bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2023–04–02
fifty-two papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial transplantation as a promising therapy for mitochondrial diseases.
  2. Mitochondrial Base Editing: Recent Advances towards Therapeutic Opportunities.
  3. The Drp1-Mediated Mitochondrial Fission Protein Interactome as an Emerging Core Player in Mitochondrial Dynamics and Cardiovascular Disease Therapy.
  4. Mitochondrial DNA Release in Innate Immune Signaling.
  5. MFN2-dependent recruitment of ATAT1 coordinates mitochondria motility with alpha-tubulin acetylation and is disrupted in CMT2A.
  6. The mitochondrial protease OMA1 acts as a metabolic safeguard upon nuclear DNA damage.
  7. The mitochondrial calcium uniporter complex-A play in five acts.
  8. Hem25p is a mitochondrial IPP transporter.
  9. High Throughput Screening of Mitochondrial Bioenergetics in Myoblasts and Differentiated Myotubes.
  10. Mitofusin 2 sustains the axonal mitochondrial network to support presynaptic Ca2+ homeostasis and the synaptic vesicle cycle in rat hippocampal axons.
  11. Impact of the m.13513G>A Variant on the Functions of the OXPHOS System and Cell Retrograde Signaling.
  12. Serum GDF-15 Levels Accurately Differentiate Patients with Primary Mitochondrial Myopathy, Manifesting with Exercise Intolerance and Fatigue, from Patients with Chronic Fatigue Syndrome.
  13. Primary mitochondrial disease as a rare cause of unclear breathlessness and distinctive performance degradation - a case report.
  14. Cytosolic and mitochondrial NADPH fluxes are independently regulated.
  15. Yeast Chromatin Mutants Reveal Altered mtDNA Copy Number and Impaired Mitochondrial Membrane Potential.
  16. The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.
  17. Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy.
  18. Evolution: 'Millefoglie' origin of mitochondrial cristae.
  19. NAMPT-dependent NAD+ biosynthesis controls circadian metabolism in a tissue-specific manner.
  20. Site-1 protease inhibits mitochondrial respiration by controlling the TGF-β target gene Mss51.
  21. Mitochondrial Dysfunction in Intensive Care Unit-Acquired Weakness and Critical Illness Myopathy: A Narrative Review.
  22. A Mitochondrial Perspective on Noncommunicable Diseases.
  23. Cristae formation is a mechanical buckling event controlled by the inner membrane lipidome.
  24. Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders.
  25. Ketogenic diet in action: Metabolic profiling of pyruvate dehydrogenase deficiency.
  26. Mitochondrial DNA abnormalities and metabolic syndrome.
  27. Disturb mitochondrial associated proteostasis: Neurodegeneration and imperfect ageing.
  28. Pathogenic BCS1L Mutation Resulting in Hypertrophic Cardiomyopathy: A Unique Presentation of Nuclear Mitochondrial Disease.
  29. Activity-dependent subcellular compartmentalization of dendritic mitochondria structure in CA1 pyramidal neurons.
  30. Using mass spectrometry imaging to visualize age-related subcellular disruption.
  31. Pathogenicity Analysis of a Novel Variant in GTPBP3 Causing Mitochondrial Disease and Systematic Literature Review.
  32. Tissue-specific heteroplasmy segregation is accompanied by a sharp mtDNA decline in Caenorhabditis elegans soma.
  33. The Role of Primary Mitochondrial Disorders in Hearing Impairment: An Overview.
  34. Edaravone and mitochondrial transfer as potential therapeutics for vanishing white matter disease astrocyte dysfunction.
  35. Computational approaches for detecting disease-associated alternative splicing events.
  36. Inferring compound heterozygosity from large-scale exome sequencing data.
  37. Mitochondrial Complex I as a Pathologic and Therapeutic Target for Parkinson's Disease.
  38. Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease.
  39. Comparison between D-loop methylation and mtDNA copy number in patients with Aicardi-Goutières Syndrome.
  40. Enhanced mitochondrial oxidative metabolism in peripheral blood mononuclear cells is associated with fatty liver in obese young adults.
  41. Reduced OPA1, Mitochondrial Fragmentation and Increased Susceptibility to Apoptosis in Granular Corneal Dystrophy Type 2 Corneal Fibroblasts.
  42. MitoEVs: A new player in multiple disease pathology and treatment.
  43. The Role of Lonp1 on Mitochondrial Functions during Cardiovascular and Muscular Diseases.
  44. Clinical exome sequencing findings in 1589 patients.
  45. Protocol for mapping double-stranded DNA break sites across the genome with translocation capture sequencing.
  46. Mitochondrial ATP synthase as a direct molecular target of chromium(III) to ameliorate hyperglycaemia stress.
  47. Theoretical Framework for the Study of Genetic Diseases Caused by Dominant Alleles.
  48. Crystal structures of dimeric and heptameric mtHsp60 reveal the mechanism of chaperonin inactivation.
  49. Mitochondria-associated membrane protein PACS2 maintains right cardiac function in hypobaric hypoxia.
  50. Pathologically high intraocular pressure induces mitochondrial dysfunction through Drp1 and leads to retinal ganglion cell PANoptosis in glaucoma.
  51. Rapid exome sequencing as a first-tier test in neonates with suspected genetic disorder: results of a prospective multicenter clinical utility study in the Netherlands.
  52. Editorial: Methods in Metabolomics 2022.
  1. Acta Pharm Sin B. 2023 Mar;13(3): 1028-1035
    Mitochondrial transplantation as a promising therapy for mitochondrial diseases.
    Tian-Guang Zhang, Chao-Yu Miao.
      Mitochondrial diseases are a group of inherited or acquired metabolic disorders caused by mitochondrial dysfunction which may affect almost all the organs in the body and present at any age. However, no satisfactory therapeutic strategies have been available for mitochondrial diseases so far. Mitochondrial transplantation is a burgeoning approach for treatment of mitochondrial diseases by recovery of dysfunctional mitochondria in defective cells using isolated functional mitochondria. Many models of mitochondrial transplantation in cells, animals, and patients have proved effective via various routes of mitochondrial delivery. This review presents different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application. Despite some unknowns and challenges, mitochondrial transplantation would provide an innovative approach for mitochondrial medicine.
    Keywords:  Ethical issue; Mitochondria; Mitochondrial delivery; Mitochondrial disease; Mitochondrial isolation; Mitochondrial storage; Mitochondrial transplantation; Mitochondrial transplantation rejection
    DOI:  https://doi.org/10.1016/j.apsb.2022.10.008
  2. Int J Mol Sci. 2023 Mar 18. pii: 5798. [Epub ahead of print]24(6):
    Mitochondrial Base Editing: Recent Advances towards Therapeutic Opportunities.
    Bibekananda Kar, Santiago R Castillo, Ankit Sabharwal, Karl J Clark, Stephen C Ekker.
      Mitochondria are critical organelles that form networks within our cells, generate energy dynamically, contribute to diverse cell and organ function, and produce a variety of critical signaling molecules, such as cortisol. This intracellular microbiome can differ between cells, tissues, and organs. Mitochondria can change with disease, age, and in response to the environment. Single nucleotide variants in the circular genomes of human mitochondrial DNA are associated with many different life-threatening diseases. Mitochondrial DNA base editing tools have established novel disease models and represent a new possibility toward personalized gene therapies for the treatment of mtDNA-based disorders.
    Keywords:  DdCBE; TALED; base editing; heteroplasmy; mitochondria; mitochondrial DNA
    DOI:  https://doi.org/10.3390/ijms24065798
  3. Int J Mol Sci. 2023 Mar 17. pii: 5785. [Epub ahead of print]24(6):
    The Drp1-Mediated Mitochondrial Fission Protein Interactome as an Emerging Core Player in Mitochondrial Dynamics and Cardiovascular Disease Therapy.
    Mulate Zerihun, Surya Sukumaran, Nir Qvit.
      Mitochondria, the membrane-bound cell organelles that supply most of the energy needed for cell function, are highly regulated, dynamic organelles bearing the ability to alter both form and functionality rapidly to maintain normal physiological events and challenge stress to the cell. This amazingly vibrant movement and distribution of mitochondria within cells is controlled by the highly coordinated interplay between mitochondrial dynamic processes and fission and fusion events, as well as mitochondrial quality-control processes, mainly mitochondrial autophagy (also known as mitophagy). Fusion connects and unites neighboring depolarized mitochondria to derive a healthy and distinct mitochondrion. In contrast, fission segregates damaged mitochondria from intact and healthy counterparts and is followed by selective clearance of the damaged mitochondria via mitochondrial specific autophagy, i.e., mitophagy. Hence, the mitochondrial processes encompass all coordinated events of fusion, fission, mitophagy, and biogenesis for sustaining mitochondrial homeostasis. Accumulated evidence strongly suggests that mitochondrial impairment has already emerged as a core player in the pathogenesis, progression, and development of various human diseases, including cardiovascular ailments, the leading causes of death globally, which take an estimated 17.9 million lives each year. The crucial factor governing the fission process is the recruitment of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, from the cytosol to the outer mitochondrial membrane in a guanosine triphosphate (GTP)-dependent manner, where it is oligomerized and self-assembles into spiral structures. In this review, we first aim to describe the structural elements, functionality, and regulatory mechanisms of the key mitochondrial fission protein, Drp1, and other mitochondrial fission adaptor proteins, including mitochondrial fission 1 (Fis1), mitochondrial fission factor (Mff), mitochondrial dynamics 49 (Mid49), and mitochondrial dynamics 51 (Mid51). The core area of the review focuses on the recent advances in understanding the role of the Drp1-mediated mitochondrial fission adaptor protein interactome to unravel the missing links of mitochondrial fission events. Lastly, we discuss the promising mitochondria-targeted therapeutic approaches that involve fission, as well as current evidence on Drp1-mediated fission protein interactions and their critical roles in the pathogeneses of cardiovascular diseases (CVDs).
