bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2022–02–27
forty-four papers selected by
Catalina Vasilescu, University of Helsinki
  1. Mitochondrial Neurodegeneration.
  2. The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics.
  3. A retrospective cohort study exploring the association between different mitochondrial diseases and hearing loss.
  4. m.3685T>C is a Novel Mitochondrial DNA Variant That Causes Leigh Syndrome.
  5. New Insights on Rotenone Resistance of Complex I Induced by the m.11778G>A/MT-ND4 Mutation Associated with Leber's Hereditary Optic Neuropathy.
  6. Site-specific mitochondrial dysfunction in neurodegeneration.
  7. Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency.
  8. Mechanisms of mitochondrial promoter recognition in humans and other mammalian species.
  9. Development and characterization of different cell models harbouring mitochondrial DNA deletions for in vitro study of Pearson syndrome.
  10. Mitochondrial variant enrichment from high-throughput single-cell RNA sequencing resolves clonal populations.
  11. Computational Pipeline for Next-Generation Sequencing (NGS) Studies in Genetics of NASH.
  12. Mitochondrial dysfunction associated with TANGO2 deficiency.
  13. Intravenous nicotinamide riboside elevates mouse skeletal muscle NAD+ without impacting respiratory capacity or insulin sensitivity.
  14. Mitochondrial Disease and Hearing Loss in Children: A Systematic Review.
  15. Circulating Mitochondrial DNA and Inter-Organelle Contact Sites in Aging and Associated Conditions.
  16. Analysis of Mitochondrial Function, Structure, and Intracellular Organization In Situ in Cardiomyocytes and Skeletal Muscles.
  17. Aberrant cyclin C nuclear release induces mitochondrial fragmentation and dysfunction in MED13L syndrome fibroblasts.
  18. Mitochondrial and metabolic remodeling in human skin fibroblasts in response to glucose availability.
  19. Promising Treatment for Multiple Sclerosis: Mitochondrial Transplantation.
  20. Neuronal mitochondria transport Pink1 mRNA via synaptojanin 2 to support local mitophagy.
  21. Mitochondrial COA7 is a heme-binding protein with disulfide reductase activity, which acts in the early stages of complex IV assembly.
  22. Redox-dependent loss of flavin by mitochondria complex I is different in brain and heart.
  23. Maintenance of NAD+ Homeostasis in Skeletal Muscle during Aging and Exercise.
  24. Tissue-specific alternative splicing separates the catalytic and cell signaling functions of human leucyl-tRNA synthetase.
  25. Neurodegenerative and functional signatures of the cerebellar cortex in m.3243A > G patients.
  26. Mitochondria Lead the Way: Mitochondrial Dynamics and Function in Cellular Movements in Development and Disease.
  27. Characterization of exonic variants of uncertain significance in very long-chain acyl-CoA dehydrogenase identified through newborn screening.
  28. SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated bymultiple physiologically relevant NAD metabolites.
  29. Impaired Mitochondrial Bioenergetics under Pathological Conditions.
  30. The Mitochondrial Epigenome: An Unexplored Avenue to Explain Unexplained Myopathies?
  31. Cytoprotective Effect of Idebenone through Modulation of the Intrinsic Mitochondrial Pathway of Apoptosis in Human Retinal Pigment Epithelial Cells Exposed to Oxidative Stress Induced by Hydrogen Peroxide.
  32. Microscopy-based cellular contractility assay for adult, neonatal, and hiPSC cardiomyocytes.
  33. Computational Genomics in the Era of Precision Medicine: Applications to Variant Analysis and Gene Therapy.
  34. Sequence determinants of human gene regulatory elements.
  35. The proteomic profile of the human myotendinous junction.
  36. Photonics tools begin to clarify astrocyte calcium transients.
  37. Increased Drp1 promotes autophagy and ESCC progression by mtDNA stress mediated cGAS-STING pathway.
  38. Monitoring the maturation of the sarcomere network: a super-resolution microscopy-based approach.
  39. Using deep learning to annotate the protein universe.
  40. PatientMatcher: a customizable Python-based open-source tool for matching undiagnosed rare disease patients via the Matchmaker Exchange network.
  41. Organellar homeostasis and innate immune sensing.
  42. CoSpar identifies early cell fate biases from single-cell transcriptomic and lineage information.
  43. Coenzyme Q10 and related quinones oxidize H2S to polysulfides and thiosulfate.
  44. Genetic Biomarkers of Metabolic Detoxification for Personalized Lifestyle Medicine.
  1. Cells. 2022 Feb 11. pii: 637. [Epub ahead of print]11(4):
    Mitochondrial Neurodegeneration.
    Massimo Zeviani, Carlo Viscomi.
      Mitochondria are cytoplasmic organelles, which generate energy as heat and ATP, the universal energy currency of the cell. This process is carried out by coupling electron stripping through oxidation of nutrient substrates with the formation of a proton-based electrochemical gradient across the inner mitochondrial membrane. Controlled dissipation of the gradient can lead to production of heat as well as ATP, via ADP phosphorylation. This process is known as oxidative phosphorylation, and is carried out by four multiheteromeric complexes (from I to IV) of the mitochondrial respiratory chain, carrying out the electron flow whose energy is stored as a proton-based electrochemical gradient. This gradient sustains a second reaction, operated by the mitochondrial ATP synthase, or complex V, which condensates ADP and Pi into ATP. Four complexes (CI, CIII, CIV, and CV) are composed of proteins encoded by genes present in two separate compartments: the nuclear genome and a small circular DNA found in mitochondria themselves, and are termed mitochondrial DNA (mtDNA). Mutations striking either genome can lead to mitochondrial impairment, determining infantile, childhood or adult neurodegeneration. Mitochondrial disorders are complex neurological syndromes, and are often part of a multisystem disorder. In this paper, we divide the diseases into those caused by mtDNA defects and those that are due to mutations involving nuclear genes; from a clinical point of view, we discuss pediatric disorders in comparison to juvenile or adult-onset conditions. The complementary genetic contributions controlling organellar function and the complexity of the biochemical pathways present in the mitochondria justify the extreme genetic and phenotypic heterogeneity of this new area of inborn errors of metabolism known as 'mitochondrial medicine'.
    Keywords:  Leigh syndrome; MELAS; MERRF; OXPHOS; POLG; mitochondrial disease; mitochondrial respiratory chain
    DOI:  https://doi.org/10.3390/cells11040637
  2. Biomedicines. 2022 Feb 18. pii: 490. [Epub ahead of print]10(2):
    The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics.
    Sanjana Saravanan, Caitlin J Lewis, Bhavna Dixit, Matthew S O'Connor, Alexandra Stolzing, Amutha Boominathan.
      Mitochondria are intracellular organelles that utilize nutrients to generate energy in the form of ATP by oxidative phosphorylation. Mitochondrial DNA (mtDNA) in humans is a 16,569 base pair double-stranded circular DNA that encodes for 13 vital proteins of the electron transport chain. Our understanding of the mitochondrial genome's transcription, translation, and maintenance is still emerging, and human pathologies caused by mtDNA dysfunction are widely observed. Additionally, a correlation between declining mitochondrial DNA quality and copy number with organelle dysfunction in aging is well-documented in the literature. Despite tremendous advancements in nuclear gene-editing technologies and their value in translational avenues, our ability to edit mitochondrial DNA is still limited. In this review, we discuss the current therapeutic landscape in addressing the various pathologies that result from mtDNA mutations. We further evaluate existing gene therapy efforts, particularly allotopic expression and its potential to become an indispensable tool for restoring mitochondrial health in disease and aging.
    Keywords:  allotopic expression; gene therapy; mitochondria; mitochondrial diseases; mtDNA; mtDNA editing; mtDNA mutations
    DOI:  https://doi.org/10.3390/biomedicines10020490
  3. Mol Genet Metab. 2022 Feb 15. pii: S1096-7192(22)00135-4. [Epub ahead of print]
    A retrospective cohort study exploring the association between different mitochondrial diseases and hearing loss.
    Carlijn M A van Kempen, Andy J Beynon, Jeroen J Smits, Mirian C H Janssen.
      Some pathogenic variants in mtDNA and nuclear DNA, affecting mitochondrial function, are associated with hearing loss. Behavioral and electrophysiological auditory performance are obtained from 62 patients, clinically diagnosed with different mitochondrial diseases (MD) using tone/speech audiometry and Auditory Brainstem Responses (ABR). Audiological variables (hearing loss type, pure tone average (PTA), interaural asymmetry, speech perception and brainstem neural conductivity) were analyzed and related to Newcastle Mitochondrial Disease Scale for Adults (NMDAS). In 35% of MDs, a mild to severe symmetrical sensorineural hearing loss (SNHL) was found. Patients with Maternally Inherited Diabetes and Deafness (MIDD) show significantly higher PTAs compared to other MDs. For all MDs, speech recognition scores were in accordance with their individual age- and gender-corrected tone audiometry, but ABR peak latencies were prolonged in patients with MIDD, Mitochondrial Encephalopathy Lactate acidosis and Stroke-like episodes (MELAS), Chronic Progressive External Ophthalmoplegia (CPEO) and Subacute necrotizing encephalopathy (Leigh). Correlations between NMDAS and audiological variables were low.
