bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2023‒05‒21
58 papers selected by
Catalina Vasilescu
Helmholz Munich
  1. Exploring mitochondrial morphology in skeletal muscle: Implications for highly trained individuals.
  2. Mitochondria and the eye-manifestations of mitochondrial diseases and their management.
  3. A Scoping Review Investigating the "Gene-Dosage Theory" of Mitochondrial DNA in the Healthy Skeletal Muscle.
  4. MitoQuicLy: a high-throughput method for quantifying cell-free DNA from human plasma, serum, and saliva.
  5. Cellular and Mitochondrial NAD Homeostasis in Health and Disease.
  6. The role of the proteasome in mitochondrial protein quality control.
  7. First baby born in the UK using mitochondrial donation therapy.
  8. Conserved cardiolipin-mitochondrial ADP/ATP carrier interactions assume distinct structural and functional roles that are clinically relevant.
  9. Mitochondrial Dynamics during Development.
  10. Mitochondrial Ca2+ signaling and Alzheimer's disease: Too much or too little?
  11. Inflamed macrophages sans mitochondrial pyruvate carrier?
  12. The Role of Exercise in Maintaining Mitochondrial Proteostasis in Parkinson's Disease.
  13. New avenues for therapy in mitochondrial optic neuropathies.
  14. y-mtPTM: Yeast Mitochondrial Post-Translational Modification Database.
  15. A case of infantile Barth syndrome with severe heart failure: Importance of splicing variants in the TAZ gene.
  16. The mitochondrial intermembrane space protein mitofissin drives mitochondrial fission required for mitophagy.
  17. Recent advances and new perspectives in mitochondrial dysfunction.
  18. The cyclic lipopeptide micafungin induces rupture of isolated mitochondria by reprograming the mitochondrial inner membrane anion channel.
  19. Low mitochondrial DNA copy number in buffy coat DNA of primary open-angle glaucoma patients.
  20. Combined Clinical, Molecular, and Muscle Biopsy Approach to Unveil Prevalence and Clinical Features of Rare Neuromuscular and Mitochondrial Diseases in Patients With Cardiomyopathies.
  21. HIF-1 signaling: an emerging mechanism for mitochondrial dynamics.
  22. Mitochondria are midfield players in steroid synthesis.
  23. Mechanisms of mitochondrial microRNA regulation in cardiovascular diseases.
  24. Mitochondrial dysfunction in glaucomatous degeneration.
  25. Polγ coordinates DNA synthesis and proofreading to ensure mitochondrial genome integrity.
  26. Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.
  27. The contribution of mitochondrial DNA alterations to aging, cancer, and neurodegeneration.
  28. Submitochondrial Protein Translocation Upon Stress Inhibits Thermogenic Energy Expenditure.
  29. Identification of peripheral vascular function measures and circulating biomarkers of mitochondrial function in patients with mitochondrial disease.
  30. A small protein coded within the mitochondrial canonical gene nd4 regulates mitochondrial bioenergetics.
  31. Metatranscriptomic analysis uncovers prevalent viral ORFs compatible with mitochondrial translation.
  32. Mitochondrial dysfunction in aging.
  33. Weight loss increases skeletal muscle mitochondrial energy efficiency in obese mice.
  34. Inhibiting de novo ceramide synthesis restores mitochondrial and protein homeostasis in muscle aging.
  35. Integration of Metabolomic and Proteomic Data to Uncover Actionable Metabolic Pathways.
  36. Human TRMT1 catalyzes m2G or m22G formation on tRNAs in a substrate-dependent manner.
  37. Rapid protein stability prediction using deep learning representations.
  38. Whole-genome long-read sequencing downsampling and its effect on variant calling precision and recall.
  39. Earlier second polar body transfer and further mitochondrial carryover removal for potential mitochondrial replacement therapy.
  40. Clinical spectrum and genetic causes of mitochondrial hepatopathy phenotype in children.
  41. Mitochondrial genome editing: Get aCcess to modeling broad disease mutations with engineered base editors.
  42. USP8 Down-Regulation Promotes Parkin-Independent Mitophagy in the Drosophila Brain and in Human Neurons.
  43. Improving variant calling using population data and deep learning.
  44. Introme accurately predicts the impact of coding and noncoding variants on gene splicing, with clinical applications.
  45. Mechanism of rotenone binding to respiratory complex I depends on ligand flexibility.
  46. The Y831C Mutation of the POLG Gene in Dementia.
  47. Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages.
  48. Mitochondria Transplantation from Stem Cell for Mitigating Sarcopenia.
  49. A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production.
  50. Mitochondrial Dynamics: Working with the Cytoskeleton and Intracellular Organelles to Mediate Mechanotransduction.
  51. Frontotemporal Dementia-Related V57E Mutation Impairs Mitochondrial Function and Alters the Structural Properties of CHCHD10.
  52. Breeze 2.0: an interactive web-tool for visual analysis and comparison of drug response data.
  53. A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides.
  54. CRMP2 Participates in Regulating Mitochondrial Morphology and Motility in Alzheimer's Disease.
  55. Rare penetrant mutations confer severe risk of common diseases.
  56. NAD+-dependent mechanism of pathological axon degeneration.
  57. Annotating and prioritizing human non-coding variants with RegulomeDB v.2.
  58. ODNA: Identification of Organellar DNA by Machine Learning.
  1. J Physiol. 2023 May 18.
    Exploring mitochondrial morphology in skeletal muscle: Implications for highly trained individuals.
    Blair MacLeod.
      
    Keywords:  mitochondria; mitochondrial cristae; resistance exercise; skeletal muscle; strength training; weightlifting
    DOI:  https://doi.org/10.1113/JP284873
  2. Eye (Lond). 2023 Apr 25.
    Mitochondria and the eye-manifestations of mitochondrial diseases and their management.
    Benson S Chen, Joshua P Harvey, Michael J Gilhooley, Neringa Jurkute, Patrick Yu-Wai-Man.
      Historically, distinct mitochondrial syndromes were recognised clinically by their ocular features. Due to their predilection for metabolically active tissue, mitochondrial diseases frequently involve the eye, resulting in a range of ophthalmic manifestations including progressive external ophthalmoplegia, retinopathy and optic neuropathy, as well as deficiencies of the retrochiasmal visual pathway. With the wider availability of genetic testing in clinical practice, it is now recognised that genotype-phenotype correlations in mitochondrial diseases can be imprecise: many classic syndromes can be associated with multiple genes and genetic variants, and the same genetic variant can have multiple clinical presentations, including subclinical ophthalmic manifestations in individuals who are otherwise asymptomatic. Previously considered rare diseases with no effective treatments, considerable progress has been made in our understanding of mitochondrial diseases with new therapies emerging, in particular, gene therapy for inherited optic neuropathies.
    DOI:  https://doi.org/10.1038/s41433-023-02523-x
  3. Int J Mol Sci. 2023 May 02. pii: 8154. [Epub ahead of print]24(9):
    A Scoping Review Investigating the "Gene-Dosage Theory" of Mitochondrial DNA in the Healthy Skeletal Muscle.
    Zandra Overgaard Pedersen, Britt Staevnsbo Pedersen, Steen Larsen, Tina Dysgaard.
      This review provides an overview of the evidence regarding mtDNA and valid biomarkers for assessing mitochondrial adaptions. Mitochondria are small organelles that exist in almost all cells throughout the human body. As the only organelle, mitochondria contain their own DNA, mitochondrial DNA (mtDNA). mtDNA-encoded polypeptides are subunits of the enzyme complexes in the electron transport chain (ETC) that are responsible for production of ATP to the cells. mtDNA is frequently used as a biomarker for mitochondrial content, since changes in mitochondrial volume are thought to induce similar changes in mtDNA. However, some exercise studies have challenged this "gene-dosage theory", and have indicated that changes in mitochondrial content can adapt without changes in mtDNA. Thus, the aim of this scoping review was to summarize the studies that used mtDNA as a biomarker for mitochondrial adaptions and address the question as to whether changes in mitochondrial content, induce changes in mtDNA in response to aerobic exercise in the healthy skeletal muscle. The literature was searched in PubMed and Embase. Eligibility criteria included: interventional study design, aerobic exercise, mtDNA measurements reported pre- and postintervention for the healthy skeletal muscle and English language. Overall, 1585 studies were identified. Nine studies were included for analysis. Eight out of the nine studies showed proof of increased oxidative capacity, six found improvements in mitochondrial volume, content and/or improved mitochondrial enzyme activity and seven studies did not find evidence of change in mtDNA copy number. In conclusion, the findings imply that mitochondrial adaptions, as a response to aerobic exercise, can occur without a change in mtDNA copy number.
    Keywords:  CS; aerobic exercise; citrate synthase; electron transport chain; mitochondrial DNA; mitochondrial adaptions; mitochondrial content; mtDNA
    DOI:  https://doi.org/10.3390/ijms24098154
  4. Mitochondrion. 2023 May 10. pii: S1567-7249(23)00038-7. [Epub ahead of print]
    MitoQuicLy: a high-throughput method for quantifying cell-free DNA from human plasma, serum, and saliva.
    Jeremy Michelson, Shannon Rausser, Amanda Peng, Temmie Yu, Gabriel Sturm, Caroline Trumpff, Brett A Kaufman, Alex J Rai, Martin Picard.
      Circulating cell-free mitochondrial DNA (cf-mtDNA) is an emerging biomarker of psychobiological stress and disease which predicts mortality and is associated with various disease states. To evaluate the contribution of cf-mtDNA to health and disease states, standardized high-throughput procedures are needed to quantify cf-mtDNA in relevant biofluids. Here, we describe MitoQuicLy: Mitochondrial DNA Quantification in cell-free samples by Lysis. We demonstrate high agreement between MitoQuicLy and the commonly used column-based method, although MitoQuicLy is faster, cheaper, and requires a smaller input sample volume. Using 10 µL of input volume with MitoQuicLy, we quantify cf-mtDNA levels from three commonly used plasma tube types, two serum tube types, and saliva. We detect, as expected, significant inter-individual differences in cf-mtDNA across different biofluids. However, cf-mtDNA levels between concurrently collected plasma, serum, and saliva from the same individual differ on average by up to two orders of magnitude and are poorly correlated with one another, pointing to different cf-mtDNA biology or regulation between commonly used biofluids in clinical and research settings. Moreover, in a small sample of healthy women and men (n=34), we show that blood and saliva cf-mtDNAs correlate with clinical biomarkers differently depending on the sample used. The biological divergences revealed between biofluids, together with the lysis-based, cost-effective, and scalable MitoQuicLy protocol for biofluid cf-mtDNA quantification, provide a foundation to examine the biological origin and significance of cf-mtDNA to human health.
    Keywords:  Cell-free DNA; Circulating nucleic acids; DNA isolation; Mitochondria; Mitochondrial DNA; Protocol
    DOI:  https://doi.org/10.1016/j.mito.2023.05.001
  5. Cells. 2023 05 06. pii: 1329. [Epub ahead of print]12(9):
    Cellular and Mitochondrial NAD Homeostasis in Health and Disease.
    Jaylyn Waddell, Rehana Khatoon, Tibor Kristian.