    Keywords:  cardiovascular diseases (CVDs); dynamin-related protein 1 (Drp1); fission; fusion; mitochondrial dynamics; mitochondrial dynamics 49 (Mid49); mitochondrial dynamics 51 (Mid51); mitochondrial fission 1 (Fis1); mitochondrial fission factor (Mff); mitochondrial fission proteins; mitophagy; protein structure; protein–protein interactions (PPIs)
    DOI:  https://doi.org/10.3390/ijms24065785
  4. Annu Rev Biochem. 2023 Mar 31.
    Mitochondrial DNA Release in Innate Immune Signaling.
    Laura E Newman, Gerald S Shadel.
      According to the endosymbiotic theory, most of the DNA of the original bacterial endosymbiont has been lost or transferred to the nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is the present-day mitochondrial DNA (mtDNA). The ability of mtDNA to escape mitochondria and integrate into the nuclear genome was discovered in budding yeast, along with genes that regulate this process. Mitochondria have emerged as key regulators of innate immunity, and it is now recognized that mtDNA released into the cytoplasm, outside of the cell, or into circulation activates multiple innate immune signaling pathways. Here, we first review the mechanisms through which mtDNA is released into the cytoplasm, including several inducible mitochondrial pores and defective mitophagy or autophagy. Next, we cover how the different forms of released mtDNA activate specific innate immune nucleic acid sensors and inflammasomes. Finally, we discuss how intracellular and extracellular mtDNA release, including circulating cell-free mtDNA that promotes systemic inflammation, are implicated in human diseases, bacterial and viral infections, and senescence and aging. Expected final online publication date for the Annual Review of Biochemistry, Volume 92 is June 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-biochem-032620-104401
  5. bioRxiv. 2023 Mar 16. pii: 2023.03.15.532838. [Epub ahead of print]
    MFN2-dependent recruitment of ATAT1 coordinates mitochondria motility with alpha-tubulin acetylation and is disrupted in CMT2A.
    Atul Kumar, Delfina Larrea, Maria Elena Pero, Paola Infante, Marilisa Conenna, Grace Ji-Eun Shin, Wesley B Grueber, Lucia Di Marcotullio, Estela Area-Gomez, Francesca Bartolini.
      Acetylated microtubules play key roles in the regulation of mitochondria dynamics. It has however remained unknown if the machinery controlling mitochondria dynamics functionally interacts with the alpha-tubulin acetylation cycle. Mitofusin-2 (MFN2), a large GTPase residing in the mitochondrial outer membrane and mutated in Charcot-Marie-Tooth type 2 disease (CMT2A), is a regulator of mitochondrial fusion, transport and tethering with the endoplasmic reticulum. The role of MFN2 in regulating mitochondrial transport has however remained elusive. Here we show that mitochondrial contacts with microtubules are sites of alpha-tubulin acetylation, which occurs through the MFN2-mediated recruitment of alpha-tubulin acetyltransferase 1 (ATAT1). We discover that this activity is critical for MFN2-dependent regulation of mitochondria transport, and that axonal degeneration caused by CMT2A MFN2 associated mutations, R94W and T105M, may depend on the inability to release ATAT1 at sites of mitochondrial contacts with microtubules. Our findings reveal a function for mitochondria in regulating acetylated alpha-tubulin and suggest that disruption of the tubulin acetylation cycle play a pathogenic role in the onset of MFN2-dependent CMT2A.
    DOI:  https://doi.org/10.1101/2023.03.15.532838
  6. Cell Rep. 2023 Mar 31. pii: S2211-1247(23)00343-1. [Epub ahead of print]42(4): 112332
    The mitochondrial protease OMA1 acts as a metabolic safeguard upon nuclear DNA damage.
    Pablo Rivera-Mejías, Álvaro Jesús Narbona-Pérez, Lidwina Hasberg, Lara Kroczek, Amir Bahat, Steffen Lawo, Kat Folz-Donahue, Anna-Lena Schumacher, Sofia Ahola, Fiona Carola Mayer, Patrick Giavalisco, Hendrik Nolte, Sergio Lavandero, Thomas Langer.
      The metabolic plasticity of mitochondria ensures cell development, differentiation, and survival. The peptidase OMA1 regulates mitochondrial morphology via OPA1 and stress signaling via DELE1 and orchestrates tumorigenesis and cell survival in a cell- and tissue-specific manner. Here, we use unbiased systems-based approaches to show that OMA1-dependent cell survival depends on metabolic cues. A metabolism-focused CRISPR screen combined with an integrated analysis of human gene expression data found that OMA1 protects against DNA damage. Nucleotide deficiencies induced by chemotherapeutic agents promote p53-dependent apoptosis of cells lacking OMA1. The protective effect of OMA1 does not depend on OMA1 activation or OMA1-mediated OPA1 and DELE1 processing. OMA1-deficient cells show reduced glycolysis and accumulate oxidative phosphorylation (OXPHOS) proteins upon DNA damage. OXPHOS inhibition restores glycolysis and confers resistance against DNA damage. Thus, OMA1 dictates the balance between cell death and survival through the control of glucose metabolism, shedding light on its role in cancerogenesis.
    Keywords:  CP: Metabolism; DNA damage; OMA1; OXPHOS; glucose metabolism; mitochondria; nucleotides; p53
    DOI:  https://doi.org/10.1016/j.celrep.2023.112332
  7. Cell Calcium. 2023 Mar 24. pii: S0143-4160(23)00032-5. [Epub ahead of print]112 102720
    The mitochondrial calcium uniporter complex-A play in five acts.
    Agnese De Mario, Donato D'Angelo, Giuseppe Zanotti, Anna Raffaello, Cristina Mammucari.
      Mitochondrial Ca2+ (mitCa2+) uptake controls both intraorganellar and cytosolic functions. Within the organelle, [Ca2+] increases regulate the activity of tricarboxylic acid (TCA) cycle enzymes, thus sustaining oxidative metabolism and ATP production. Reactive oxygen species (ROS) are also generated as side products of oxygen consumption. At the same time, mitochondria act as buffers of cytosolic Ca2+ (cytCa2+) increases, thus regulating Ca2+-dependent cellular processes. In pathological conditions, mitCa2+ overload triggers the opening of the mitochondrial permeability transition pore (mPTP) and the release of apoptotic cofactors. MitCa2+ uptake occurs in response of local [Ca2+] increases in sites of proximity between the endoplasmic reticulum (ER) and the mitochondria and is mediated by the mitochondrial Ca2+ uniporter (MCU), a highly selective channel of the inner mitochondrial membrane (IMM). Both channel and regulatory subunits form the MCU complex (MCUC). Cryogenic electron microscopy (Cryo-EM) and crystal structures revealed the correct assembly of MCUC and the function of critical residues for the regulation of Ca2+ conductance.
    DOI:  https://doi.org/10.1016/j.ceca.2023.102720
  8. bioRxiv. 2023 Mar 14. pii: 2023.03.14.532620. [Epub ahead of print]
    Hem25p is a mitochondrial IPP transporter.
    Jonathan Tai, Rachel M Guerra, Sean W Rogers, Zixiang Fang, Laura K Muehlbauer, Evgenia Shishkova, Katherine A Overmyer, Joshua J Coon, David J Pagliarini.
      Coenzyme Q (CoQ, ubiquinone) is an essential cellular cofactor comprised of a redox-active quinone head group and a long hydrophobic polyisoprene tail. How mitochondria access cytosolic isoprenoids for CoQ biosynthesis is a longstanding mystery. Here, via a combination of genetic screening, metabolic tracing, and targeted uptake assays, we reveal that Hem25p-a mitochondrial glycine transporter required for heme biosynthesis-doubles as an isopentenyl pyrophosphate (IPP) transporter in Saccharomyces cerevisiae . Mitochondria lacking Hem25p fail to efficiently incorporate IPP into early CoQ precursors, leading to loss of CoQ and turnover of CoQ biosynthetic proteins. Expression of Hem25p in Escherichia coli enables robust IPP uptake demonstrating that Hem25p is sufficient for IPP transport. Collectively, our work reveals that Hem25p drives the bulk of mitochondrial isoprenoid transport for CoQ biosynthesis in yeast.
    DOI:  https://doi.org/10.1101/2023.03.14.532620
  9. Methods Mol Biol. 2023 ;2640 89-98
    High Throughput Screening of Mitochondrial Bioenergetics in Myoblasts and Differentiated Myotubes.
    Kohei Takeda, Tohru Takemasa, Ryo Fujita.
      Skeletal muscles contain stem cells called satellite cells, which are essential for muscle regeneration. The population of satellite cells declines with aging and the incidence of pathological conditions such as muscular dystrophy. There is increasing evidence that metabolic switches and mitochondrial function are critical regulators of cell fate decision (quiescence, activation, differentiation, and self-renewal) during myogenesis. Thus, monitoring and identifying the metabolic profile in live cells using the Seahorse XF Bioanalyzer could provide new insights on the molecular mechanisms governing stem cell dynamics during regeneration and tissue maintenance. Here we described a method to assess mitochondrial respiration (oxygen consumption rate) and glycolysis (ECAR) in primary murine satellite cells, multinucleated myotubes, and C2C12 myoblasts.
    Keywords:  Metabolism; Mitochondria; Myotube; Oxygen consumption rate; Satellite cell; Seahorse XF Analyzer; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-1-0716-3036-5_7
  10. J Neurosci. 2023 Mar 30. pii: JN-RM-1356-22. [Epub ahead of print]
    Mitofusin 2 sustains the axonal mitochondrial network to support presynaptic Ca2+ homeostasis and the synaptic vesicle cycle in rat hippocampal axons.
    Jason D Vevea, Edwin R Chapman.