    Keywords:  Audiological assessment; Auditory brainstem responses; Hearing loss; Mitochondrial disease; NMDAS; Speech perception; Tonal audiogram
    DOI:  https://doi.org/10.1016/j.ymgme.2022.02.003
  4. Cold Spring Harb Mol Case Stud. 2022 Feb 25. pii: mcs.a006136. [Epub ahead of print]
    m.3685T>C is a Novel Mitochondrial DNA Variant That Causes Leigh Syndrome.
    Jeffrey Jean, Eirini Christodoulou, Xiaowu Gai, Benita Tamrazi, Moin Vera, Wendy G Mitchell, Ryan J Schmidt.
      Variants in the mitochondrial genome can result in dysfunction of Complex I within the electron transport chain, thus causing disruptions in oxidative phosphorylation. Pathogenic variants in the MT-ND1 (NADH:ubiquinone oxidoreductase core subunit 1) gene that result in Complex I dysfunction are a known cause of Leigh syndrome. The patient is a four year-old female who initially presented with generalized tonic-clonic seizures, with other symptoms of Leigh syndrome becoming apparent after the seizures. A three-generation pedigree revealed no family history of mitochondrial disorders. Laboratory studies were remarkable for elevated blood lactate, alanine, and GDF15. T2-weighted MRI revealed bilateral asymmetric signal hyperintensities in the basal ganglia, specifically in the bilateral putamen and right caudate. Magnetic resonance spectroscopy showed regionally elevated glucose and lactate. Mitochondrial respiratory chain enzyme analysis on skin fibroblasts demonstrated slightly reduced Complex I function. A 16-gene dystonia panel and chromosomal microarray analysis did not identify any disease-causing variants. Combined exome and mitochondrial genome sequencing identified the m.3685T>C (MT-ND1 p.Tyr127His) variant with 62.3% heteroplasmy with no alternative cause for the patient's condition. Mitochondrial genome sequencing of the mother demonstrated that the m.3685T>C variant occurred de novo. The m.3685T>C variant is absent from population databases. The tyrosine 127 residue is highly conserved, and several nearby pathogenic variants in the MT-ND1 gene have been previously associated with Leigh syndrome. We propose that the m.3685T>C variant is a novel mitochondrial DNA variant that causes Leigh syndrome, and we classify this variant as likely pathogenic based on currently available information.
    Keywords:  Elevated brain lactate level by MRS; Focal T2 hyperintense basal ganglia lesion; Generalized clonic seizures; Generalized tonic seizures; Hyperalaninemia
    DOI:  https://doi.org/10.1101/mcs.a006136
  5. Molecules. 2022 Feb 16. pii: 1341. [Epub ahead of print]27(4):
    New Insights on Rotenone Resistance of Complex I Induced by the m.11778G>A/MT-ND4 Mutation Associated with Leber's Hereditary Optic Neuropathy.
    Francesco Musiani, Laura Rigobello, Luisa Iommarini, Valerio Carelli, Mauro Degli Esposti, Anna Maria Ghelli.
      The finding that the most common mitochondrial DNA mutation m.11778G>A/MT-ND4 (p.R340H) associated with Leber's hereditary optic neuropathy (LHON) induces rotenone resistance has produced a long-standing debate, because it contrasts structural evidence showing that the ND4 subunit is far away from the quinone-reaction site in complex I, where rotenone acts. However, recent cryo-electron microscopy data revealed that rotenone also binds to the ND4 subunit. We investigated the possible structural modifications induced by the LHON mutation and found that its amino acid replacement would disrupt a possible hydrogen bond between native R340 and Q139 in ND4, thereby destabilizing rotenone binding. Our analysis thus explains rotenone resistance in LHON patients as a biochemical signature of its pathogenic effect on complex I.
    Keywords:  LHON; complex I; mtDNA mutations; rotenone
    DOI:  https://doi.org/10.3390/molecules27041341
  6. Mitochondrion. 2022 Feb 16. pii: S1567-7249(22)00010-1. [Epub ahead of print]64 1-18
    Site-specific mitochondrial dysfunction in neurodegeneration.
    Anežka Vodičková, Shon A Koren, Andrew P Wojtovich.
      Mitochondria are essential for neuronal survival and mitochondrial dysfunction is a hallmark of neurodegeneration. The loss in mitochondrial energy production, oxidative stress, and changes in calcium handling are associated with neurodegenerative diseases; however, different sites and types of mitochondrial dysfunction are linked to distinct neuropathologies. Understanding the causal or correlative relationship between changes in mitochondria and neuropathology will lead to new therapeutic strategies. Here, we summarize the evidence of site-specific mitochondrial dysfunction and mitochondrial-related clinical trials for neurodegenerative diseases. We further discuss potential therapeutic approaches, such as mitochondrial transplantation, restoration of mitochondrial function, and pharmacological alleviation of mitochondrial dysfunction.
    Keywords:  Mitochondria-targeting therapeutics; Mitochondrial dysfunction; Neurodegeneration; Optogenetics; Transplantation
    DOI:  https://doi.org/10.1016/j.mito.2022.02.004
  7. Elife. 2022 02 21. pii: e72595. [Epub ahead of print]11
    Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency.
    Andres De La Rossa, Marine H Laporte, Simone Astori, Thomas Marissal, Sylvie Montessuit, Preethi Sheshadri, Eva Ramos-Fernández, Pablo Mendez, Abbas Khani, Charles Quairiaux, Eric B Taylor, Jared Rutter, José Manuel Nunes, Alan Carleton, Michael R Duchen, Carmen Sandi, Jean-Claude Martinou.
      Neuronal excitation imposes a high demand of ATP in neurons. Most of the ATP derives primarily from pyruvate-mediated oxidative phosphorylation, a process that relies on import of pyruvate into mitochondria occuring exclusively via the mitochondrial pyruvate carrier (MPC). To investigate whether deficient oxidative phosphorylation impacts neuron excitability, we generated a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the MPC, specifically in adult glutamatergic neurons. We found that, despite decreased levels of oxidative phosphorylation and decreased mitochondrial membrane potential in these excitatory neurons, mice were normal at rest. Surprisingly, in response to mild inhibition of GABA mediated synaptic activity, they rapidly developed severe seizures and died, whereas under similar conditions the behavior of control mice remained unchanged. We report that neurons with a deficient MPC were intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduced M-type potassium channel activity. Provision of ketone bodies restored energy status, calcium homeostasis and M-channel activity and attenuated seizures in animals fed a ketogenic diet. Our results provide an explanation for the seizures that frequently accompany a large number of neuropathologies, including cerebral ischemia and diverse mitochondriopathies, in which neurons experience an energy deficit.
    Keywords:  calcium; kcnq kv.7 channel; ketogenic diet; metabolism; mitochondrial pyruvate carrier; mouse; neuronal excitability; neuroscience
    DOI:  https://doi.org/10.7554/eLife.72595
  8. Nucleic Acids Res. 2022 Feb 22. pii: gkac103. [Epub ahead of print]
    Mechanisms of mitochondrial promoter recognition in humans and other mammalian species.
    Angelica Zamudio-Ochoa, Yaroslav I Morozov, Azadeh Sarfallah, Michael Anikin, Dmitry Temiakov.
      Recognition of mammalian mitochondrial promoters requires the concerted action of mitochondrial RNA polymerase (mtRNAP) and transcription initiation factors TFAM and TFB2M. In this work, we found that transcript slippage results in heterogeneity of the human mitochondrial transcripts in vivo and in vitro. This allowed us to correctly interpret the RNAseq data, identify the bona fide transcription start sites (TSS), and assign mitochondrial promoters for > 50% of mammalian species and some other vertebrates. The divergent structure of the mammalian promoters reveals previously unappreciated aspects of mtDNA evolution. The correct assignment of TSS also enabled us to establish the precise register of the DNA in the initiation complex and permitted investigation of the sequence-specific protein-DNA interactions. We determined the molecular basis of promoter recognition by mtRNAP and TFB2M, which cooperatively recognize bases near TSS in a species-specific manner. Our findings reveal a role of mitochondrial transcription machinery in mitonuclear coevolution and speciation.
    DOI:  https://doi.org/10.1093/nar/gkac103
  9. Dis Model Mech. 2022 Feb 22. pii: dmm.049083. [Epub ahead of print]
    Development and characterization of different cell models harbouring mitochondrial DNA deletions for in vitro study of Pearson syndrome.
    Carmen Hernández-Ainsa, Ester López-Gallardo, María Concepción García-Jiménez, Francisco José Climent-Alcalá, Carmen Rodríguez-Vigil, Marta García Fernández de Villalta, Rafael Artuch, Julio Montoya, Eduardo Ruiz-Pesini, Sonia Emperador.
      Pearson syndrome (PS) is a rare multisystem disease caused by single large scale mitochondrial DNA deletions (SLSMDs). PS presents early in infancy and it is mainly characterized by refractory sideroblastic anaemia. Prognosis is poor and treatment is supportive, thus development of new models for the study of PS and new therapy strategies is essential. In this work we report three different cell models carrying a SLMSD: fibroblasts, transmitochondrial cybrids and induced pluripotent stem cells (iPSC). All studied models exhibited an aberrant mitochondrial ultrastructure and defective OXPHOS function, showing a decrease in different parameters such as mitochondrial ATP, respiratory complex IV activity and quantity or oxygen consumption. Despite that, iPSC harbouring "common deletion" were able to differentiate into three germ layers. Besides, cybrids clones only showed mitochondrial dysfunction when heteroplasmy level reached 70%. Some differences observed among models may depend on their metabolic profile, therefore we consider these three models are useful for the in vitro study of the PS as well as for testing new specific therapies.