      The mitochondrion has a unique position among other cellular organelles due to its dynamic properties and symbiotic nature, which is reflected in an active exchange of metabolites and cofactors between the rest of the intracellular compartments. The mitochondrial energy metabolism is greatly dependent on nicotinamide adenine dinucleotide (NAD) as a cofactor that is essential for both the activity of respiratory and TCA cycle enzymes. The NAD level is determined by the rate of NAD synthesis, the activity of NAD-consuming enzymes, and the exchange rate between the individual subcellular compartments. In this review, we discuss the NAD synthesis pathways, the NAD degradation enzymes, and NAD subcellular localization, as well as NAD transport mechanisms with a focus on mitochondria. Finally, the effect of the pathologic depletion of mitochondrial NAD pools on mitochondrial proteins' post-translational modifications and its role in neurodegeneration will be reviewed. Understanding the physiological constraints and mechanisms of NAD maintenance and the exchange between subcellular compartments is critical given NAD's broad effects and roles in health and disease.
    Keywords:  NAD; brain; mitochondria
    DOI:  https://doi.org/10.3390/cells12091329
  6. IUBMB Life. 2023 May 13.
    The role of the proteasome in mitochondrial protein quality control.
    Saskia Rödl, Johannes M Herrmann.
      The abundance of each cellular protein is dynamically adjusted to the prevailing metabolic and stress conditions by modulation of their synthesis and degradation rates. The proteasome represents the major machinery for the degradation of proteins in eukaryotic cells. How the ubiquitin-proteasome system (UPS) controls protein levels and removes superfluous and damaged proteins from the cytosol and the nucleus is well characterized. However, recent studies showed that the proteasome also plays a crucial role in mitochondrial protein quality control. This mitochondria-associated degradation (MAD) thereby acts on two layers: first, the proteasome removes mature, functionally compromised or mis-localized proteins from the mitochondrial surface; and second, the proteasome cleanses the mitochondrial import pore of import intermediates of nascent proteins that are stalled during translocation. In this review, we provide an overview about the components and their specific functions that facilitate proteasomal degradation of mitochondrial proteins in the yeast Saccharomyces cerevisiae. Thereby we explain how the proteasome, in conjunction with a set of intramitochondrial proteases, maintains mitochondrial protein homeostasis and dynamically adapts the levels of mitochondrial proteins to specific conditions.
    Keywords:  mitochondria; mitochondria-associated degradation; proteasome; protein degradation; protein import; ubiquitin
    DOI:  https://doi.org/10.1002/iub.2734
  7. BMJ. 2023 05 12. 381 1091
    First baby born in the UK using mitochondrial donation therapy.
    Jacqui Wise.
      
    DOI:  https://doi.org/10.1136/bmj.p1091
  8. bioRxiv. 2023 May 06. pii: 2023.05.05.539595. [Epub ahead of print]
    Conserved cardiolipin-mitochondrial ADP/ATP carrier interactions assume distinct structural and functional roles that are clinically relevant.
    Nanami Senoo, Dinesh K Chinthapalli, Matthew G Baile, Vinaya K Golla, Bodhisattwa Saha, Oluwaseun B Ogunbona, James A Saba, Teona Munteanu, Yllka Valdez, Kevin Whited, Dror Chorev, Nathan N Alder, Eric R May, Carol V Robinson, Steven M Claypool.
      The mitochondrial phospholipid cardiolipin (CL) promotes bioenergetics via oxidative phosphorylation (OXPHOS). Three tightly bound CLs are evolutionarily conserved in the ADP/ATP carrier (AAC in yeast; adenine nucleotide translocator, ANT in mammals) which resides in the inner mitochondrial membrane and exchanges ADP and ATP to enable OXPHOS. Here, we investigated the role of these buried CLs in the carrier using yeast Aac2 as a model. We introduced negatively charged mutations into each CL-binding site of Aac2 to disrupt the CL interactions via electrostatic repulsion. While all mutations disturbing the CL-protein interaction destabilized Aac2 monomeric structure, transport activity was impaired in a pocket-specific manner. Finally, we determined that a disease-associated missense mutation in one CL-binding site in ANT1 compromised its structure and transport activity, resulting in OXPHOS defects. Our findings highlight the conserved significance of CL in AAC/ANT structure and function, directly tied to specific lipid-protein interactions.
    DOI:  https://doi.org/10.1101/2023.05.05.539595
  9. Newborn (Clarksville). 2023 Jan-Mar;2(1):2(1): 19-44
    Mitochondrial Dynamics during Development.
    Ling He, Karl Johan Tronstad, Akhil Maheshwari.
      Mitochondria are dynamic membrane-bound organelles in eukaryotic cells. These are important for the generation of chemical energy needed to power various cellular functions and also support metabolic, energetic, and epigenetic regulation in various cells. These organelles are also important for communication with the nucleus and other cellular structures, to maintain developmental sequences and somatic homeostasis, and for cellular adaptation to stress. Increasing information shows mitochondrial defects as an important cause of inherited disorders in different organ systems. In this article, we provide an extensive review of ontogeny, ultrastructural morphology, biogenesis, functional dynamics, important clinical manifestations of mitochondrial dysfunction, and possibilities for clinical intervention. We present information from our own clinical and laboratory research in conjunction with information collected from an extensive search in the databases PubMed, EMBASE, and Scopus.
    Keywords:  Archezoan; Inner membrane; Intermembrane space; Matrix; Mitochondrial DNA; Mitophagy; Neonate; Ontogeny; Outer membrane; Parkin
    DOI:  https://doi.org/10.5005/jp-journals-11002-0053
  10. Cell Calcium. 2023 May 11. pii: S0143-4160(23)00069-6. [Epub ahead of print]113 102757
    Mitochondrial Ca2+ signaling and Alzheimer's disease: Too much or too little?
    Paloma Garcia-Casas, Michela Rossini, Riccardo Filadi, Paola Pizzo.
      Alzheimer's disease (AD) is a neurodegenerative disease, caused by poorly known pathogenic mechanisms and aggravated by delayed therapeutic intervention, that still lacks an effective cure. However, it is clear that some important neurophysiological processes are altered years before the onset of clinical symptoms, offering the possibility of identifying biological targets useful for implementation of new therapies. Of note, evidence has been provided suggesting that mitochondria, pivotal organelles in sustaining neuronal energy demand and modulating synaptic activity, are dysfunctional in AD samples. In particular, alterations in mitochondrial Ca2+ signaling have been proposed as causal events for neurodegeneration, although the exact outcomes and molecular mechanisms of these defects, as well as their longitudinal progression, are not always clear. Here, we discuss the importance of a correct mitochondrial Ca2+ handling for neuronal physiology and summarize the latest findings on dysfunctional mitochondrial Ca2+ pathways in AD, analysing possible consequences contributing to the neurodegeneration that characterizes the disease.
    Keywords:  Alzheimer's disease; ER-mitochondria contacts; MCU; Mitochondrial calcium signaling; NCLX; Presenilin
    DOI:  https://doi.org/10.1016/j.ceca.2023.102757
  11. Nat Metab. 2023 May 15.
    Inflamed macrophages sans mitochondrial pyruvate carrier?
    Laurent Yvan-Charvet, Edward Benjamin Thorp.
      
    DOI:  https://doi.org/10.1038/s42255-023-00789-9
  12. Int J Mol Sci. 2023 Apr 28. pii: 7994. [Epub ahead of print]24(9):
    The Role of Exercise in Maintaining Mitochondrial Proteostasis in Parkinson's Disease.
    Jingwen Li, Yanli Xu, Tingting Liu, Yuxiang Xu, Xiantao Zhao, Jianshe Wei.
      Parkinson's disease (PD) is the second most common rapidly progressive neurodegenerative disease and has serious health and socio-economic consequences. Mitochondrial dysfunction is closely related to the onset and progression of PD, and the use of mitochondria as a target for PD therapy has been gaining traction in terms of both recognition and application. The disruption of mitochondrial proteostasis in the brain tissue of PD patients leads to mitochondrial dysfunction, which manifests as mitochondrial unfolded protein response, mitophagy, and mitochondrial oxidative phosphorylation. Physical exercise is important for the maintenance of human health, and has the great advantage of being a non-pharmacological therapy that is non-toxic, low-cost, and universally applicable. In this review, we investigate the relationships between exercise, mitochondrial proteostasis, and PD and explore the role and mechanisms of mitochondrial proteostasis in delaying PD through exercise.
    Keywords:  Parkinson’s disease; exercise; mitochondria; mitochondrial proteostasis; neurodegenerative disease
    DOI:  https://doi.org/10.3390/ijms24097994
  13. Ther Adv Rare Dis. 2021 Jan-Dec;2:2 26330040211029037
    New avenues for therapy in mitochondrial optic neuropathies.
    Wing Sum Vincent Ng, Matthieu Trigano, Thomas Freeman, Carmine Varrichio, Dinesh Kumar Kandaswamy, Ben Newland, Andrea Brancale, Malgorzata Rozanowska, Marcela Votruba.
      Mitochondrial optic neuropathies are a group of optic nerve atrophies exemplified by the two commonest conditions in this group, autosomal dominant optic atrophy (ADOA) and Leber's hereditary optic neuropathy (LHON). Their clinical features comprise reduced visual acuity, colour vision deficits, centro-caecal scotomas and optic disc pallor with thinning of the retinal nerve fibre layer. The primary aetiology is genetic, with underlying nuclear or mitochondrial gene mutations. The primary pathology is owing to retinal ganglion cell dysfunction and degeneration. There is currently only one approved treatment and no curative therapy is available. In this review we summarise the genetic and clinical features of ADOA and LHON and then examine what new avenues there may be for therapeutic intervention. The therapeutic strategies to manage LHON and ADOA can be split into four categories: prevention, compensation, replacement and repair. Prevention is technically an option by modifying risk factors such as smoking cessation, or by utilising pre-implantation genetic diagnosis, although this is unlikely to be applied in mitochondrial optic neuropathies due to the non-life threatening and variable nature of these conditions. Compensation involves pharmacological interventions that ameliorate the mitochondrial dysfunction at a cellular and tissue level. Replacement and repair are exciting new emerging areas. Clinical trials, both published and underway, in this area are likely to reveal future potential benefits, since new therapies are desperately needed.Plain language summary: Optic nerve damage leading to loss of vision can be caused by a variety of insults. One group of conditions leading to optic nerve damage is caused by defects in genes that are essential for cells to make energy in small organelles called mitochondria. These conditions are known as mitochondrial optic neuropathies and two predominant examples are called autosomal dominant optic atrophy and Leber's hereditary optic neuropathy. Both conditions are caused by problems with the energy powerhouse of cells: mitochondria. The cells that are most vulnerable to this mitochondrial malfunction are called retinal ganglion cells, otherwise collectively known as the optic nerve, and they take the electrical impulse from the retina in the eye to the brain. The malfunction leads to death of some of the optic nerve cells, the degree of vision loss being linked to the number of those cells which are impacted in this way. Patients will lose visual acuity and colour vision and develop a central blind spot in their field of vision. There is currently no cure and very few treatment options. New treatments are desperately needed for patients affected by these devastating diseases. New treatments can potentially arise in four ways: prevention, compensation, replacement and repair of the defects. Here we explore how present and possible future treatments might provide hope for those suffering from these conditions.
    Keywords:  LHON; OPA1; mitochondria; mitochondrial dysfunction; optic neuropathy; therapy
    DOI:  https://doi.org/10.1177/26330040211029037
  14. Genetics. 2023 May 15. pii: iyad087. [Epub ahead of print]
    y-mtPTM: Yeast Mitochondrial Post-Translational Modification Database.
    Bronislava Brejová, Veronika Vozáriková, Ivan Agarský, Hana Derková, Matej Fedor, Dominika Harmanová, Lukáš Kiss, Andrej Korman, Martin Pašen, Filip Brázdovič, Tomáš Vinař, Jozef Nosek, Ľubomír Tomáška.