      Mitochondria exert powerful control over cellular physiology, contributing to ion homeostasis, energy production, and metabolite biosynthesis. The trafficking and function of these organelles are particularly important in neurons, with impaired mitochondrial function or altered morphology observed in every neurodegenerative disorder studied. While mitochondrial biosynthetic products play a crucial role in maintaining cellular function, their resulting byproducts can have negative consequences. Thus, organelle quality control (QC) mechanisms that maintain mitochondrial function are imperative to restrict destructive signaling cascades in the cell. Axons are particularly sensitive to damage, and there is little consensus regarding the mechanisms that mediate mitochondrial QC in this compartment.Here, we first investigated the unstressed behavior of mitochondria in rat hippocampal neurons of mixed sex, focusing on mitochondrial trafficking and fusion to better understand potential QC mechanisms. We observed size and redox asymmetry of mitochondrial traffic in axons, suggesting an active QC mechanism in this compartment. We also document biochemical complementation upon the fusion and fission of axonal mitochondria. Eliminating fusion by knocking down the neuronal mitochondrial fusion protein mitofusin 2 (MFN2) reduced the rates of axonal mitochondrial trafficking and fusion, decreased the levels of synaptic vesicle (SV) proteins, inhibited exocytosis, and impaired SV recruitment from the reserve pool during extended stimulation. MFN2 knockdown also resulted in presynaptic Ca2+ dyshomeostasis. Remarkably, upon MFN2 knockdown, presynaptic mitochondria sequestered Ca2+ more efficiently, effectively limiting presynaptic Ca2+ transients during stimulation. These results support an active mitochondrial trafficking and fusion-related QC process that supports presynaptic Ca2+ handling and the SV cycle.Significance statement:Decreased or altered mitochondrial function is observed in many disease states. All neurodegenerative diseases co-present with some sort of mitochondrial abnormality. Therefore, identifying quality control mechanisms that sustain the mitochondrial network in neurons, and particularly in axons, is of significant interest. The response of axonal mitochondria to acutely applied toxins or injury has been studied in detail. Although informative, the response of neurons to these insults might not be physiologically relevant, so it is crucial to also study the basal behavior of axonal mitochondria. Here, we use fluorescent biosensors to investigate the mitochondrial network in neurons and examine the role of mitofusin 2 in maintaining the axonal mitochondrial network and in supporting the synaptic vesicle cycle.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1356-22.2023
  11. Curr Issues Mol Biol. 2023 Feb 22. 45(3): 1794-1809
    Impact of the m.13513G>A Variant on the Functions of the OXPHOS System and Cell Retrograde Signaling.
    Dita Kidere, Pawel Zayakin, Diana Livcane, Marina Makrecka-Kuka, Janis Stavusis, Baiba Lace, Tsu-Kung Lin, Chia-Wei Liou, Inna Inashkina.
      Mitochondria are involved in many vital functions in living cells, including the synthesis of ATP by oxidative phosphorylation (OXPHOS) and regulation of nuclear gene expression through retrograde signaling. Leigh syndrome is a heterogeneous neurological disorder resulting from an isolated complex I deficiency that causes damage to mitochondrial energy production. The pathogenic mitochondrial DNA (mtDNA) variant m.13513G>A has been associated with Leigh syndrome. The present study investigated the effects of this mtDNA variant on the OXPHOS system and cell retrograde signaling. Transmitochondrial cytoplasmic hybrid (cybrid) cell lines harboring 50% and 70% of the m.13513G>A variant were generated and tested along with wild-type (WT) cells. The functionality of the OXPHOS system was evaluated by spectrophotometric assessment of enzyme activity and high-resolution respirometry. Nuclear gene expression was investigated by RNA sequencing and droplet digital PCR. Increasing levels of heteroplasmy were associated with reduced OXPHOS system complex I, IV, and I + III activities, and high-resolution respirometry also showed a complex I defect. Profound changes in transcription levels of nuclear genes were observed in the cell lines harboring the pathogenic mtDNA variant, indicating the physiological processes associated with defective mitochondria.
    Keywords:  Leigh syndrome; OXPHOS system; RNA sequencing; mitochondrial diseases; retrograde signaling
    DOI:  https://doi.org/10.3390/cimb45030115
  12. J Clin Med. 2023 Mar 22. pii: 2435. [Epub ahead of print]12(6):
    Serum GDF-15 Levels Accurately Differentiate Patients with Primary Mitochondrial Myopathy, Manifesting with Exercise Intolerance and Fatigue, from Patients with Chronic Fatigue Syndrome.
    Laura Bermejo-Guerrero, Carlos Pablo de Fuenmayor-Fernández de la Hoz, María Paz Guerrero-Molina, Paloma Martín-Jiménez, Alberto Blázquez, Pablo Serrano-Lorenzo, David Lora, Montserrat Morales-Conejo, Irene González-Martínez, Elena Ana López-Jiménez, Miguel A Martín, Cristina Domínguez-González.
      Primary mitochondrial myopathies (PMM) are a clinically and genetically highly heterogeneous group that, in some cases, may manifest exclusively as fatigue and exercise intolerance, with minimal or no signs on examination. On these occasions, the symptoms can be confused with the much more common chronic fatigue syndrome (CFS). Nonetheless, other possibilities must be excluded for the final diagnosis of CFS, with PMM being one of the primary differential diagnoses. For this reason, many patients with CFS undergo extensive studies, including extensive genetic testing and muscle biopsies, to rule out this possibility. This study evaluated the diagnostic performance of growth differentiation factor-15 (GDF-15) as a potential biomarker to distinguish which patient with chronic fatigue has a mitochondrial disorder. We studied 34 adult patients with symptoms of fatigue and exercise intolerance with a definitive diagnosis of PMM (7), CFS (22), or other non-mitochondrial disorders (5). The results indicate that GDF-15 can accurately discriminate between patients with PMM and CFS (AUC = 0.95) and between PMM and patients with fatigue due to other non-mitochondrial disorders (AUC = 0.94). Therefore, GDF-15 emerges as a promising biomarker to select which patients with fatigue should undergo further studies to exclude mitochondrial disease.
    Keywords:  GDF-15; chronic fatigue syndrome; differential diagnosis; mitochondrial myopathy
    DOI:  https://doi.org/10.3390/jcm12062435
  13. BMC Pulm Med. 2023 Mar 29. 23(1): 104
    Primary mitochondrial disease as a rare cause of unclear breathlessness and distinctive performance degradation - a case report.
    Ralf Ewert, Mohamed A Elhadad, Dirk Habedank, Alexander Heine, Beate Stubbe.
       BACKGROUND: Primary muscular disorders (metabolic myopathies, including mitochondrial disorders) are a rare cause of dyspnea. We report a case of dyspnea caused by a mitochondrial disorder with a pattern of clinical findings that can be classified in the known pathologies of mitochondrial deletion syndrome.
    CASE PRESENTATION: The patient presented to us at 29 years of age, having had tachycardia, dyspnea, and functional impairment since childhood. She had been diagnosed with bronchial asthma and mild left ventricular hypertrophy and treated accordingly, but her symptoms had worsened. After more than 20 years of progressive physical and social limitations was a mitochondrial disease suspected in the exercise testing. We performed cardiopulmonary exercise testing (CPET) with right heart catheterization showed typical signs of mitochondrial myopathy. Genetic testing confirmed the presence of a ~ 13 kb deletion in mitochondrial DNA from the muscle. The patient was treated with dietary supplements for 1 year. In the course of time, the patient gave birth to a healthy child, which is developing normally.
    CONCLUSION: CPET and lung function data over 5 years demonstrated stable disease. We conclude that CPET and lung function analysis should be used consistently to evaluate the cause of dyspnea and for long-term observation.
    Keywords:  Case report; Dyspnea; Invasive cardiopulmonary exercise testing; Lactate; Metabolic myopathy; Mitochondriopathy
    DOI:  https://doi.org/10.1186/s12890-023-02391-x
  14. Nat Chem Biol. 2023 Mar 27.
    Cytosolic and mitochondrial NADPH fluxes are independently regulated.
    Xiangfeng Niu, Ethan Stancliffe, Susan J Gelman, Lingjue Wang, Michaela Schwaiger-Haber, Joe L Rowles, Leah P Shriver, Gary J Patti.
      Although nicotinamide adenine dinucleotide phosphate (NADPH) is produced and consumed in both the cytosol and mitochondria, the relationship between NADPH fluxes in each compartment has been difficult to assess due to technological limitations. Here we introduce an approach to resolve cytosolic and mitochondrial NADPH fluxes that relies on tracing deuterium from glucose to metabolites of proline biosynthesis localized to either the cytosol or mitochondria. We introduced NADPH challenges in either the cytosol or mitochondria of cells by using isocitrate dehydrogenase mutations, administering chemotherapeutics or with genetically encoded NADPH oxidase. We found that cytosolic challenges influenced NADPH fluxes in the cytosol but not NADPH fluxes in mitochondria, and vice versa. This work highlights the value of using proline labeling as a reporter system to study compartmentalized metabolism and reveals that NADPH homeostasis in the cytosolic and mitochondrial locations of a cell are independently regulated, with no evidence for NADPH shuttle activity.
    DOI:  https://doi.org/10.1038/s41589-023-01283-9
  15. J Fungi (Basel). 2023 Mar 07. pii: 329. [Epub ahead of print]9(3):
    Yeast Chromatin Mutants Reveal Altered mtDNA Copy Number and Impaired Mitochondrial Membrane Potential.
    Dessislava Staneva, Bela Vasileva, Petar Podlesniy, George Miloshev, Milena Georgieva.