    Keywords:  Cybrid; IPSC; Mitochondrial DNA; Mitochondrial disease; MtDNA deletion; Pearson syndrome
    DOI:  https://doi.org/10.1242/dmm.049083
  10. Nat Biotechnol. 2022 Feb 24.
    Mitochondrial variant enrichment from high-throughput single-cell RNA sequencing resolves clonal populations.
    Tyler E Miller, Caleb A Lareau, Julia A Verga, Erica A K DePasquale, Vincent Liu, Daniel Ssozi, Katalin Sandor, Yajie Yin, Leif S Ludwig, Chadi A El Farran, Duncan M Morgan, Ansuman T Satpathy, Gabriel K Griffin, Andrew A Lane, J Christopher Love, Bradley E Bernstein, Vijay G Sankaran, Peter van Galen.
      The combination of single-cell transcriptomics with mitochondrial DNA variant detection can be used to establish lineage relationships in primary human cells, but current methods are not scalable to interrogate complex tissues. Here, we combine common 3' single-cell RNA-sequencing protocols with mitochondrial transcriptome enrichment to increase coverage by more than 50-fold, enabling high-confidence mutation detection. The method successfully identifies skewed immune-cell expansions in primary human clonal hematopoiesis.
    DOI:  https://doi.org/10.1038/s41587-022-01210-8
  11. Methods Mol Biol. 2022 ;2455 203-222
    Computational Pipeline for Next-Generation Sequencing (NGS) Studies in Genetics of NASH.
    Adrian Salatino, Silvia Sookoian, Carlos J Pirola.
      High-throughput sequencing (HTS) technologies have contributed to expand current knowledge of the biology of complex diseases, including nonalcoholic fatty liver disease (NAFLD). Genome-wide association studies, whole exome sequencing, and sequencing of entire genes are used to identify variants and/or mutations that predispose to the disease pathogenesis. Here, we present a tutorial that may guide readers to manage high volume of genetics data in the context of Next-Generation Sequencing (NGS) studies.
    Keywords:  Allele; Amplicon; Annotation; Association; Bioconda; Fisher; InDel; NAFLD; SNV; Sequencing; Short-read; Variant calling
    DOI:  https://doi.org/10.1007/978-1-0716-2128-8_16
  12. Sci Rep. 2022 02 23. 12(1): 3045
    Mitochondrial dysfunction associated with TANGO2 deficiency.
    Paige Heiman, Al-Walid Mohsen, Anuradha Karunanidhi, Claudette St Croix, Simon Watkins, Erik Koppes, Richard Haas, Jerry Vockley, Lina Ghaloul-Gonzalez.
      Transport and Golgi Organization protein 2 Homolog (TANGO2)-related disease is an autosomal recessive disorder caused by mutations in the TANGO2 gene. Symptoms typically manifest in early childhood and include developmental delay, stress-induced episodic rhabdomyolysis, and cardiac arrhythmias, along with severe metabolic crises including hypoglycemia, lactic acidosis, and hyperammonemia. Severity varies among and within families. Previous studies have reported contradictory evidence of mitochondrial dysfunction. Since the clinical symptoms and metabolic abnormalities are suggestive of a broad dysfunction of mitochondrial energy metabolism, we undertook a broad examination of mitochondrial bioenergetics in TANGO2 deficient patients utilizing skin fibroblasts derived from three patients exhibiting TANGO2-related disease. Functional studies revealed that TANGO2 protein was present in mitochondrial extracts of control cells but not patient cells. Superoxide production was increased in patient cells, while oxygen consumption rate, particularly under stress, along with relative ATP levels and β-oxidation of oleate were reduced. Our findings suggest that mitochondrial function should be assessed and monitored in all patients with TANGO2 mutation as targeted treatment of the energy dysfunction could improve outcome in this condition.
    DOI:  https://doi.org/10.1038/s41598-022-07076-9
  13. iScience. 2022 Feb 18. 25(2): 103863
    Intravenous nicotinamide riboside elevates mouse skeletal muscle NAD+ without impacting respiratory capacity or insulin sensitivity.
    Mads V Damgaard, Thomas S Nielsen, Astrid L Basse, Sabina Chubanava, Kajetan Trost, Thomas Moritz, Ryan W Dellinger, Steen Larsen, Jonas T Treebak.
      In clinical trials, oral supplementation with nicotinamide riboside (NR) fails to increase muscle mitochondrial respiratory capacity and insulin sensitivity but also does not increase muscle NAD+ levels. This study tests the feasibility of chronically elevating skeletal muscle NAD+ in mice and investigates the putative effects on mitochondrial respiratory capacity, insulin sensitivity, and gene expression. Accordingly, to improve bioavailability to skeletal muscle, we developed an experimental model for administering NR repeatedly through a jugular vein catheter. Mice on a Western diet were treated with various combinations of NR, pterostilbene (PT), and voluntary wheel running, but the metabolic effects of NR and PT treatment were modest. We conclude that the chronic elevation of skeletal muscle NAD+ by the intravenous injection of NR is possible but does not affect muscle respiratory capacity or insulin sensitivity in either sedentary or physically active mice. Our data have implications for NAD+ precursor supplementation regimens.
    Keywords:  Drugs; Molecular physiology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2022.103863
  14. Laryngoscope. 2022 Feb 21.
    Mitochondrial Disease and Hearing Loss in Children: A Systematic Review.
    Sebastian Roesch, Anna O'Sullivan, Georg Zimmermann, Alois Mair, Cvetka Lipuš, Johannes A Mayr, Saskia B Wortmann, Gerd Rasp.
       OBJECTIVES: Hearing loss is a clinical symptom, frequently mentioned in the context of mitochondrial disease. With no cure available for mitochondrial disease, supportive treatment of clinical symptoms like hearing loss is of the utmost importance. The aim of this study was to summarize current knowledge on hearing loss in genetically proven mitochondrial disease in children and deduce possible and necessary consequences in patient care.
    METHODS: Systematic literature review, including Medline, Embase, and Cochrane library. Review protocol was established and registered prior to conduction (International prospective register of systematic reviews-PROSPERO: CRD42020165356). Conduction of this review was done in accordance with MOOSE criteria.
    RESULTS: A total of 23 articles, meeting predefined criteria and providing sufficient information on 75 individuals with childhood onset hearing loss was included for analysis. Both cochlear and retro-cochlear origin of hearing loss can be identified among different types of mitochondrial disease. Analysis was hindered by inhomogeneous reporting and methodical limitations.
    CONCLUSION: Overall, the findings do not allow for a general statement on hearing loss in children with mitochondrial disease. Retro-cochlear hearing loss seems to be found more often than expected. A common feature appears to be progression of hearing loss over time. However, hearing loss in these patients shows manifold characteristics. Therefore, awareness of mitochondrial disease as a possible causative background is important for otolaryngologists. Future attempts rely on standardized reporting and long-term follow-up.
    LEVEL OF EVIDENCE: NA Laryngoscope, 2022.
    Keywords:  audiometric testing; audiometry; auditory neuropathy; brainstem evoked auditory potentials; hearing; hearing loss; mitochondria; mitochondrial disease; mitochondriopathy; treatment
    DOI:  https://doi.org/10.1002/lary.30067
  15. Cells. 2022 Feb 15. pii: 675. [Epub ahead of print]11(4):
    Circulating Mitochondrial DNA and Inter-Organelle Contact Sites in Aging and Associated Conditions.
    Anna Picca, Flora Guerra, Riccardo Calvani, Roberta Romano, Hélio José Coelho-Junior, Francesco P Damiano, Cecilia Bucci, Emanuele Marzetti.
      Mitochondria are primarily involved in cell bioenergetics, regulation of redox homeostasis, and cell death/survival signaling. An immunostimulatory property of mitochondria has also been recognized which is deployed through the extracellular release of entire or portioned organelle and/or mitochondrial DNA (mtDNA) unloading. Dynamic homo- and heterotypic interactions involving mitochondria have been described. Each type of connection has functional implications that eventually optimize mitochondrial activity according to the bioenergetic demands of a specific cell/tissue. Inter-organelle communications may also serve as molecular platforms for the extracellular release of mitochondrial components and subsequent ignition of systemic inflammation. Age-related chronic inflammation (inflamm-aging) has been associated with mitochondrial dysfunction and increased extracellular release of mitochondrial components-in particular, cell-free mtDNA. The close relationship between mitochondrial dysfunction and cellular senescence further supports the central role of mitochondria in the aging process and its related conditions. Here, we provide an overview of (1) the mitochondrial genetic system and the potential routes for generating and releasing mtDNA intermediates; (2) the pro-inflammatory pathways elicited by circulating mtDNA; (3) the participation of inter-organelle contacts to mtDNA homeostasis; and (4) the link of these processes with senescence and age-associated conditions.
    Keywords:  exosomes; extracellular vesicles; inflamm-aging; mitochondrial damage; mitochondrial dynamics; mitochondrial-derived vesicles; mitochondrial-lysosomal axis; mitophagy; oxidative stress; senescence
    DOI:  https://doi.org/10.3390/cells11040675
  16. Int J Mol Sci. 2022 Feb 18. pii: 2252. [Epub ahead of print]23(4):
    Analysis of Mitochondrial Function, Structure, and Intracellular Organization In Situ in Cardiomyocytes and Skeletal Muscles.