      One powerful strategy of how to increase the complexity of cellular proteomes is through post-translational modifications (PTMs) of proteins. Currently there are approximately 400 types of PTMs, the different combinations of which yield a large variety of protein isoforms with distinct biochemical properties. Although mitochondrial proteins undergoing PTMs were identified nearly six decades ago, studies on the roles and extent of PTMs on mitochondrial functions lagged behind the other cellular compartments. The application of mass spectrometry for the characterization of the mitochondrial proteome as well as for the detection of various PTMs resulted in the identification of thousands of amino acid positions that can be modified by different chemical groups. However, the data on mitochondrial PTMs are scattered in several datasets, and the available databases do not contain a complete list of modified residues. To integrate information on PTMs of the mitochondrial proteome of the yeast Saccharomyces cerevisiae, we built the y-mtPTM (Yeast Mitochondrial Post-Translational Modification) Database (http://compbio.fmph.uniba.sk/y-mtptm/). It lists nearly 20,000 positions on mitochondrial proteins affected by approximately twenty various PTMs, with phosphorylated, succinylated, acetylated and ubiquitylated sites being the most abundant. A simple search of a protein of interest reveals the modified amino acid residues, their position within the primary sequence as well as on its 3D structure and links to the source reference(s). The database will serve yeast mitochondrial researchers as a comprehensive platform to investigate the functional significance of the PTMs of mitochondrial proteins.
    Keywords:  acetylation; database; mitochondria; phosphorylation; post-translational modifications; succinylation; yeast
    DOI:  https://doi.org/10.1093/genetics/iyad087
  15. Mol Genet Genomic Med. 2023 Apr 25. e2190
    A case of infantile Barth syndrome with severe heart failure: Importance of splicing variants in the TAZ gene.
    Atsuhito Takeda, Masahiro Ueki, Jiro Abe, Kazuhiro Maeta, Tomoko Horiguchi, Hirokuni Yamazawa, Gaku Izumi, Ayako Chida-Nagai, Daisuke Sasaki, Takao Tsujioka, Itsumi Sato, Masahiro Shiraishi, Masafumi Matsuo.
      Barth syndrome (BTHS) is an X-linked disorder characterized by cardiomyopathy, skeletal myopathy, and 3-methylglutaconic aciduria. The causative pathogenic variants for BTHS are in TAZ, which encodes a putative acyltransferase named tafazzin and is involved in the remodeling of cardiolipin in the inner mitochondrial membranes. Pathogenic variants in TAZ result in mitochondrial structural and functional abnormalities. We report a case of infantile BTHS with severe heart failure, left ventricular noncompaction, and lactic acidosis, having a missense c.640C>T (p.His214Tyr) variant in TAZ, which is considered a pathogenic variant based on the previously reported amino acid substitution at the same site (c.641A>G, p.His214Arg). However, in this previously reported case, heart function was compensated and not entirely similar to the present case. Silico prediction analysis suggested that c.640C>T could alter the TAZ messenger RNA (mRNA) splicing process. TAZ mRNAs in isolated peripheral mononuclear cells from the patient and in vitro splicing analysis using minigenes of TAZ found an 8 bp deletion at the 3' end of exon 8, which resulted in the formation of a termination codon in the coding region of exon 9 (H214Nfs*3). These findings suggest that splicing abnormalities should always be considered in BTHS.
    Keywords:  Barth syndrome; cardiomyopathy; left ventricular noncompaction; minigene; splicing variants
    DOI:  https://doi.org/10.1002/mgg3.2190
  16. Mol Cell. 2023 May 06. pii: S1097-2765(23)00316-7. [Epub ahead of print]
    The mitochondrial intermembrane space protein mitofissin drives mitochondrial fission required for mitophagy.
    Tomoyuki Fukuda, Kentaro Furukawa, Tatsuro Maruyama, Shun-Ichi Yamashita, Daisuke Noshiro, Chihong Song, Yuta Ogasawara, Kentaro Okuyama, Jahangir Md Alam, Manabu Hayatsu, Tetsu Saigusa, Keiichi Inoue, Kazuho Ikeda, Akira Takai, Lin Chen, Vikramjit Lahiri, Yasushi Okada, Shinsuke Shibata, Kazuyoshi Murata, Daniel J Klionsky, Nobuo N Noda, Tomotake Kanki.
      Mitophagy plays an important role in mitochondrial homeostasis by selective degradation of mitochondria. During mitophagy, mitochondria should be fragmented to allow engulfment within autophagosomes, whose capacity is exceeded by the typical mitochondria mass. However, the known mitochondrial fission factors, dynamin-related proteins Dnm1 in yeasts and DNM1L/Drp1 in mammals, are dispensable for mitophagy. Here, we identify Atg44 as a mitochondrial fission factor that is essential for mitophagy in yeasts, and we therefore term Atg44 and its orthologous proteins mitofissin. In mitofissin-deficient cells, a part of the mitochondria is recognized by the mitophagy machinery as cargo but cannot be enwrapped by the autophagosome precursor, the phagophore, due to a lack of mitochondrial fission. Furthermore, we show that mitofissin directly binds to lipid membranes and brings about lipid membrane fragility to facilitate membrane fission. Taken together, we propose that mitofissin acts directly on lipid membranes to drive mitochondrial fission required for mitophagy.
    Keywords:  Atg44; autophagy; crystal structure analysis; dynamin-related protein; high-speed atomic force microscopy; mitochondria; mitochondrial fission; mitofissin; mitophagy; yeast
    DOI:  https://doi.org/10.1016/j.molcel.2023.04.022
  17. Sci Rep. 2023 May 17. 13(1): 7977
    Recent advances and new perspectives in mitochondrial dysfunction.
    Cecilia Giulivi, Kezhong Zhang, Hirofumi Arakawa.
      
    DOI:  https://doi.org/10.1038/s41598-023-34624-8
  18. Mitochondrion. 2023 May 16. pii: S1567-7249(23)00037-5. [Epub ahead of print]
    The cyclic lipopeptide micafungin induces rupture of isolated mitochondria by reprograming the mitochondrial inner membrane anion channel.
    Jonathan Hosler, Ngoc Hoang, Kristin Shirey Edwards.
      The antifungal activity of the drug micafungin, a cyclic lipopeptide that interacts with membrane proteins, may involve inhibition of fungal mitochondria. In humans, mitochondria are spared by the inability of micafungin to cross the cytoplasmic membrane. Using isolated mitochondria, we find that micafungin initiates the uptake of salts, causing rapid swelling and rupture of mitochondria with release of cytochrome c. The inner membrane anion channel (IMAC) is altered by micafungin to transfer both cations and anions. We propose that binding of anionic micafungin to IMAC attracts cations into the ion pore for the rapid transfer of ion pairs.
    Keywords:  Anion transport; Cyclic lipopeptides; Inner mitochondrial anion channel; Ion channel; Micafungin; Mitochondrial respiratory chain complex; Mitochondrial transport
    DOI:  https://doi.org/10.1016/j.mito.2023.05.004
  19. Exp Eye Res. 2023 May 11. pii: S0014-4835(23)00121-5. [Epub ahead of print] 109500
    Low mitochondrial DNA copy number in buffy coat DNA of primary open-angle glaucoma patients.
    Antoni Vallbona-Garcia, Ilse H J Hamers, Florence H J van Tienen, Juan Ochoteco-Asensio, Tos T J M Berendschot, Irenaeus F M de Coo, Birke J Benedikter, Carroll A B Webers, Hubert J M Smeets, Theo G M F Gorgels.
      Primary open-angle glaucoma (POAG) is characterized by optic nerve degeneration and irreversible loss of retinal ganglion cells (RGCs). The pathophysiology is not fully understood. Since RGCs have a high energy demand, suboptimal mitochondrial function may put the survival of these neurons at risk. In the present study, we explored whether mtDNA copy number or mtDNA deletions could reveal a mitochondrial component in POAG pathophysiology. Buffy coat DNA was isolated from EDTA blood of age- and sex-matched study groups, namely POAG patients with high intraocular pressure (IOP) at diagnosis (high tension glaucoma: HTG; n = 97), normal tension glaucoma patients (NTG, n = 37), ocular hypertensive controls (n = 9), and cataract controls (without glaucoma; n = 32), all without remarkable comorbidities. The number of mtDNA copies was assessed through qPCR quantification of the mitochondrial D-loop and nuclear B2M gene. Presence of the common 4977 base pair mtDNA deletion was assessed by a highly sensitive breakpoint PCR. Analysis showed that HTG patients had a lower number of mtDNA copies per nuclear DNA than NTG patients (p-value <0.01, Dunn test) and controls (p-value <0.001, Dunn test). The common 4977 base pair mtDNA deletion was not detected in any of the participants. A lower mtDNA copy number in blood of HTG patients suggests a role for a genetically defined, deficient mtDNA replication in the pathology of HTG. This may cause a low number of mtDNA copies in RGCs, which together with aging and high IOP, may lead to mitochondrial dysfunction, and contribute to glaucoma pathology.
    DOI:  https://doi.org/10.1016/j.exer.2023.109500
  20. Circ Genom Precis Med. 2023 May 17. e004122
    Combined Clinical, Molecular, and Muscle Biopsy Approach to Unveil Prevalence and Clinical Features of Rare Neuromuscular and Mitochondrial Diseases in Patients With Cardiomyopathies.
    Michele Lioncino, Emanuele Monda, Martina Caiazza, Vincenzo Simonelli, Claudia Nesti, Alfredo Mauriello, Alberta Budillon, Alessandro Di Santo, Giorgia Bruno, Antonio Varone, Vincenzo Nigro, Filippo Maria Santorelli, Giuseppe Pacileo, Maria Giovanna Russo, Giulia Frisso, Simone Sampaolo, Giuseppe Limongelli.
      
    Keywords:  biopsy; cardiomyopathies; cardiovascular disease; mitochondrial disease; morbidity
    DOI:  https://doi.org/10.1161/CIRCGEN.123.004122
  21. J Physiol Biochem. 2023 May 13.
    HIF-1 signaling: an emerging mechanism for mitochondrial dynamics.
    Yu Xin, Li Zhao, Ruiyun Peng.
      A growing emphasis has been paid to the function of mitochondria in tumors, neurodegenerative disorders (NDs), and cardiovascular diseases. Mitochondria are oxygen-sensitive organelles whose function depends on their structural basis. Mitochondrial dynamics are critical in regulating the structure. Mitochondrial dynamics include fission, fusion, motility, cristae remodeling, and mitophagy. These processes could alter mitochondrial morphology, number, as well as distribution, to regulate complicated cellular signaling processes like metabolism. Meanwhile, they also could modulate cell proliferation and apoptosis. The initiation and progression of several diseases, such as tumors, NDs, cardiovascular disease, were all interrelated with mitochondrial dynamics. HIF-1 is a nuclear protein presented as heterodimers, and its transcriptional activity is triggered by hypoxia. It plays an important role in numerous physiological processes including the development of cardiovascular system, immune system, and cartilage. Additionally, it could evoke compensatory responses in cells during hypoxia through upstream and downstream signaling networks. Moreover, the alteration of oxygen level is a pivotal factor to promote mitochondrial dynamics and HIF-1 activation. HIF-1α might be a promising target for modulating mitochondrial dynamics to develop therapeutic approaches for NDs, immunological diseases, and other related diseases. Here, we reviewed the research progress of mitochondrial dynamics and the potential regulatory mechanism of HIF-1 in mitochondrial dynamics.