      Mitochondria are multifunctional, dynamic organelles important for stress response, cell longevity, ageing and death. Although the mitochondrion has its genome, nuclear-encoded proteins are essential in regulating mitochondria biogenesis, morphology, dynamics and function. Moreover, chromatin structure and epigenetic mechanisms govern the accessibility to DNA and control gene transcription, indirectly influencing nucleo-mitochondrial communications. Thus, they exert crucial functions in maintaining proper chromatin structure, cell morphology, gene expression, stress resistance and ageing. Here, we present our studies on the mtDNA copy number in Saccharomyces cerevisiae chromatin mutants and investigate the mitochondrial membrane potential throughout their lifespan. The mutants are arp4 (with a point mutation in the ARP4 gene, coding for actin-related protein 4-Arp4p), hho1Δ (lacking the HHO1 gene, coding for the linker histone H1), and the double mutant arp4 hho1Δ cells with the two mutations. Our findings showed that the three chromatin mutants acquired strain-specific changes in the mtDNA copy number. Furthermore, we detected the disrupted mitochondrial membrane potential in their chronological lifespan. In addition, the expression of nuclear genes responsible for regulating mitochondria biogenesis and turnover was changed. The most pronounced were the alterations found in the double mutant arp4 hho1Δ strain, which appeared as the only petite colony-forming mutant, unable to grow on respiratory substrates and with partial depletion of the mitochondrial genome. The results suggest that in the studied chromatin mutants, hho1Δ, arp4 and arp4 hho1Δ, the nucleus-mitochondria communication was disrupted, leading to impaired mitochondrial function and premature ageing phenotype in these mutants, especially in the double mutant.
    Keywords:  ageing; arp4; chromatin; chronological lifespan; hho1Δ; mitochondria; mitochondrial membrane potential; mtDNA; rho- phenotype
    DOI:  https://doi.org/10.3390/jof9030329
  16. Life Sci Alliance. 2023 Jun;pii: e202301914. [Epub ahead of print]6(6):
    The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.
    Jana Schuettpelz, Alexandre Janer, Hana Antonicka, Eric A Shoubridge.
      Mutations in SLC25A46 underlie a wide spectrum of neurodegenerative diseases associated with alterations in mitochondrial morphology. We established an SLC25A46 knock-out cell line in human fibroblasts and studied the pathogenicity of three variants (p.T142I, p.R257Q, and p.E335D). Mitochondria were fragmented in the knock-out cell line and hyperfused in all pathogenic variants. The loss of SLC25A46 led to abnormalities in the mitochondrial cristae ultrastructure that were not rescued by the expression of the variants. SLC25A46 was present in discrete puncta at mitochondrial branch points and tips of mitochondrial tubules, co-localizing with DRP1 and OPA1. Virtually, all fission/fusion events were demarcated by a SLC25A46 focus. SLC25A46 co-immunoprecipitated with the fusion machinery, and loss of function altered the oligomerization state of OPA1 and MFN2. Proximity interaction mapping identified components of the ER membrane, lipid transfer proteins, and mitochondrial outer membrane proteins, indicating that it is present at interorganellar contact sites. SLC25A46 loss of function led to altered mitochondrial lipid composition, suggesting that it may facilitate interorganellar lipid flux or play a role in membrane remodeling associated with mitochondrial fusion and fission.
    DOI:  https://doi.org/10.26508/lsa.202301914
  17. Brain Pathol. 2023 Mar 28. e13157
    Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy.
    Tingting Dong, Zai-Qiang Zhang, Li-Hong Sun, Weilong Zhang, Zhaohui Zhu, Lin Lin, Lin Yang, An Lv, Chunying Liu, Qing Li, Rui-Feng Yang, Xiuru Zhang, Yamei Niu, Hou-Zao Chen, De-Pei Liu, Wei-Min Tong.
      Mitochondrial encephalomyopathies (ME) are frequently associated with mutations of mitochondrial DNA, but the pathogenesis of a subset of ME (sME) remains elusive. Here we report that haploinsufficiency of a mitochondrial inner membrane protein, Mic60, causes progressive neurological abnormalities with insulted mitochondrial structure and neuronal loss in mice. In addition, haploinsufficiency of Mic60 reduces mitochondrial membrane potential and cellular ATP production, increases reactive oxygen species, and alters mitochondrial oxidative phosphorylation complexes in neurons in an age-dependent manner. Moreover, haploinsufficiency of Mic60 compromises brain glucose intake and oxygen consumption in mice, resembling human ME syndrome. We further discover that MIC60 protein expression declined significantly in human sME, implying that insufficient MIC60 may contribute for pathogenesis of human ME. Notably, systemic administration of antioxidant N-acetylcysteine largely reverses mitochondrial dysfunctions and metabolic disorders in haplo-insufficient Mic60 mice, also restores neurological abnormal symptom. These results reveal Mic60 is required in the maintenance of mitochondrial integrity and function, and likely a potential therapeutics target for mitochondrial encephalomyopathies.
    Keywords:  Mic60; antioxidant; mitochondria; mitochondrial encephalomyopathies; neurodegeneration; reactive oxygen species
    DOI:  https://doi.org/10.1111/bpa.13157
  18. Curr Biol. 2023 Mar 27. pii: S0960-9822(23)00177-X. [Epub ahead of print]33(6): R219-R221
    Evolution: 'Millefoglie' origin of mitochondrial cristae.
    Paul A M Michels, Michael L Ginger.
      Striated intracytoplasmic membranes in alphaproteobacteria are often reminiscent of millefoglie pastries. A new study reveals a protein complex homologous to that responsible for mitochondrial cristae formation drives intracytoplasmic membrane formation, thereby establishing bacterial ancestry for the biogenesis of mitochondrial cristae.
    DOI:  https://doi.org/10.1016/j.cub.2023.02.037
  19. Proc Natl Acad Sci U S A. 2023 Apr 04. 120(14): e2220102120
    NAMPT-dependent NAD+ biosynthesis controls circadian metabolism in a tissue-specific manner.
    Astrid L Basse, Karen N Nielsen, Iuliia Karavaeva, Lars R Ingerslev, Tao Ma, Jesper F Havelund, Thomas S Nielsen, Mikkel Frost, Julia Peics, Emilie Dalbram, Morten Dall, Juleen R Zierath, Romain Barrès, Nils J Færgeman, Jonas T Treebak, Zachary Gerhart-Hines.
      Molecular clocks in the periphery coordinate tissue-specific daily biorhythms by integrating input from the hypothalamic master clock and intracellular metabolic signals. One such key metabolic signal is the cellular concentration of NAD+, which oscillates along with its biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT). NAD+ levels feed back into the clock to influence rhythmicity of biological functions, yet whether this metabolic fine-tuning occurs ubiquitously across cell types and is a core clock feature is unknown. Here, we show that NAMPT-dependent control over the molecular clock varies substantially between tissues. Brown adipose tissue (BAT) requires NAMPT to sustain the amplitude of the core clock, whereas rhythmicity in white adipose tissue (WAT) is only moderately dependent on NAD+ biosynthesis, and the skeletal muscle clock is completely refractory to loss of NAMPT. In BAT and WAT, NAMPT differentially orchestrates oscillation of clock-controlled gene networks and the diurnality of metabolite levels. NAMPT coordinates the rhythmicity of TCA cycle intermediates in BAT, but not in WAT, and loss of NAD+ abolishes these oscillations similarly to high-fat diet-induced circadian disruption. Moreover, adipose NAMPT depletion improved the ability of animals to defend body temperature during cold stress but in a time-of-day-independent manner. Thus, our findings reveal that peripheral molecular clocks and metabolic biorhythms are shaped in a highly tissue-specific manner by NAMPT-dependent NAD+ synthesis.
    Keywords:  Brown adipose tissue; Circadian metabolism; Clock rhythm; NAD; Skeletal muscle
    DOI:  https://doi.org/10.1073/pnas.2220102120
  20. Cell Rep. 2023 Mar 31. pii: S2211-1247(23)00347-9. [Epub ahead of print]42(4): 112336
    Site-1 protease inhibits mitochondrial respiration by controlling the TGF-β target gene Mss51.
    Muhammad G Mousa, Lahari Vuppaladhadiam, Meredith O Kelly, Terri Pietka, Shelby Ek, Karen C Shen, Gretchen A Meyer, Brian N Finck, Rita T Brookheart.
      The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGF)-β1 target gene Mss51, an inhibitor of skeletal muscle mitochondrial respiration. Although Mss51 is implicated in the pathophysiology of obesity and musculoskeletal disease, how Mss51 is regulated is not entirely understood. Site-1 protease (S1P) is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle is unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial respiration. S1P disruption in mouse skeletal muscle reduces Mss51 expression and increases muscle mass and mitochondrial respiration. The effects of S1P deficiency on mitochondrial activity are counteracted by overexpressing Mss51, suggesting that one way S1P inhibits respiration is by regulating Mss51. These discoveries expand our understanding of TGF-β signaling and S1P function.
    Keywords:  CP: Metabolism; Mss51; TGF-β; metabolism; mitochondria; muscle mass; respiration; site-1 protease; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2023.112336
  21. Int J Mol Sci. 2023 Mar 14. pii: 5516. [Epub ahead of print]24(6):
    Mitochondrial Dysfunction in Intensive Care Unit-Acquired Weakness and Critical Illness Myopathy: A Narrative Review.
    Felix Klawitter, Johannes Ehler, Rika Bajorat, Robert Patejdl.
      Mitochondria are key structures providing most of the energy needed to maintain homeostasis. They are the main source of adenosine triphosphate (ATP), participate in glucose, lipid and amino acid metabolism, store calcium and are integral components in various intracellular signaling cascades. However, due to their crucial role in cellular integrity, mitochondrial damage and dysregulation in the context of critical illness can severely impair organ function, leading to energetic crisis and organ failure. Skeletal muscle tissue is rich in mitochondria and, therefore, particularly vulnerable to mitochondrial dysfunction. Intensive care unit-acquired weakness (ICUAW) and critical illness myopathy (CIM) are phenomena of generalized weakness and atrophying skeletal muscle wasting, including preferential myosin breakdown in critical illness, which has also been linked to mitochondrial failure. Hence, imbalanced mitochondrial dynamics, dysregulation of the respiratory chain complexes, alterations in gene expression, disturbed signal transduction as well as impaired nutrient utilization have been proposed as underlying mechanisms. This narrative review aims to highlight the current known molecular mechanisms immanent in mitochondrial dysfunction of patients suffering from ICUAW and CIM, as well as to discuss possible implications for muscle phenotype, function and therapeutic approaches.
