bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2023‒08‒27
58 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Structural mechanism of mitochondrial membrane remodelling by human OPA1.
  2. Mutational burden of XPNPEP3 leads to defects in mitochondrial complex I and cilia in NPHPL1.
  3. Leigh Syndrome Spectrum: A Portuguese Population Cohort in an Evolutionary Genetic Era.
  4. Mitochondrial impairment and synaptic dysfunction are associated with neurological defects in iPSCs-derived cortical neurons of MERRF patients.
  5. Ca2+ signalling: A common language for organelles crosstalk in Parkinson's disease.
  6. Defining Mitochondrial Cristae Morphology Changes Induced by Aging in Brown Adipose Tissue.
  7. APOGEE 2: multi-layer machine-learning model for the interpretable prediction of mitochondrial missense variants.
  8. Let's make it clear: systematic exploration of mitochondrial DNA- and RNA-protein complexes by complexome profiling.
  9. Regulation of Mitochondrial Respiration by Hydrogen Sulfide.
  10. Healthy mitochondrial DNA in balanced mitochondrial dynamics: A potential marker for neuro‑aging prediction (Review).
  11. The potential for mitochondrial therapeutics in the treatment of primary open-angle glaucoma: a review.
  12. MAVS Positively Regulates Mitochondrial Integrity and Metabolic Fitness in B Cells.
  13. Mitochondrial Dysfunction in Bacterial Infections.
  14. Diagnostic Yield of Investigations in Symmetric Optic Neuropathy.
  15. Mitochondrial morphology governs ATP production rate.
  16. Evaluation of Mitochondrial Dysfunction and Idebenone Responsiveness in Fibroblasts from Leber's Hereditary Optic Neuropathy (LHON) Subjects.
  17. OPA1 helical structures give perspective to mitochondrial dysfunction.
  18. Glial-derived mitochondrial signals impact neuronal proteostasis and aging.
  19. Rare PMP22 variants in mild to severe neuropathy uncorrelated to plasma GDF15 or neurofilament light.
  20. Cyclophilin D in Mitochondrial Dysfunction: A Key Player in Neurodegeneration?
  21. Menthol causes mitochondrial Ca2+-influx, affects structure-function relationship and cools mitochondria.
  22. Post-translational modifications and protein quality control of mitochondrial channels and transporters.
  23. Mitochondrial function and phenotype are defined by bioenergetics.
  24. A Missense Variant in AIFM1 Caused Mitochondrial Dysfunction and Intolerance to Riboflavin Deficiency.
  25. Multiset correlation and factor analysis enables exploration of multi-omics data.
  26. Distinctive metabolic remodeling in TYMP deficiency beyond mitochondrial dysfunction.
  27. OPA1, a molecular regulator of dilated cardiomyopathy.
  28. Role of Mitochondria-ER Contact Sites in Mitophagy.
  29. Three-Dimensional Mitochondria Reconstructions of Murine Cardiac Muscle Changes in Size Across Aging.
  30. Succinylation of a KEAP1 sensor lysine promotes NRF2 activation.
  31. Juvenile-Onset Recurrent Rhabdomyolysis Due to Compound Heterozygote Variants in the ACADVL Gene.
  32. Nix interacts with WIPI2 to induce mitophagy.
  33. Mitochondria: between aging, frailty and sarcopenia.
  34. The actin binding protein profilin 1 is critical for mitochondria function.
  35. Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.
  36. Leigh-like syndrome with progressive cerebellar atrophy caused by novel HIBCH variants.
  37. Development of Precision Therapies for Rare Inborn Errors of Metabolism: Functional Investigations in Cell Culture Models.
  38. A link between mitochondrial damage and the immune microenvironment of delayed onset muscle soreness.
  39. Mitochondria-associated programmed cell death as a therapeutic target for age-related disease.
  40. Spatiotemporal Distribution and Function of Mitochondria in Oocytes.
  41. Mitochondrial Dysfunction in Repeat Expansion Diseases.
  42. CHDH, a key mitochondrial enzyme, plays a diagnostic role in metabolic disorders diseases and tumor progression.
  43. Mitochondrial disorders due to m.3243A>G not meeting diagnostic criteria for MELAS require comprehensive work-up.
  44. Mitochondrial Volume Regulation and Swelling Mechanisms in Cardiomyocytes.
  45. GAA variants associated with reduced enzymatic activity but lack of Pompe-related symptoms, incidentally identified by exome sequencing.
  46. Allotopic expression of COX6 elucidates Atco-driven co-assembly of cytochrome oxidase and ATP synthase.
  47. The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease.
  48. A medical odyssey of a 72-year-old man with Charcot-Marie-Tooth disease type 2 newly diagnosed with biallelic variants in SORD gene causing sorbitol dehydrogenase deficiency.
  49. Mitochondrial unfolded protein response (mtUPR) and diseases.
  50. Nicotinamide Riboside Improves Stemness of Human Adipose-Derived Stem Cells and Inhibits Terminal Adipocyte Differentiation.
  51. RFC1 in an Australasian neurological disease cohort: extending the genetic heterogeneity and implications for diagnostics.
  52. The Role of Swelling in the Regulation of OPA1-Mediated Mitochondrial Function in the Heart In Vitro.
  53. Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits.
  54. Principles and methods for transferring polygenic risk scores across global populations.
  55. Treatment of a patient with severe lactic acidosis and multiple organ failure due to mitochondrial myopathy: A case report.
  56. The fate of mitochondria during platelet activation.
  57. Principles of metabolome conservation in animals.
  58. Human Exome Sequencing and Prospects for Predictive Medicine: Analysis of International Data and Own Experience.
  1. Nature. 2023 Aug 23.
    Structural mechanism of mitochondrial membrane remodelling by human OPA1.
    Alexander von der Malsburg, Gracie M Sapp, Kelly E Zuccaro, Alexander von Appen, Frank R Moss, Raghav Kalia, Jeremy A Bennett, Luciano A Abriata, Matteo Dal Peraro, Martin van der Laan, Adam Frost, Halil Aydin.
      Distinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate1-3. The mechanochemical GTPase optic atrophy 1 (OPA1) influences the architecture of cristae and catalyses the fusion of the mitochondrial inner membrane4,5. Despite its fundamental importance, the molecular mechanisms by which OPA1 modulates mitochondrial morphology are unclear. Here, using a combination of cellular and structural analyses, we illuminate the molecular mechanisms that are key to OPA1-dependent membrane remodelling and fusion. Human OPA1 embeds itself into cardiolipin-containing membranes through a lipid-binding paddle domain. A conserved loop within the paddle domain inserts deeply into the bilayer, further stabilizing the interactions with cardiolipin-enriched membranes. OPA1 dimerization through the paddle domain promotes the helical assembly of a flexible OPA1 lattice on the membrane, which drives mitochondrial fusion in cells. Moreover, the membrane-bending OPA1 oligomer undergoes conformational changes that pull the membrane-inserting loop out of the outer leaflet and contribute to the mechanics of membrane remodelling. Our findings provide a structural framework for understanding how human OPA1 shapes mitochondrial morphology and show us how human disease mutations compromise OPA1 functions.
    DOI:  https://doi.org/10.1038/s41586-023-06441-6
  2. iScience. 2023 Aug 18. 26(8): 107446
    Mutational burden of XPNPEP3 leads to defects in mitochondrial complex I and cilia in NPHPL1.
    Lingxiao Tong, Jia Rao, Chenxi Yang, Jie Xu, Yijun Lu, Yuchen Zhang, Xiaohui Cang, Shanshan Xie, Jianhua Mao, Pingping Jiang.
      Nephronophthisis-like nephropathy-1 (NPHPL1) is a rare ciliopathy, caused by mutations of XPNPEP3. Despite a well-described monogenic etiology, the pathogenesis of XPNPEP3 associated with mitochondrial and ciliary function remains elusive. Here, we identified novel compound heterozygous mutations in NPHPL1 patients with renal lesion only or with extra bone cysts together. Patient-derived lymphoblasts carrying c.634G>A and c.761G>T together exhibit elevated mitochondrial XPNPEP3 levels via the reduction of mRNA degradation, leading to mitochondrial dysfunction in both urine tubular epithelial cells and lymphoblasts from patient. Mitochondrial XPNPEP3 was co-immunoprecipitated with respiratory chain complex I and was required for the stability and activity of complex I. Deletion of Xpnpep3 in mice resulted in lower activity of complex I, elongated primary cilium, and predisposition to tubular dilation and fibrosis under stress. Our findings provide valuable insights into the mitochondrial functions involved in the pathogenesis of NPHP.
    Keywords:  cell biology; disease; human Genetics
    DOI:  https://doi.org/10.1016/j.isci.2023.107446
  3. Genes (Basel). 2023 Jul 27. pii: 1536. [Epub ahead of print]14(8):
    Leigh Syndrome Spectrum: A Portuguese Population Cohort in an Evolutionary Genetic Era.
    Manuela Schubert Baldo, Célia Nogueira, Cristina Pereira, Patrícia Janeiro, Sara Ferreira, Charles M Lourenço, Anabela Bandeira, Esmeralda Martins, Marina Magalhães, Esmeralda Rodrigues, Helena Santos, Ana Cristina Ferreira, Laura Vilarinho.
      Mitochondrial diseases are the most common inherited inborn error of metabolism resulting in deficient ATP generation, due to failure in homeostasis and proper bioenergetics. The most frequent mitochondrial disease manifestation in children is Leigh syndrome (LS), encompassing clinical, neuroradiological, biochemical, and molecular features. It typically affects infants but occurs anytime in life. Considering recent updates, LS clinical presentation has been stretched, and is now named LS spectrum (LSS), including classical LS and Leigh-like presentations. Apart from clinical diagnosis challenges, the molecular characterization also progressed from Sanger techniques to NGS (next-generation sequencing), encompassing analysis of nuclear (nDNA) and mitochondrial DNA (mtDNA). This upgrade resumed steps and favored diagnosis. Hereby, our paper presents molecular and clinical data on a Portuguese cohort of 40 positive cases of LSS. A total of 28 patients presented mutation in mtDNA and 12 in nDNA, with novel mutations identified in a heterogeneous group of genes. The present results contribute to the better knowledge of the molecular basis of LS and expand the clinical spectrum associated with this syndrome.
    Keywords:  NGS; clinical spectrum; leigh syndrome; mitochondrial disorders; mutational spectrum
    DOI:  https://doi.org/10.3390/genes14081536
  4. J Biomed Sci. 2023 Aug 21. 30(1): 70
    Mitochondrial impairment and synaptic dysfunction are associated with neurological defects in iPSCs-derived cortical neurons of MERRF patients.
    Yu-Ting Wu, Hui-Yi Tay, Jung-Tse Yang, Hsiao-Hui Liao, Yi-Shing Ma, Yau-Huei Wei.
      BACKGROUND: Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a rare inherited mitochondrial disease mainly caused by the m.8344A > G mutation in mitochondrial tRNALys gene, and usually manifested as complex neurological disorders and muscle weakness. Currently, the pathogenic mechanism of this disease has not yet been resolved, and there is no effective therapy for MERRF syndrome. In this study, MERRF patients-derived iPSCs were used to model patient-specific neurons for investigation of the pathogenic mechanism of neurological disorders in mitochondrial disease.METHODS: MERRF patient-derived iPSCs were differentiated into excitatory glutamatergic neurons to unravel the effects of the m.8344A > G mutation on mitochondrial bioenergetic function, neural-lineage differentiation and neuronal function. By the well-established differentiation protocol and electrophysiological activity assay platform, we examined the pathophysiological behaviors in cortical neurons of MERRF patients.
    RESULTS: We have successfully established the iPSCs-derived neural progenitor cells and cortical-like neurons of patients with MERRF syndrome that retained the heteroplasmy of the m.8344A > G mutation from the patients' skin fibroblasts and exhibited the phenotype of the mitochondrial disease. MERRF neural cells harboring the m.8344A > G mutation exhibited impaired mitochondrial bioenergetic function, elevated ROS levels and imbalanced expression of antioxidant enzymes. Our findings indicate that neural immaturity and synaptic protein loss led to the impairment of neuronal activity and plasticity in MERRF neurons harboring the m.8344A > G mutation. By electrophysiological recordings, we monitored the in vivo neuronal behaviors of MERRF neurons and found that neurons harboring a high level of the m.8344A > G mutation exhibited impairment of the spontaneous and evoked potential-stimulated neuronal activities.