    Keywords:  HIF-1; Interaction; Mitochondrial dynamics; Review
    DOI:  https://doi.org/10.1007/s13105-023-00966-0
  22. Int J Biochem Cell Biol. 2023 May 17. pii: S1357-2725(23)00070-5. [Epub ahead of print] 106431
    Mitochondria are midfield players in steroid synthesis.
    Philipp Melchinger, Bruna Martins Garcia.
      Steroids are important membrane components and signaling metabolites and thus are required for cellular homeostasis. All mammalian cells retain the ability to uptake and synthesize steroids. Dysregulation of steroid levels leads to profound effects on cellular function and organismal health. Hence it comes as no surprise that steroid synthesis is tightly regulated. It is well established that the main site for steroid synthesis and regulation is the endoplasmic reticulum. However, mitochondria are essential for: (1) cholesterol production (the precursor of all steroids) by exporting citrate and; (2) the products of steroidogenesis (such as mineralocorticoids and glucocorticoids). In this review, we describe the midfield player role of mitochondria in steroid synthesis and bring the idea of mitochondria actively participating in steroid synthesis regulation. A better understanding of the mitochondrial regulatory roles in steroid synthesis would open new avenues to targeted approaches aiming to control steroid levels.
    Keywords:  Cholesterol synthesis; Mitochondria-ER contact; Steroid hormones
    DOI:  https://doi.org/10.1016/j.biocel.2023.106431
  23. Mech Ageing Dev. 2023 May 12. pii: S0047-6374(23)00048-9. [Epub ahead of print]212 111822
    Mechanisms of mitochondrial microRNA regulation in cardiovascular diseases.
    David Roiz-Valle, Xurde M Caravia, Carlos López-Otín.
      In the past years, microRNAs (miRNAs) have emerged as important biomarkers and essential regulators of many pathophysiological processes. Several studies have focused on the importance of these noncoding RNAs (ncRNAs) in maintaining mitochondrial function, introducing the term mitochondrial microRNAs (mitomiRs) to refer to those miRNAs controlling mitochondrial activity, either by targeting cytoplasmatic messenger RNAs (mRNAs) or by acting inside the mitochondria. Mitochondrial homeostasis is paramount in the cardiovascular system, where an important energy supply is needed to maintain the homeostasis of tissues, such as the myocardium. In this review, we will address the relevance of mitomiRs in cardiovascular pathologies by dissecting and categorizing their effect in mitochondrial function in order to provide a robust framework for new mitomiR-based therapeutical approaches to this group of diseases.
    Keywords:  Cardiovascular diseases; MiRNAs; Mitochondria; MitomiR
    DOI:  https://doi.org/10.1016/j.mad.2023.111822
  24. Int J Ophthalmol. 2023 ;16(5): 811-823
    Mitochondrial dysfunction in glaucomatous degeneration.
    Zi-Qiao Zhang, Zhi Xie, Sen-Yuan Chen, Xu Zhang.
      Glaucoma is a kind of optic neuropathy mainly manifested in the permanent death of retinal ganglion cells (RGCs), atrophy of the optic nerve, and loss of visual ability. The main risk factors for glaucoma consist of the pathological elevation of intraocular pressure (IOP) and aging. Although the mechanism of glaucoma remains an open question, a theory related to mitochondrial dysfunction has been emerging in the last decade. Reactive oxygen species (ROS) from the mitochondrial respiratory chain are abnormally produced as a result of mitochondrial dysfunction. Oxidative stress takes place when the cellular antioxidant system fails to remove excessive ROS promptly. Meanwhile, more and more studies show that there are other common features of mitochondrial dysfunction in glaucoma, including damage of mitochondrial DNA (mtDNA), defective mitochondrial quality control, ATP reduction, and other cellular changes, which are worth summarizing and further exploring. The purpose of this review is to explore mitochondrial dysfunction in the mechanism of glaucomatous optic neuropathy. Based on the mechanism, the existing therapeutic options are summarized, including medications, gene therapy, and red-light therapy, which are promising to provide feasible neuroprotective ideas for the treatment of glaucoma.
    Keywords:  glaucoma; mitochondrial dynamics; mitochondrial dysfunction; mitophagy; neuroprotection; oxidative stress
    DOI:  https://doi.org/10.18240/ijo.2023.05.20
  25. Nat Struct Mol Biol. 2023 May 18.
    Polγ coordinates DNA synthesis and proofreading to ensure mitochondrial genome integrity.
    Joon Park, Geoffrey K Herrmann, Patrick G Mitchell, Michael B Sherman, Y Whitney Yin.
      Accurate replication of mitochondrial DNA (mtDNA) by DNA polymerase γ (Polγ) is essential for maintaining cellular energy supplies, metabolism, and cell cycle control. To illustrate the structural mechanism for Polγ coordinating polymerase (pol) and exonuclease (exo) activities to ensure rapid and accurate DNA synthesis, we determined four cryo-EM structures of Polγ captured after accurate or erroneous incorporation to a resolution of 2.4-3.0 Å. The structures show that Polγ employs a dual-checkpoint mechanism to sense nucleotide misincorporation and initiate proofreading. The transition from replication to error editing is accompanied by increased dynamics in both DNA and enzyme, in which the polymerase relaxes its processivity and the primer-template DNA unwinds, rotates, and backtracks to shuttle the mismatch-containing primer terminus 32 Å to the exo site for editing. Our structural and functional studies also provide a foundation for analyses of Polγ mutation-induced human diseases and aging.
    DOI:  https://doi.org/10.1038/s41594-023-00980-2
  26. J Transl Med. 2023 May 19. 21(1): 331
    Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.
    Emily B Warren, Eliza M Gordon-Lipkin, Foo Cheung, Jinguo Chen, Amrita Mukherjee, Richard Apps, John S Tsang, Jillian Jetmore, Melissa L Schlein, Shannon Kruk, Yuanjiu Lei, A Phillip West, Peter J McGuire.
      BACKGROUND: People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyper-responsiveness to pathogens and neurodegeneration. We sought to examine transcriptional changes between MtD patients and healthy controls to identify common gene signatures of immune dysregulation in MtD.METHODS: We collected whole blood from a cohort of MtD patients and healthy controls and performed RNAseq to examine transcriptomic differences. We performed GSEA analyses to compare our findings against existing studies to identify commonly dysregulated pathways.
    RESULTS: Gene sets involved in inflammatory signaling, including type I interferons, interleukin-1β and antiviral responses, are enriched in MtD patients compared to controls. Monocyte and dendritic cell gene clusters are also enriched in MtD patients, while T cell and B cell gene sets are negatively enriched. The enrichment of antiviral response corresponds with an independent set of MELAS patients, and two mouse models of mtDNA dysfunction.
    CONCLUSIONS: Through the convergence of our results, we demonstrate translational evidence of systemic peripheral inflammation arising from MtD, predominantly through antiviral response gene sets. This provides key evidence linking mitochondrial dysfunction to inflammation, which may contribute to the pathogenesis of primary MtD and other chronic inflammatory disorders associated with mitochondrial dysfunction.
    Keywords:  Anti-viral signaling; Inflammation; Interferon; Mitochondrial disease; PBMCs
    DOI:  https://doi.org/10.1186/s12967-023-04180-w
  27. Exp Gerontol. 2023 May 10. pii: S0531-5565(23)00124-9. [Epub ahead of print] 112203
    The contribution of mitochondrial DNA alterations to aging, cancer, and neurodegeneration.
    Anna Picca, Flora Guerra, Riccardo Calvani, Hélio José Coelho-Júnior, Christiaan Leeuwenburgh, Cecilia Bucci, Emanuele Marzetti.
      Mitochondrial DNA (mtDNA) is as a multi-copy genome existing in hundreds to thousands copies in cells depending on cell metabolism and exposure to endogenous and/or environmental stressors. The coordination of mtDNA replication and transcription regulates the pace of mitochondrial biogenesis to guarantee the minimum number of organelles per cell. mtDNA inheritance follows a maternal lineage, although bi-parental inheritance has been reported in some species and in the case of mitochondrial diseases in humans. mtDNA mutations (e.g., point mutations, deletions, copy number variations) have been identified in the setting of several human diseases. For instance, sporadic and inherited rare disorders involving the nervous system as well higher risk of developing cancer and neurodegenerative conditions, including Parkinson's and Alzheimer's disease, have been associated with polymorphic mtDNA variants. Accrual of mtDNA mutations has also been identified in several tissues and organs, including heart and muscle, of old experimental animals and older adults, which may contribute to the development of aging phenotypes. The role played by mtDNA homeostasis and mtDNA quality control pathways in human health is actively investigated for the possibility of developing targeted therapeutics for a wide range of conditions.
    Keywords:  Heteroplasmy; Mitochondrial biogenesis; Mitochondrial diseases; Mitochondrial quality; mtDNA deletions; mtDNA mutations
    DOI:  https://doi.org/10.1016/j.exger.2023.112203
  28. bioRxiv. 2023 May 04. pii: 2023.05.04.539294. [Epub ahead of print]
    Submitochondrial Protein Translocation Upon Stress Inhibits Thermogenic Energy Expenditure.
    Fahrettin Haczeyni, Sandra Steensels, Benjamin D Stein, James M Jordan, Le Li, Vincent Dartigue, Selenay S Sarklioglu, Jixuan Qiao, Xi K Zhou, Andrew J Dannenberg, Neil M Iyengar, Haiyuan Yu, Lewis C Cantley, Baran A Ersoy.
      Mitochondria-rich brown adipocytes dissipate cellular fuel as heat by thermogenic energy expenditure (TEE). Prolonged nutrient excess or cold exposure impair TEE and contribute to the pathogenesis of obesity, but the mechanisms remain incompletely understood. Here we report that stress-induced proton leak into the matrix interface of mitochondrial innermembrane (IM) mobilizes a group of proteins from IM into matrix, which in turn alter mitochondrial bioenergetics. We further determine a smaller subset that correlates with obesity in human subcutaneous adipose tissue. We go on to show that the top factor on this short list, acyl-CoA thioesterase 9 (ACOT9), migrates from the IM into the matrix upon stress where it enzymatically deactivates and prevents the utilization of acetyl-CoA in TEE. The loss of ACOT9 protects mice against the complications of obesity by maintaining unobstructed TEE. Overall, our results introduce aberrant protein translocation as a strategy to identify pathogenic factors.One-Sentence Summary: Thermogenic stress impairs mitochondrial energy utilization by forcing translocation of IM-bound proteins into the matrix.
    DOI:  https://doi.org/10.1101/2023.05.04.539294
  29. Clin Transl Sci. 2023 May 12.
    Identification of peripheral vascular function measures and circulating biomarkers of mitochondrial function in patients with mitochondrial disease.
    Sebastiaan J W van Kraaij, Diana R Pereira, Bastiaan Smal, Luciana Summo, Anne Konkel, Janine Lossie, Andreas Busjahn, Tom N Grammatopoulos, Erica Klaassen, Robert Fischer, Wolf-Hagen Schunck, Pim Gal, Matthijs Moerland.