    Andrey V Kuznetsov, Sabzali Javadov, Raimund Margreiter, Judith Hagenbuchner, Michael J Ausserlechner.
      Analysis of the function, structure, and intracellular organization of mitochondria is important for elucidating energy metabolism and intracellular energy transfer. In addition, basic and clinically oriented studies that investigate organ/tissue/cell dysfunction in various human diseases, including myopathies, cardiac/brain ischemia-reperfusion injuries, neurodegenerative diseases, cancer, and aging, require precise estimation of mitochondrial function. It should be noted that the main metabolic and functional characteristics of mitochondria obtained in situ (in permeabilized cells and tissue samples) and in vitro (in isolated organelles) are quite different, thereby compromising interpretations of experimental and clinical data. These differences are explained by the existence of the mitochondrial network, which possesses multiple interactions between the cytoplasm and other subcellular organelles. Metabolic and functional crosstalk between mitochondria and extra-mitochondrial cellular environments plays a crucial role in the regulation of mitochondrial metabolism and physiology. Therefore, it is important to analyze mitochondria in vivo or in situ without their isolation from the natural cellular environment. This review summarizes previous studies and discusses existing approaches and methods for the analysis of mitochondrial function, structure, and intracellular organization in situ.
    Keywords:  cardiac mitochondria; confocal fluorescent imaging; heterogeneity; mitochondrial intracellular organization; mitochondrial respiratory function; mitochondrial swelling; oxidative phosphorylation; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms23042252
  17. iScience. 2022 Feb 18. 25(2): 103823
    Aberrant cyclin C nuclear release induces mitochondrial fragmentation and dysfunction in MED13L syndrome fibroblasts.
    Kai-Ti Chang, Jan Jezek, Alicia N Campbell, David C Stieg, Zachary A Kiss, Kevin Kemper, Ping Jiang, Hyung-Ok Lee, Warren D Kruger, Peter M van Hasselt, Randy Strich.
      MED13L syndrome is a haploinsufficiency developmental disorder characterized by intellectual disability, heart malformation, and hypotonia. MED13L controls transcription by tethering the cyclin C-Cdk8 kinase module (CKM) to the Mediator complex. In addition, cyclin C has CKM-independent roles in the cytoplasm directing stress-induced mitochondrial fragmentation and regulated cell death. Unstressed MED13L S1497 F/fs patient fibroblasts exhibited aberrant cytoplasmic cyclin C localization, mitochondrial fragmentation, and a 6-fold reduction in respiration. In addition, the fibroblasts exhibited reduced mtDNA copy number, reduction in mitochondrial membrane integrity, and hypersensitivity to oxidative stress. Finally, transcriptional analysis of MED13L mutant fibroblasts revealed reduced mRNA levels for several genes necessary for normal mitochondrial function. Pharmacological or genetic approaches preventing cyclin C-mitochondrial localization corrected the fragmented mitochondrial phenotype and partially restored organelle function. In conclusion, this study found that mitochondrial dysfunction is an underlying defect in cells harboring the MED13L S1497 F/fs allele and identified cyclin C mis-localization as the likely cause. These results provide a new avenue for understanding this disorder.
    Keywords:  Biochemistry; Biological sciences; Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2022.103823
  18. FEBS J. 2022 Feb 25.
    Mitochondrial and metabolic remodeling in human skin fibroblasts in response to glucose availability.
    Sónia A Pinho, Cláudio F Costa, Cláudia M Deus, Sonia L C Pinho, Inês Miranda-Santos, Gonçalo Afonso, Olivia Bagshaw, Jeffrey Stuart, Paulo J Oliveira, Teresa Cunha-Oliveira.
      Cell culture conditions highly influence cell metabolism in vitro. This is relevant for preclinical assays, for which fibroblasts are an interesting cell model, with applications in regenerative medicine, diagnostics and therapeutic development for personalized medicine, and the validation of ingredients for cosmetics. Given these cells' short lifespan in culture, we aimed to identify the best cell culture conditions and promising markers to study mitochondrial health and stress in Normal Human Dermal Fibroblasts (NHDF). We tested the effect of reducing glucose concentration in the cell medium from high glucose (HGm) to a more physiological level (LGm), or its complete removal and replacement by galactose (OXPHOSm), always in the presence of glutamine and pyruvate. We have demonstrated that only with OXPHOSm was it possible to observe the selective inhibition of mitochondrial ATP production. This reliance on mitochondrial ATP was accompanied by changes in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), oxidation of citric acid cycle substrates, fatty acids, lactate, and other substrates, increased mitochondrial network extension and polarization, increased protein content of VDAC and PGC1α and changes in several key transcripts related to energy metabolism. LGm did not promote significant metabolic changes in NHDF, although mitochondrial network extension and VDAC protein content were increased compared to HGm-cultured cells. Our results indicate that short-term adaptation to OXPHOSm is ideal for studying mitochondrial health and stress in NHDF.
    Keywords:  bioenergetics; human fibroblasts; metabolic remodeling; metabolism; mitochondrial health
    DOI:  https://doi.org/10.1111/febs.16413
  19. Int J Mol Sci. 2022 Feb 17. pii: 2245. [Epub ahead of print]23(4):
    Promising Treatment for Multiple Sclerosis: Mitochondrial Transplantation.
    Pasquale Picone, Domenico Nuzzo.
      In recent years, several studies have examined the multifaceted role of mitochondria in Multiple Sclerosis (MS), suggesting that, besides inflammation and demyelination, mitochondrial aberration is a crucial factor in mediating axonal degeneration, the latter being responsible for persistent disabilities in MS patients. Therefore, mitochondria have been recognized as a possible multiple sclerosis therapeutic target. Recently, mitochondrial transplantation has become a new term for the transfer of live mitochondria into damaged cells for the treatment of various diseases, including neurodegenerative diseases. In this hypothesis, we propose mitochondrial transplantation as a new, potentially applicable approach to counteract axonal degeneration in multiple sclerosis.
    Keywords:  biotechnology; mitochondria; mitochondrial transplantation; multiple sclerosis
    DOI:  https://doi.org/10.3390/ijms23042245
  20. Neuron. 2022 Feb 19. pii: S0896-6273(22)00105-2. [Epub ahead of print]
    Neuronal mitochondria transport Pink1 mRNA via synaptojanin 2 to support local mitophagy.
    Angelika B Harbauer, J Tabitha Hees, Simone Wanderoy, Inmaculada Segura, Whitney Gibbs, Yiming Cheng, Martha Ordonez, Zerong Cai, Romain Cartoni, Ghazaleh Ashrafi, Chen Wang, Fabiana Perocchi, Zhigang He, Thomas L Schwarz.
      PTEN-induced kinase 1 (PINK1) is a short-lived protein required for the removal of damaged mitochondria through Parkin translocation and mitophagy. Because the short half-life of PINK1 limits its ability to be trafficked into neurites, local translation is required for this mitophagy pathway to be active far from the soma. The Pink1 transcript is associated and cotransported with neuronal mitochondria. In concert with translation, the mitochondrial outer membrane proteins synaptojanin 2 binding protein (SYNJ2BP) and synaptojanin 2 (SYNJ2) are required for tethering Pink1 mRNA to mitochondria via an RNA-binding domain in SYNJ2. This neuron-specific adaptation for the local translation of PINK1 provides distal mitochondria with a continuous supply of PINK1 for the activation of mitophagy.
    Keywords:  OMP25; PINK1; Parkinson disease; RNA transport; SYNJ2BP; hitchhiking; local translation; mitophagy; synaptojanin2
    DOI:  https://doi.org/10.1016/j.neuron.2022.01.035
  21. Proc Natl Acad Sci U S A. 2022 Mar 01. pii: e2110357119. [Epub ahead of print]119(9):
    Mitochondrial COA7 is a heme-binding protein with disulfide reductase activity, which acts in the early stages of complex IV assembly.
    Luke E Formosa, Shadi Maghool, Alice J Sharpe, Boris Reljic, Linden Muellner-Wong, David A Stroud, Michael T Ryan, Megan J Maher.
      Cytochrome c oxidase (COX) assembly factor 7 (COA7) is a metazoan-specific assembly factor, critical for the biogenesis of mitochondrial complex IV (cytochrome c oxidase). Although mutations in COA7 have been linked to complex IV assembly defects and neurological conditions such as peripheral neuropathy, ataxia, and leukoencephalopathy, the precise role COA7 plays in the biogenesis of complex IV is not known. Here, we show that loss of COA7 blocks complex IV assembly after the initial step where the COX1 module is built, progression from which requires the incorporation of copper and addition of the COX2 and COX3 modules. The crystal structure of COA7, determined to 2.4 Å resolution, reveals a banana-shaped molecule composed of five helix-turn-helix (α/α) repeats, tethered by disulfide bonds. COA7 interacts transiently with the copper metallochaperones SCO1 and SCO2 and catalyzes the reduction of disulfide bonds within these proteins, which are crucial for copper relay to COX2. COA7 binds heme with micromolar affinity, through axial ligation to the central iron atom by histidine and methionine residues. We therefore propose that COA7 is a heme-binding disulfide reductase for regenerating the copper relay system that underpins complex IV assembly.
    Keywords:  COA7; X-ray crystallography; cytochrome c oxidase; heme; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2110357119
  22. Redox Biol. 2022 Feb 06. pii: S2213-2317(22)00030-1. [Epub ahead of print]51 102258
    Redox-dependent loss of flavin by mitochondria complex I is different in brain and heart.