    Keywords:  ICUAW; critical illness; critical illness myopathy; intensive care medicine; mitochondria; muscle wasting
    DOI:  https://doi.org/10.3390/ijms24065516
  22. Biomedicines. 2023 Feb 21. pii: 647. [Epub ahead of print]11(3):
    A Mitochondrial Perspective on Noncommunicable Diseases.
    Yifan Zheng, Jing Zhang, Xiaohong Zhu, Yuanjuan Wei, Wuli Zhao, Shuyi Si, Yan Li.
      Mitochondria are the center of energy metabolism in eukaryotic cells and play a central role in the metabolism of living organisms. Mitochondrial diseases characterized by defects in oxidative phosphorylation are the most common congenital diseases. Meanwhile, mitochondrial dysfunction caused by secondary factors such as non-inherited genetic mutations can affect normal physiological functions of human cells, induce apoptosis, and lead to the development of various diseases. This paper reviewed several major factors and mechanisms that contribute to mitochondrial dysfunction and discussed the development of diseases closely related to mitochondrial dysfunction and drug treatment strategies discovered in recent years.
    Keywords:  OXPHOS; mitochondria; mitochondrial diseases; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/biomedicines11030647
  23. bioRxiv. 2023 Mar 15. pii: 2023.03.13.532310. [Epub ahead of print]
    Cristae formation is a mechanical buckling event controlled by the inner membrane lipidome.
    Kailash Venkatraman, Christopher T Lee, Guadalupe C Garcia, Arijit Mahapatra, Guy Perkins, Keun-Young Kim, Hilda Amalia Pasolli, Sebastien Phan, Jennifer Lippincott-Schwartz, Mark Ellisman, Padmini Rangamani, Itay Budin.
      The inner mitochondrial membrane (IMM) is the site of bulk ATP generation in cells and has a broadly conserved lipid composition enriched in unsaturated phospholipids and cardiolipin (CL). While proteins that shape the IMM and its characteristic cristae membranes (CM) have been defined, specific mechanisms by which mitochondrial lipids dictate its structure and function have yet to be elucidated. Here we combine experimental lipidome dissection with multi-scale modeling to investigate how lipid interactions shape CM morphology and ATP generation. When modulating fatty acid unsaturation in engineered yeast strains, we observed that loss of di-unsaturated phospholipids (PLs) led to a breakpoint in IMM topology and respiratory capacity. We found that PL unsaturation modulates the organization of ATP synthases that shape cristae ridges. Based on molecular modeling of mitochondrial-specific membrane adaptations, we hypothesized that conical lipids like CL buffer against the effects of saturation on the IMM. In cells, we discovered that loss of CL collapses the IMM at intermediate levels of PL saturation, an effect that is independent of ATP synthase oligomerization. To explain this interaction, we employed a continuum modeling approach, finding that lipid and protein-mediated curvatures are predicted to act in concert to form curved membranes in the IMM. The model highlighted a snapthrough instability in cristae tubule formation, which could drive IMM collapse upon small changes in composition. The interaction between CL and di-unsaturated PLs suggests that growth conditions that alter the fatty acid pool, such as oxygen availability, could define CL function. While loss of CL only has a minimal phenotype under standard laboratory conditions, we show that its synthesis is essential under microaerobic conditions that better mimic natural yeast fermentation. Lipid and protein-mediated mechanisms of curvature generation can thus act together to support mitochondrial architecture under changing environments.
    DOI:  https://doi.org/10.1101/2023.03.13.532310
  24. Antioxidants (Basel). 2023 Mar 14. pii: 718. [Epub ahead of print]12(3):
    Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders.
    Juliane Münch, Jannik Prasuhn, Lucia Laugwitz, Cheuk-Wing Fung, Brian H-Y Chung, Marcello Bellusci, Ertan Mayatepek, Dirk Klee, Felix Distelmaier.
      Coenzyme Q10 (CoQ10) is an endogenously synthesized lipid molecule. It is best known for its role as a cofactor within the mitochondrial respiratory chain where it functions in electron transfer and ATP synthesis. However, there are many other cellular pathways that also depend on the CoQ10 supply (redox homeostasis, ferroptosis and sulfide oxidation). The CoQ10 biosynthesis pathway consists of several enzymes, which are encoded by the nuclear DNA. The majority of these enzymes are responsible for modifications of the CoQ-head group (benzoquinone ring). Only three enzymes (PDSS1, PDSS2 and COQ2) are required for assembly and attachment of the polyisoprenoid side chain. The head-modifying enzymes may assemble into resolvable domains, representing COQ complexes. During the last two decades, numerous inborn errors in CoQ10 biosynthesis enzymes have been identified. Thus far, 11 disease genes are known (PDSS1, PDSS2, COQ2, COQ4, COQ5, COQ6, COQ7, COQ8A, COQ8B, COQ9 and HPDL). Disease onset is highly variable and ranges from the neonatal period to late adulthood. CoQ10 deficiency exerts detrimental effects on the nervous system. Potential consequences are neuronal death, neuroinflammation and cerebral gliosis. Clinical features include encephalopathy, regression, movement disorders, epilepsy and intellectual disability. Brain magnetic resonance imaging (MRI) is the most important tool for diagnostic evaluation of neurological damage in individuals with CoQ10 deficiency. However, due to the rarity of the different gene defects, information on disease manifestations within the central nervous system is scarce. This review aims to provide an overview of brain MRI patterns observed in primary CoQ10 biosynthesis disorders and to highlight disease-specific findings.
    Keywords:  Leigh syndrome; mitochondrial oxidative phosphorylation; multiple system atrophy; neurodegeneration; ubiquinone
    DOI:  https://doi.org/10.3390/antiox12030718
  25. Mol Genet Metab Rep. 2023 Jun;35 100968
    Ketogenic diet in action: Metabolic profiling of pyruvate dehydrogenase deficiency.
    Eri Ogawa, Takako Hishiki, Noriyo Hayakawa, Hisato Suzuki, Kenjiro Kosaki, Makoto Suematsu, Toshiki Takenouchi.
      The pyruvate dehydrogenase complex serves as the main connection between cytosolic glycolysis and the tricarboxylic acid cycle within mitochondria. An infant with pyruvate dehydrogenase complex deficiency was treated with vitamin B1 supplementation and a ketogenic diet. These dietary modifications resolved the renal tubular reabsorption, central apnea, and transfusion-dependent anemia. A concurrent metabolome analysis demonstrated the resolution of the amino aciduria and an increased total amount of substrates in the tricarboxylic acid cycle, reflecting the improved mitochondrial energetics. Glutamate was first detected in the cerebrospinal fluid, accompanied by a clinical improvement, after the ketogenic ratio was increased to 3:1; thus, glutamate levels in cerebrospinal fluid may represent a biomarker for neuronal recovery. Metabolomic analyses of body fluids are useful for monitoring therapeutic effects in infants with inborn errors of carbohydrate metabolism.
    Keywords:  Ketogenic diet; Metabolome; Pyruvate dehydrogenase deficiency; Whole genome sequencing
    DOI:  https://doi.org/10.1016/j.ymgmr.2023.100968
  26. Front Cell Dev Biol. 2023 ;11 1153174
    Mitochondrial DNA abnormalities and metabolic syndrome.
    Xudong Ding, Tingting Fang, Xiaoqi Pang, Xueru Pan, Aiying Tong, Ziyi Lin, Shikuan Zheng, Ningning Zheng.
      Metabolic syndrome (MetS) is a complex pathological condition that involves disrupted carbohydrate, protein, and fat metabolism in the human body, and is a major risk factor for several chronic diseases, including diabetes, cardiovascular disease, and cerebrovascular disease. While the exact pathogenesis of metabolic syndrome is not yet fully understood, there is increasing evidence linking mitochondrial dysfunction, which is closely related to the mitochondrial genome and mitochondrial dynamics, to the development of this condition. Recent advancements in genetic sequencing technologies have allowed for more accurate detection of mtDNA mutations and other mitochondrial abnormalities, leading to earlier diagnosis and intervention in patients with metabolic syndrome. Additionally, the identification of specific mechanisms by which reduced mtDNA copy number and gene mutations, as well as abnormalities in mtDNA-encoded proteins and mitochondrial dynamics, contribute to metabolic syndrome may promote the development of novel therapeutic targets and interventions, such as the restoration of mitochondrial function through the targeting of specific mitochondrial defects. Additionally, advancements in genetic sequencing technologies may allow for more accurate detection of mtDNA mutations and other mitochondrial abnormalities, leading to earlier diagnosis and intervention in patients with MetS. Therefore, strategies to promote the restoration of mitochondrial function by addressing these defects may offer new options for treating MetS. This review provides an overview of the research progress and significance of mitochondrial genome and mitochondrial dynamics in MetS.
    Keywords:  metabolic syndrome; mitochondrial copy number; mitochondrial dynamics; mitochondrial gene mutations; mitochondrial proteases; mitochondrial-encoded proteins
    DOI:  https://doi.org/10.3389/fcell.2023.1153174
  27. Front Cell Dev Biol. 2023 ;11 1146564
    Disturb mitochondrial associated proteostasis: Neurodegeneration and imperfect ageing.
    Yuvraj Anandrao Jagtap, Prashant Kumar, Sumit Kinger, Ankur Rakesh Dubey, Akash Choudhary, Ravi Kumar Gutti, Sarika Singh, Hem Chandra Jha, Krishna Mohan Poluri, Amit Mishra.
