acute oxygen (O2) sensing is essential for adaptation of organisms to hypoxic environments or medical conditions with restricted exchange of gases in the lung. The main acute O2-sensing organ is the carotid body (CB), which contains neurosecretory chemoreceptor (glomus) cells innervated by sensory fibers whose activation by hypoxia elicits hyperventilation and increased cardiac output. Glomus cells have mitochondria with specialized metabolic and electron transport chain (ETC) properties. Reduced mitochondrial complex (MC) IV activity by hypoxia leads to production of signaling molecules (NADH and reactive O2 species) in MCI and MCIII that modulate membrane ion channel activity. We studied mice with conditional genetic ablation of MCIII that disrupts the ETC in the CB and other catecholaminergic tissues. Glomus cells survived MCIII dysfunction but showed selective abolition of responsiveness to hypoxia (increased [Ca2+] and transmitter release) with normal responses to other stimuli. Mitochondrial hypoxic NADH and reactive O2 species signals were also suppressed. MCIII-deficient mice exhibited strong inhibition of the hypoxic ventilatory response and altered acclimatization to sustained hypoxia. These data indicate that a functional ETC, with coupling between MCI and MCIV, is required for acute O2 sensing. O2 regulation of breathing results from the integrated action of mitochondrial ETC complexes in arterial chemoreceptors.
    Keywords:  acute O2 sensing; carotid body glomus cell; hypoxia; mitochondrial O2 sensing and signaling; mitochondrial complex III
    DOI:  https://doi.org/10.1073/pnas.2202178119
  24. Biomed Res Int. 2022 ;2022 5250254
    Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants.
    Dong Woo Nam, Sang Soo Park, So Min Lee, Myung-Whan Suh, Moo Kyun Park, Jae-Jin Song, Byung Yoon Choi, Jun Ho Lee, Seung Ha Oh, Kyung Chul Moon, Yo Han Ahn, Hee Gyung Kang, Hae Il Cheong, Ji Hyun Kim, Sang-Yeon Lee.
      Primary coenzyme Q10 (CoQ10) deficiency refers to a group of mitochondrial cytopathies caused by genetic defects in CoQ10 biosynthesis. Primary coenzyme Q10 deficiency-6 (COQ10D6) is an autosomal recessive disorder attributable to biallelic COQ6 variants; the cardinal phenotypes are steroid-resistant nephrotic syndrome (SRNS), which inevitably progresses to kidney failure, and sensorineural hearing loss (SNHL). Here, we describe the phenotypes and genotypes of 12 children with COQ10D6 from 11 unrelated Korean families and quantitatively explore the beneficial effects of CoQ10 replacement therapy on SNHL. A diagnosis of SRNS generally precedes SNHL documentation. COQ10D6 is associated with progressive SNHL. Four causative COQ6 variants were identified in either homozygotes or compound heterozygotes: c.189_191delGAA, c.484C>T, c.686A>C, and c.782C>T. The response rate (no further hearing loss or improvement) was 42.9%; CoQ10 replacement therapy may thus limit and even improve hearing loss. Notably, the audiological benefit appeared to be genotype-specific, suggesting a genotype-phenotype correlation. The results of cochlear implantation were generally favorable, and the effects were sustained over time. Our results thus propose the beneficial effects of CoQ10 replacement therapy on hearing loss. Our work with COQ10D6 patients is a good example of personalized, genetically tailored, audiological rehabilitation of patients with syndromic deafness.
    DOI:  https://doi.org/10.1155/2022/5250254
  25. Metabolites. 2022 Aug 24. pii: 779. [Epub ahead of print]12(9):
    Targeted Proteomics for Monitoring One-Carbon Metabolism in Liver Diseases.
    Laura Guerrero, Alberto Paradela, Fernando J Corrales.
      Liver diseases cause approximately 2 million deaths per year worldwide and had an increasing incidence during the last decade. Risk factors for liver diseases include alcohol consumption, obesity, diabetes, the intake of hepatotoxic substances like aflatoxin, viral infection, and genetic determinants. Liver cancer is the sixth most prevalent cancer and the third in mortality (second in males). The low survival rate (less than 20% in 5 years) is partially explained by the late diagnosis, which remarks the need for new early molecular biomarkers. One-carbon metabolism integrates folate and methionine cycles and participates in essential cell processes such as redox homeostasis maintenance and the regulation of methylation reactions through the production of intermediate metabolites such as cysteine and S-Adenosylmethionine. One-carbon metabolism has a tissue specific configuration, and in the liver, the participating enzymes are abundantly expressed-a requirement to maintain hepatocyte differentiation. Targeted proteomics studies have revealed significant differences in hepatocellular carcinoma and cirrhosis, suggesting that monitoring one-carbon metabolism enzymes can be useful for stratification of liver disease patients and to develop precision medicine strategies for their clinical management. Here, reprogramming of one-carbon metabolism in liver diseases is described and the role of mass spectrometry to follow-up these alterations is discussed.
    Keywords:  hepatocellular carcinoma; liver disease; one-carbon metabolism; proteomics
    DOI:  https://doi.org/10.3390/metabo12090779
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