    Belem Yoval-Sánchez, Fariha Ansari, Joel James, Zoya Niatsetskaya, Sergey Sosunov, Peter Filipenko, Irina G Tikhonova, Vadim Ten, Ilka Wittig, Ruslan Rafikov, Alexander Galkin.
      Pathologies associated with tissue ischemia/reperfusion (I/R) in highly metabolizing organs such as the brain and heart are leading causes of death and disability in humans. Molecular mechanisms underlying mitochondrial dysfunction during acute injury in I/R are tissue-specific, but their details are not completely understood. A metabolic shift and accumulation of substrates of reverse electron transfer (RET) such as succinate are observed in tissue ischemia, making mitochondrial complex I of the respiratory chain (NADH:ubiquinone oxidoreductase) the most vulnerable enzyme to the following reperfusion. It has been shown that brain complex I is predisposed to losing its flavin mononucleotide (FMN) cofactor when maintained in the reduced state in conditions of RET both in vitro and in vivo. Here we investigated the process of redox-dependent dissociation of FMN from mitochondrial complex I in brain and heart mitochondria. In contrast to the brain enzyme, cardiac complex I does not lose FMN when reduced in RET conditions. We proposed that the different kinetics of FMN loss during RET is due to the presence of brain-specific long 50 kDa isoform of the NDUFV3 subunit of complex I, which is absent in the heart where only the canonical 10 kDa short isoform is found. Our simulation studies suggest that the long NDUFV3 isoform can reach toward the FMN binding pocket and affect the nucleotide affinity to the apoenzyme. For the first time, we demonstrated a potential functional role of tissue-specific isoforms of complex I, providing the distinct molecular mechanism of I/R-induced mitochondrial impairment in cardiac and cerebral tissues. By combining functional studies of intact complex I and molecular structure simulations, we defined the critical difference between the brain and heart enzyme and suggested insights into the redox-dependent inactivation mechanisms of complex I during I/R injury in both tissues.
    Keywords:  Brain; Cardiac infarction; Flavin mononucleotide; Heart; Isoforms; Mitochondrial complex I; Reverse electron transfer; Stroke; Tissue-specificity
    DOI:  https://doi.org/10.1016/j.redox.2022.102258
  23. Cells. 2022 Feb 17. pii: 710. [Epub ahead of print]11(4):
    Maintenance of NAD+ Homeostasis in Skeletal Muscle during Aging and Exercise.
    Li Li Ji, Dongwook Yeo.
      Nicotinamide adenine dinucleotide (NAD) is a versatile chemical compound serving as a coenzyme in metabolic pathways and as a substrate to support the enzymatic functions of sirtuins (SIRTs), poly (ADP-ribose) polymerase-1 (PARP-1), and cyclic ADP ribose hydrolase (CD38). Under normal physiological conditions, NAD+ consumption is matched by its synthesis primarily via the salvage pathway catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). However, aging and muscular contraction enhance NAD+ utilization, whereas NAD+ replenishment is limited by cellular sources of NAD+ precursors and/or enzyme expression. This paper will briefly review NAD+ metabolic functions, its roles in regulating cell signaling, mechanisms of its degradation and biosynthesis, and major challenges to maintaining its cellular level in skeletal muscle. The effects of aging, physical exercise, and dietary supplementation on NAD+ homeostasis will be highlighted based on recent literature.
    Keywords:  NAD+; aging; exercise; mitochondria; sirtuin; skeletal muscle
    DOI:  https://doi.org/10.3390/cells11040710
  24. J Biol Chem. 2022 Feb 21. pii: S0021-9258(22)00197-1. [Epub ahead of print] 101757
    Tissue-specific alternative splicing separates the catalytic and cell signaling functions of human leucyl-tRNA synthetase.
    Max Baymiller, Benjamin Nordick, Connor M Forsyth, Susan A Martinis.
      The aminoacyl-tRNA synthetases are an ancient and ubiquitous component of all life. Many eukaryotic synthetases balance their essential function, preparing aminoacyl-tRNA for use in mRNA translation, with diverse roles in cell signaling. Herein, we use long-read sequencing to discover a leukocyte-specific exon skipping event in human leucyl-tRNA synthetase (LARS). We show that this highly expressed splice variant, LSV3, is regulated by serine-arginine rich splicing factor 1 (SRSF1) in a cell type-specific manner. LSV3 has a 71 amino acid deletion in the catalytic domain and lacks any tRNA leucylation activity in vitro. However, we demonstrate that this LARS splice variant retains its role as a leucine sensor and signal transducer for the proliferation-promoting mTOR kinase. This is despite the exon deletion in LSV3 including a portion of the previously mapped Vps34-binding domain used for one of two distinct pathways from LARS to mTOR. In conclusion, alternative splicing of LARS has separated the ancient catalytic activity of this housekeeping enzyme from its more recent evolutionary role in cell signaling, providing an opportunity for functional specificity in human immune cells.
    Keywords:  Aminoacyl-tRNA synthetase; alternative splicing; mammalian target of rapamycin (mTOR); serine/arginine-rich splicing factor 1 (SRSF1); transfer RNA (tRNA); translation
    DOI:  https://doi.org/10.1016/j.jbc.2022.101757
  25. Brain Commun. 2022 ;4(1): fcac024
    Neurodegenerative and functional signatures of the cerebellar cortex in m.3243A > G patients.
    Roy A M Haast, Irenaeus F M De Coo, Dimo Ivanov, Ali R Khan, Jacobus F A Jansen, Hubert J M Smeets, Kâmil Uludağ.
      Mutations of the mitochondrial DNA are an important cause of inherited diseases that can severely affect the tissue's homeostasis and integrity. The m.3243A > G mutation is the most commonly observed across mitochondrial disorders and is linked to multisystemic complications, including cognitive deficits. In line with in vitro experiments demonstrating the m.3243A > G's negative impact on neuronal energy production and integrity, m.3243A > G patients show cerebral grey matter tissue changes. However, its impact on the most neuron dense, and therefore energy-consuming brain structure-the cerebellum-remains elusive. In this work, we used high-resolution structural and functional data acquired using 7 T MRI to characterize the neurodegenerative and functional signatures of the cerebellar cortex in m.3243A > G patients. Our results reveal altered tissue integrity within distinct clusters across the cerebellar cortex, apparent by their significantly reduced volume and longitudinal relaxation rate compared with healthy controls, indicating macroscopic atrophy and microstructural pathology. Spatial characterization reveals that these changes occur especially in regions related to the frontoparietal brain network that is involved in information processing and selective attention. In addition, based on resting-state functional MRI data, these clusters exhibit reduced functional connectivity to frontal and parietal cortical regions, especially in patients characterized by (i) a severe disease phenotype and (ii) reduced information-processing speed and attention control. Combined with our previous work, these results provide insight into the neuropathological changes and a solid base to guide longitudinal studies aimed to track disease progression.
    Keywords:  MRI; cerebellum; function; m.3243A > G; structure
    DOI:  https://doi.org/10.1093/braincomms/fcac024
  26. Front Cell Dev Biol. 2021 ;9 781933
    Mitochondria Lead the Way: Mitochondrial Dynamics and Function in Cellular Movements in Development and Disease.
    Somya Madan, Bhavin Uttekar, Sayali Chowdhary, Richa Rikhy.
      The dynamics, distribution and activity of subcellular organelles are integral to regulating cell shape changes during various physiological processes such as epithelial cell formation, cell migration and morphogenesis. Mitochondria are famously known as the powerhouse of the cell and play an important role in buffering calcium, releasing reactive oxygen species and key metabolites for various activities in a eukaryotic cell. Mitochondrial dynamics and morphology changes regulate these functions and their regulation is, in turn, crucial for various morphogenetic processes. In this review, we evaluate recent literature which highlights the role of mitochondrial morphology and activity during cell shape changes in epithelial cell formation, cell division, cell migration and tissue morphogenesis during organism development and in disease. In general, we find that mitochondrial shape is regulated for their distribution or translocation to the sites of active cell shape dynamics or morphogenesis. Often, key metabolites released locally and molecules buffered by mitochondria play crucial roles in regulating signaling pathways that motivate changes in cell shape, mitochondrial shape and mitochondrial activity. We conclude that mechanistic analysis of interactions between mitochondrial morphology, activity, signaling pathways and cell shape changes across the various cell and animal-based model systems holds the key to deciphering the common principles for this interaction.
    Keywords:  cell division; cell migration; embryogenesis; epithelial cell morphogenesis; epithelial to mesenchymal transition; mitochondrial fission; mitochondrial fusion; wound healing
    DOI:  https://doi.org/10.3389/fcell.2021.781933
  27. J Inherit Metab Dis. 2022 Feb 26.
    Characterization of exonic variants of uncertain significance in very long-chain acyl-CoA dehydrogenase identified through newborn screening.
    Olivia M D'Annibale, Erik A Koppes, Meena Sethuraman, Kaitlyn Bloom, Al-Walid Mohsen, Jerry Vockley.
      Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is an autosomal recessive disease resulting from mutations in the ACADVL gene and is among the disorders tested for in newborn screening (NBS). Confirmatory sequencing following suspected VLCADD NBS results often identifies variants of uncertain significance (VUS) in the ACADVL gene, leading to uncertainty of diagnosis and providing effective treatment regimen. Currently, ACADVL has >300 VUSs in the ClinVar database that requiring characterization to determine potential pathogenicity. In this study, CRISPR/Cas9 genome editing was used to knock out ACADVL in HEK293T cells, and targeted deletion was confirmed by droplet digital PCR. No VLCAD protein was detected and an 84% decrease in enzyme activity using the ETF fluorescence reduction assay and C21-CoA as substrate was observed compared to control. Plasmids containing control or variant ACADVL coding sequence were transfected into the ACADVL null HEK293T. While transfection of control ACADVL restored VLCAD protein and enzyme activity, cells expressing the VLCAD Val283Ala mutant had 18% VLCAD enzyme activity and reduced protein compared to control. VLCAD Ile420Leu, Gly179Arg, and Gln406Pro produced protein comparable to control but 25%, 4%, and 5% VLCAD enzyme activity, respectively. Leu540Pro and Asp570_Ala572dup had reduced VLCAD protein and 10% and 3% VLCAD enzyme activity, respectively. VLCADD fibroblasts containing the same variations had decreased VLCAD protein and activity comparable to the transfection experiments. Generating ACADVL null HEK293T cell line allowed functional studies to determine pathogenicity of ACADVL exonic variants. This approach can be applied to multiple genes for other disorders identified through NBS. This article is protected by copyright. All rights reserved.
    Keywords:  Very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency; fatty acid oxidation disorders; high through-put screening; inborn errors of metabolism; newborn screening; variants of uncertain significance
    DOI:  https://doi.org/10.1002/jimd.12492
  28. iScience. 2022 Feb 18. 25(2): 103812
    SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated bymultiple physiologically relevant NAD metabolites.
    Carlo Angeletti, Adolfo Amici, Jonathan Gilley, Andrea Loreto, Antonio G Trapanotto, Christina Antoniou, Elisa Merlini, Michael P Coleman, Giuseppe Orsomando.
      SARM1 is an NAD(P) glycohydrolase and TLR adapter with an essential, prodegenerative role in programmed axon death (Wallerian degeneration). Like other NAD(P)ases, it catalyzes multiple reactions that need to be fully investigated. Here, we compare these multiple activities for recombinant human SARM1, human CD38, and Aplysia californica ADP ribosyl cyclase. SARM1 has the highest transglycosidation (base exchange) activity at neutral pH and with some bases this dominates NAD(P) hydrolysis and cyclization. All SARM1 activities, including base exchange at neutral pH, are activated by an increased NMN:NAD ratio, at physiological levels of both metabolites. SARM1 base exchange occurs also in DRG neurons and is thus a very likely physiological source of calcium-mobilizing agent NaADP. Finally, we identify regulation by free pyridines, NADP, and nicotinic acid riboside (NaR) on SARM1, all of therapeutic interest. Understanding which specific SARM1 function(s) is responsible for axon degeneration is essential for its targeting in disease.
    Keywords:  Biological sciences; Molecular physiology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2022.103812
  29. Life (Basel). 2022 Jan 29. pii: 205. [Epub ahead of print]12(2):
    Impaired Mitochondrial Bioenergetics under Pathological Conditions.
    Salvatore Nesci, Giorgio Lenaz.
      Mitochondria are the powerhouses of cells; however, mitochondrial dysfunction causes energy depletion and cell death in various diseases [...].
    DOI:  https://doi.org/10.3390/life12020205
  30. Int J Mol Sci. 2022 Feb 16. pii: 2197. [Epub ahead of print]23(4):
    The Mitochondrial Epigenome: An Unexplored Avenue to Explain Unexplained Myopathies?
    Archibold Mposhi, Lin Liang, Kevin P Mennega, Dilemin Yildiz, Crista Kampert, Ingrid H Hof, Pytrick G Jellema, Tom J de Koning, Klaas Nico Faber, Marcel H J Ruiters, Klary E Niezen-Koning, Marianne G Rots.
      Mutations in either mitochondrial DNA (mtDNA) or nuclear genes that encode mitochondrial proteins may lead to dysfunctional mitochondria, giving rise to mitochondrial diseases. Some mitochondrial myopathies, however, present without a known underlying cause. Interestingly, methylation of mtDNA has been associated with various clinical pathologies. The present study set out to assess whether mtDNA methylation could explain impaired mitochondrial function in patients diagnosed with myopathy without known underlying genetic mutations. Enhanced mtDNA methylation was indicated by pyrosequencing for muscle biopsies of 14 myopathy patients compared to four healthy controls, at selected cytosines in the Cytochrome B (CYTB) gene, but not within the displacement loop (D-loop) region. The mtDNA methylation patterns of the four healthy muscle biopsies were highly consistent and showed intriguing tissue-specific differences at particular cytosines with control skin fibroblasts cultured in vitro. Within individual myopathy patients, the overall mtDNA methylation pattern correlated well between muscle and skin fibroblasts. Despite this correlation, a pilot analysis of four myopathy and five healthy fibroblast samples did not reveal a disease-associated difference in mtDNA methylation. We did, however, detect increased expression of solute carrier family 25A26 (SLC25A26), encoding the importer of S-adenosylmethionine, together with enhanced mtDNA copy numbers in myopathy fibroblasts compared to healthy controls. To confirm that pyrosequencing indeed reflected DNA methylation and not bisulfite accessibility, mass spectrometry was employed. Although no myopathy-related differences in total amount of methylated cytosines were detected at this stage, a significant contribution of contaminating nuclear DNA (nDNA) was revealed, and steps to improve enrichment for mtDNA are reported. In conclusion, in this explorative study we show that analyzing the mitochondrial genome beyond its sequence opens novel avenues to identify potential molecular biomarkers assisting in the diagnosis of unexplained myopathies.
    Keywords:  cytochrome B; mitochondrial DNA methylation; mitochondrial epigenome; myopathies
    DOI:  https://doi.org/10.3390/ijms23042197
  31. Biomedicines. 2022 Feb 21. pii: 503. [Epub ahead of print]10(2):
    Cytoprotective Effect of Idebenone through Modulation of the Intrinsic Mitochondrial Pathway of Apoptosis in Human Retinal Pigment Epithelial Cells Exposed to Oxidative Stress Induced by Hydrogen Peroxide.
    Maria Elisabetta Clementi, Michela Pizzoferrato, Giada Bianchetti, Anna Brancato, Beatrice Sampaolese, Giuseppe Maulucci, Giuseppe Tringali.
      Idebenone is a ubiquinone short-chain synthetic analog with antioxidant properties, which is believed to restore mitochondrial ATP synthesis. As such, idebenone is investigated in numerous clinical trials for diseases of mitochondrial aetiology and it is authorized as a drug for the treatment of Leber's hereditary optic neuropathy. Mitochondria of retinal pigment epithelium (RPE) are particularly vulnerable to oxidative damage associated with cellular senescence. Therefore, the aim of this study was to explore idebenone's cytoprotective effect and its underlying mechanism. We used a human-RPE cell line (ARPE-19) exposed to idebenone pre-treatment for 24 h followed by conditions inducing H2O2 oxidative damage for a further 24 h. We found that idebenone: (a) ameliorated H2O2-lowered cell viability in the RPE culture; (b) activated Nrf2 signaling pathway by promoting Nrf2 nuclear translocation; (c) increased Bcl-2 protein levels, leaving unmodified those of Bax, thereby reducing the Bax/Bcl-2 ratio; (d) maintained the mitochondrial membrane potential (ΔΨm) at physiological levels, preserving the functionality of mitochondrial respiratory complexes and counteracting the excessive production of ROS; and (e) reduced mitochondrial cytochrome C-mediated caspase-3 activity. Taken together, our findings show that idebenone protects RPE from oxidative damage by modulating the intrinsic mitochondrial pathway of apoptosis, suggesting its possible role in retinal epitheliopathies associated with mitochondrial dysfunction.
    Keywords:  ARPE-19 (human-RPE cell line); apoptosis; idebenone; mitochondria; nuclear factor erythroid 2-related factor (Nrf2); oxidative stress
    DOI:  https://doi.org/10.3390/biomedicines10020503
  32. STAR Protoc. 2022 Mar 18. 3(1): 101144
    Microscopy-based cellular contractility assay for adult, neonatal, and hiPSC cardiomyocytes.
    Sérgio Scalzo, Carolina A T F Mendonça, Christopher Kushmerick, Ubirajara Agero, Silvia Guatimosim.
      This protocol provides instructions to acquire high-quality cellular contractility data from adult, neonatal, and human induced pluripotent stem cell-derived cardiomyocytes. Contractility parameters are key to unravel mechanisms underlying cardiac pathologies, yet difficulties in acquiring data can compromise measurement accuracy and reproducibility. We provide optimized steps for microscope and camera setup, as well as cellular selection criteria for different cardiomyocyte cell types, aiming to obtain robust and reliable data. Moreover, we use CONTRACTIONWAVE software to analyze and show the optimized results. For complete details on the use and execution of this profile, please refer to Scalzo et al. (2021).
    Keywords:  Biophysics; Cell Biology; Cell culture; Cell isolation; Cell-based Assays; Microscopy; Single Cell; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2022.101144
  33. J Pers Med. 2022 Jan 27. pii: 175. [Epub ahead of print]12(2):
    Computational Genomics in the Era of Precision Medicine: Applications to Variant Analysis and Gene Therapy.
    Yung-Chun Wang, Yuchang Wu, Julie Choi, Garrett Allington, Shujuan Zhao, Mariam Khanfar, Kuangying Yang, Po-Ying Fu, Max Wrubel, Xiaobing Yu, Kedous Y Mekbib, Jack Ocken, Hannah Smith, John Shohfi, Kristopher T Kahle, Qiongshi Lu, Sheng Chih Jin.