      The disturbance in mitochondrial functions and homeostasis are the major features of neuron degenerative conditions, like Parkinson's disease, Amyotrophic Lateral Sclerosis, and Alzheimer's disease, along with protein misfolding. The aberrantly folded proteins are known to link with impaired mitochondrial pathways, further contributing to disease pathogenesis. Despite their central significance, the implications of mitochondrial homeostasis disruption on other organelles and cellular processes remain insufficiently explored. Here, we have reviewed the dysfunction in mitochondrial physiology, under neuron degenerating conditions. The disease misfolded proteins impact quality control mechanisms of mitochondria, such as fission, fusion, mitophagy, and proteasomal clearance, to the detriment of neuron. The adversely affected mitochondrial functional roles, like oxidative phosphorylation, calcium homeostasis, and biomolecule synthesis as well as its axes and contacts with endoplasmic reticulum and lysosomes are also discussed. Mitochondria sense and respond to multiple cytotoxic stress to make cell adapt and survive, though chronic dysfunction leads to cell death. Mitochondria and their proteins can be candidates for biomarkers and therapeutic targets. Investigation of internetworking between mitochondria and neurodegeneration proteins can enhance our holistic understanding of such conditions and help in designing more targeted therapies.
    Keywords:  autophagy; mitochondria; mitostasis; neurodegeneration; oxidative stress; proteasome
    DOI:  https://doi.org/10.3389/fcell.2023.1146564
  28. Tex Heart Inst J. 2023 Mar 01. pii: e217730. [Epub ahead of print]50(2):
    Pathogenic BCS1L Mutation Resulting in Hypertrophic Cardiomyopathy: A Unique Presentation of Nuclear Mitochondrial Disease.
    Cameron Incognito, Jeffrey Hedley, Kristine T Posadas, Xiangling Wang, Milind Desai.
      A 21-year-old man with sensorineural hearing loss and glaucoma presented with severely limited exercise capacity since childhood. He was found to have biventricular concentric hypertrophy with greatest wall thickening at the posterior and lateral walls of the left ventricle apex (1.7 cm) and the free wall of the right ventricle (1.1 cm). There was no inducible left ventricular outflow tract obstruction. Metabolic testing revealed marked lactic aciduria (1,650.1 μmol/mmol creatinine) and plasma lactate (3.9 mmol/L). A sarcomeric hypertrophic cardiomyopathy gene panel was unremarkable, but mitochondrial gene analysis revealed a homozygous c.385G>A (p.Gly129Arg) pathogenic mutation in the BCS1L gene. This gene is responsible for an assembly subunit of cytochrome complex III in the respiratory transport chain and is the rarest respiratory chain defect. This gene has not frequently been implicated in cardiomyopathy. Mitochondrial hypertrophic cardiomyopathy is more rare than hypertrophic cardiomyopathy resulting from sarcomeric mutations and is more likely to be symmetric, less frequently results in left ventricular outflow tract obstruction, and is more likely to progress to dilated cardiomyopathy. Evidence-based screening protocols have not been established; treatment follows guideline-directed medical therapy for congestive heart failure, including evaluation for heart transplantation. This report expands the phenotype of the BCS1L mutation and suggests that affected patients may need screening for underlying cardiomyopathy.
    Keywords:  BCS1L protein, human; cardiomyopathy; mitochondrial diseases
    DOI:  https://doi.org/10.14503/THIJ-21-7730
  29. bioRxiv. 2023 Mar 26. pii: 2023.03.25.534233. [Epub ahead of print]
    Activity-dependent subcellular compartmentalization of dendritic mitochondria structure in CA1 pyramidal neurons.
    Daniel M Virga, Stevie Hamilton, Bertha Osei, Abigail Morgan, Emiliano Zamponi, Natalie J Park, Victoria L Hewitt, David Zhang, Kevin C Gonzalez, Erik Bloss, Franck Polleux, Tommy L Lewis.
      Neuronal mitochondria play important roles beyond ATP generation, including Ca2+ uptake, and therefore have instructive roles in synaptic function and neuronal response properties. Mitochondrial morphology differs significantly in the axon and dendrites of a given neuronal subtype, but in CA1 pyramidal neurons (PNs) of the hippocampus, mitochondria within the dendritic arbor also display a remarkable degree of subcellular, layer-specific compartmentalization. In the dendrites of these neurons, mitochondria morphology ranges from highly fused and elongated in the apical tuft, to more fragmented in the apical oblique and basal dendritic compartments, and thus occupy a smaller fraction of dendritic volume than in the apical tuft. However, the molecular mechanisms underlying this striking degree of subcellular compartmentalization of mitochondria morphology are unknown, precluding the assessment of its impact on neuronal function. Here, we demonstrate that this compartment-specific morphology of dendritic mitochondria requires activity-dependent, Camkk2-dependent activation of AMPK and its ability to phosphorylate two direct effectors: the pro-fission Drp1 receptor Mff and the recently identified anti-fusion, Opa1-inhibiting protein, Mtfr1l. Our study uncovers a new activity-dependent molecular mechanism underlying the extreme subcellular compartmentalization of mitochondrial morphology in dendrites of neurons in vivo through spatially precise regulation of mitochondria fission/fusion balance.
    DOI:  https://doi.org/10.1101/2023.03.25.534233
  30. Front Mol Biosci. 2023 ;10 906606
    Using mass spectrometry imaging to visualize age-related subcellular disruption.
    Kelly A Hogan, Julianna D Zeidler, Heather K Beasley, Abrar I Alsaadi, Abdulkareem A Alshaheeb, Yi-Chin Chang, Hua Tian, Antentor O Hinton, Melanie R McReynolds.
      Metabolic homeostasis balances the production and consumption of energetic molecules to maintain active, healthy cells. Cellular stress, which disrupts metabolism and leads to the loss of cellular homeostasis, is important in age-related diseases. We focus here on the role of organelle dysfunction in age-related diseases, including the roles of energy deficiencies, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, changes in metabolic flux in aging (e.g., Ca2+ and nicotinamide adenine dinucleotide), and alterations in the endoplasmic reticulum-mitochondria contact sites that regulate the trafficking of metabolites. Tools for single-cell resolution of metabolite pools and metabolic flux in animal models of aging and age-related diseases are urgently needed. High-resolution mass spectrometry imaging (MSI) provides a revolutionary approach for capturing the metabolic states of individual cells and cellular interactions without the dissociation of tissues. mass spectrometry imaging can be a powerful tool to elucidate the role of stress-induced cellular dysfunction in aging.
    Keywords:  Golgi complex; MERCs; aging; mass spec imaging; metabolic flux; mitocchondrial dysfunction; spatial omics
    DOI:  https://doi.org/10.3389/fmolb.2023.906606
  31. Genes (Basel). 2023 Feb 22. pii: 552. [Epub ahead of print]14(3):
    Pathogenicity Analysis of a Novel Variant in GTPBP3 Causing Mitochondrial Disease and Systematic Literature Review.
    Qin Zhang, Qianqian Ouyang, Jingjing Xiang, Hong Li, Haitao Lv, Yu An.
      Defect of GTPBP3, the human mitochondrial tRNA-modifying enzyme, can lead to Combined Oxidative Phosphorylation Deficiency 23 (COXPD23). Up to now, about 20 different variants of the GTPBP3 gene have been reported; however, genotype-phenotype analysis has rarely been described. Here, we reported a 9-year-old boy with COXPD23 who presented with hyperlactatemia, hypertrophic cardiomyopathy, seizures, feeding difficulties, intellectual disability and motor developmental delay, and abnormal visual development. Biallelic pathogenic variants of the GTPBP3 gene were identified in this boy, one novel variant c.1102dupC (p. Arg368Profs*22) inherited from the mother and the other known variant c.689A>C (p. Gln230Pro) inherited from father. We curated 18 COXPD23 patients with GTPBP3 variants to investigate the genotype-phenotype correlation. We found that hyperlactatemia and cardiomyopathy were critical clinical features in COXPD23 and the average onset age was 1.7 years (3 months of age for the homozygote). Clinical classification of COXPD23 for the two types, severe and mild, was well described in this study. We observed arrhythmia and congestive heart failure frequently in the severe type with early childhood mortality, while developmental delay was mainly observed in the mild type. The proportion of homozygous variants (71.4%) significantly differed from that of compound heterozygous variants (18.1%) in the severe type. Compared with the variants in gnomAD, the proportion of LOFVs in GTPBP3 was higher in COXPD23 patients (48.6% versus 8.9%, p < 0.0001 ****), and 31% of them were frameshift variants, showing the LOF mechanism of GTPBP3. Additionally, the variants in patients were significantly enriched in the TrmE-type G domain, indicating that the G domain was crucial for GTPBP3 protein function. The TrmE-type G domain contained several significant motifs involved in the binding of guanine nucleotides and Mg2+, the hydrolysis of GTP, and the regulation of the functional status of GTPases. In conclusion, we reported a mild COXPD23 case with typical GTPBP3-related symptoms, including seizures and abnormal visual development seldom observed previously. Our study provides novel insight into understanding the clinical diagnosis and genetic counseling of patients with COXPD23 by exploring the genetic pathogenesis and genotype-phenotype correlation of COXPD23.
    Keywords:  COXPD23; GTPBP3; mitochondrial diseases; taurine modification; variants
    DOI:  https://doi.org/10.3390/genes14030552
  32. iScience. 2023 Apr 21. 26(4): 106349
    Tissue-specific heteroplasmy segregation is accompanied by a sharp mtDNA decline in Caenorhabditis elegans soma.
    Nikita Tsyba, Gaomin Feng, Lantana K Grub, James P Held, Adrianna M Strozak, Kristopher Burkewitz, Maulik R Patel.
      Mutations in the mitochondrial genome (mtDNA) can be pathogenic. Owing to the multi-copy nature of mtDNA, wild-type copies can compensate for the effects of mutant mtDNA. Wild-type copies available for compensation vary depending on the mutant load and the total copy number. Here, we examine both mutant load and copy number in the tissues of Caenorhabditis elegans. We found that neurons, but not muscles, have modestly higher mutant load than rest of the soma. We also uncovered different effect of aak-2 knockout on the mutant load in the two tissues. The most surprising result was a sharp decline in somatic mtDNA content over time. The scale of the copy number decline surpasses the modest shifts in mutant load, suggesting that it may exert a substantial effect on mitochondrial function. In summary, measuring both the copy number and the mutant load provides a more comprehensive view of the mutant mtDNA dynamics.