    CONCLUSIONS: We demonstrated for the first time the link of mitochondrial impairment and synaptic dysfunction to neurological defects through impeding synaptic plasticity in excitatory neurons derived from iPSCs of MERRF patients harboring the m.8344A > G mutation. This study has provided new insight into the pathogenic mechanism of the tRNALys gene mutation of mtDNA, which is useful for the development of a patient-specific iPSCs platform for disease modeling and screening of new drugs to treat patients with MERRF syndrome.
    Keywords:  AMPARs; Disease modeling; Electrophysiological activity; Excitatory neurons; MERRF syndrome; Neurological defect; Synaptic plasticity; Synaptophysin; iPSCs; mtDNA mutation
    DOI:  https://doi.org/10.1186/s12929-023-00966-8
  5. Cell Calcium. 2023 Jul 27. pii: S0143-4160(23)00094-5. [Epub ahead of print]115 102783
    Ca2+ signalling: A common language for organelles crosstalk in Parkinson's disease.
    Caterina Peggion, Lucia Barazzuol, Elena Poggio, Tito Calì, Marisa Brini.
      Parkinson's disease (PD) is a neurodegenerative disease caused by multifactorial pathogenic mechanisms. Familial PD is linked with genetic mutations in genes whose products are either associated with mitochondrial function or endo-lysosomal pathways. Of note, mitochondria are essential to sustain high energy demanding synaptic activity of neurons and alterations in mitochondrial Ca2+ signaling have been proposed as causal events for neurodegenerative process, although the mechanisms responsible for the selective loss of specific neuronal populations in the different neurodegenerative diseases is still not clear. Here, we specifically discuss the importance of a correct mitochondrial communication with the other organelles occurring at regions where their membranes become in close contact. We discuss the nature and the role of contact sites that mitochondria establish with ER, lysosomes, and peroxisomes, and how PD related proteins participate in the regulation/dysregulation of the tethering complexes. Unravelling molecular details of mitochondria tethering could contribute to identify specific therapeutic targets and develop new strategies to counteract the progression of the disease.
    Keywords:  Calcium signalling; Mitochondria; Organelles contact sites; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.ceca.2023.102783
  6. Adv Biol (Weinh). 2023 Aug 21. e2300186
    Defining Mitochondrial Cristae Morphology Changes Induced by Aging in Brown Adipose Tissue.
    Amber Crabtree, Kit Neikirk, Andrea G Marshall, Larry Vang, Aaron J Whiteside, Qiana Williams, Christopher T Altamura, Trinity Celeste Owens, Dominique Stephens, Bryanna Shao, Alice Koh, Mason Killion, Edgar Garza Lopez, Jacob Lam, Ben Rodriguez, Margaret Mungai, Jade Stanley, E Danielle Dean, Ho-Jin Koh, Jennifer A Gaddy, Estevão Scudese, Mariya T Sweetwyne, Jamaine Davis, Elma Zaganjor, Sandra A Murray, Prasanna Katti, Steven M Damo, Zer Vue, Antentor Hinton.
      Mitochondria are required for energy production and even give brown adipose tissue (BAT) its characteristic color due to their high iron content and abundance. The physiological function and bioenergetic capacity of mitochondria are connected to the structure, folding, and organization of its inner-membrane cristae. During the aging process, mitochondrial dysfunction is observed, and the regulatory balance of mitochondrial dynamics is often disrupted, leading to increased mitochondrial fragmentation in aging cells. Therefore, it is hypothesized that significant morphological changes in BAT mitochondria and cristae will be present with aging. A quantitative 3D electron microscopy approach is developed to map cristae network organization in mouse BAT to test this hypothesis. Using this methodology, the 3D morphology of mitochondrial cristae is investigated in adult (3-month) and aged (2-year) murine BAT tissue via serial block face-scanning electron microscopy (SBF-SEM) and 3D reconstruction software for manual segmentation, analysis, and quantification. Upon investigation, an increase is found in mitochondrial volume, surface area, and complexity and decreased sphericity in aged BAT, alongside significant decreases in cristae volume, area, perimeter, and score. Overall, these data define the nature of the mitochondrial structure in murine BAT across aging.
    Keywords:  3D reconstruction; BAT; aging; brown adipose tissue; mitochondria
    DOI:  https://doi.org/10.1002/adbi.202300186
  7. Nat Commun. 2023 Aug 19. 14(1): 5058
    APOGEE 2: multi-layer machine-learning model for the interpretable prediction of mitochondrial missense variants.
    Salvatore Daniele Bianco, Luca Parca, Francesco Petrizzelli, Tommaso Biagini, Agnese Giovannetti, Niccolò Liorni, Alessandro Napoli, Massimo Carella, Vincent Procaccio, Marie T Lott, Shiping Zhang, Angelo Luigi Vescovi, Douglas C Wallace, Viviana Caputo, Tommaso Mazza.
      Mitochondrial dysfunction has pleiotropic effects and is frequently caused by mitochondrial DNA mutations. However, factors such as significant variability in clinical manifestations make interpreting the pathogenicity of variants in the mitochondrial genome challenging. Here, we present APOGEE 2, a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology, APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2's ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics.
    DOI:  https://doi.org/10.1038/s41467-023-40797-7
  8. Nucleic Acids Res. 2023 Aug 24. pii: gkad697. [Epub ahead of print]
    Let's make it clear: systematic exploration of mitochondrial DNA- and RNA-protein complexes by complexome profiling.
    Alisa Potter, Alfredo Cabrera-Orefice, Johannes N Spelbrink.
      Complexome profiling (CP) is a powerful tool for systematic investigation of protein interactors that has been primarily applied to study the composition and dynamics of mitochondrial protein complexes. Here, we further optimized this method to extend its application to survey mitochondrial DNA- and RNA-interacting protein complexes. We established that high-resolution clear native gel electrophoresis (hrCNE) is a better alternative to preserve DNA- and RNA-protein interactions that are otherwise disrupted when samples are separated by the widely used blue native gel electrophoresis (BNE). In combination with enzymatic digestion of DNA, our CP approach improved the identification of a wide range of protein interactors of the mitochondrial gene expression system without compromising the detection of other multiprotein complexes. The utility of this approach was particularly demonstrated by analysing the complexome changes in human mitochondria with impaired gene expression after transient, chemically induced mitochondrial DNA depletion. Effects of RNase on mitochondrial protein complexes were also evaluated and discussed. Overall, our adaptations significantly improved the identification of mitochondrial DNA- and RNA-protein interactions by CP, thereby unlocking the comprehensive analysis of a near-complete mitochondrial complexome in a single experiment.
    DOI:  https://doi.org/10.1093/nar/gkad697
  9. Antioxidants (Basel). 2023 Aug 20. pii: 1644. [Epub ahead of print]12(8):
    Regulation of Mitochondrial Respiration by Hydrogen Sulfide.
    Dandan Huang, Guangqin Jing, Shuhua Zhu.
      Hydrogen sulfide (H2S), the third gasotransmitter, has positive roles in animals and plants. Mitochondria are the source and the target of H2S and the regulatory hub in metabolism, stress, and disease. Mitochondrial bioenergetics is a vital process that produces ATP and provides energy to support the physiological and biochemical processes. H2S regulates mitochondrial bioenergetic functions and mitochondrial oxidative phosphorylation. The article summarizes the recent knowledge of the chemical and biological characteristics, the mitochondrial biosynthesis of H2S, and the regulatory effects of H2S on the tricarboxylic acid cycle and the mitochondrial respiratory chain complexes. The roles of H2S on the tricarboxylic acid cycle and mitochondrial respiratory complexes in mammals have been widely studied. The biological function of H2S is now a hot topic in plants. Mitochondria are also vital organelles regulating plant processes. The regulation of H2S in plant mitochondrial functions is gaining more and more attention. This paper mainly summarizes the current knowledge on the regulatory effects of H2S on the tricarboxylic acid cycle (TCA) and the mitochondrial respiratory chain. A study of the roles of H2S in mitochondrial respiration in plants to elucidate the botanical function of H2S in plants would be highly desirable.
    Keywords:  hydrogen sulfide; mitochondria; mitochondrial respiratory complex; oxidative phosphorylation; tricarboxylic acid cycle
    DOI:  https://doi.org/10.3390/antiox12081644
  10. Biomed Rep. 2023 Sep;19(3): 64
    Healthy mitochondrial DNA in balanced mitochondrial dynamics: A potential marker for neuro‑aging prediction (Review).
    Made Putra Semadhi, Dewi Mulyaty, Eli Halimah, Jutti Levita.
      The mitochondrial genome or mitochondrial DNA (mtDNA) is released as a response to cellular stress. In mitochondrial biogenesis, active communication between the mitochondria genome and nucleus is associated with the mtDNA profile that affects the mitochondrial quality. The present review aimed to assess the molecular mechanism and potential roles of mitochondria in neuro-aging, including the importance of evaluating the health status of mtDNA via mitochondrial dynamics. The normal condition of mitochondria, defined as mitochondrial dynamics, includes persistent changes in morphology due to fission and fusion events and autophagy-mitophagy in the mitochondrial quality control process. The calculated copy number of mtDNA in the mitochondria genome represents cellular health, which can be affected by a long-term imbalance between the production and accumulation of reactive oxygen species in the neuroendocrine system, which leads to an abnormal function of mitochondria and mtDNA damage. Mitochondria health is a new approach to discovering a potential indicator for the health status of the nervous system and several types of neurodegenerative disorders. Mitochondrial dynamics is a key contributor to predicting neuro-aging development, which affects the self-renewal and differentiation of neurons in cell metabolism. Neuro-aging is associated with uncontrolled mitochondrial dynamics, which generates age-associated diseases via various mechanisms and signaling routes that lead to the mtDNA damage that has been associated with neurodegeneration. Future studies on the strategic positioning of mtDNA health profile are needed to detect early neurodegenerative disorders.
    Keywords:  cellular health; mitochondrial DNA; mitochondrial dynamics; neuro-aging
    DOI:  https://doi.org/10.3892/br.2023.1646
  11. Front Physiol. 2023 ;14 1184060
    The potential for mitochondrial therapeutics in the treatment of primary open-angle glaucoma: a review.
    Grace Kuang, Mina Halimitabrizi, Amy-Ann Edziah, Rebecca Salowe, Joan M O'Brien.
      Glaucoma, an age-related neurodegenerative disease, is characterized by the death of retinal ganglion cells (RGCs) and the corresponding loss of visual fields. This disease is the leading cause of irreversible blindness worldwide, making early diagnosis and effective treatment paramount. The pathophysiology of primary open-angle glaucoma (POAG), the most common form of the disease, remains poorly understood. Current available treatments, which target elevated intraocular pressure (IOP), are not effective at slowing disease progression in approximately 30% of patients. There is a great need to identify and study treatment options that target other disease mechanisms and aid in neuroprotection for POAG. Increasingly, the role of mitochondrial injury in the development of POAG has become an emphasized area of research interest. Disruption in the function of mitochondria has been linked to problems with neurodevelopment and systemic diseases. Recent studies have shown an association between RGC death and damage to the cells' mitochondria. In particular, oxidative stress and disrupted oxidative phosphorylation dynamics have been linked to increased susceptibility of RGC mitochondria to secondary mechanical injury. Several mitochondria-targeted treatments for POAG have been suggested, including physical exercise, diet and nutrition, antioxidant supplementation, stem cell therapy, hypoxia exposure, gene therapy, mitochondrial transplantation, and light therapy. Studies have shown that mitochondrial therapeutics may have the potential to slow the progression of POAG by protecting against mitochondrial decline associated with age, genetic susceptibility, and other pathology. Further, these therapeutics may potentially target already present neuronal damage and symptom manifestations. In this review, the authors outline potential mitochondria-targeted treatment strategies and discuss their utility for use in POAG.
    Keywords:  glaucoma; mitochondrial dysfunction; mitochondrial therapeutics; neurodegeneration; oxidative Stress
    DOI:  https://doi.org/10.3389/fphys.2023.1184060
  12. Immunohorizons. 2023 Aug 01. 7(8): 587-599
    MAVS Positively Regulates Mitochondrial Integrity and Metabolic Fitness in B Cells.