      Rapid methodological advances in statistical and computational genomics have enabled researchers to better identify and interpret both rare and common variants responsible for complex human diseases. As we continue to see an expansion of these advances in the field, it is now imperative for researchers to understand the resources and methodologies available for various data types and study designs. In this review, we provide an overview of recent methods for identifying rare and common variants and understanding their roles in disease etiology. Additionally, we discuss the strategy, challenge, and promise of gene therapy. As computational and statistical approaches continue to improve, we will have an opportunity to translate human genetic findings into personalized health care.
    Keywords:  bioinformatics; common variant; gene therapy; genomics; precision medicine; rare variant; statistical genetics
    DOI:  https://doi.org/10.3390/jpm12020175
  34. Nat Genet. 2022 Feb 21.
    Sequence determinants of human gene regulatory elements.
    Biswajyoti Sahu, Tuomo Hartonen, Päivi Pihlajamaa, Bei Wei, Kashyap Dave, Fangjie Zhu, Eevi Kaasinen, Katja Lidschreiber, Michael Lidschreiber, Carsten O Daub, Patrick Cramer, Teemu Kivioja, Jussi Taipale.
      DNA can determine where and when genes are expressed, but the full set of sequence determinants that control gene expression is unknown. Here, we measured the transcriptional activity of DNA sequences that represent an ~100 times larger sequence space than the human genome using massively parallel reporter assays (MPRAs). Machine learning models revealed that transcription factors (TFs) generally act in an additive manner with weak grammar and that most enhancers increase expression from a promoter by a mechanism that does not appear to involve specific TF-TF interactions. The enhancers themselves can be classified into three types: classical, closed chromatin and chromatin dependent. We also show that few TFs are strongly active in a cell, with most activities being similar between cell types. Individual TFs can have multiple gene regulatory activities, including chromatin opening and enhancing, promoting and determining transcription start site (TSS) activity, consistent with the view that the TF binding motif is the key atomic unit of gene expression.
    DOI:  https://doi.org/10.1038/s41588-021-01009-4
  35. iScience. 2022 Feb 18. 25(2): 103836
    The proteomic profile of the human myotendinous junction.
    Anders Karlsen, Alba Gonzalez-Franquesa, Jens R Jakobsen, Michael R Krogsgaard, Manuel Koch, Michael Kjaer, Stefano Schiaffino, Abigail L Mackey, Atul S Deshmukh.
      Proteomics analysis of skeletal muscle has recently progressed from whole muscle tissue to single myofibers. Here, we further focus on a specific myofiber domain crucial for force transmission from muscle to tendon, the myotendinous junction (MTJ). To overcome the anatomical constraints preventing the isolation of pure MTJs, we performed in-depth analysis of the MTJ by progressive removal of the muscle component in semitendinosus muscle-tendon samples. Using detergents with increasing stringency, we quantified >3000 proteins across all samples, and identified 112 significantly enriched MTJ proteins, including 24 known MTJ-enriched proteins. Of the 88 novel MTJ markers, immunofluorescence analysis confirmed the presence of tetraspanin-24 (CD151), kindlin-2 (FERMT2), cartilage intermediate layer protein 1 (CILP), and integrin-alpha10 (ITGA10), at the human MTJ. Together, these human data constitute the first detailed MTJ proteomics resource that will contribute to advance understanding of the biology of the MTJ and its failure in pathological conditions.
    Keywords:  Biology experimental methods; Molecular physiology; Musculoskeletal anatomy; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2022.103836
  36. Neurophotonics. 2022 Apr;9(2): 021907
    Photonics tools begin to clarify astrocyte calcium transients.
    Kelsea A Gorzo, Grant R Gordon.
      Astrocytes integrate information from neurons and the microvasculature to coordinate brain activity and metabolism. Using a variety of calcium-dependent cellular mechanisms, these cells impact numerous aspects of neurophysiology in health and disease. Astrocyte calcium signaling is highly diverse, with complex spatiotemporal features. Here, we review astrocyte calcium dynamics and the optical imaging tools used to measure and analyze these events. We briefly cover historical calcium measurements, followed by our current understanding of how calcium transients relate to the structure of astrocytes. We then explore newer photonics tools including super-resolution techniques and genetically encoded calcium indicators targeted to specific cellular compartments and how these have been applied to astrocyte biology. Finally, we provide a brief overview of analysis software used to accurately quantify the data and ultimately aid in our interpretation of the various functions of astrocyte calcium transients.
    Keywords:  analysis; astrocyte; calcium; genetically encoded fluorescent calcium indicator; stimulation emission depletion; two-photon
    DOI:  https://doi.org/10.1117/1.NPh.9.2.021907
  37. J Exp Clin Cancer Res. 2022 Feb 24. 41(1): 76
    Increased Drp1 promotes autophagy and ESCC progression by mtDNA stress mediated cGAS-STING pathway.
    Yujia Li, Hui Chen, Qi Yang, Lixin Wan, Jing Zhao, Yuanyuan Wu, Jiaxin Wang, Yating Yang, Menglan Niu, Hongliang Liu, Junqi Liu, Hushan Yang, Shaogui Wan, Yanming Wang, Dengke Bao.
       BACKGROUND: Mitochondrial dynamics homeostasis is important for cell metabolism, growth, proliferation, and immune responses. The critical GTPase for mitochondrial fission, Drp1 is frequently upregulated in many cancers and is closely implicated in tumorigenesis. However, the mechanism underling Drp1 to influence tumor progression is largely unknown, especially in esophageal squamous cell carcinoma (ESCC).
    METHODS: Immunohistochemistry was used to examine Drp1 and LC3B expression in tissues of ESCC patients. Autophagic vesicles were investigated by transmission electron microscopy. Fluorescent LC3B puncta and mitochondrial nucleoid were observed by fluorescent and confocal microscopy. Mitochondrial function was evaluated by mitochondrial membrane potential, ROS and ATP levels. Xenograft tumor model was performed in BALB/c nude mice to analyze the role of Drp1 on ESCC progression.
    RESULTS: We found that Drp1 high expression is correlated with poor overall survival of ESCC patients. Drp1 overexpression promotes cell proliferation and xenograft ESCC tumor growth by triggering autophagy. Furthermore, we demonstrated that Drp1 overexpression disturbs mitochondrial function and subsequent induces mitochondrial DNA (mtDNA) released into the cytosol thereby inducing cytosolic mtDNA stress. Mechanistically, cytosolic mtDNA activates the cGAS-STING pathway and facilitates autophagy, which promotes ESCC cancer growth. Moreover, mtDNA digestion with DNase I and autophagy inhibition with chloroquine attenuates the cGAS-STING pathway activation and ESCC cancer growth.
    CONCLUSIONS: Our finding reveals that Drp1 overexpression induces mitochondrial dysfunction and cytosolic mtDNA stress, which subsequently activates the cGAS-STING pathway, triggers autophagy and promotes ESCC progression.
    Keywords:  Autophagy; Drp1; Esophageal Squamous Cell Carcinoma; Mitochondrial DNA stress; cGAS-STING signaling pathway
    DOI:  https://doi.org/10.1186/s13046-022-02262-z
  38. Cell Mol Life Sci. 2022 Feb 23. 79(3): 149
    Monitoring the maturation of the sarcomere network: a super-resolution microscopy-based approach.
    Anna Skorska, Lisa Johann, Oleksandra Chabanovska, Praveen Vasudevan, Sophie Kussauer, Maximilian Hillemanns, Markus Wolfien, Anika Jonitz-Heincke, Olaf Wolkenhauer, Rainer Bader, Hermann Lang, Robert David, Heiko Lemcke.
      The in vitro generation of human cardiomyocytes derived from induced pluripotent stem cells (iPSC) is of great importance for cardiac disease modeling, drug-testing applications and for regenerative medicine. Despite the development of various cultivation strategies, a sufficiently high degree of maturation is still a decisive limiting factor for the successful application of these cardiac cells. The maturation process includes, among others, the proper formation of sarcomere structures, mediating the contraction of cardiomyocytes. To precisely monitor the maturation of the contractile machinery, we have established an imaging-based strategy that allows quantitative evaluation of important parameters, defining the quality of the sarcomere network. iPSC-derived cardiomyocytes were subjected to different culture conditions to improve sarcomere formation, including prolonged cultivation time and micro patterned surfaces. Fluorescent images of α-actinin were acquired using super-resolution microscopy. Subsequently, we determined cell morphology, sarcomere density, filament alignment, z-Disc thickness and sarcomere length of iPSC-derived cardiomyocytes. Cells from adult and neonatal heart tissue served as control. Our image analysis revealed a profound effect on sarcomere content and filament orientation when iPSC-derived cardiomyocytes were cultured on structured, line-shaped surfaces. Similarly, prolonged cultivation time had a beneficial effect on the structural maturation, leading to a more adult-like phenotype. Automatic evaluation of the sarcomere filaments by machine learning validated our data. Moreover, we successfully transferred this approach to skeletal muscle cells, showing an improved sarcomere formation cells over different differentiation periods. Overall, our image-based workflow can be used as a straight-forward tool to quantitatively estimate the structural maturation of contractile cells. As such, it can support the establishment of novel differentiation protocols to enhance sarcomere formation and maturity.