    Keywords:  Biological sciences; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.106349
  33. Medicina (Kaunas). 2023 Mar 19. pii: 608. [Epub ahead of print]59(3):
    The Role of Primary Mitochondrial Disorders in Hearing Impairment: An Overview.
    Virginia Fancello, Giuseppe Fancello, Silvia Palma, Daniele Monzani, Elisabetta Genovese, Chiara Bianchini, Andrea Ciorba.
      Background. Defects of mitochondrial DNA (mtDNA) involved in the function of the mitochondrial electron transport chain can result in primary mitochondrial diseases (PMDs). Various features can influence the phenotypes of different PMDs, with relevant consequences on clinical presentation, including the presence of hearing impairment. This paper aims to describe the hearing loss related to different PMDs, and when possible, their phenotype. Methods. A systematic review was performed according to PRISMA guidelines, searching Medline until December 2022. A total of 485 papers were identified, and based on specified criteria, 7 were included in this study. Results. A total of 759 patients affected by PMDs and hearing loss were included. The age of patients ranged from 2 days to 78 years old, and the male-to-female ratio was 1.3:1. The percentage of subjects affected by hearing loss was 40.8%, (310/759), and in most cases, hearing impairment was described as sensorineural, bilateral, symmetrical, and progressive, with different presentations depending on age and syndrome severity. Conclusions. PMDs are challenging conditions with different clinical phenotypes. Hearing loss, especially when bilateral and progressive, may represent a red flag; its association with other systemic disorders (particularly neuromuscular, ocular, and endocrine) should alert clinicians, and confirmation via genetic testing is mandatory nowadays.
    Keywords:  genetics; metabolic disorders; mitochondrial diseases; sensorineural hearing loss
    DOI:  https://doi.org/10.3390/medicina59030608
  34. CNS Neurosci Ther. 2023 Mar 27.
    Edaravone and mitochondrial transfer as potential therapeutics for vanishing white matter disease astrocyte dysfunction.
    Neville S Ng, Michelle Newbery, Aude Touffu, Simon Maksour, Johnson Chung, Luke Carroll, Thiri Zaw, Yunqi Wu, Lezanne Ooi.
       INTRODUCTION: Previous research has suggested that vanishing white matter disease (VWMD) astrocytes fail to fully differentiate and respond differently to cellular stresses compared to healthy astrocytes. However, few studies have investigated potential VWMD therapeutics in monoculture patient-derived cell-based models.
    METHODS: To investigate the impact of alterations in astrocyte expression and function in VWMD, astrocytes were differentiated from patient and control induced pluripotent stem cells and analyzed by proteomics, pathway analysis, and functional assays, in the absence and presence of stressors or potential therapeutics.
    RESULTS: Vanishing white matter disease astrocytes demonstrated significantly reduced expression of astrocyte markers and markers of inflammatory activation or cellular stress relative to control astrocytes. These alterations were identified both in the presence and absence of polyinosinic:polycytidylic acid stimuli, which is used to simulate viral infections. Pathway analysis highlighted differential signaling in multiple pathways in VWMD astrocytes, including eukaryotic initiation factor 2 (EIF2) signaling, oxidative stress, oxidative phosphorylation (OXPHOS), mitochondrial function, the unfolded protein response (UPR), phagosome regulation, autophagy, ER stress, tricarboxylic acid cycle (TCA) cycle, glycolysis, tRNA signaling, and senescence pathways. Since oxidative stress and mitochondrial function were two of the key pathways affected, we investigated whether two independent therapeutic strategies could ameliorate astrocyte dysfunction: edaravone treatment and mitochondrial transfer. Edaravone treatment reduced differential VWMD protein expression of the UPR, phagosome regulation, ubiquitination, autophagy, ER stress, senescence, and TCA cycle pathways. Meanwhile, mitochondrial transfer decreased VWMD differential expression of the UPR, glycolysis, calcium transport, phagosome formation, and ER stress pathways, while further modulating EIF2 signaling, tRNA signaling, TCA cycle, and OXPHOS pathways. Mitochondrial transfer also increased the gene and protein expression of the astrocyte marker, glial fibrillary acidic protein (GFAP) in VWMD astrocytes.
    CONCLUSION: This study provides further insight into the etiology of VWMD astrocytic failure and suggests edaravone and mitochondrial transfer as potential candidate VWMD therapeutics that can ameliorate disease pathways in astrocytes related to oxidative stress, mitochondrial dysfunction, and proteostasis.
    Keywords:  astrocyte; edaravone; induced pluripotent stem cells; mitochondria; mitochondrial transfer; vanishing white matter disease
    DOI:  https://doi.org/10.1111/cns.14190
  35. Brief Bioinform. 2023 Mar 28. pii: bbad106. [Epub ahead of print]
    Computational approaches for detecting disease-associated alternative splicing events.
    Jiashu Liu, Cui-Xiang Lin, Xiaoqi Zhang, Zongxuan Li, Wenkui Huang, Jin Liu, Yuanfang Guan, Hong-Dong Li.
      Alternative splicing (AS) is a key transcriptional regulation pathway. Recent studies have shown that AS events are associated with the occurrence of complex diseases. Various computational approaches have been developed for the detection of disease-associated AS events. In this review, we first describe the metrics used for quantitative characterization of AS events. Second, we review and discuss the three types of methods for detecting disease-associated splicing events, which are differential splicing analysis, aberrant splicing detection and splicing-related network analysis. Third, to further exploit the genetic mechanism of disease-associated AS events, we describe the methods for detecting genetic variants that potentially regulate splicing. For each type of methods, we conducted experimental comparison to illustrate their performance. Finally, we discuss the limitations of these methods and point out potential ways to address them. We anticipate that this review provides a systematic understanding of computational approaches for the analysis of disease-associated splicing.
    Keywords:  aberrant splicing; alternative splicing; differential splicing; disease; splicing QTL; splicing-related network
    DOI:  https://doi.org/10.1093/bib/bbad106
  36. bioRxiv. 2023 Mar 23. pii: 2023.03.19.533370. [Epub ahead of print]
    Inferring compound heterozygosity from large-scale exome sequencing data.
    gnomAD Project Consortium
      Severe recessive diseases arise when both the maternal and the paternal copies of a gene carry, or are impacted by, a damaging genetic variant in the affected individual. When a patient carries two different potentially causal variants, accurate diagnosis requires determining that these two variants occur on different copies of the chromosome (i.e., are in trans ) rather than on the same copy (i.e., in cis ). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. We developed a strategy for inferring phase for rare variant pairs within genes, leveraging haplotype patterns observed in exome sequencing data from the Genome Aggregation Database (gnomAD v2, n=125,748). When applied to trio data where phase is known, our approach estimates phase with high accuracy, even for very rare variants (frequency <1x10 - 4 ), and also correctly phases 95.2% of variant pairs in a set of 293 patients carrying presumed causal compound heterozygous variants. We provide a public resource of phasing estimates from gnomAD, including phasing estimates for coding variants across the genome and counts per gene of rare variants in trans , that can aid interpretation of rare co-occurring variants in the context of recessive disease.
    DOI:  https://doi.org/10.1101/2023.03.19.533370
  37. ACS Chem Neurosci. 2023 Mar 29.
    Mitochondrial Complex I as a Pathologic and Therapeutic Target for Parkinson's Disease.
    Kamatham Pushpa Tryphena, Uppala Sai Nikhil, Poojitha Pinjala, Saurabh Srivastava, Shashi Bala Singh, Dharmendra Kumar Khatri.
      The prevalence of Parkinson's disease (PD) continues to increase despite substantial research. Mounting evidence states that dysfunctional mitochondrial bioenergetics play a vital role in PD etiology. A disturbance in the electron transport chain, more precisely, disruption of the mitochondrial complex I (MCI), is the most detrimental factor. Due to increased susceptibility toward MCI damage, the dopaminergic neurons experience oxidative stress and a compromise in ATP production, leading to neurodegeneration and PD. This article reviews the association of MCI with pathological mechanisms like α-synucleinopathy, neuroinflammation, oxidative stress, and ER stress and also describes the potential therapeutic options explored to overcome MCI dysfunction and related consequences.
    Keywords:  Parkinson’s disease (PD); antioxidants; gene transplantation; mitochondrial complex I (MCI); reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1021/acschemneuro.2c00819
  38. Mol Metab. 2023 Mar 28. pii: S2212-8778(23)00050-9. [Epub ahead of print] 101716
    Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease.
    Courtney R Green, Roberto Bonelli, Brendan R E Ansell, Simone Tzaridis, Michal K Handzlik, Grace H McGregor, Barbara Hart, Jennifer Trombley, Mary M Reilly, Paul S Bernstein, Catherine Egan, Marcus Fruttiger, Martina Wallace, Melanie Bahlo, Martin Friedlander, Christian M Metallo, Marin L Gantner.
       OBJECTIVES: The non-essential amino acids serine, glycine, and alanine, as well as diverse sphingolipid species, are implicated in inherited neuro-retinal disorders and are metabolically linked by serine palmitoyltransferase (SPT), a key enzyme in membrane lipid biogenesis. To gain insight into the pathophysiological mechanisms linking these pathways to neuro-retinal diseases we compared patients diagnosed with two metabolically intertwined diseases: macular telangiectasia type II (MacTel), hereditary sensory autonomic neuropathy type 1 (HSAN1), or both.
    METHODS: We performed targeted metabolomic analyses of amino acids and broad sphingolipids in sera from a cohort of MacTel (205), HSAN1 (25) and Control (151) participants.