    Hongsheng Wang, Wenxiang Sun, Javier Traba, Juan Wu, Chen-Feng Qi, Laura Amo, Hemanta K Kole, Bethany Scott, Komudi Singh, Michael N Sack, Silvia Bolland.
      Activated B cells experience metabolic changes that require mitochondrial remodeling, in a process incompletely defined. In this study, we report that mitochondrial antiviral signaling protein (MAVS) is involved in BCR-initiated cellular proliferation and prolonged survival. MAVS is well known as a mitochondrial-tethered signaling adaptor with a central role in viral RNA-sensing pathways that induce type I IFN. The role of MAVS downstream of BCR stimulation was recognized in absence of IFN, indicative of a path for MAVS activation that is independent of viral infection. Mitochondria of BCR-activated MAVS-deficient mouse B cells exhibited a damaged phenotype including disrupted mitochondrial morphology, excess mitophagy, and the temporal progressive blunting of mitochondrial oxidative capacity with mitochondrial hyperpolarization and cell death. Costimulation of MAVS-deficient B cells with anti-CD40, in addition to BCR stimulation, partially corrected the mitochondrial structural defects and functionality. Our data reveal a (to our knowledge) previously unrecognized role of MAVS in controlling the metabolic fitness of B cells, most noticeable in the absence of costimulatory help.
    DOI:  https://doi.org/10.4049/immunohorizons.2300038
  13. Pathogens. 2023 Aug 01. pii: 1005. [Epub ahead of print]12(8):
    Mitochondrial Dysfunction in Bacterial Infections.
    Nicholas M Maurice, Ruxana T Sadikot.
      Mitochondria are critical in numerous cellular processes, including energy generation. Bacterial pathogens target host cell mitochondria through various mechanisms to disturb the host response and improve bacterial survival. We review recent advances in the understanding of how bacteria cause mitochondrial dysfunction through perturbations in mitochondrial cell-death pathways, energy production, mitochondrial dynamics, mitochondrial quality control, DNA repair, and the mitochondrial unfolded protein response. We also briefly highlight possible therapeutic approaches aimed at restoring the host mitochondrial function as a novel strategy to enhance the host response to bacterial infection.
    Keywords:  bacterial infection; innate immunity; metabolism; mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.3390/pathogens12081005
  14. J Neuroophthalmol. 2023 Aug 24.
    Diagnostic Yield of Investigations in Symmetric Optic Neuropathy.
    Armin Handzic, Jim S Xie, Edward A Margolin.
      BACKGROUND: Symmetric optic neuropathy (SON) is commonly seen in neuro-ophthalmic practice and is often discovered incidentally. Although multiple investigations might be performed to discover the underlying cause, they are not always indicated. The aim of this study was to report a clinically reasonable and cost-effective approach to investigating patients with SON.METHODS: SON was defined as bilateral optic neuropathy with normal and/or symmetrically decreased central visual acuity, absence of relative afferent pupillary defect, presence of symmetric optic disc pallor, symmetric thinning of peripapillary retinal nerve fiber layer on optical coherence tomography, and absence of other identifiable causes of optic neuropathy. Records of all patients diagnosed with SON seen at a tertiary university-affiliated neuro-ophthalmology practice from 2016 to 2022 were reviewed to identify the yield of various investigations. Clinical data from the initial and last follow-up visit were obtained. Subgroup analysis was performed to ascertain whether diagnostic yield is higher in patients with severe visual loss (central acuity worse than 20/40) compared with those with mild visual loss (acuity 20/40 or better).
    RESULTS: One hundred thirty-six patients met inclusion criteria. Testing for OPA1 and OPA2 mutations had the highest diagnostic yield (16.0%), followed by mitochondrial genome sequencing (13.6%), serum vitamin B12 (6.1%), and serum folate (1.6%). MRI brain was performed in 54.4% of patients and had a diagnostic yield of only 5%. Both patients who had abnormal MRI had symptoms of demyelination at presentation. Patients were followed for a mean of 15.0 (SD 21.3) months. The most frequently identified etiologies of SON were Leber hereditary optic neuropathy (8.1%), alcohol/tobacco amblyopia (7.4%), vitamin B12 deficiency (5.9%), and dominant optic atrophy (2.9%). Patients with severe visual impairment were more likely to have a final diagnosis compared with those with milder visual impairment (63.9% vs 12.0%, P < 0.001).
    CONCLUSIONS: The diagnostic yield of investigating SON in patients with preserved visual function, normal diet, and absence of other neurological symptoms is very low. It is reasonable to observe patients with SON with mild visual impairment, reserving costly investigations for those with the visual acuity worse than 20/40 or progressive course.
    DOI:  https://doi.org/10.1097/WNO.0000000000001947
  15. J Gen Physiol. 2023 09 04. pii: e202213263. [Epub ahead of print]155(9):
    Mitochondrial morphology governs ATP production rate.
    Guadalupe C Garcia, Kavya Gupta, Thomas M Bartol, Terrence J Sejnowski, Padmini Rangamani.
      Life is based on energy conversion. In particular, in the nervous system, significant amounts of energy are needed to maintain synaptic transmission and homeostasis. To a large extent, neurons depend on oxidative phosphorylation in mitochondria to meet their high energy demand. For a comprehensive understanding of the metabolic demands in neuronal signaling, accurate models of ATP production in mitochondria are required. Here, we present a thermodynamically consistent model of ATP production in mitochondria based on previous work. The significant improvement of the model is that the reaction rate constants are set such that detailed balance is satisfied. Moreover, using thermodynamic considerations, the dependence of the reaction rate constants on membrane potential, pH, and substrate concentrations are explicitly provided. These constraints assure that the model is physically plausible. Furthermore, we explore different parameter regimes to understand in which conditions ATP production or its export are the limiting steps in making ATP available in the cytosol. The outcomes reveal that, under the conditions used in our simulations, ATP production is the limiting step and not its export. Finally, we performed spatial simulations with nine 3-D realistic mitochondrial reconstructions and linked the ATP production rate in the cytosol with morphological features of the organelles.
    DOI:  https://doi.org/10.1085/jgp.202213263
  16. Int J Mol Sci. 2023 Aug 08. pii: 12580. [Epub ahead of print]24(16):
    Evaluation of Mitochondrial Dysfunction and Idebenone Responsiveness in Fibroblasts from Leber's Hereditary Optic Neuropathy (LHON) Subjects.
    Mirko Baglivo, Alessia Nasca, Eleonora Lamantea, Stefano Vinci, Manuela Spagnolo, Silvia Marchet, Holger Prokisch, Alessia Catania, Costanza Lamperti, Daniele Ghezzi.
      Leber's hereditary optic neuropathy (LHON) is a disease that affects the optical nerve, causing visual loss. The diagnosis of LHON is mostly defined by the identification of three pathogenic variants in the mitochondrial DNA. Idebenone is widely used to treat LHON patients, but only some of them are responders to treatment. In our study, we assessed the maximal respiration rate (MRR) and other respiratory parameters in eight fibroblast lines from subjects carrying LHON pathogenic variants. We measured also the effects of idebenone treatment on cell growth and mtDNA amounts. Results showed that LHON fibroblasts had significantly reduced respiratory parameters in untreated conditions, but no significant gain in MRR after idebenone supplementation. No major toxicity toward mitochondrial function and no relevant compensatory effect in terms of mtDNA quantity were found for the treatment at the tested conditions. Our findings confirmed that fibroblasts from subjects harboring LHON pathogenic variants displayed impaired respiration, regardless of the disease penetrance and severity. Testing responsiveness to idebenone treatment in cultured cells did not fully recapitulate in vivo data. The in-depth evaluation of cellular respiration in fibroblasts is a good approach to evaluating novel mtDNA variants associated with LHON but needs further evaluation as a potential biomarker for disease prognosis and treatment responsiveness.
    Keywords:  LHON; Leber’s hereditary optic neuropathy; biomarker; fibroblasts; idebenone; mtDNA; responsiveness
    DOI:  https://doi.org/10.3390/ijms241612580
  17. Nature. 2023 Aug 23.
    OPA1 helical structures give perspective to mitochondrial dysfunction.
    Sarah B Nyenhuis, Xufeng Wu, Marie-Paule Strub, Yang-In Yim, Abigail E Stanton, Valentina Baena, Zulfeqhar A Syed, Bertram Canagarajah, John A Hammer, Jenny E Hinshaw.
      Dominant optic atrophy is one of the leading causes of childhood blindness. Around 60-80% of cases1 are caused by mutations of the gene that encodes optic atrophy protein 1 (OPA1), a protein that has a key role in inner mitochondrial membrane fusion and remodelling of cristae and is crucial for the dynamic organization and regulation of mitochondria2. Mutations in OPA1 result in the dysregulation of the GTPase-mediated fusion process of the mitochondrial inner and outer membranes3. Here we used cryo-electron microscopy methods to solve helical structures of OPA1 assembled on lipid membrane tubes, in the presence and absence of nucleotide. These helical assemblies organize into densely packed protein rungs with minimal inter-rung connectivity, and exhibit nucleotide-dependent dimerization of the GTPase domains-a hallmark of the dynamin superfamily of proteins4. OPA1 also contains several unique secondary structures in the paddle domain that strengthen its membrane association, including membrane-inserting helices. The structural features identified in this study shed light on the effects of pathogenic point mutations on protein folding, inter-protein assembly and membrane interactions. Furthermore, mutations that disrupt the assembly interfaces and membrane binding of OPA1 cause mitochondrial fragmentation in cell-based assays, providing evidence of the biological relevance of these interactions.
    DOI:  https://doi.org/10.1038/s41586-023-06462-1
  18. bioRxiv. 2023 Aug 08. pii: 2023.07.20.549924. [Epub ahead of print]
    Glial-derived mitochondrial signals impact neuronal proteostasis and aging.
    Raz Bar-Ziv, Naibedya Dutta, Adam Hruby, Edward Sukarto, Maxim Averbukh, Athena Alcala, Hope R Henderson, Jenni Durieux, Sarah U Tronnes, Qazi Ahmad, Theodore Bolas, Joel Perez, Julian G Dishart, Matthew Vega, Gilberto Garcia, Ryo Higuchi-Sanabria, Andrew Dillin.
      The nervous system plays a critical role in maintaining whole-organism homeostasis; neurons experiencing mitochondrial stress can coordinate the induction of protective cellular pathways, such as the mitochondrial unfolded protein response (UPR MT ), between tissues. However, these studies largely ignored non-neuronal cells of the nervous system. Here, we found that UPR MT activation in four, astrocyte-like glial cells in the nematode, C. elegans , can promote protein homeostasis by alleviating protein aggregation in neurons. Surprisingly, we find that glial cells utilize small clear vesicles (SCVs) to signal to neurons, which then relay the signal to the periphery using dense-core vesicles (DCVs). This work underlines the importance of glia in establishing and regulating protein homeostasis within the nervous system, which can then impact neuron-mediated effects in organismal homeostasis and longevity.One-Sentence Summary: Glial cells sense mitochondrial stress and signal a beneficial stress signal to promote neuronal health and longevity.
    DOI:  https://doi.org/10.1101/2023.07.20.549924
  19. Neurogenetics. 2023 Aug 22.
    Rare PMP22 variants in mild to severe neuropathy uncorrelated to plasma GDF15 or neurofilament light.
    Edouard Palu, Julius Järvilehto, Jana Pennonen, Nadine Huber, Sanna-Kaisa Herukka, Annakaisa Haapasalo, Pirjo Isohanni, Henna Tyynismaa, Mari Auranen, Emil Ylikallio.