      The development of pharmacological therapies for mitochondrial diseases is hampered by the lack of tissue-level and circulating biomarkers reflecting effects of compounds on endothelial and mitochondrial function. This phase 0 study aimed to identify biomarkers differentiating between patients with mitochondrial disease and healthy volunteers (HVs). In this cross-sectional case-control study, eight participants with mitochondrial disease and eight HVs matched on age, sex, and body mass index underwent study assessments consisting of blood collection for evaluation of plasma and serum biomarkers, mitochondrial function in peripheral blood mononuclear cells (PBMCs), and an array of imaging methods for assessment of (micro)circulation. Plasma biomarkers GDF-15, IL-6, NT-proBNP, and cTNI were significantly elevated in patients compared to HVs, as were several clinical chemistry and hematology markers. No differences between groups were found for mitochondrial membrane potential, mitochondrial reactive oxygen production, oxygen consumption rate, or extracellular acidification rate in PBMCs. Imaging revealed significantly higher nicotinamide-adenine-dinucleotide-hydrogen (NADH) content in skin as well as reduced passive leg movement-induced hyperemia in patients. This study confirmed results of earlier studies regarding plasma biomarkers in mitochondrial disease and identified several imaging techniques that could detect functional differences at the tissue level between participants with mitochondrial disease and HVs. However, assays of mitochondrial function in PBMCs did not show differences between participants with mitochondrial disease and HVs, possibly reflecting compensatory mechanisms and heterogeneity in mutational load. In future clinical trials, using a mix of imaging and blood-based biomarkers may be advisable, as well as combining these with an in vivo challenge to disturb homeostasis.
    DOI:  https://doi.org/10.1111/cts.13530
  30. BMC Biol. 2023 May 18. 21(1): 111
    A small protein coded within the mitochondrial canonical gene nd4 regulates mitochondrial bioenergetics.
    Laura Kienzle, Stefano Bettinazzi, Thierry Choquette, Marie Brunet, Hajar Hosseini Khorami, Jean-François Jacques, Mathilde Moreau, Xavier Roucou, Christian R Landry, Annie Angers, Sophie Breton.
      BACKGROUND: Mitochondria have a central role in cellular functions, aging, and in certain diseases. They possess their own genome, a vestige of their bacterial ancestor. Over the course of evolution, most of the genes of the ancestor have been lost or transferred to the nucleus. In humans, the mtDNA is a very small circular molecule with a functional repertoire limited to only 37 genes. Its extremely compact nature with genes arranged one after the other and separated by short non-coding regions suggests that there is little room for evolutionary novelties. This is radically different from bacterial genomes, which are also circular but much larger, and in which we can find genes inside other genes. These sequences, different from the reference coding sequences, are called alternatives open reading frames or altORFs, and they are involved in key biological functions. However, whether altORFs exist in mitochondrial protein-coding genes or elsewhere in the human mitogenome has not been fully addressed.RESULTS: We found a downstream alternative ATG initiation codon in the + 3 reading frame of the human mitochondrial nd4 gene. This newly characterized altORF encodes a 99-amino-acid-long polypeptide, MTALTND4, which is conserved in primates. Our custom antibody, but not the pre-immune serum, was able to immunoprecipitate MTALTND4 from HeLa cell lysates, confirming the existence of an endogenous MTALTND4 peptide. The protein is localized in mitochondria and cytoplasm and is also found in the plasma, and it impacts cell and mitochondrial physiology.
    CONCLUSIONS: Many human mitochondrial translated ORFs might have so far gone unnoticed. By ignoring mtaltORFs, we have underestimated the coding potential of the mitogenome. Alternative mitochondrial peptides such as MTALTND4 may offer a new framework for the investigation of mitochondrial functions and diseases.
    Keywords:  Alternative open reading frame; Homo sapiens; Mitochondria; Mitochondrial bioenergetics; Mitochondrial proteome; Mitogenome; Protein coding potential; nd4
    DOI:  https://doi.org/10.1186/s12915-023-01609-y
  31. mSystems. 2023 May 18. e0100222
    Metatranscriptomic analysis uncovers prevalent viral ORFs compatible with mitochondrial translation.
    Adam Begeman, Artem Babaian, Samantha C Lewis.
      RNA viruses are ubiquitous components of the global virosphere, yet relatively little is known about their genetic diversity or the cellular mechanisms by which they exploit the biology of their diverse eukaryotic hosts. A hallmark of (+)ssRNA viruses is the ability to remodel host endomembranes for their own replication. However, the subcellular interplay between RNA viruses and host organelles that harbor gene expression systems, such as mitochondria, is complex and poorly understood. Here we report the discovery of 763 new virus sequences belonging to the family Mitoviridae by metatranscriptomic analysis, the identification of previously uncharacterized mitovirus clades, and a putative new viral class. With this expanded understanding of the diversity of mitovirus and encoded RNA-dependent RNA polymerases, we annotate mitovirus-specific protein motifs and identify hallmarks of mitochondrial translation, including mitochondrion-specific codons. This study expands the known diversity of mitochondrial viruses, and provides additional evidence that they co-opt mitochondrial biology for their survival.IMPORTANCEMetatranscriptomic studies have rapidly expanded the cadre of known RNA viruses, yet our understanding of how these viruses navigate the cytoplasmic milieu of their hosts to survive remains poorly characterized. In this study, we identify and assemble 763 new viral sequences belonging to the Mitoviridae, a family of (+)ssRNA viruses thought to interact with and remodel host host mitochondria. We exploit this genetic diversity to identify new clades of Mitoviridae, annotate clade-specific sequence motifs that distinguish the mitoviral RNA-dependent RNA polymerase, and reveal patterns of RdRp codon usage consistent with translation on host cell mitoribosomes. These results serve as a foundation for understanding how mitoviruses co-opt mitochondrial biology for their proliferation.
    Keywords:  RNA virus; metagenomics; mitochondria; mitovirus; translation; virus evolution
    DOI:  https://doi.org/10.1128/msystems.01002-22
  32. Ageing Res Rev. 2023 May 15. pii: S1568-1637(23)00114-9. [Epub ahead of print] 101955
    Mitochondrial dysfunction in aging.
    Ying Guo, Teng Guan, Kashfia Shafiq, Qiang Yu, Xin Jiao, Donghui Na, Meiyu Li, Guohui Zhang, Jiming Kong.
      Aging is a complex process that features a functional decline in many organelles. Although mitochondrial dysfunction is suggested as one of the determining factors of aging, the role of mitochondrial quality control (MQC) in aging is still poorly understood. A growing body of evidence points out that reactive oxygen species (ROS) stimulates mitochondrial dynamic changes and accelerates the accumulation of oxidized by-products through mitochondrial proteases and mitochondrial unfolded protein response (UPRmt). Mitochondrial-derived vesicles (MDVs) are the first line of MQC to dispose of oxidized derivatives. Besides, mitophagy helps remove partially damaged mitochondria to ensure that mitochondria are healthy and functional. Although abundant interventions on MQC have been explored, over-activation or inhibition of any type of MQC may even accelerate abnormal energy metabolism and mitochondrial dysfunction-induced senescence. This review summarizes mechanisms essential for maintaining mitochondrial homeostasis and emphasizes that imbalanced MQC may accelerate cellular senescence and aging. Thus, appropriate interventions on MQC may delay the aging process and extend lifespan.
    Keywords:  Aging; mitochondrial dysfunction; mitochondrial quality control; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.arr.2023.101955
  33. Life Metab. 2023 Apr;pii: load014. [Epub ahead of print]2(2):
    Weight loss increases skeletal muscle mitochondrial energy efficiency in obese mice.
    Patrick J Ferrara, Marisa J Lang, Jordan M Johnson, Shinya Watanabe, Kelsey L McLaughlin, J Alan Maschek, Anthony R P Verkerke, Piyarat Siripoksup, Amandine Chaix, James E Cox, Kelsey H Fisher-Wellman, Katsuhiko Funai.
      Weight loss from an overweight state is associated with a disproportionate decrease in whole-body energy expenditure that may contribute to the heightened risk for weight regain. Evidence suggests that this energetic mismatch originates from lean tissue. Although this phenomenon is well documented, the mechanisms have remained elusive. We hypothesized that increased mitochondrial energy efficiency in skeletal muscle is associated with reduced expenditure under weight loss. Wildtype (WT) male C57BL6/N mice were fed with high fat diet for 10 weeks, followed by a subset of mice that were maintained on the obesogenic diet (OB) or switched to standard chow to promote weight loss (WL) for additional 6 weeks. Mitochondrial energy efficiency was evaluated using high-resolution respirometry and fluorometry. Mass spectrometric analyses were employed to describe the mitochondrial proteome and lipidome. Weight loss promoted ~50% increase in the efficiency of oxidative phosphorylation (ATP produced per O2 consumed, or P/O) in skeletal muscle. However, weight loss did not appear to induce significant changes in mitochondrial proteome, nor any changes in respiratory supercomplex formation. Instead, it accelerated the remodeling of mitochondrial cardiolipin (CL) acyl-chains to increase tetralinoleoyl CL (TLCL) content, a species of lipids thought to be functionally critical for the respiratory enzymes. We further show that lowering TLCL by deleting the CL transacylase tafazzin was sufficient to reduce skeletal muscle P/O and protect mice from diet-induced weight gain. These findings implicate skeletal muscle mitochondrial efficiency as a novel mechanism by which weight loss reduces energy expenditure in obesity.
    Keywords:  energy efficiency; energy expenditure; mitochondria; oxidative phosphorylation; phospholipids; weight loss
    DOI:  https://doi.org/10.1093/lifemeta/load014
  34. Sci Transl Med. 2023 May 17. 15(696): eade6509
    Inhibiting de novo ceramide synthesis restores mitochondrial and protein homeostasis in muscle aging.
    Tanes I Lima, Pirkka-Pekka Laurila, Martin Wohlwend, Jean David Morel, Ludger J E Goeminne, Hao Li, Mario Romani, Xiaoxu Li, Chang-Myung Oh, Dohyun Park, Sandra Rodríguez-López, Julijana Ivanisevic, Hector Gallart-Ayala, Barbara Crisol, Florence Delort, Sabrina Batonnet-Pichon, Leonardo R Silveira, Lakshmi Sankabattula Pavani Veera Venkata, Anil K Padala, Suresh Jain, Johan Auwerx.
      Disruption of mitochondrial function and protein homeostasis plays a central role in aging. However, how these processes interact and what governs their failure in aging remain poorly understood. Here, we showed that ceramide biosynthesis controls the decline in mitochondrial and protein homeostasis during muscle aging. Analysis of transcriptome datasets derived from muscle biopsies obtained from both aged individuals and patients with a diverse range of muscle disorders revealed that changes in ceramide biosynthesis, as well as disturbances in mitochondrial and protein homeostasis pathways, are prevalent features in these conditions. By performing targeted lipidomics analyses, we found that ceramides accumulated in skeletal muscle with increasing age across Caenorhabditis elegans, mice, and humans. Inhibition of serine palmitoyltransferase (SPT), the rate-limiting enzyme of the ceramide de novo synthesis, by gene silencing or by treatment with myriocin restored proteostasis and mitochondrial function in human myoblasts, in C. elegans, and in the skeletal muscles of mice during aging. Restoration of these age-related processes improved health and life span in the nematode and muscle health and fitness in mice. Collectively, our data implicate pharmacological and genetic suppression of ceramide biosynthesis as potential therapeutic approaches to delay muscle aging and to manage related proteinopathies via mitochondrial and proteostasis remodeling.
    DOI:  https://doi.org/10.1126/scitranslmed.ade6509
  35. Methods Mol Biol. 2023 ;2660 137-148
    Integration of Metabolomic and Proteomic Data to Uncover Actionable Metabolic Pathways.
    Christian Heckendorf, Benjamin C Blum, Weiwei Lin, Matthew L Lawton, Andrew Emili.