    Keywords:  Maturation; Sarcomere network; Super resolution microscopy; iPSC cardiomyocytes
    DOI:  https://doi.org/10.1007/s00018-022-04196-3
  39. Nat Biotechnol. 2022 Feb 21.
    Using deep learning to annotate the protein universe.
    Maxwell L Bileschi, David Belanger, Drew H Bryant, Theo Sanderson, Brandon Carter, D Sculley, Alex Bateman, Mark A DePristo, Lucy J Colwell.
      Understanding the relationship between amino acid sequence and protein function is a long-standing challenge with far-reaching scientific and translational implications. State-of-the-art alignment-based techniques cannot predict function for one-third of microbial protein sequences, hampering our ability to exploit data from diverse organisms. Here, we train deep learning models to accurately predict functional annotations for unaligned amino acid sequences across rigorous benchmark assessments built from the 17,929 families of the protein families database Pfam. The models infer known patterns of evolutionary substitutions and learn representations that accurately cluster sequences from unseen families. Combining deep models with existing methods significantly improves remote homology detection, suggesting that the deep models learn complementary information. This approach extends the coverage of Pfam by >9.5%, exceeding additions made over the last decade, and predicts function for 360 human reference proteome proteins with no previous Pfam annotation. These results suggest that deep learning models will be a core component of future protein annotation tools.
    DOI:  https://doi.org/10.1038/s41587-021-01179-w
  40. Hum Mutat. 2022 Feb 22.
    PatientMatcher: a customizable Python-based open-source tool for matching undiagnosed rare disease patients via the Matchmaker Exchange network.
    Chiara Rasi, Daniel Nilsson, Måns Magnusson, Nicole Lesko, Kristina Lagerstedt-Robinson, Anna Wedell, Anna Lindstrand, Valtteri Wirta, Henrik Stranneheim.
      The amount of data available from genomic medicine has revolutionized the approach to identify the determinants underlying many rare diseases. The task of confirming a genotype-phenotype causality for a patient affected with a rare genetic disease is often challenging. In this context, the establishment of the Matchmaker Exchange (MME) network has assumed a pivotal role in bridging heterogeneous patient information stored on different medical and research servers. MME has made it possible to solve rare disease cases by "matching" the genotypic and phenotypic characteristics of a patient of interest with patient data available at other clinical facilities participating in the network. Here, we present PatientMatcher (https://github.com/Clinical-Genomics/patientMatcher), an open-source Python and MongoDB-based software solution developed by Clinical Genomics facility at the Science for Life Laboratory in Stockholm. PatientMatcher is designed as a standalone MME server, but can easily communicate via REST API with external applications managing genetic analyses and patient data. The MME node is being implemented in clinical routine in collaboration with the Genomic Medicine Center Karolinska at the Karolinska University Hospital. PatientMatcher is written to implement the MME API and provides several customizable settings, including a custom-fit similarity score algorithm and adjustable matching results notifications. This article is protected by copyright. All rights reserved.
    Keywords:  Matchmaker exchange; gene discovery; genomic API; matchmaking; rare disease
    DOI:  https://doi.org/10.1002/humu.24358
  41. Nat Rev Immunol. 2022 Feb 23.
    Organellar homeostasis and innate immune sensing.
    Cassandra R Harapas, Elina Idiiatullina, Mahmoud Al-Azab, Katja Hrovat-Schaale, Thomas Reygaerts, Annemarie Steiner, Pawat Laohamonthonkul, Sophia Davidson, Chien-Hsiung Yu, Lee Booty, Seth L Masters.
      A cell is delimited by numerous borders that define specific organelles. The walls of some organelles are particularly robust, such as in mitochondria or endoplasmic reticulum, but some are more fluid such as in phase-separated stress granules. Either way, all organelles can be damaged at times, leading their contents to leak out into the surrounding environment. Therefore, an elegant way to construct an innate immune defence system is to recognize host molecules that do not normally reside within a particular compartment. Here, we provide several examples where organellar homeostasis is lost, leading to the activation of a specific innate immune sensor; these include NLRP3 activation owing to a disrupted trans-Golgi network, Pyrin activation due to cytoskeletal damage, and cGAS-STING activation following the leakage of nuclear or mitochondrial DNA. Frequently, organelle damage is observed downstream of pathogenic infection but it can also occur in sterile settings as associated with auto-inflammatory disease. Therefore, understanding organellar homeostasis is central to efforts that will identify new innate immune pathways, and therapeutics that balance organellar homeostasis, or target the breakdown pathways that trigger innate immune sensors, could be useful treatments for infection and chronic inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41577-022-00682-8
  42. Nat Biotechnol. 2022 Feb 21.
    CoSpar identifies early cell fate biases from single-cell transcriptomic and lineage information.
    Shou-Wen Wang, Michael J Herriges, Kilian Hurley, Darrell N Kotton, Allon M Klein.
      A goal of single-cell genome-wide profiling is to reconstruct dynamic transitions during cell differentiation, disease onset and drug response. Single-cell assays have recently been integrated with lineage tracing, a set of methods that identify cells of common ancestry to establish bona fide dynamic relationships between cell states. These integrated methods have revealed unappreciated cell dynamics, but their analysis faces recurrent challenges arising from noisy, dispersed lineage data. In this study, we developed coherent, sparse optimization (CoSpar) as a robust computational approach to infer cell dynamics from single-cell transcriptomics integrated with lineage tracing. Built on assumptions of coherence and sparsity of transition maps, CoSpar is robust to severe downsampling and dispersion of lineage data, which enables simpler experimental designs and requires less calibration. In datasets representing hematopoiesis, reprogramming and directed differentiation, CoSpar identifies early fate biases not previously detected, predicting transcription factors and receptors implicated in fate choice. Documentation and detailed examples for common experimental designs are available at https://cospar.readthedocs.io/ .
    DOI:  https://doi.org/10.1038/s41587-022-01209-1
  43. Free Radic Biol Med. 2022 Feb 21. pii: S0891-5849(22)00072-7. [Epub ahead of print]
    Coenzyme Q10 and related quinones oxidize H2S to polysulfides and thiosulfate.
    Kenneth R Olson, Kasey Clear, Paul Derry, Yan Gao, Zhilin Ma, Gang Wu, Thomas Kent, Karl D Straub.
      In the canonical pathway for mitochondrial H2S oxidation electrons are transferred from sulfide:quinone oxidoreductase (SQR) to complex III via ubiquinone (CoQ10). We previously observed that a number of quinones directly oxidize H2S and we hypothesize that CoQ10 may have similar properties. Here we examine H2S oxidation by CoQ10 and more hydrophilic, truncated forms, CoQ1 and CoQ0, in buffer using H2S and polysulfide fluorophores (AzMC and SSP4), silver nanoparticles to measure thiosulfate (H2S2O3), mass spectrometry to identify polysulfides and O2-sensitive optodes to measure O2 consumption. We show that all three quinones concentration-dependently catalyze the oxidization of H2S to polysulfides and thiosulfate in buffer with the potency CoQ0>CoQ1>CoQ10 and that CoQ0 specifically oxidizes H2S to per-polysulfides, H2S2,3,4. These reactions consume and require oxygen and are augmented by addition of SOD suggesting that the quinones, not superoxide, oxidize H2S. Related quinones, MitoQ, menadione and idebenone, oxidize H2S in similar reactions. Exogenous CoQ0 decreases cellular H2S and increases polysulfides and thiosulfate production and this is also O2-dependent, suggesting that the quinone has similar effects on sulfur metabolism in cells. Collectively, these results suggest an additional endogenous mechanism for H2S metabolism and a potential therapeutic approach in H2S-related metabolic disorders.
    Keywords:  Antioxidants; CoQ(10); Down syndrome; Reactive oxygen species; Reactive sulfur species
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.02.018
  44. Nutrients. 2022 Feb 11. pii: 768. [Epub ahead of print]14(4):
    Genetic Biomarkers of Metabolic Detoxification for Personalized Lifestyle Medicine.
    Lucia Aronica, Jose M Ordovas, Andrey Volkov, Joseph J Lamb, Peter Michael Stone, Deanna Minich, Michelle Leary, Monique Class, Dina Metti, Ilona A Larson, Nikhat Contractor, Brent Eck, Jeffrey S Bland.
      Metabolic detoxification (detox)-or biotransformation-is a physiological function that removes toxic substances from our body. Genetic variability and dietary factors may affect the function of detox enzymes, thus impacting the body's sensitivity to toxic substances of endogenous and exogenous origin. From a genetic perspective, most of the current knowledge relies on observational studies in humans or experimental models in vivo and in vitro, with very limited proof of causality and clinical value. This review provides health practitioners with a list of single nucleotide polymorphisms (SNPs) located within genes involved in Phase I and Phase II detoxification reactions, for which evidence of clinical utility does exist. We have selected these SNPs based on their association with interindividual variability of detox metabolism in response to certain nutrients in the context of human clinical trials. In order to facilitate clinical interpretation and usage of these SNPs, we provide, for each of them, a strength of evidence score based on recent guidelines for genotype-based dietary advice. We also present the association of these SNPs with functional biomarkers of detox metabolism in a pragmatic clinical trial, the LIFEHOUSE study.
    Keywords:  LIFEHOUSE study; biomarkers; biotransformation; detoxification; environmental health; functional medicine; nutrigenomics; personalized lifestyle medicine; pragmatic clinical trials; single nucleotide polymorphisms
    DOI:  https://doi.org/10.3390/nu14040768
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:23.