      Charcot-Marie-Tooth disease (CMT) is a heterogeneous set of hereditary neuropathies whose genetic causes are not fully understood. Here, we characterize three previously unknown variants in PMP22 and assess their effect on the recently described potential CMT biomarkers' growth differentiation factor 15 (GDF15) and neurofilament light (NFL): first, a heterozygous PMP22 c.178G > A (p.Glu60Lys) in one mother-son pair with adult-onset mild axonal neuropathy. The variant led to abnormal splicing, confirmed in fibroblasts by reverse transcription PCR. Second, a de novo PMP22 c.35A > C (p.His12Pro), and third, a heterozygous 3.2 kb deletion predicting loss of exon 4. The latter two had severe CMT and ultrasonography showing strong nerve enlargement similar to a previous case of exon 4 loss due to a larger deletion. We further studied patients with PMP22 duplication (CMT1A) finding slightly elevated plasma NFL, as measured by the single molecule array immunoassay (SIMOA). In addition, plasma GDF15, as measured by ELISA, correlated with symptom severity for CMT1A. However, in the severely affected individuals with PMP22 exon 4 deletion or p.His12Pro, these biomarkers were within the range of variability of CMT1A and controls, although they had more pronounced nerve hypertrophy. This study adds p.His12Pro and confirms PMP22 exon 4 deletion as causes of severe CMT, whereas the previously unknown splice variant p.Glu60Lys leads to mild axonal neuropathy. Our results suggest that GDF15 and NFL do not distinguish CMT1A from advanced hypertrophic neuropathy caused by rare PMP22 variants.
    Keywords:  Biomarker; CMT1E; Charcot-Marie-Tooth disease; Genetic neuropathy; PMP22
    DOI:  https://doi.org/10.1007/s10048-023-00729-5
  20. Biomolecules. 2023 Aug 18. pii: 1265. [Epub ahead of print]13(8):
    Cyclophilin D in Mitochondrial Dysfunction: A Key Player in Neurodegeneration?
    Gabriele Coluccino, Valentina Pia Muraca, Alessandra Corazza, Giovanna Lippe.
      Mitochondrial dysfunction plays a pivotal role in numerous complex diseases. Understanding the molecular mechanisms by which the "powerhouse of the cell" turns into the "factory of death" is an exciting yet challenging task that can unveil new therapeutic targets. The mitochondrial matrix protein CyPD is a peptidylprolyl cis-trans isomerase involved in the regulation of the permeability transition pore (mPTP). The mPTP is a multi-conductance channel in the inner mitochondrial membrane whose dysregulated opening can ultimately lead to cell death and whose involvement in pathology has been extensively documented over the past few decades. Moreover, several mPTP-independent CyPD interactions have been identified, indicating that CyPD could be involved in the fine regulation of several biochemical pathways. To further enrich the picture, CyPD undergoes several post-translational modifications that regulate both its activity and interaction with its clients. Here, we will dissect what is currently known about CyPD and critically review the most recent literature about its involvement in neurodegenerative disorders, focusing on Alzheimer's Disease and Parkinson's Disease, supporting the notion that CyPD could serve as a promising therapeutic target for the treatment of such conditions. Notably, significant efforts have been made to develop CyPD-specific inhibitors, which hold promise for the treatment of such complex disorders.
    Keywords:  Alzheimer’s disease (AD); Cyclophilin D (CyPD); Parkinson’s disease (PD); mitochondria; mitochondrial permeability transition (mPTP); neurodegeneration
    DOI:  https://doi.org/10.3390/biom13081265
  21. Life Sci. 2023 Aug 19. pii: S0024-3205(23)00667-7. [Epub ahead of print] 122032
    Menthol causes mitochondrial Ca2+-influx, affects structure-function relationship and cools mitochondria.
    Shamit Kumar, Tusar Kanta Acharya, Ramizur Rahaman Halder, Parnasree Mahapatra, Young-Tae Chang, Chandan Goswami.
      Menthol is a small bioactive compound able to cause several physiological changes and has multiple molecular targets. Therefore, cellular response against menthol is complex, and still poorly understood. In this work, we used a human osteosarcoma cell line (Saos-2) and analysed the effect of menthol, especially in terms of cellular, subcellular and molecular aspects. We demonstrate that menthol causes increased mitochondrial Ca2+ in a complex manner, which is mainly contributed by intracellular sources, including ER. Menthol also changes the Ca2+-load of individual mitochondrial particles in different conditions. Menthol increases ER-mito contact points, causes mitochondrial morphological changes, and increases mitochondrial ATP, cardiolipin, mitochondrial ROS and reduces mitochondrial membrane potential (ΔΨm). Menthol also prevents the mitochondrial quality damaged by sub-lethal and lethal doses of CCCP. In addition, menthol lowers the mitochondrial temperature within cell and also serves as a cooling agent for the isolated mitochondria in a cell free system too. Notably, menthol-induced reduction of mitochondrial temperature is observed in diverse types of cells, including neuronal, immune and cancer cells. As the higher mitochondrial temperature is a hallmark of several inflammatory, metabolic, disease and age-related disorders, we propose that menthol can serve as an active anti-aging compound against all these disorders. These findings may have relevance in case of several pharmacological and clinical applications of menthol. SIGNIFICANCE STATEMENT: Menthol is a plant-derived bioactive compound that is widely used for several physiological, behavioural, addictive, and medicinal purposes. It is a well-established "cooling and analgesic agent". However, the exact cellular and sub-cellular responses of menthol is poorly understood. In this work, we have characterized the effects of menthol on mitochondrial metabolism. Menthol regulates mitochondrial Ca2+, ATP, superoxides, cardiolipin, membrane-potential, and ER-mito contact sites. Moreover, the cooling agent menthol also cools down mitochondria and protects mitochondrial damage by certain toxins. These findings may promote use of menthol as a useful supplementary agent for anti-aging, anti-cancer, anti-inflammatory purposes where higher mitochondrial temperature is prevalent.
    Keywords:  Cardiolipin; ER-Mito contact points; Mitochondrial Ca(2+)-influx; Mitochondrial temperature; Neuro-degeneration; ROS
    DOI:  https://doi.org/10.1016/j.lfs.2023.122032
  22. Front Cell Dev Biol. 2023 ;11 1196466
    Post-translational modifications and protein quality control of mitochondrial channels and transporters.
    Ashlesha Kadam, Pooja Jadiya, Dhanendra Tomar.
      Mitochondria play a critical role in energy metabolism and signal transduction, which is tightly regulated by proteins, metabolites, and ion fluxes. Metabolites and ion homeostasis are mainly mediated by channels and transporters present on mitochondrial membranes. Mitochondria comprise two distinct compartments, the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM), which have differing permeabilities to ions and metabolites. The OMM is semipermeable due to the presence of non-selective molecular pores, while the IMM is highly selective and impermeable due to the presence of specialized channels and transporters which regulate ion and metabolite fluxes. These channels and transporters are modulated by various post-translational modifications (PTMs), including phosphorylation, oxidative modifications, ions, and metabolites binding, glycosylation, acetylation, and others. Additionally, the mitochondrial protein quality control (MPQC) system plays a crucial role in ensuring efficient molecular flux through the mitochondrial membranes by selectively removing mistargeted or defective proteins. Inefficient functioning of the transporters and channels in mitochondria can disrupt cellular homeostasis, leading to the onset of various pathological conditions. In this review, we provide a comprehensive overview of the current understanding of mitochondrial channels and transporters in terms of their functions, PTMs, and quality control mechanisms.
    Keywords:  MCU; MPQC; MPTP; SLCs; VDAC; mitochondrial channels; mitochondrial transporters; posttranslational modifications
    DOI:  https://doi.org/10.3389/fcell.2023.1196466
  23. Nat Metab. 2023 Aug 21.
    Mitochondrial function and phenotype are defined by bioenergetics.
    Ryan J Mailloux, Jason Treberg, Cathryn Grayson, Luis B Agellon, Helmut Sies.
      
    DOI:  https://doi.org/10.1038/s42255-023-00885-w
  24. Neuromolecular Med. 2023 Aug 21.
    A Missense Variant in AIFM1 Caused Mitochondrial Dysfunction and Intolerance to Riboflavin Deficiency.
    Ying Zhao, Yan Lin, Bin Wang, Fuchen Liu, Dandan Zhao, Wei Wang, Hong Ren, Jiayin Wang, Zhihong Xu, Chuanzhu Yan, Kunqian Ji.
      AIFM1 is a mitochondrial flavoprotein involved in caspase-independent cell death and regulation of respiratory chain complex biogenesis. Mutations in the AIFM1 gene have been associated with multiple clinical phenotypes, but the effectiveness of riboflavin treatment remains controversial. Furthermore, few studies explored the reasons underlying this controversy. We reported a 7-year-old boy with ataxia, sensorimotor neuropathy and muscle weakness. Genetic and histopathological analyses were conducted, along with assessments of mitochondrial function and apoptosis level induced by staurosporine. Riboflavin deficiency and supplementation experiments were performed using fibroblasts. A missense c.1019T > C (p. Met340Thr) variant of AIFM1 was detected in the proband, which caused reduced expression of AIFM1 protein and mitochondrial dysfunction as evidenced by downregulation of mitochondrial complex subunits, respiratory deficiency and collapse of ΔΨm. The proportion of apoptotic cells in mutant fibroblasts was lower than controls after induction of apoptosis. Riboflavin deficiency resulted in decreased AIFM1 protein levels, while supplementation with high concentrations of riboflavin partially increased AIFM1 protein levels in variant fibroblasts. In addition, mitochondrial respiratory function of mutant fibroblasts was partly improved after riboflavin supplementation. Our study elucidated the pathogenicity of the AIFM1 c.1019T > C variant and revealed mutant fibroblasts was intolerant to riboflavin deficiency. Riboflavin supplementation is helpful in maintaining the level of AIFM1 protein and mitochondrial respiratory function. Early riboflavin treatment may serve as a valuable attempt for patients with AIFM1 variant.
    Keywords:  AIFM1; Apoptosis inducing factor; Ataxia; Mitochondrial diseases; Riboflavin
    DOI:  https://doi.org/10.1007/s12017-023-08750-5
  25. Cell Genom. 2023 Aug 09. 3(8): 100359
    Multiset correlation and factor analysis enables exploration of multi-omics data.
    Brielin C Brown, Collin Wang, Silva Kasela, François Aguet, Daniel C Nachun, Kent D Taylor, Russell P Tracy, Peter Durda, Yongmei Liu, W Craig Johnson, David Van Den Berg, Namrata Gupta, Stacy Gabriel, Joshua D Smith, Robert Gerzsten, Clary Clish, Quenna Wong, George Papanicolau, Thomas W Blackwell, Jerome I Rotter, Stephen S Rich, R Graham Barr, Kristin G Ardlie, David A Knowles, Tuuli Lappalainen.
      Multi-omics datasets are becoming more common, necessitating better integration methods to realize their revolutionary potential. Here, we introduce multi-set correlation and factor analysis (MCFA), an unsupervised integration method tailored to the unique challenges of high-dimensional genomics data that enables fast inference of shared and private factors. We used MCFA to integrate methylation markers, protein expression, RNA expression, and metabolite levels in 614 diverse samples from the Trans-Omics for Precision Medicine/Multi-Ethnic Study of Atherosclerosis multi-omics pilot. Samples cluster strongly by ancestry in the shared space, even in the absence of genetic information, while private spaces frequently capture dataset-specific technical variation. Finally, we integrated genetic data by conducting a genome-wide association study (GWAS) of our inferred factors, observing that several factors are enriched for GWAS hits and trans-expression quantitative trait loci. Two of these factors appear to be related to metabolic disease. Our study provides a foundation and framework for further integrative analysis of ever larger multi-modal genomic datasets.
    DOI:  https://doi.org/10.1016/j.xgen.2023.100359
  26. J Mol Med (Berl). 2023 Aug 21.
    Distinctive metabolic remodeling in TYMP deficiency beyond mitochondrial dysfunction.
    Jixiang Du, Chao Zhang, Fuchen Liu, Xihan Liu, Dongdong Wang, Dandan Zhao, Guanghou Shui, Yuying Zhao, Chuanzhu Yan.
      Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by mutations in the TYMP gene, which encodes thymidine phosphorylase (TP). As a cytosolic metabolic enzyme, TP defects affect biological processes that are thought to not be limited to the abnormal replication of mitochondrial DNA. This study aimed to elucidate the characteristic metabolic alterations and associated homeostatic regulation caused by TYMP deficiency. The pathogenicity of novel TYMP variants was evaluated in terms of clinical features, genetic analysis, and structural instability. We analyzed plasma samples from three patients with MNGIE; three patients with m.3243A > G mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); and four healthy controls (HC) using both targeted and untargeted metabolomics techniques. Transcriptomics analysis and bioenergetic studies were performed on skin fibroblasts from participants in these three groups. A TYMP overexpression experiment was conducted to rescue the observed changes. Compared with controls, specific alterations in nucleosides, bile acids, and steroid metabolites were identified in the plasma of MNGIE patients. Comparable mitochondrial dysfunction was present in fibroblasts from patients with TYMP deficiency and in those from patients with the m.3243A > G mutation. Distinctively decreased sterol regulatory element binding protein (SREBP) regulated cholesterol metabolism and fatty acid (FA) biosynthesis as well as reduced FA degradation were revealed in fibroblasts with TYMP deficiency. The restoration of thymidine phosphorylase activity rescued the observed changes in MNGIE fibroblasts. Our findings indicated that more widespread metabolic disturbance may be caused by TYMP deficiency in addition to mitochondrial dysfunction, which expands our knowledge of the biochemical outcome of TYMP deficiency. KEY MESSAGES: Distinct metabolic profiles in patients with TYMP deficiency compared to those with m.3243A > G mutation. TYMP deficiency leads to a global disruption of nucleoside metabolism. Cholesterol and fatty acid metabolism are inhibited in individuals with MNGIE. TYMP is functionally related to SREBP-regulated pathways. Potential metabolite biomarkers that could be valuable clinical tools to improve the diagnosis of MNGIE.
    Keywords:  Cholesterol metabolism; Fatty acid metabolism; MNGIE; Metabolomics; TYMP
    DOI:  https://doi.org/10.1007/s00109-023-02358-9
  27. J Cell Mol Med. 2023 Aug 21.
    OPA1, a molecular regulator of dilated cardiomyopathy.
    Jiaqi Chen, Jianan Shao, Yaoyao Wang, Kangxiang Wu, Mingyuan Huang.
      Dilated cardiomyopathy (DCM) is a disease with no specific treatment, poor prognosis and high mortality. During DCM development, there is apoptosis, mitochondrial dynamics imbalance and changes in cristae structure. Optic atrophy 1 (OPA1) appears at high frequency in these three aspects. DCM LMNA (LaminA/C) gene mutation can activate TP53, and the study of P53 shows that P53 affects OPA1 through Bak/Bax and OMA1(a metalloprotease). OPA1 can be considered the missing link between DCMp53 and DCM apoptosis, mitochondrial dynamics imbalance and changes in cristae structure. OPA1 regulates apoptosis by regulating the release of cytochrome c from the mitochondrial matrix through CJs (crisp linkages, located in the inner mitochondrial membrane) and unbalances mitochondrial fusion and fission by affecting mitochondrial inner membrane (IM) fusion. OPA1 is also associated with the formation and maintenance of mitochondrial cristae. OPA1 is not the root cause of DCM, but it is an essential mediator in P53 mediating the occurrence and development of DCM, so OPA1 also becomes a molecular regulator of DCM. This review discusses the implication of OPA1 for DCM from three aspects: apoptosis, mitochondrial dynamics and ridge structure.
    Keywords:  OPA1; P53; apoptosis; cristae; dilated cardiomyopathy; fusion
    DOI:  https://doi.org/10.1111/jcmm.17918
  28. Biomolecules. 2023 Jul 31. pii: 1198. [Epub ahead of print]13(8):
    Role of Mitochondria-ER Contact Sites in Mitophagy.
    Alina Rühmkorf, Angelika Bettina Harbauer.
      Mitochondria are often referred to as the "powerhouse" of the cell. However, this organelle has many more functions than simply satisfying the cells' metabolic needs. Mitochondria are involved in calcium homeostasis and lipid metabolism, and they also regulate apoptotic processes. Many of these functions require contact with the ER, which is mediated by several tether proteins located on the respective organellar surfaces, enabling the formation of mitochondria-ER contact sites (MERCS). Upon damage, mitochondria produce reactive oxygen species (ROS) that can harm the surrounding cell. To circumvent toxicity and to maintain a functional pool of healthy organelles, damaged and excess mitochondria can be targeted for degradation via mitophagy, a form of selective autophagy. Defects in mitochondria-ER tethers and the accumulation of damaged mitochondria are found in several neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, which argues that the interplay between the two organelles is vital for neuronal health. This review provides an overview of the different mechanisms of mitochondrial quality control that are implicated with the different mitochondria-ER tether proteins, and also provides a novel perspective on how MERCS are involved in mediating mitophagy upon mitochondrial damage.
    Keywords:  mitochondria; mitophagy; organellar contact sites
    DOI:  https://doi.org/10.3390/biom13081198
  29. Am J Physiol Heart Circ Physiol. 2023 Aug 25.
    Three-Dimensional Mitochondria Reconstructions of Murine Cardiac Muscle Changes in Size Across Aging.
    Zer Vue, Kit Neikirk, Larry Vang, Edgar Garza-Lopez, Trace A Christensen, Jianqiang Shao, Jacob Lam, Heather K Beasley, Andrea G Marshall, Amber Crabtree, Josephs Anudokem, Benjamin Rodriguez, Benjamin Kirk, Serif Bacevac, Taylor Barongan, Bryanna Shao, Dominique C Stephens, Kinuthia Kabugi, Ho-Jin Koh, Alice Koh, Chantell S Evans, Brittany Taylor, Anilkumar K Reddy, Tyne Miller-Fleming, Ky'Era V Actkins, Elma Zaganjor, Nastaran Daneshgar, Sandra A Murray, Bret C Mobley, Steven Damo, Jennifer A Gaddy, Blake Riggs, Celestine Wanjalla, Annet Kirabo, Melanie McReynolds, Jose A Gomez, Mark A Phillips, Vernat Exil, Dao-Fu Dai, Antentor Hinton.
      With sparse treatment options, cardiac disease remains a significant cause of death among humans. As a person ages, mitochondria break down and the heart becomes less efficient. Heart failure is linked to many mitochondria-associated processes, including endoplasmic reticulum stress, mitochondrial bioenergetics, insulin signaling, autophagy, and oxidative stress. The roles of key mitochondrial complexes that dictate the ultrastructure, such as the mitochondrial contact site and cristae organizing system (MICOS), in aging cardiac muscle are poorly understood. To better understand the cause of age-related alteration in mitochondrial structure in cardiac muscle, we used transmission electron microscopy (TEM) and serial block facing-scanning electron microscopy (SBF-SEM) to quantitatively analyze the 3D networks in cardiac muscle samples of male mice at aging intervals of 3 months, 1 year, and 2 years. Here, we present the loss of cristae morphology, the inner folds of the mitochondria, across age. In conjunction with this, the 3D volume of mitochondria decreased. These findings mimicked observed phenotypes in murine cardiac fibroblasts with CRISPR/Cas9 knockout of Mitofilin, Chchd3, Chchd6 (some members of the MICOS complex), and Opa1, which showed poorer oxidative consumption rate and mitochondria with decreased mitochondrial length and volume. In combination, these data show the need to explore if loss of the MICOS complex in the heart may be involved in age-associated mitochondrial and cristae structural changes.
    Keywords:  3D morphometry; Cardiac Muscle; MICOS; Mitochondria; serial block-face SEM
    DOI:  https://doi.org/10.1152/ajpheart.00202.2023
  30. Cell Chem Biol. 2023 Aug 11. pii: S2451-9456(23)00243-X. [Epub ahead of print]
    Succinylation of a KEAP1 sensor lysine promotes NRF2 activation.
    Lara Ibrahim, Caroline Stanton, Kayla Nutsch, Thu Nguyen, Chloris Li-Ma, Yeonjin Ko, Gabriel C Lander, R Luke Wiseman, Michael J Bollong.
      Cross talk between metabolism and stress-responsive signaling is essential for maintaining cellular homeostasis. This cross talk is often achieved through covalent modification of proteins by endogenous, reactive metabolites that regulate key stress-responsive transcription factors like NRF2. Metabolites including methylglyoxal, glyceraldehyde 3-phosphate, fumarate, and itaconate covalently modify sensor cysteines of the NRF2 repressor KEAP1, resulting in stabilization of NRF2 and activation of its cytoprotective transcriptional program. Here, we employed a shRNA-based screen targeting the enzymes of central carbon metabolism to identify additional regulatory nodes bridging metabolism to NRF2 activation. Succinic anhydride, increased by genetic depletion of the TCA cycle enzyme succinyl-CoA synthetase or by direct administration, results in N-succinylation of lysine 131 of KEAP1 to activate NRF2 signaling. This study identifies KEAP1 as capable of sensing reactive metabolites not only by several cysteine residues but also by a conserved lysine residue, indicating its potential to sense an expanded repertoire of reactive metabolic messengers.
    DOI:  https://doi.org/10.1016/j.chembiol.2023.07.014
  31. Brain Sci. 2023 Aug 08. pii: 1178. [Epub ahead of print]13(8):
    Juvenile-Onset Recurrent Rhabdomyolysis Due to Compound Heterozygote Variants in the ACADVL Gene.
    Beatrice Labella, Gaetana Lanzi, Stefano Cotti Piccinelli, Filomena Caria, Simona Damioli, Barbara Risi, Enrica Bertella, Loris Poli, Alessandro Padovani, Massimiliano Filosto.
      Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare autosomal recessive long-chain fatty acid oxidation disorder caused by mutations in the ACADVL gene. The myopathic form presents with exercise intolerance, exercise-related rhabdomyolysis, and muscle pain, usually starting during adolescence or adulthood. We report on a 17-year-old boy who has presented with exercise-induced muscle pain and fatigue since childhood. In recent clinical history, episodes of exercise-related severe hyperCKemia and myoglobinuria were reported. Electromyography was normal, and a muscle biopsy showed only "moth-eaten" fibers, and a mild increase in lipid storage in muscle fibers. NGS analysis displayed the already known heterozygote c.1769G>A variant and the unreported heterozygote c.523G>C change in ACADVL both having disease-causing predictions. Plasma acylcarnitine profiles revealed high long-chain acylcarnitine species levels, especially C14:1. Clinical, histopathological, biochemical, and genetic tests supported the diagnosis of VLCAD deficiency. Our report of a novel pathogenic missense variant in ACADVL expands the allelic heterogeneity of the disease. Since dietary treatment is the only therapy available for treating VLCAD deficiency and it is more useful the earlier it is started, prompt diagnosis is essential in order to minimize muscle damage and slow the disease progression.
    Keywords:  ACADVL; VLCAD; VLCADD; lipid myopathy; myoglobinuria; rhabdomyolysis
    DOI:  https://doi.org/10.3390/brainsci13081178
  32. EMBO J. 2023 Aug 25. e113491
    Nix interacts with WIPI2 to induce mitophagy.
    Eric N Bunker, François Le Guerroué, Chunxin Wang, Marie-Paule Strub, Achim Werner, Nico Tjandra, Richard J Youle.
      Nix is a membrane-anchored outer mitochondrial protein that induces mitophagy. While Nix has an LC3-interacting (LIR) motif that binds to ATG8 proteins, it also contains a minimal essential region (MER) that induces mitophagy through an unknown mechanism. We used chemically induced dimerization (CID) to probe the mechanism of Nix-mediated mitophagy and found that both the LIR and MER are required for robust mitophagy. We find that the Nix MER interacts with the autophagy effector WIPI2 and recruits WIPI2 to mitochondria. The Nix LIR motif is also required for robust mitophagy and converts a homogeneous WIPI2 distribution on the surface of the mitochondria into puncta, even in the absence of ATG8s. Together, this work reveals unanticipated mechanisms in Nix-induced mitophagy and the elusive role of the MER, while also describing an interesting example of autophagy induction that acts downstream of the canonical initiation complexes.
    Keywords:  Autophagy; BNIP3; FIP200; LIR; p62
    DOI:  https://doi.org/10.15252/embj.2023113491
  33. Aging (Albany NY). 2023 Aug 22. undefined
    Mitochondria: between aging, frailty and sarcopenia.
    Annalisa Davin, Riccardo Rocco Ferrari, Orietta Pansarasa.
      
    Keywords:  biomarkers; frailty; mitochondrial dysfunction; mtDNA; sarcopenia
    DOI:  https://doi.org/10.18632/aging.204998
  34. bioRxiv. 2023 Aug 16. pii: 2023.08.07.552354. [Epub ahead of print]
    The actin binding protein profilin 1 is critical for mitochondria function.