      Mass spectrometry (MS) is an important tool for biological studies because it is capable of interrogating a diversity of biomolecules (proteins, drugs, metabolites) not captured via alternate genomic platforms. Unfortunately, downstream data analysis becomes complicated when attempting to evaluate and integrate measurements of different molecular classes and requires the aggregation of expertise from different relevant disciplines. This complexity represents a significant bottleneck that limits the routine deployment of MS-based multi-omic methods, despite the unmatched biological and functional insight the data can provide. To address this unmet need, our group introduced Omics Notebook as an open-source framework for facilitating exploratory analysis, reporting and integrating MS-based multi-omic data in a way that is automated, reproducible and customizable. By deploying this pipeline, we have devised a framework for researchers to more rapidly identify functional patterns across complex data types and focus on statistically significant and biologically interesting aspects of their multi-omic profiling experiments. This chapter aims to describe a protocol which leverages our publicly accessible tools to analyze and integrate data from high-throughput proteomics and metabolomics experiments and produce reports that will facilitate more impactful research, cross-institutional collaborations, and wider data dissemination.
    Keywords:  Automated pipeline; Biological functional modules; Graphical user interface (GUI); Mass spectrometry; Metabolomics; Multi-omics data integration; Omics Notebook R package; Omics Notebook interface; Pathway enrichment; Principal component analysis (PCA); Proteomics; Proteomics search engines; Systems biology
    DOI:  https://doi.org/10.1007/978-1-0716-3163-8_10
  36. Sci China Life Sci. 2023 May 11.
    Human TRMT1 catalyzes m2G or m22G formation on tRNAs in a substrate-dependent manner.
    Qing-Ping Xiong, Jing Li, Hao Li, Zhi-Xuan Huang, Han Dong, En-Duo Wang, Ru-Juan Liu.
      TRMT1 is an N2-methylguanosine (m2G) and N2,N2-methylguanosine (m22G) methyltransferase that targets G26 of both cytoplasmic and mitochondrial tRNAs. In higher eukaryotes, most cytoplasmic tRNAs with G26 carry m22G26, although the majority of mitochondrial G26-containing tRNAs carry m2G26 or G26, suggesting differences in the mechanisms by which TRMT1 catalyzes modification of these tRNAs. Loss-of-function mutations of human TRMT1 result in neurological disorders and completely abrogate tRNA:m22G26 formation. However, the mechanism underlying the independent catalytic activity of human TRMT1 and identity of its specific substrate remain elusive, hindering a comprehensive understanding of the pathogenesis of neurological disorders caused by TRMT1 mutations. Here, we showed that human TRMT1 independently catalyzes formation of the tRNA:m2G26 or m22G26 modification in a substrate-dependent manner, which explains the distinct distribution of m2G26 and m22G26 on cytoplasmic and mitochondrial tRNAs. For human TRMT1-mediated tRNA:m22G26 formation, the semi-conserved C11:G24 serves as the determinant, and the U10:A25 or G10:C25 base pair is also required, while the size of the variable loop has no effect. We defined the requirements of this recognition mechanism as the "m22G26 criteria". We found that the m22G26 modification occurred in almost all the higher eukaryotic tRNAs conforming to these criteria, suggesting the "m22G26 criteria" are applicable to other higher eukaryotic tRNAs.
    Keywords:  RNA modification; TRMT1; m2 2G; m2G; neurological disease; tRNA
    DOI:  https://doi.org/10.1007/s11427-022-2295-0
  37. Elife. 2023 May 15. pii: e82593. [Epub ahead of print]12
    Rapid protein stability prediction using deep learning representations.
    Lasse M Blaabjerg, Maher M Kassem, Lydia L Good, Nicolas Jonsson, Matteo Cagiada, Kristoffer E Johansson, Wouter Boomsma, Amelie Stein, Kresten Lindorff-Larsen.
      Predicting the thermodynamic stability of proteins is a common and widely used step in protein engineering, and when elucidating the molecular mechanisms behind evolution and disease. Here, we present RaSP, a method for making rapid and accurate predictions of changes in protein stability by leveraging deep learning representations. RaSP performs on-par with biophysics-based methods and enables saturation mutagenesis stability predictions in less than a second per residue. We use RaSP to calculate ∼ 300 million stability changes for nearly all single amino acid changes in the human proteome, and examine variants observed in the human population. We find that variants that are common in the population are substantially depleted for severe destabilization, and that there are substantial differences between benign and pathogenic variants, highlighting the role of protein stability in genetic diseases. RaSP is freely available-including via a Web interface-and enables large-scale analyses of stability in experimental and predicted protein structures.
    Keywords:  computational biology; molecular biophysics; none; structural biology; systems biology
    DOI:  https://doi.org/10.7554/eLife.82593
  38. bioRxiv. 2023 May 04. pii: 2023.05.04.539448. [Epub ahead of print]
    Whole-genome long-read sequencing downsampling and its effect on variant calling precision and recall.
    William T Harvey, Peter Ebert, Jana Ebler, Peter A Audano, Katherine M Munson, Kendra Hoekzema, David Porubsky, Christine R Beck, Tobias Marschall, Kiran Garimella, Evan E Eichler.
      Advances in long-read sequencing (LRS) technology continue to make whole-genome sequencing more complete, affordable, and accurate. LRS provides significant advantages over short-read sequencing approaches, including phased de novo genome assembly, access to previously excluded genomic regions, and discovery of more complex structural variants (SVs) associated with disease. Limitations remain with respect to cost, scalability, and platform-dependent read accuracy and the tradeoffs between sequence coverage and sensitivity of variant discovery are important experimental considerations for the application of LRS. We compare the genetic variant calling precision and recall of Oxford Nanopore Technologies (ONT) and PacBio HiFi platforms over a range of sequence coverages. For read-based applications, LRS sensitivity begins to plateau around 12-fold coverage with a majority of variants called with reasonable accuracy (F1 score above 0.5), and both platforms perform well for SV detection. Genome assembly increases variant calling precision and recall of SVs and indels in HiFi datasets with HiFi outperforming ONT in quality as measured by the F1 score of assembly-based variant callsets. While both technologies continue to evolve, our work offers guidance to design cost-effective experimental strategies that do not compromise on discovering novel biology.
    DOI:  https://doi.org/10.1101/2023.05.04.539448
  39. MedComm (2020). 2023 Jun;4(3): e217
    Earlier second polar body transfer and further mitochondrial carryover removal for potential mitochondrial replacement therapy.
    Wenzhi Li, Xiaoyu Liao, Kaibo Lin, Renfei Cai, Haiyan Guo, Meng Ma, Yao Wang, Yating Xie, Shaozhen Zhang, Zhiguang Yan, Jiqiang Si, Hongyuan Gao, Leiwen Zhao, Li Chen, Weina Yu, Chen Chen, Yun Wang, Yanping Kuang, Qifeng Lyu.
      The second polar body (PB2) transfer in assisted reproductive technology is regarded as the most promising mitochondrial replacement scheme for preventing the mitochondrial disease inheritance owing to its less mitochondrial carryover and stronger operability. However, the mitochondrial carryover was still detectable in the reconstructed oocyte in conventional second polar body transfer scheme. Moreover, the delayed operating time would increase the second polar body DNA damage. In this study, we established a spindle-protrusion-retained second polar body separation technique, which allowed us to perform earlier second polar body transfer to avoid DNA damage accumulation. We could also locate the fusion site after the transfer through the spindle protrusion. Then, we further eliminated the mitochondrial carryover in the reconstructed oocytes through a physically based residue removal method. The results showed that our scheme could produce a nearly normal proportion of normal-karyotype blastocysts with further reduced mitochondrial carryover, both in mice and humans. Additionally, we also obtained mouse embryonic stem cells and healthy live-born mice with almost undetectable mitochondrial carryover. These findings indicate that our improvement in the second polar body transfer is conducive to the development and further mitochondria carryover elimination of reconstructed embryos, which provides a valuable choice for future clinical applications of mitochondrial replacement.
    Keywords:  assisted reproductive technology; mitochondrial disease inheritance; mitochondrial genetic drift; mitochondrial replacement therapy; second polar body transfer
    DOI:  https://doi.org/10.1002/mco2.217
  40. Hepatol Commun. 2023 Jun 01. pii: e0139. [Epub ahead of print]7(6):
    Clinical spectrum and genetic causes of mitochondrial hepatopathy phenotype in children.
    Childhood Liver Disease Research Network (ChiLDReN)
      BACKGROUND: Alterations in both mitochondrial DNA (mtDNA) and nuclear DNA genes affect mitochondria function, causing a range of liver-based conditions termed mitochondrial hepatopathies (MH), which are subcategorized as mtDNA depletion, RNA translation, mtDNA deletion, and enzymatic disorders. We aim to enhance the understanding of pathogenesis and natural history of MH.METHODS: We analyzed data from patients with MH phenotypes to identify genetic causes, characterize the spectrum of clinical presentation, and determine outcomes.
    RESULTS: Three enrollment phenotypes, that is, acute liver failure (ALF, n = 37), chronic liver disease (Chronic, n = 40), and post-liver transplant (n = 9), were analyzed. Patients with ALF were younger [median 0.8 y (range, 0.0, 9.4) vs 3.4 y (0.2, 18.6), p < 0.001] with fewer neurodevelopmental delays (40.0% vs 81.3%, p < 0.001) versus Chronic. Comprehensive testing was performed more often in Chronic than ALF (90.0% vs 43.2%); however, etiology was identified more often in ALF (81.3% vs 61.1%) with mtDNA depletion being most common (ALF: 77% vs Chronic: 41%). Of the sequenced cohort (n = 60), 63% had an identified mitochondrial disorder. Cluster analysis identified a subset without an underlying genetic etiology, despite comprehensive testing. Liver transplant-free survival was 40% at 2 years (ALF vs Chronic, 16% vs 65%, p < 0.001). Eighteen (21%) underwent transplantation. With 33 patient-years of follow-up after the transplant, 3 deaths were reported.
    CONCLUSIONS: Differences between ALF and Chronic MH phenotypes included age at diagnosis, systemic involvement, transplant-free survival, and genetic etiology, underscoring the need for ultra-rapid sequencing in the appropriate clinical setting. Cluster analysis revealed a group meeting enrollment criteria but without an identified genetic or enzymatic diagnosis, highlighting the need to identify other etiologies.
    DOI:  https://doi.org/10.1097/HC9.0000000000000139
  41. Mol Ther Nucleic Acids. 2023 Jun 13. 32 566-567
    Mitochondrial genome editing: Get aCcess to modeling broad disease mutations with engineered base editors.
    Chunlong Xu, Pengyu Huang.
      
    DOI:  https://doi.org/10.1016/j.omtn.2023.04.014
  42. Cells. 2023 04 13. pii: 1143. [Epub ahead of print]12(8):
    USP8 Down-Regulation Promotes Parkin-Independent Mitophagy in the Drosophila Brain and in Human Neurons.
    Sofia Mauri, Greta Bernardo, Aitor Martinez, Mariavittoria Favaro, Marta Trevisan, Gael Cobraiville, Marianne Fillet, Federico Caicci, Alexander J Whitworth, Elena Ziviani.
      Stress-induced mitophagy, a tightly regulated process that targets dysfunctional mitochondria for autophagy-dependent degradation, mainly relies on two proteins, PINK1 and Parkin, which genes are mutated in some forms of familiar Parkinson's Disease (PD). Upon mitochondrial damage, the protein kinase PINK1 accumulates on the organelle surface where it controls the recruitment of the E3-ubiquitin ligase Parkin. On mitochondria, Parkin ubiquitinates a subset of mitochondrial-resident proteins located on the outer mitochondrial membrane, leading to the recruitment of downstream cytosolic autophagic adaptors and subsequent autophagosome formation. Importantly, PINK1/Parkin-independent mitophagy pathways also exist that can be counteracted by specific deubiquitinating enzymes (DUBs). Down-regulation of these specific DUBs can presumably enhance basal mitophagy and be beneficial in models in which the accumulation of defective mitochondria is implicated. Among these DUBs, USP8 is an interesting target because of its role in the endosomal pathway and autophagy and its beneficial effects, when inhibited, in models of neurodegeneration. Based on this, we evaluated autophagy and mitophagy levels when USP8 activity is altered. We used genetic approaches in D. melanogaster to measure autophagy and mitophagy in vivo and complementary in vitro approaches to investigate the molecular pathway that regulates mitophagy via USP8. We found an inverse correlation between basal mitophagy and USP8 levels, in that down-regulation of USP8 correlates with increased Parkin-independent mitophagy. These results suggest the existence of a yet uncharacterized mitophagic pathway that is inhibited by USP8.
    Keywords:  DUBs; Parkin; USP8; autophagy; mitophagy
    DOI:  https://doi.org/10.3390/cells12081143
  43. BMC Bioinformatics. 2023 May 12. 24(1): 197
    Improving variant calling using population data and deep learning.
    Nae-Chyun Chen, Alexey Kolesnikov, Sidharth Goel, Taedong Yun, Pi-Chuan Chang, Andrew Carroll.
      Large-scale population variant data is often used to filter and aid interpretation of variant calls in a single sample. These approaches do not incorporate population information directly into the process of variant calling, and are often limited to filtering which trades recall for precision. In this study, we develop population-aware DeepVariant models with a new channel encoding allele frequencies from the 1000 Genomes Project. This model reduces variant calling errors, improving both precision and recall in single samples, and reduces rare homozygous and pathogenic clinvar calls cohort-wide. We assess the use of population-specific or diverse reference panels, finding the greatest accuracy with diverse panels, suggesting that large, diverse panels are preferable to individual populations, even when the population matches sample ancestry. Finally, we show that this benefit generalizes to samples with different ancestry from the training data even when the ancestry is also excluded from the reference panel.
    DOI:  https://doi.org/10.1186/s12859-023-05294-0
  44. Genome Biol. 2023 May 17. 24(1): 118
    Introme accurately predicts the impact of coding and noncoding variants on gene splicing, with clinical applications.
    Patricia J Sullivan, Velimir Gayevskiy, Ryan L Davis, Marie Wong, Chelsea Mayoh, Amali Mallawaarachchi, Yvonne Hort, Mark J McCabe, Sarah Beecroft, Matilda R Jackson, Peer Arts, Andrew Dubowsky, Nigel Laing, Marcel E Dinger, Hamish S Scott, Emily Oates, Mark Pinese, Mark J Cowley.
      Predicting the impact of coding and noncoding variants on splicing is challenging, particularly in non-canonical splice sites, leading to missed diagnoses in patients. Existing splice prediction tools are complementary but knowing which to use for each splicing context remains difficult. Here, we describe Introme, which uses machine learning to integrate predictions from several splice detection tools, additional splicing rules, and gene architecture features to comprehensively evaluate the likelihood of a variant impacting splicing. Through extensive benchmarking across 21,000 splice-altering variants, Introme outperformed all tools (auPRC: 0.98) for the detection of clinically significant splice variants. Introme is available at https://github.com/CCICB/introme .
    Keywords:  Clinical genetics; Deep intronic; Genomics; Intronic variant; Splice region; Splice site; Splicing; Splicing regulatory element; Variant interpretation
    DOI:  https://doi.org/10.1186/s13059-023-02936-7
  45. Sci Rep. 2023 Apr 25. 13(1): 6738
    Mechanism of rotenone binding to respiratory complex I depends on ligand flexibility.
    Caroline S Pereira, Murilo H Teixeira, David A Russell, Judy Hirst, Guilherme M Arantes.
      Respiratory complex I is a major cellular energy transducer located in the inner mitochondrial membrane. Its inhibition by rotenone, a natural isoflavonoid, has been used for centuries by indigenous peoples to aid in fishing and, more recently, as a broad-spectrum pesticide or even a possible anticancer therapeutic. Unraveling the molecular mechanism of rotenone action will help to design tuned derivatives and to understand the still mysterious catalytic mechanism of complex I. Although composed of five fused rings, rotenone is a flexible molecule and populates two conformers, bent and straight. Here, a rotenone derivative locked in the straight form was synthesized and found to inhibit complex I with 600-fold less potency than natural rotenone. Large-scale molecular dynamics and free energy simulations of the pathway for ligand binding to complex I show that rotenone is more stable in the bent conformer, either free in the membrane or bound to the redox active site in the substrate-binding Q-channel. However, the straight conformer is necessary for passage from the membrane through the narrow entrance of the channel. The less potent inhibition of the synthesized derivative is therefore due to its lack of internal flexibility, and interconversion between bent and straight forms is required to enable efficient kinetics and high stability for rotenone binding. The ligand also induces reconfiguration of protein loops and side-chains inside the Q-channel similar to structural changes that occur in the open to closed conformational transition of complex I. Detailed understanding of ligand flexibility and interactions that determine rotenone binding may now be exploited to tune the properties of synthetic derivatives for specific applications.
    DOI:  https://doi.org/10.1038/s41598-023-33333-6
  46. Biomedicines. 2023 Apr 13. pii: 1172. [Epub ahead of print]11(4):
    The Y831C Mutation of the POLG Gene in Dementia.
    Eugenia Borgione, Mariangela Lo Giudice, Sandro Santa Paola, Marika Giuliano, Giuseppe Lanza, Mariagiovanna Cantone, Raffaele Ferri, Carmela Scuderi.
      BACKGROUND: The POLG gene encodes the catalytic subunit of DNA polymerase γ, which is crucial for mitochondrial DNA (mtDNA) repair and replication. Gene mutation alters the stability of mtDNA and is associated with several clinical presentations, such as dysarthria and ophthalmoplegia (SANDO), progressive external ophthalmoplegia (PEO), spinocerebellar ataxia and epilepsy (SCAE), Alpers syndrome, and sensory ataxic neuropathy. Recent evidence has also indicated that POLG mutations may be involved in some neurodegenerative disorders, although systematic screening is currently lacking.METHODS: To investigate the frequency of POLG gene mutations in neurodegenerative disorders, we screened a group of 33 patients affected by neurodegenerative diseases, including Parkinson's disease, some atypical parkinsonisms, and dementia of different types.
    RESULTS: Mutational analysis revealed the presence of the heterozygous Y831C mutation in two patients, one with frontotemporal dementia and one with Lewy body dementia. The allele frequency of this mutation reported by the 1000 Genomes Project in the healthy population is 0.22%, while in our group of patients, it was 3.03%, thus showing a statistically significant difference between the two groups.
    CONCLUSIONS: Our results may expand the genotype-phenotype spectrum associated with mutations in the POLG gene and strengthen the hypothesis of a pathogenic role of the Y831C mutation in neurodegeneration.
    Keywords:  POLG; Y831C; dementia; movement disorders; neurodegeneration
    DOI:  https://doi.org/10.3390/biomedicines11041172
  47. Nat Metab. 2023 May 15.
    Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages.
    Linyu Ran, Song Zhang, Guosheng Wang, Pei Zhao, Jiaxing Sun, Jiaqi Zhou, Haiyun Gan, Ryounghoon Jeon, Qiang Li, Joerg Herrmann, Feilong Wang.
      Glycolysis is essential for the classical activation of macrophages (M1), but how glycolytic pathway metabolites engage in this process remains to be elucidated. Glycolysis leads to production of pyruvate, which can be transported into the mitochondria by the mitochondrial pyruvate carrier (MPC) followed by utilization in the tricarboxylic acid cycle. Based on studies that used the MPC inhibitor UK5099, the mitochondrial route has been considered to be of significance for M1 activation. Using genetic approaches, here we show that the MPC is dispensable for metabolic reprogramming and activation of M1 macrophages. In addition, MPC depletion in myeloid cells has no impact on inflammatory responses and macrophage polarization toward the M1 phenotype in a mouse model of endotoxemia. While UK5099 reaches maximal MPC inhibitory capacity at approximately 2-5 μM, higher concentrations are required to inhibit inflammatory cytokine production in M1 and this is independent of MPC expression. Taken together, MPC-mediated metabolism is dispensable for the classical activation of macrophages and UK5099 inhibits inflammatory responses in M1 macrophages due to effects other than MPC inhibition.
    DOI:  https://doi.org/10.1038/s42255-023-00800-3
  48. Aging Dis. 2023 Feb 13.
    Mitochondria Transplantation from Stem Cell for Mitigating Sarcopenia.
    Xiulin Tian, Mengxiong Pan, Mengting Zhou, Qiaomin Tang, Miao Chen, Wenwu Hong, Fangling Zhao, Kaiming Liu.
      Sarcopenia is defined as the age-related loss of muscle mass and function that can lead to prolonged hospital stays and decreased independence. It is a significant health and financial burden for individuals, families, and society as a whole. The accumulation of damaged mitochondria in skeletal muscle contributes to the degeneration of muscles with age. Currently, the treatment of sarcopenia is limited to improving nutrition and physical activity. Studying effective methods to alleviate and treat sarcopenia to improve the quality of life and lifespan of older people is a growing area of interest in geriatric medicine. Therapies targeting mitochondria and restoring mitochondrial function are promising treatment strategies. This article provides an overview of stem cell transplantation for sarcopenia, including the mitochondrial delivery pathway and the protective role of stem cells. It also highlights recent advances in preclinical and clinical research on sarcopenia and presents a new treatment method involving stem cell-derived mitochondrial transplantation, outlining its advantages and challenges.
    DOI:  https://doi.org/10.14336/AD.2023.0210
  49. Sci Adv. 2023 May 19. 9(20): eadg2235
    A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production.
    Niek Wit, Ewa Gogola, James A West, Tristan Vornbäumen, Rachel V Seear, Peter S J Bailey, Guillermo Burgos-Barragan, Meng Wang, Patrycja Krawczyk, Daphne H E W Huberts, Fanni Gergely, Nicholas J Matheson, Arthur Kaser, James A Nathan, Ketan J Patel.
      Cells produce considerable genotoxic formaldehyde from an unknown source. We carry out a genome-wide CRISPR-Cas9 genetic screen in metabolically engineered HAP1 cells that are auxotrophic for formaldehyde to find this cellular source. We identify histone deacetylase 3 (HDAC3) as a regulator of cellular formaldehyde production. HDAC3 regulation requires deacetylase activity, and a secondary genetic screen identifies several components of mitochondrial complex I as mediators of this regulation. Metabolic profiling indicates that this unexpected mitochondrial requirement for formaldehyde detoxification is separate from energy generation. HDAC3 and complex I therefore control the abundance of a ubiquitous genotoxic metabolite.
    DOI:  https://doi.org/10.1126/sciadv.adg2235
  50. Aging Dis. 2023 Feb 15.
    Mitochondrial Dynamics: Working with the Cytoskeleton and Intracellular Organelles to Mediate Mechanotransduction.
    Danyuan Huang, Shuo Chen, Ding Xiong, Han Wang, Li Zhu, Yuanyuan Wei, Yuyu Li, Shujuan Zou.