    Tracy-Ann Read, Bruno A Cisterna, Kristen Skruber, Samah Ahmadieh, Halli L Lindamood, Josefine A Vitriol, Yang Shi, Austin E Y T Lefebvre, Joseph B Black, Mitchell T Butler, James A Bear, Alena Cherezova, Daria V Ilatovskaya, Neil L Weintraub, Eric A Vitriol.
      Profilin 1 (PFN1) is an actin binding protein that is vital for the polymerization of monomeric actin into filaments. Here we screened knockout cells for novel functions of PFN1 and discovered that mitophagy, a type of selective autophagy that removes defective or damaged mitochondria from the cell, was significantly upregulated in the absence of PFN1. Despite successful autophagosome formation and fusion with the lysosome, and activation of additional mitochondrial quality control pathways, PFN1 knockout cells still accumulate damaged, dysfunctional mitochondria. Subsequent imaging and functional assays showed that loss of PFN1 significantly affects mitochondria morphology, dynamics, and respiration. Further experiments revealed that PFN1 is located to the mitochondria matrix and is likely regulating mitochondria function from within rather than through polymerizing actin at the mitochondria surface. Finally, PFN1 mutants associated with amyotrophic lateral sclerosis (ALS) fail to rescue PFN1 knockout mitochondrial phenotypes and form aggregates within mitochondria, further perturbing them. Together, these results suggest a novel function for PFN1 in regulating mitochondria and identify a potential pathogenic mechanism of ALS-linked PFN1 variants.
    DOI:  https://doi.org/10.1101/2023.08.07.552354
  35. Aging Cell. 2023 Aug 23. e13954
    Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.
    Natalia Oleinik, Onder Albayram, Mohamed Faisal Kassir, F Cansu Atilgan, Chase Walton, Eda Karakaya, John Kurtz, Alexander Alekseyenko, Habeeb Alsudani, Megan Sheridan, Zdzislaw M Szulc, Besim Ogretmen.
      The metabolic consequences of mitophagy alterations due to age-related stress in healthy aging brains versus neurodegeneration remain unknown. Here, we demonstrate that ceramide synthase 1 (CerS1) is transported to the outer mitochondrial membrane by the p17/PERMIT transporter that recognizes mislocalized mitochondrial ribosomes (mitoribosomes) via 39-FLRN-42 residues, inducing ceramide-mediated mitophagy. P17/PERMIT-CerS1-mediated mitophagy attenuated the argininosuccinate/fumarate/malate axis and induced d-glucose and fructose accumulation in neurons in culture and brain tissues (primarily in the cerebellum) of wild-type mice in vivo. These metabolic changes in response to sodium-selenite were nullified in the cerebellum of CerS1to/to (catalytically inactive for C18-ceramide production CerS1 mutant), PARKIN-/- or p17/PERMIT-/- mice that have dysfunctional mitophagy. Whereas sodium selenite induced mitophagy in the cerebellum and improved motor-neuron deficits in aged wild-type mice, exogenous fumarate or malate prevented mitophagy. Attenuating ceramide-mediated mitophagy enhanced damaged mitochondria accumulation and age-dependent sensorimotor abnormalities in p17/PERMIT-/- mice. Reinstituting mitophagy using a ceramide analog drug with selenium conjugate, LCL768, restored mitophagy and reduced malate/fumarate metabolism, improving sensorimotor deficits in old p17/PERMIT-/- mice. Thus, these data describe the metabolic consequences of alterations to p17/PERMIT/ceramide-mediated mitophagy associated with the loss of mitochondrial quality control in neurons and provide therapeutic options to overcome age-dependent sensorimotor deficits and related disorders like amyotrophic lateral sclerosis (ALS).
    Keywords:  CerS1; Drp1; aging; ceramide; mitochondrial metabolism; mitophagy; neurodegeneration; sensorimotor defects
    DOI:  https://doi.org/10.1111/acel.13954
  36. Hum Genome Var. 2023 Aug 22. 10(1): 23
    Leigh-like syndrome with progressive cerebellar atrophy caused by novel HIBCH variants.
    Yoshihiro Taura, Takenori Tozawa, Kenichi Isoda, Satori Hirai, Tomohiro Chiyonobu, Naoko Yano, Takahiro Hayashi, Takeshi Yoshida, Tomoko Iehara.
      Pathogenic variants in the HIBCH gene cause HIBCH deficiency, leading to mitochondrial disorders associated with valine metabolism. Patients typically present with symptoms such as developmental regression/delay, encephalopathy, hypotonia and dystonia. Brain magnetic resonance imaging (MRI) shows bilateral lesions in the basal ganglia with/without brainstem involvement. Here, we report a case of a Japanese patient with Leigh-like syndrome caused by novel HIBCH variants. Long-term follow-up MRI revealed progressive cerebellar atrophy, which expands the phenotypic spectrum of HIBCH deficiency.
    DOI:  https://doi.org/10.1038/s41439-023-00251-y
  37. J Inherit Metab Dis. 2023 Aug 22.
    Development of Precision Therapies for Rare Inborn Errors of Metabolism: Functional Investigations in Cell Culture Models.
    Miroslava Didiasova, Antje Banning, Ritva Tikkanen.
      Due to the low number of patients, rare genetic diseases are a special challenge for the development of therapies, especially for diseases that result from numerous, patient-specific pathogenic variants. Precision medicine makes use of various kinds of molecular information about a specific variant, so that the possibilities for an effective therapy based on the molecular features of the variants can be elucidated. The attention to personalized precision therapies has increased among scientists and clinicians, since the "single drug for all patients" approach does not allow the classification of individuals in subgroups according to the differences in the disease genotype or phenotype. This review article summarizes some approaches of personalized precision medicine that can be used for a cost-effective and fast development of therapies, even for single patients. We have focused on specific examples on inborn errors of metabolism, with special attention on drug repurposing. Furthermore, we provide an overview of cell culture models that are suitable for precision medicine approaches. This article is protected by copyright. All rights reserved.
    Keywords:  drug repurposing; inborn errors of metabolism; pathogenic variants; personalized medicine; precision medicine; rare diseases
    DOI:  https://doi.org/10.1002/jimd.12674
  38. BMC Med Genomics. 2023 Aug 23. 16(1): 196
    A link between mitochondrial damage and the immune microenvironment of delayed onset muscle soreness.
    Zheng Li, Lina Peng, Lili Sun, Juncheng Si.
      BACKGROUND: Delayed onset muscle soreness (DOMS) is a self-healing muscle pain disorder. Inflammatory pain is the main feature of DOMS. More and more researchers have realized that changes in mitochondrial morphology are related to pain. However, the role of mitochondria in the pathogenesis of DOMS and the abnormal immune microenvironment is still unknown.METHODS: Mitochondria-related genes and gene expression data were obtained from MitoCarta3.0 and NCBI GEO databases. The network of mitochondrial function and the immune microenvironment of DOMS was constructed by computer algorithm. Subsequently, the skeletal muscle of DOMS rats was subjected to qPCR to verify the bioinformatics results. DOMS and non-DOMS histological samples were further studied by staining and transmission electron microscopy.
    RESULTS: Bioinformatics results showed that expression of mitochondria-related genes was changed in DOMS. The results of qPCR showed that four hub genes (AMPK, PGC1-α, SLC25A25, and ARMCX1) were differentially expressed in DOMS. These hub genes are related to the degree of skeletal muscle immune cell infiltration, mitochondrial respiratory chain complex, DAMPs, the TCA cycle, and mitochondrial metabolism. Bayesian network inference showed that IL-6 and PGC1-α may be the main regulatory genes of mitochondrial damage in DOMS. Transmission electron microscopy revealed swelling of skeletal muscle mitochondria and disorganization of myofilaments.
    CONCLUSIONS: Our study found that skeletal muscle mitochondrial damage is one of the causes of inflammatory factor accumulation in DOMS. According to the screened-out hub genes, this study provides a reference for follow-up clinical application.
    Keywords:  Immune cells5; Inflammatory factors1; Inflammatory pain3; Mitochondrial4; Sports injury2
    DOI:  https://doi.org/10.1186/s12920-023-01621-9
  39. Exp Mol Med. 2023 Aug 23.
    Mitochondria-associated programmed cell death as a therapeutic target for age-related disease.
    Thanh T Nguyen, Shibo Wei, Thu Ha Nguyen, Yunju Jo, Yan Zhang, Wonyoung Park, Karim Gariani, Chang-Myung Oh, Hyeon Ho Kim, Ki-Tae Ha, Kyu Sang Park, Raekil Park, In-Kyu Lee, Minho Shong, Riekelt H Houtkooper, Dongryeol Ryu.
      Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse cell death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed cell death. Thus, dysfunctional cellular pathways eventually lead or contribute to various age-related diseases, such as neurodegenerative, cardiovascular and metabolic diseases. Thus, mitochondrion-associated programmed cell death-based treatments show great therapeutic potential, providing novel insights in clinical trials. This review discusses mitochondrial quality control networks with activity triggered by stimuli and that maintain cellular homeostasis via mitohormesis, the mitochondrial unfolded protein response, and mitophagy. The review also presents details on various forms of mitochondria-associated programmed cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and paraptosis, and highlights their involvement in age-related disease pathogenesis, collectively suggesting therapeutic directions for further research.
    DOI:  https://doi.org/10.1038/s12276-023-01046-5
  40. Reprod Sci. 2023 Aug 21.
    Spatiotemporal Distribution and Function of Mitochondria in Oocytes.
    Xin Kang, Liying Yan, Jing Wang.
      Mitochondria are energy provider organelles in eukaryotic cells that contain their own specific genome. This review addresses structural and functional properties of mitochondria, focusing on recent discoveries about the changes in quality and number of mitochondria per cell during oocyte development. We highlight how oocyte mitochondria exhibit stage-specific morphology and characteristics at different stages of development, in sharp contrast to the elongated mitochondria present in somatic cells. We then evaluate the latest transcriptomic data to elucidate the complex functions of mitochondria during oocyte maturation and the impact of mitochondria on oocyte development. Finally, we describe the methodological progress of mitochondrial replacement therapy to rescue oocytes with developmental disorders or mitochondrial diseases, hoping to provide a guiding reference to future clinical applications.
    Keywords:  Mitochondria; Mitochondria distribution; Oocyte maturation; Transcriptome; mtDNA copy number
    DOI:  https://doi.org/10.1007/s43032-023-01331-8
  41. Antioxidants (Basel). 2023 Aug 10. pii: 1593. [Epub ahead of print]12(8):
    Mitochondrial Dysfunction in Repeat Expansion Diseases.
    Alberto Giménez-Bejarano, Eva Alegre-Cortés, Sokhna M S Yakhine-Diop, Patricia Gómez-Suaga, José M Fuentes.
      Repeat expansion diseases are a group of neuromuscular and neurodegenerative disorders characterized by expansions of several successive repeated DNA sequences. Currently, more than 50 repeat expansion diseases have been described. These disorders involve diverse pathogenic mechanisms, including loss-of-function mechanisms, toxicity associated with repeat RNA, or repeat-associated non-ATG (RAN) products, resulting in impairments of cellular processes and damaged organelles. Mitochondria, double membrane organelles, play a crucial role in cell energy production, metabolic processes, calcium regulation, redox balance, and apoptosis regulation. Its dysfunction has been implicated in the pathogenesis of repeat expansion diseases. In this review, we provide an overview of the signaling pathways or proteins involved in mitochondrial functioning described in these disorders. The focus of this review will be on the analysis of published data related to three representative repeat expansion diseases: Huntington's disease, C9orf72-frontotemporal dementia/amyotrophic lateral sclerosis, and myotonic dystrophy type 1. We will discuss the common effects observed in all three repeat expansion disorders and their differences. Additionally, we will address the current gaps in knowledge and propose possible new lines of research. Importantly, this group of disorders exhibit alterations in mitochondrial dynamics and biogenesis, with specific proteins involved in these processes having been identified. Understanding the underlying mechanisms of mitochondrial alterations in these disorders can potentially lead to the development of neuroprotective strategies.
    Keywords:  C9orf72; Ca2+, mitophagy; Huntington disease; ROS; apoptosis; myotonic dystrophy type 1
    DOI:  https://doi.org/10.3390/antiox12081593
  42. Front Genet. 2023 ;14 1240650
    CHDH, a key mitochondrial enzyme, plays a diagnostic role in metabolic disorders diseases and tumor progression.