      Cells are constantly exposed to various mechanical environments; therefore, it is important that they are able to sense and adapt to changes. It is known that the cytoskeleton plays a critical role in mediating and generating extra- and intracellular forces and that mitochondrial dynamics are crucial for maintaining energy homeostasis. Nevertheless, the mechanisms by which cells integrate mechanosensing, mechanotransduction, and metabolic reprogramming remain poorly understood. In this review, we first discuss the interaction between mitochondrial dynamics and cytoskeletal components, followed by the annotation of membranous organelles intimately related to mitochondrial dynamic events. Finally, we discuss the evidence supporting the participation of mitochondria in mechanotransduction and corresponding alterations in cellular energy conditions. Notable advances in bioenergetics and biomechanics suggest that the mechanotransduction system composed of mitochondria, the cytoskeletal system, and membranous organelles is regulated through mitochondrial dynamics, which may be a promising target for further investigation and precision therapies.
    DOI:  https://doi.org/10.14336/AD.2023.0201
  51. ACS Chem Neurosci. 2023 May 16.
    Frontotemporal Dementia-Related V57E Mutation Impairs Mitochondrial Function and Alters the Structural Properties of CHCHD10.
    Hakan Alici, Vladimir N Uversky, Tian Liu, David E Kang, Junga Alexa Woo, Orkid Coskuner-Weber.
      The V57E pathological variant of the mitochondrial coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10) plays a role in frontotemporal dementia. The wild-type and V57E mutant CHCHD10 proteins contain intrinsically disordered regions, and therefore, these regions hampered structural characterization of these proteins using conventional experimental tools. For the first time in the literature, we represent that the V57E mutation is pathogenic to mitochondria as it increases mitochondrial superoxide and impairs mitochondrial respiration. In addition, we represent here the structural ensemble properties of the V57E mutant CHCHD10 and describe the impacts of V57E mutation on the structural ensembles of wild-type CHCHD10 in aqueous solution. We conducted experimental and computational studies for this research. Namely, MitoSOX Red staining and Seahorse Mito Stress experiments, atomic force microscopy measurements, bioinformatics, homology modeling, and multiple-run molecular dynamics simulation computational studies were conducted. Our experiments show that the V57E mutation results in mitochondrial dysfunction, and our computational studies present that the structural ensemble properties of wild-type CHCHD10 are impacted by the frontotemporal dementia-associated V57E genetic mutation.
    Keywords:  CHCHD10; G58R; bioinformatics; genetics; mitochondrial myopathy; multiple-run molecular dynamics simulations; structural properties
    DOI:  https://doi.org/10.1021/acschemneuro.3c00125
  52. Nucleic Acids Res. 2023 May 13. pii: gkad390. [Epub ahead of print]
    Breeze 2.0: an interactive web-tool for visual analysis and comparison of drug response data.
    Swapnil Potdar, Filipp Ianevski, Aleksandr Ianevski, Ziaurrehman Tanoli, Krister Wennerberg, Brinton Seashore-Ludlow, Olli Kallioniemi, Päivi Östling, Tero Aittokallio, Jani Saarela.
      Functional precision medicine (fPM) offers an exciting, simplified approach to finding the right applications for existing molecules and enhancing therapeutic potential. Integrative and robust tools ensuring high accuracy and reliability of the results are critical. In response to this need, we previously developed Breeze, a drug screening data analysis pipeline, designed to facilitate quality control, dose-response curve fitting, and data visualization in a user-friendly manner. Here, we describe the latest version of Breeze (release 2.0), which implements an array of advanced data exploration capabilities, providing users with comprehensive post-analysis and interactive visualization options that are essential for minimizing false positive/negative outcomes and ensuring accurate interpretation of drug sensitivity and resistance data. The Breeze 2.0 web-tool also enables integrative analysis and cross-comparison of user-uploaded data with publicly available drug response datasets. The updated version incorporates new drug quantification metrics, supports analysis of both multi-dose and single-dose drug screening data and introduces a redesigned, intuitive user interface. With these enhancements, Breeze 2.0 is anticipated to substantially broaden its potential applications in diverse domains of fPM.
    DOI:  https://doi.org/10.1093/nar/gkad390
  53. Nat Commun. 2023 May 16. 14(1): 2803
    A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides.
    Kimberly C Paul, Richard C Krolewski, Edinson Lucumi Moreno, Jack Blank, Kristina M Holton, Tim Ahfeldt, Melissa Furlong, Yu Yu, Myles Cockburn, Laura K Thompson, Alexander Kreymerman, Elisabeth M Ricci-Blair, Yu Jun Li, Heer B Patel, Richard T Lee, Jeff Bronstein, Lee L Rubin, Vikram Khurana, Beate Ritz.
      Parkinson's disease (PD) is a complex neurodegenerative disease with etiology rooted in genetic vulnerability and environmental factors. Here we combine quantitative epidemiologic study of pesticide exposures and PD with toxicity screening in dopaminergic neurons derived from PD patient induced pluripotent stem cells (iPSCs) to identify Parkinson's-relevant pesticides. Agricultural records enable investigation of 288 specific pesticides and PD risk in a comprehensive, pesticide-wide association study. We associate long-term exposure to 53 pesticides with PD and identify co-exposure profiles. We then employ a live-cell imaging screening paradigm exposing dopaminergic neurons to 39 PD-associated pesticides. We find that 10 pesticides are directly toxic to these neurons. Further, we analyze pesticides typically used in combinations in cotton farming, demonstrating that co-exposures result in greater toxicity than any single pesticide. We find trifluralin is a driver of toxicity to dopaminergic neurons and leads to mitochondrial dysfunction. Our paradigm may prove useful to mechanistically dissect pesticide exposures implicated in PD risk and guide agricultural policy.
    DOI:  https://doi.org/10.1038/s41467-023-38215-z
  54. Cells. 2023 04 29. pii: 1287. [Epub ahead of print]12(9):
    CRMP2 Participates in Regulating Mitochondrial Morphology and Motility in Alzheimer's Disease.
    Tatiana Brustovetsky, Rajesh Khanna, Nickolay Brustovetsky.
      Mitochondrial bioenergetics and dynamics (alterations in morphology and motility of mitochondria) play critical roles in neuronal reactions to varying energy requirements in health and disease. In Alzheimer's disease (AD), mitochondria undergo excessive fission and become less motile. The mechanisms leading to these alterations are not completely clear. Here, we show that collapsin response mediator protein 2 (CRMP2) is hyperphosphorylated in AD and that is accompanied by a decreased interaction of CRMP2 with Drp1, Miro 2, and Mitofusin 2, which are proteins involved in regulating mitochondrial morphology and motility. CRMP2 was hyperphosphorylated in postmortem brain tissues of AD patients, in brain lysates, and in cultured cortical neurons from the double transgenic APP/PS1 mice, an AD mouse model. CRMP2 hyperphosphorylation and dissociation from its binding partners correlated with increased Drp1 recruitment to mitochondria, augmented mitochondrial fragmentation, and reduced mitochondrial motility. (S)-lacosamide ((S)-LCM), a small molecule that binds to CRMP2, decreased its phosphorylation at Ser 522 and Thr 509/514, and restored CRMP2's interaction with Miro 2, Drp1, and Mitofusin 2. This was paralleled by decreased Drp1 recruitment to mitochondria, diminished mitochondrial fragmentation, and improved motility of the organelles. Additionally, (S)-LCM-protected cultured cortical AD neurons from cell death. Thus, our data suggest that CRMP2, in a phosphorylation-dependent manner, participates in the regulation of mitochondrial morphology and motility, and modulates neuronal survival in AD.
    Keywords:  Alzheimer’s disease; CRMP2; cortical neurons; mitochondrial morphology; mitochondrial motility; neuronal cell death
    DOI:  https://doi.org/10.3390/cells12091287
  55. medRxiv. 2023 May 08. pii: 2023.05.01.23289356. [Epub ahead of print]
    Rare penetrant mutations confer severe risk of common diseases.
    Petko Fiziev, Jeremy McRae, Jacob C Ulirsch, Jacqueline S Dron, Tobias Hamp, Yanshen Yang, Pierrick Wainschtein, Zijian Ni, Joshua G Schraiber, Hong Gao, Dylan Cable, Yair Field, Francois Aguet, Marc Fasnacht, Ahmed Metwally, Jeffrey Rogers, Tomas Marques-Bonet, Heidi L Rehm, Anne O'Donnell-Luria, Amit V Khera, Kyle Kai-How Farh.
      We examined 454,712 exomes for genes associated with a wide spectrum of complex traits and common diseases and observed that rare, penetrant mutations in genes implicated by genome-wide association studies confer ∼10-fold larger effects than common variants in the same genes. Consequently, an individual at the phenotypic extreme and at the greatest risk for severe, early-onset disease is better identified by a few rare penetrant variants than by the collective action of many common variants with weak effects. By combining rare variants across phenotype-associated genes into a unified genetic risk model, we demonstrate superior portability across diverse global populations compared to common variant polygenic risk scores, greatly improving the clinical utility of genetic-based risk prediction.One sentence summary: Rare variant polygenic risk scores identify individuals with outlier phenotypes in common human diseases and complex traits.
    DOI:  https://doi.org/10.1101/2023.05.01.23289356
  56. Cell Insight. 2022 Apr;1(2): 100019
    NAD+-dependent mechanism of pathological axon degeneration.
    Ying Cao, Yi Wang, Jing Yang.
      Pathological axon degeneration is broadly observed in neurodegenerative diseases. This unique process of axonal pathology could directly interfere with the normal functions of neurocircuitries and contribute to the onset of clinical symptoms in patients. It has been increasingly recognized that functional preservation of axonal structures is an indispensable part of therapeutic strategies for treating neurological disorders. In the past decades, the research field has witnessed significant breakthroughs in understanding the stereotyped self-destruction of axons upon neurodegenerative insults, which is distinct from all the known types of programmed cell death. In particular, the novel NAD+-dependent mechanism involving the WLDs, NMNAT2, and SARM1 proteins has emerged. This review summarizes the landmark discoveries elucidating the molecular pathway of pathological axon degeneration and highlights the evolving concept that neurodegeneration would be intrinsically linked to NAD+ and energy metabolism.
    Keywords:  Energy deficit; NAD+ metabolism; Pathological axon degeneration; SARM1; Wlds mutation
    DOI:  https://doi.org/10.1016/j.cellin.2022.100019
  57. Nat Genet. 2023 05;55(5): 724-726
    Annotating and prioritizing human non-coding variants with RegulomeDB v.2.
    Shengcheng Dong, Nanxiang Zhao, Emma Spragins, Meenakshi S Kagda, Mingjie Li, Pedro Assis, Otto Jolanki, Yunhai Luo, J Michael Cherry, Alan P Boyle, Benjamin C Hitz.
      
    DOI:  https://doi.org/10.1038/s41588-023-01365-3
  58. Bioinformatics. 2023 May 17. pii: btad326. [Epub ahead of print]
    ODNA: Identification of Organellar DNA by Machine Learning.
    Roman Martin, Minh Kien Nguyen, Nick Lowack, Dominik Heider.
      MOTIVATION: Identifying organellar DNA, such as mitochondrial or plastid sequences, inside a whole genome assembly, remains challenging and requires biological background knowledge. To address this, we developed ODNA based on genome annotation and machine learning to fulfill.RESULTS: ODNA is a software that classifies organellar DNA sequences within a genome assembly by machine learning based on a pre-defined genome annotation workflow. We trained our model with 829,769 DNA sequences from 405 genome assemblies and achieved high predictive performance (e.g., MCC of 0.61 for mitochondria and 0.73 for chloroplasts) on independent validation data, thus outperforming existing approaches significantly.
    AVAILABILITY: Our software ODNA is freely accessible as a web service at https://odna.mathematik.uni-marburg.de and can also be run in a docker container. The source code can be found at https://gitlab.com/mosga/odna and the processed data at Zenodo (DOI: 10.5281/zenodo.7506483).
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btad326
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