    Yifei Li, Xinzhuang Shen, Xiaowen Yang, Fuming Lian, Yanping Li, Jinmeng Li, Yongming Huang, Wenzhi Shen, Huan Liu.
      Human choline dehydrogenase (CHDH) is a transmembrane protein located in mitochondria. CHDH has been shown to be one of the important catalytic enzymes that catalyze the oxidation of choline to betaine and is involved in mitochondrial autophagy after mitochondrial damage. In recent years, an increasing number of studies have focused on CHDH and found a close association with the pathogenesis of various diseases, including tumor prognosis. Here we summarized the genomic localization, protein structure and basic functions of CHDH and discuss the progress of CHDH research in metabolic disorders and other diseases. Moreover, we described the regulatory role of CHDH on the progression of different types of malignant tumors. In addition, major pathogenic mechanisms of CHDH in multiple diseases may be associated with single nucleotide polymorphism (SNP). We look forward to providing new strategies and basis for clinical diagnosis and prognosis prediction of diseases by diagnosing SNP loci of CHDH genes. Our work evaluates the feasibility of CHDH as a molecular marker relevant to the diagnosis of some metabolic disorders diseases and tumors, which may provide new targets for the treatment of related diseases and tumors.
    Keywords:  biomarker; choline dehydrogenase (CHDH); metabolic disorders diseases; mitochondrial enzyme; single nucleotide polymorphism (SNP); tumor
    DOI:  https://doi.org/10.3389/fgene.2023.1240650
  43. Eur Heart J Case Rep. 2023 Aug;7(8): ytad294
    Mitochondrial disorders due to m.3243A>G not meeting diagnostic criteria for MELAS require comprehensive work-up.
    Josef Finsterer, Sounira Mehri.
      
    DOI:  https://doi.org/10.1093/ehjcr/ytad294
  44. Antioxidants (Basel). 2023 Jul 28. pii: 1517. [Epub ahead of print]12(8):
    Mitochondrial Volume Regulation and Swelling Mechanisms in Cardiomyocytes.
    Xavier R Chapa-Dubocq, Keishla M Rodríguez-Graciani, Nelson Escobales, Sabzali Javadov.
      Mitochondrion, known as the "powerhouse" of the cell, regulates ion homeostasis, redox state, cell proliferation and differentiation, and lipid synthesis. The inner mitochondrial membrane (IMM) controls mitochondrial metabolism and function. It possesses high levels of proteins that account for ~70% of the membrane mass and are involved in the electron transport chain, oxidative phosphorylation, energy transfer, and ion transport, among others. The mitochondrial matrix volume plays a crucial role in IMM remodeling. Several ion transport mechanisms, particularly K+ and Ca2+, regulate matrix volume. Small increases in matrix volume through IMM alterations can activate mitochondrial respiration, whereas excessive swelling can impair the IMM topology and initiates mitochondria-mediated cell death. The opening of mitochondrial permeability transition pores, the well-characterized phenomenon with unknown molecular identity, in low- and high-conductance modes are involved in physiological and pathological increases of matrix volume. Despite extensive studies, the precise mechanisms underlying changes in matrix volume and IMM structural remodeling in response to energy and oxidative stressors remain unknown. This review summarizes and discusses previous studies on the mechanisms involved in regulating mitochondrial matrix volume, IMM remodeling, and the crosstalk between these processes.
    Keywords:  heart; ions; ischemia-reperfusion; mitochondria; permeability transition pore
    DOI:  https://doi.org/10.3390/antiox12081517
  45. Mol Genet Metab Rep. 2023 Sep;36 100997
    GAA variants associated with reduced enzymatic activity but lack of Pompe-related symptoms, incidentally identified by exome sequencing.
    Anna Malekkou, Athina Theodosiou, Angelos Alexandrou, Ioannis Papaevripidou, Carolina Sismani, Edwin H Jacobs, George J G Ruijter, Violetta Anastasiadou, Sofia Ourani, Emilia Athanasiou, Anthi Drousiotou, Olga Grafakou, Petros P Petrou.
      Pompe disease is a rare metabolic myopathy caused by pathogenic variants affecting the activity of the lysosomal glycogen-degrading enzyme acid alpha-glucosidase (GAA). Impaired GAA function results in the accumulation of undegraded glycogen within lysosomes in multiple tissues but predominantly affects the skeletal, smooth and cardiac muscle. The degree of residual enzymatic activity appears to roughly correlate with the age of onset and the severity of the clinical symptoms. Here, we report four siblings in which the GAA variants NM_000152.5:c.2237G > C p.(Trp746Ser) and NM_000152.5:c.266G > A p.(Arg89His) were identified as an incidental finding of clinical exome sequencing. These variants are listed in the ClinVar and the Pompe disease GAA variant databases but are reported here for the first time in compound heterozygosity. All four siblings displayed normal urine tetrasaccharide levels and no clinical manifestations related to Pompe disease. Nevertheless, GAA enzymatic activity was within the range for late onset Pompe patients. Our report shows an association between a novel genotype and attenuated GAA enzymatic activity. The clinical significance can only be established by the regular monitoring of these individuals. The study highlights the major challenges for clinical care arising from incidental findings of next generation sequencing.
    Keywords:  Acid alpha glucosidase; Case report; Exome sequencing; Glycogen storage disorder; Pompe disease; Variants
    DOI:  https://doi.org/10.1016/j.ymgmr.2023.100997
  46. Life Sci Alliance. 2023 Nov;pii: e202301965. [Epub ahead of print]6(11):
    Allotopic expression of COX6 elucidates Atco-driven co-assembly of cytochrome oxidase and ATP synthase.
    Leticia Veloso R Franco, Chen-Hsien Su, Lorisa Simas Teixeira, Jhulia Almeida Clarck Chagas, Mario Henrique Barros, Alexander Tzagoloff.
      The Cox6 subunit of Saccharomyces cerevisiae cytochrome oxidase (COX) and the Atp9 subunit of the ATP synthase are encoded in nuclear and mitochondrial DNA, respectively. The two proteins interact to form Atco complexes that serve as the source of Atp9 for ATP synthase assembly. To determine if Atco is also a precursor of COX, we pulse-labeled Cox6 in isolated mitochondria of a cox6 nuclear mutant with COX6 in mitochondrial DNA. Only a small fraction of the newly translated Cox6 was found to be present in Atco, which can explain the low concentration of COX and poor complementation of the cox6 mutation by the allotopic gene. This and other pieces of evidence presented in this study indicate that Atco is an obligatory source of Cox6 for COX biogenesis. Together with our finding that atp9 mutants fail to assemble COX, we propose a regulatory model in which Atco unidirectionally couples the biogenesis of COX to that of the ATP synthase to maintain a proper ratio of these two complexes of oxidative phosphorylation.
    DOI:  https://doi.org/10.26508/lsa.202301965
  47. Nat Rev Mol Cell Biol. 2023 Aug 23.
    The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease.
    Claire Goul, Roberta Peruzzo, Roberto Zoncu.
      The Ser/Thr kinase mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolism. As part of mTOR complex 1 (mTORC1), mTOR integrates signals such as the levels of nutrients, growth factors, energy sources and oxygen, and triggers responses that either boost anabolism or suppress catabolism. mTORC1 signalling has wide-ranging consequences for the growth and homeostasis of key tissues and organs, and its dysregulated activity promotes cancer, type 2 diabetes, neurodegeneration and other age-related disorders. How mTORC1 integrates numerous upstream cues and translates them into specific downstream responses is an outstanding question with major implications for our understanding of physiology and disease mechanisms. In this Review, we discuss recent structural and functional insights into the molecular architecture of mTORC1 and its lysosomal partners, which have greatly increased our mechanistic understanding of nutrient-dependent mTORC1 regulation. We also discuss the emerging involvement of aberrant nutrient-mTORC1 signalling in multiple diseases.
    DOI:  https://doi.org/10.1038/s41580-023-00641-8
  48. Am J Med Genet A. 2023 Aug 25.
    A medical odyssey of a 72-year-old man with Charcot-Marie-Tooth disease type 2 newly diagnosed with biallelic variants in SORD gene causing sorbitol dehydrogenase deficiency.
    Undiagnosed Diseases Network
      A 72-year-old man was referred to the Undiagnosed Diseases Network (UDN) because of gradual progressive weakness in both lower extremities for the past 45 years. He was initially diagnosed as having Charcot-Marie-Tooth disease type 2 (CMT2) without a defined molecular genetic cause. Exome sequencing (ES) failed to detect deleterious neuromuscular variants. Very recently, biallelic variants in sorbitol dehydrogenase (SORD) were discovered to be a novel cause of inherited neuropathies including CMT2 or distal hereditary motor neuropathy (dHMN) referred to as Sorbitol Dehydrogenase Deficiency with Peripheral Neuropathy (SORDD, OMIM 618912). The most common variant identified was c.757delG; p.A253Qfs*27. Through the Vanderbilt UDN clinical site, this patient was formally diagnosed with SORDD after the identification of homozygosity for the above SORD frameshift through UDN Genome Sequencing (GS). His medical odyssey was solved by GS and detection of extremely high levels of sorbitol. The diagnosis provided him the opportunity to receive potential treatment with an investigational drug in a clinical trial for SORDD. We suggest that similar studies be considered in other individuals thought to possibly have CMT2 or dHMN.
    Keywords:  Charcot-Marie-Tooth disease type 2; SORD deficiency (SORDD); distal hereditary motor neuropathy; sorbitol
    DOI:  https://doi.org/10.1002/ajmg.a.63383
  49. Curr Med Chem. 2023 Aug 22.
    Mitochondrial unfolded protein response (mtUPR) and diseases.
    Ming Yang, Shilu Luo, Wei Chen, Liyu He, Di Liu, Xi Wang, Li Xiao, Lin Sun.
      Mitochondria are the energy factories of cells, and their functions are closely related to cell homeostasis. The mitochondrial unfolded protein response (mtUPR) is a newly discovered mechanism for regulating mitochondrial homeostasis. When unfolded/misfolded proteins accumulate in mitochondria, the mitochondria release signals that regulate the transcription of certain proteins in the nucleus, thereby inducing the correct folding or degradation of proteins in mitochondria. Many studies have also shown that an abnormality of mtUPR is closely related to the occurrence and development of diseases. Here, we summarized the pathways regulating mtUPR signaling and reviewed the research progress on mtUPR in diseases. Finally, we summarized the currently identified agonists and inhibitors of the mtUPR and discussed the potential of the mtUPR as a therapeutic target for diseases.
    Keywords:  ATFS-1; aging; kidney diseases; mitochondria; mtUPR
    DOI:  https://doi.org/10.2174/0929867331666230822095924
  50. Pharmaceuticals (Basel). 2023 Aug 10. pii: 1134. [Epub ahead of print]16(8):
    Nicotinamide Riboside Improves Stemness of Human Adipose-Derived Stem Cells and Inhibits Terminal Adipocyte Differentiation.
    Somaiah Chinnapaka, Hamid Malekzadeh, Zayaan Tirmizi, José A Arellano, Asim Ejaz.
      Adipose tissue plays a crucial role in maintaining metabolic homeostasis by serving as a storage site for excess fat and protecting other organs from the detrimental effects of lipotoxicity. However, the aging process is accompanied by a redistribution of fat, characterized by a decrease in insulin-sensitive subcutaneous adipose depot and an increase in insulin-resistant visceral adipose depot. This age-related alteration in adipose tissue distribution has implications for metabolic health. Adipose-derived stem cells (ASCs) play a vital role in the regeneration of adipose tissue. However, aging negatively impacts the stemness and regenerative potential of ASCs. The accumulation of oxidative stress and mitochondrial dysfunction-associated cellular damage contributes to the decline in stemness observed in aged ASCs. Nicotinamide adenine dinucleotide (NAD+) is a crucial metabolite that is involved in maintaining cellular homeostasis and stemness. The dysregulation of NAD+ levels with age has been associated with metabolic disorders and the loss of stemness. In this study, we aimed to investigate the effects of nicotinamide riboside (NR), a precursor of NAD+, on the stemness of human ASCs in cell culture. Our findings reveal that adipogenesis is accompanied by an increase in mitochondrial activity and the production of reactive oxygen species (ROS). However, treatment with NR leads to a reduction in mitochondrial activity and ROS production in ASCs. Furthermore, NR administration improves the stemness-related genes expression in ASCs and mitigates their propensity for adipocyte differentiation. These results suggest that NR treatment holds promise as a potential strategy to rejuvenate the stemness of aged ASCs. Further investigations, including in vivo evaluations using animal models and human studies, will be necessary to validate these findings and establish the clinical potential of this well-established drug for enhancing the stemness of aged stem cells.
    Keywords:  adipose stem cells; adipose tissue; differentiation; nicotinamide riboside; proliferation; reactive oxygen species; stemness
    DOI:  https://doi.org/10.3390/ph16081134
  51. Brain Commun. 2023 ;5(4): fcad208
    RFC1 in an Australasian neurological disease cohort: extending the genetic heterogeneity and implications for diagnostics.
    Carolin K Scriba, Igor Stevanovski, Sanjog R Chintalaphani, Hasindu Gamaarachchi, Roula Ghaoui, Darshan Ghia, Robert D Henderson, Nerissa Jordan, Antony Winkel, Phillipa J Lamont, Miriam J Rodrigues, Richard H Roxburgh, Ben Weisburd, Nigel G Laing, Ira W Deveson, Mark R Davis, Gianina Ravenscroft.
      Cerebellar ataxia, neuropathy and vestibular areflexia syndrome is a progressive, generally late-onset, neurological disorder associated with biallelic pentanucleotide expansions in Intron 2 of the RFC1 gene. The locus exhibits substantial genetic variability, with multiple pathogenic and benign pentanucleotide repeat alleles previously identified. To determine the contribution of pathogenic RFC1 expansions to neurological disease within an Australasian cohort and further investigate the heterogeneity exhibited at the locus, a combination of flanking and repeat-primed PCR was used to screen a cohort of 242 Australasian patients with neurological disease. Patients whose data indicated large gaps within expanded alleles following repeat-primed PCR, underwent targeted long-read sequencing to identify novel repeat motifs at the locus. To increase diagnostic yield, additional probes at the RFC1 repeat region were incorporated into the PathWest diagnostic laboratory targeted neurological disease gene panel to enable first-pass screening of the locus for all samples tested on the panel. Within the Australasian cohort, we detected known pathogenic biallelic expansions in 15.3% (n = 37) of patients. Thirty indicated biallelic AAGGG expansions, two had biallelic 'Māori alleles' [(AAAGG)exp(AAGGG)exp], two samples were compound heterozygous for the Māori allele and an AAGGG expansion, two samples had biallelic ACAGG expansions and one sample was compound heterozygous for the ACAGG and AAGGG expansions. Forty-five samples tested indicated the presence of biallelic expansions not known to be pathogenic. A large proportion (84%) showed complex interrupted patterns following repeat-primed PCR, suggesting that these expansions are likely to be comprised of more than one repeat motif, including previously unknown repeats. Using targeted long-read sequencing, we identified three novel repeat motifs in expanded alleles. Here, we also show that short-read sequencing can be used to reliably screen for the presence or absence of biallelic RFC1 expansions in all samples tested using the PathWest targeted neurological disease gene panel. Our results show that RFC1 pathogenic expansions make a substantial contribution to neurological disease in the Australasian population and further extend the heterogeneity of the locus. To accommodate the increased complexity, we outline a multi-step workflow utilizing both targeted short- and long-read sequencing to achieve a definitive genotype and provide accurate diagnoses for patients.
    Keywords:  CANVAS; RFC1; STR; ataxia; sensory neuropathy
    DOI:  https://doi.org/10.1093/braincomms/fcad208
  52. Cells. 2023 Aug 08. pii: 2017. [Epub ahead of print]12(16):
    The Role of Swelling in the Regulation of OPA1-Mediated Mitochondrial Function in the Heart In Vitro.
    Xavier R Chapa-Dubocq, Keishla M Rodríguez-Graciani, Jorge García-Báez, Alyssa Vadovsky, Jason N Bazil, Sabzali Javadov.
      Optic atrophy-1 (OPA1) plays a crucial role in the regulation of mitochondria fusion and participates in maintaining the structural integrity of mitochondrial cristae. Here we elucidate the role of OPA1 cleavage induced by calcium swelling in the presence of Myls22 (an OPA1 GTPase activity inhibitor) and TPEN (an OMA1 inhibitor). The rate of ADP-stimulated respiration was found diminished by both inhibitors, and they did not prevent Ca2+-induced mitochondrial respiratory dysfunction, membrane depolarization, or swelling. L-OPA1 cleavage was stimulated at state 3 respiration; therefore, our data suggest that L-OPA1 cleavage produces S-OPA1 to maintain mitochondrial bioenergetics in response to stress.
    Keywords:  OPA1; calcium retention capacity; heart mitochondria; membrane potential; mitochondrial respiration; mitochondrial swelling
    DOI:  https://doi.org/10.3390/cells12162017
  53. Nat Commun. 2023 Aug 21. 14(1): 5062
    Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits.
    DIRECT Consortium
      We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.
    DOI:  https://doi.org/10.1038/s41467-023-40569-3
  54. Nat Rev Genet. 2023 Aug 24.
    Principles and methods for transferring polygenic risk scores across global populations.
    Polygenic Risk Methods in Diverse Populations (PRIMED) Consortium Methods Working Group
      Polygenic risk scores (PRSs) summarize the genetic predisposition of a complex human trait or disease and may become a valuable tool for advancing precision medicine. However, PRSs that are developed in populations of predominantly European genetic ancestries can increase health disparities due to poor predictive performance in individuals of diverse and complex genetic ancestries. We describe genetic and modifiable risk factors that limit the transferability of PRSs across populations and review the strengths and weaknesses of existing PRS construction methods for diverse ancestries. Developing PRSs that benefit global populations in research and clinical settings provides an opportunity for innovation and is essential for health equity.
    DOI:  https://doi.org/10.1038/s41576-023-00637-2
  55. World J Clin Cases. 2023 Aug 06. 11(22): 5398-5406
    Treatment of a patient with severe lactic acidosis and multiple organ failure due to mitochondrial myopathy: A case report.
    Ling Chen, Tian-Kui Shuai, Yu-Wei Gao, Min Li, Peng-Zhong Fang, Waydhas Christian, Li-Ping Liu.
      BACKGROUND: Mitochondrial myopathy is a rare genetic disease with maternal inheritance that may involve multiple organ systems. Due to the lack of typical characteristics, its clinical diagnosis is difficult, and it is often misdiagnosed or even missed.CASE SUMMARY: The patient was a young college student. When he presented at the hospital, he had severe lactic acidosis, respiratory failure, and shock with multiple organ dysfunction syndrome (MODS). He was treated by mechanical ventilation, veno-arterial extracorporeal membrane oxygenation, and other organ support. However, his condition continued to worsen. After a thorough and detailed medical and family history was taken, a mitochondrial crisis was suspected. A muscle biopsy was taken. Further genetic testing confirmed a mitochondrial gene mutation (TRNL1 3243A>G). The final diagnosis of mitochondrial myopathy was made. Although there is no known specific treatment, intravenous methylprednisone and intravenous immunoglobulin were started. The patient's shock eventually improved. The further course was complicated by severe infection in multiple sites, severe muscle weakness, and recurrent MODS. After 2 mo of multidisciplinary management and intensive rehabilitation, the patient could walk with assistance 4 mo after admission and walk independently 6 mo after admission.
    CONCLUSION: More attention should be paid to mitochondrial myopathy to avoid missed diagnosis and misdiagnosis.
    Keywords:  Case report; Extracorporeal membrane oxygenation; Hyperlactatemia; Mitochondrial crisis; Mitochondrial myopathy; Multiple organ dysfunction syndrome
    DOI:  https://doi.org/10.12998/wjcc.v11.i22.5398
  56. Blood Adv. 2023 Aug 25. pii: bloodadvances.2023010423. [Epub ahead of print]
    The fate of mitochondria during platelet activation.
    Alexei Grichine, Shancy P Jacob, Anita E Eckly, Joran Villaret, Clotilde Joubert, Florence Appaix, Mylène Pezet, Anne-Sophie Ribba, Eric Denarier, Jacques Mazzega, Jean-Yves Rinckel, Laurence Lafanechère, Bénédicte Elena-Herrmann, Jesse W Rowley, Karin Sadoul.
      Blood platelets undergo several successive motor-driven reorganizations of the cytoskeleton when they are recruited to an injured part of a vessel. These reorganizations take place during the platelet activation phase, the spreading process on the injured vessel or between fibrin fibers of the forming clot and during clot retraction. All these steps require a lot of energy, especially the retraction of the clot when platelets develop strong forces similar to those of muscle cells. Platelets can produce energy through glycolysis and mitochondrial respiration. However, although resting platelets have only 5-8 individual mitochondria, they produce ATP predominantly via oxidative phosphorylation. Activated, spread platelets show an increase in size compared to resting platelets and the question arises as to where the few mitochondria are located in these larger platelets. Using expansion microscopy, we show that the number of mitochondria per platelet is increased in spread platelets. Live imaging and Focused Ion Beam-Scanning Electron Microscopy suggest that a mitochondrial fission event takes place during platelet activation. Fission is Drp1 dependent since Drp1 deficient platelets have fused mitochondria. In nucleated cells, mitochondrial fission is associated with a shift to a glycolytic phenotype and using clot retraction assays, we show that platelets have a more glycolytic energy production during clot retraction and Drp1 deficient platelets show a defect in clot retraction.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010423
  57. Proc Natl Acad Sci U S A. 2023 Aug 29. 120(35): e2302147120
    Principles of metabolome conservation in animals.
    Orsolya Liska, Gábor Boross, Charles Rocabert, Balázs Szappanos, Roland Tengölics, Balázs Papp.
      Metabolite levels shape cellular physiology and disease susceptibility, yet the general principles governing metabolome evolution are largely unknown. Here, we introduce a measure of conservation of individual metabolite levels among related species. By analyzing multispecies tissue metabolome datasets in phylogenetically diverse mammals and fruit flies, we show that conservation varies extensively across metabolites. Three major functional properties, metabolite abundance, essentiality, and association with human diseases predict conservation, highlighting a striking parallel between the evolutionary forces driving metabolome and protein sequence conservation. Metabolic network simulations recapitulated these general patterns and revealed that abundant metabolites are highly conserved due to their strong coupling to key metabolic fluxes in the network. Finally, we show that biomarkers of metabolic diseases can be distinguished from other metabolites simply based on evolutionary conservation, without requiring any prior clinical knowledge. Overall, this study uncovers simple rules that govern metabolic evolution in animals and implies that most tissue metabolome differences between species are permitted, rather than favored by natural selection. More broadly, our work paves the way toward using evolutionary information to identify biomarkers, as well as to detect pathogenic metabolome alterations in individual patients.
    Keywords:  metabolic networks; molecular evolution; neutral evolution; phylogenetic comparative method; systems biology
    DOI:  https://doi.org/10.1073/pnas.2302147120
  58. J Pers Med. 2023 Aug 08. pii: 1236. [Epub ahead of print]13(8):
    Human Exome Sequencing and Prospects for Predictive Medicine: Analysis of International Data and Own Experience.
    Oleg S Glotov, Alexander N Chernov, Andrey S Glotov.
      Today, whole-exome sequencing (WES) is used to conduct the massive screening of structural and regulatory genes in order to identify the allele frequencies of disease-associated polymorphisms in various populations and thus detect pathogenic genetic changes (mutations or polymorphisms) conducive to malfunctional protein sequences. With its extensive capabilities, exome sequencing today allows both the diagnosis of monogenic diseases (MDs) and the examination of seemingly healthy populations to reveal a wide range of potential risks prior to disease manifestation (in the future, exome sequencing may outpace costly and less informative genome sequencing to become the first-line examination technique). This review establishes the human genetic passport as a new WES-based clinical concept for the identification of new candidate genes, gene variants, and molecular mechanisms in the diagnosis, prediction, and treatment of monogenic, oligogenic, and multifactorial diseases. Various diseases are addressed to demonstrate the extensive potential of WES and consider its advantages as well as disadvantages. Thus, WES can become a general test with a broad spectrum pf applications, including opportunistic screening.
    Keywords:  human monogenic diseases; oligogenic and multifactorial diseases; personalized medicine; whole-exome sequencing
    DOI:  https://doi.org/10.3390/jpm13081236
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