    RESULTS: MacTel patients exhibited broad alterations of amino acids, including changes in serine, glycine, alanine, glutamate, and branched-chain amino acids reminiscent of diabetes. MacTel patients had elevated 1-deoxysphingolipids but reduced levels of complex sphingolipids in circulation. A mouse model of retinopathy indicates dietary serine and restriction can drive this depletion in complex sphingolipids. HSAN1 patients exhibited elevated serine, lower alanine, and a reduction in canonical ceramides and sphingomyelins compared to controls. Those patients diagnosed with both HSAN1 and MacTel showed the most significant decrease in circulating sphingomyelins.
    CONCLUSIONS: These results highlight metabolic distinctions between these two diseases, emphasize the importance of membrane lipids in the progression of MacTel, and suggest distinct therapeutic approaches.
    Keywords:  HSAN1; amino acids; macular telangiectasia; peripheral neuropathy; retinopathy; sphingolipids
    DOI:  https://doi.org/10.1016/j.molmet.2023.101716
  39. Front Endocrinol (Lausanne). 2023 ;14 1152237
    Comparison between D-loop methylation and mtDNA copy number in patients with Aicardi-Goutières Syndrome.
    Francesca Dragoni, Jessica Garau, Simona Orcesi, Costanza Varesio, Matteo Bordoni, Eveljn Scarian, Rosalinda Di Gerlando, Elisa Fazzi, Roberta Battini, Altea Gjurgjaj, Bartolo Rizzo, Orietta Pansarasa, Stella Gagliardi.
       Introduction: Aicardi-Goutières Syndrome (AGS) is a rare encephalopathy with early onset that can be transmitted in both dominant and recessive forms. Its phenotypic covers a wide range of neurological and extraneurological symptoms. Nine genes that are all involved in nucleic acids (NAs) metabolism or signaling have so far been linked to the AGS phenotype. Recently, a link between autoimmune or neurodegenerative conditions and mitochondrial dysfunctions has been found. As part of the intricate system of epigenetic control, the mtDNA goes through various alterations. The displacement (D-loop) region represents one of the most methylated sites in the mtDNA. The term "mitoepigenetics" has been introduced as a result of increasing data suggesting that epigenetic processes may play a critical role in the control of mtDNA transcription and replication. Since we showed that RNASEH2B and RNASEH2A-mutated Lymphoblastoid Cell Lines (LCLs) derived from AGS patients had mitochondrial alterations, highlighting changes in the mtDNA content, the main objective of this study was to examine any potential methylation changes in the D-loop regulatory region of mitochondria and their relationship to the mtDNA copy number in peripheral blood cells of AGS patients with mutations in various AGS genes and healthy controls.
    Materials and methods: We collected blood samples from 25 AGS patients and we performed RT-qPCR to assess the mtDNA copy number and pyrosequencing to measure DNA methylation levels in the D-loop region.
    Results: Comparing AGS patients to healthy controls, D-loop methylation levels and mtDNA copy number increased significantly. We also observed that in AGS patients, the mtDNA copy number increased with age at sampling, but not the D-loop methylation levels, and there was no relationship between sex and mtDNA copy number. In addition, the D-loop methylation levels and mtDNA copy number in the AGS group showed a non-statistically significant positive relation.
    Conclusion: These findings, which contradict the evidence for an inverse relationship between D-loop methylation levels and mtDNA copy number, show that AGS patients have higher D-loop methylation levels than healthy control subjects. Additional research is needed to identify the function of these features in the etiology and course of AGS.
    Keywords:  Aicardi-Goutières Syndrome (AGS); D-loop (control region); epigenetics (DNA methylation); methylation; mitoepigenetics; mtDNA
    DOI:  https://doi.org/10.3389/fendo.2023.1152237
  40. Sci Rep. 2023 Mar 30. 13(1): 5203
    Enhanced mitochondrial oxidative metabolism in peripheral blood mononuclear cells is associated with fatty liver in obese young adults.
    Ryosuke Shirakawa, Takayuki Nakajima, Aya Yoshimura, Yukako Kawahara, Chieko Orito, Miwako Yamane, Haruka Handa, Shingo Takada, Takaaki Furihata, Arata Fukushima, Naoki Ishimori, Masao Nakagawa, Isao Yokota, Hisataka Sabe, Satoshi Hashino, Shintaro Kinugawa, Takashi Yokota.
      Systemic inflammation underlies the association between obesity and nonalcoholic fatty liver disease (NAFLD). Here, we investigated functional changes in leukocytes' mitochondria in obese individuals and their associations with NAFLD. We analyzed 14 obese male Japanese university students whose body mass index was > 30 kg/m2 and 15 healthy age- and sex-matched lean university students as controls. We observed that the mitochondrial oxidative phosphorylation (OXPHOS) capacity with complex I + II-linked substrates in peripheral blood mononuclear cells (PBMCs), which was measured using a high-resolution respirometry, was significantly higher in the obese group versus the controls. The PBMCs' mitochondrial complex IV capacity was also higher in the obese subjects. All of the obese subjects had hepatic steatosis defined by a fatty liver index (FLI) score ≥ 60, and there was a positive correlation between their FLI scores and their PBMCs' mitochondrial OXPHOS capacity. The increased PBMCs' mitochondrial OXPHOS capacity was associated with insulin resistance, systemic inflammation, and higher serum levels of interleukin-6 in the entire series of subjects. Our results suggest that the mitochondrial respiratory capacity is increased in the PBMCs at the early stage of obesity, and the enhanced PBMCs' mitochondrial oxidative metabolism is associated with hepatic steatosis in obese young adults.
    DOI:  https://doi.org/10.1038/s41598-023-32549-w
  41. Genes (Basel). 2023 Feb 24. pii: 566. [Epub ahead of print]14(3):
    Reduced OPA1, Mitochondrial Fragmentation and Increased Susceptibility to Apoptosis in Granular Corneal Dystrophy Type 2 Corneal Fibroblasts.
    Seung-Il Choi, Ga-Hyun Lee, Jong-Hwan Woo, Ikhyun Jun, Eung Kweon Kim.
      The progressive degeneration of granular corneal dystrophy type 2 (GCD2) corneal fibroblasts is associated with altered mitochondrial function, but the underlying mechanisms are incompletely understood. We investigated whether an imbalance of mitochondrial dynamics contributes to mitochondrial dysfunction of GCD2 corneal fibroblasts. Transmission electron microscopy revealed several small, structurally abnormal mitochondria with altered cristae morphology in GCD2 corneal fibroblasts. Confocal microscopy showed enhanced mitochondrial fission and fragmented mitochondrial tubular networks. Western blotting revealed higher levels of MFN1, MFN2, and pDRP1 and decreased levels of OPA1 and FIS1 in GCD2. OPA1 reduction by short hairpin RNA (shRNA) resulted in fragmented mitochondrial tubular networks and increased susceptibility to mitochondrial stress-induced apoptosis. A decrease in the mitochondrial biogenesis-related transcription factors NRF1 and PGC1α was observed, while there was an increase in the mitochondrial membrane proteins TOM20 and TIM23. Additionally, reduced levels of mitochondrial DNA (mtDNA) were exhibited in GCD2 corneal fibroblasts. These observations suggest that altered mitochondrial fission/fusion and biogenesis are the critical molecular mechanisms that cause mitochondrial dysfunction contributing to the degeneration of GCD2 corneal fibroblasts.
    Keywords:  NRF1; OPA1; PGC1α; corneal fibroblasts; fission and fusion; granular corneal dystrophy type 2; mitochondria
    DOI:  https://doi.org/10.3390/genes14030566
  42. J Extracell Vesicles. 2023 Apr;12(4): e12320
    MitoEVs: A new player in multiple disease pathology and treatment.
    Xiyue Zhou, Shuyun Liu, Yanrong Lu, Meihua Wan, Jingqiu Cheng, Jingping Liu.
      Mitochondrial damage plays vital roles in the pathology of many diseases, such as cancers, neurodegenerative diseases, aging, metabolic diseases and many types of organ injury. However, the regulatory mechanism of mitochondrial functions among different cells or organs in vivo is still unclear, and efficient therapies for attenuating mitochondrial damage are urgently needed. Extracellular vesicles (EVs) are cell-derived nanovesicles that can deliver bioactive cargoes among cells or organs. Interestingly, recent evidence shows that diverse mitochondrial contents are enriched in certain EV subpopulations, and such mitoEVs can deliver mitochondrial components to affect the functions of recipient cells under different conditions, which has emerged as a hot topic in this field. However, the overview and many essential questions with respect to this event remain elusive. In this review, we provide a global view of mitoEVs biology and mainly focus on the detailed sorting mechanisms, functional mitochondrial contents, and diverse biological effects of mitoEVs. We also discuss the pathogenic or therapeutic roles of mitoEVs in different diseases and highlight their potential as disease biomarkers or therapies in clinical translation. This review will provide insights into the pathology and drug development for various mitochondrial injury-related diseases.
    Keywords:  extracellular vesicle; immune response; metabolism; mitoEV; mitochondria
    DOI:  https://doi.org/10.1002/jev2.12320
  43. Antioxidants (Basel). 2023 Feb 28. pii: 598. [Epub ahead of print]12(3):
    The Role of Lonp1 on Mitochondrial Functions during Cardiovascular and Muscular Diseases.
    Giada Zanini, Valentina Selleri, Mara Malerba, Kateryna Solodka, Giorgia Sinigaglia, Milena Nasi, Anna Vittoria Mattioli, Marcello Pinti.
      The mitochondrial protease Lonp1 is a multifunctional enzyme that regulates crucial mitochondrial functions, including the degradation of oxidized proteins, folding of imported proteins and maintenance the correct number of copies of mitochondrial DNA. A series of recent studies has put Lonp1 at the center of the stage in the homeostasis of cardiomyocytes and muscle skeletal cells. During heart development, Lonp1 allows the metabolic shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation. Knock out of Lonp1 arrests heart development and determines cardiomyocyte apoptosis. In adults, Lonp1 acts as a cardioprotective protein, as its upregulation mitigates cardiac injury by preventing the oxidative damage of proteins and lipids, and by preserving mitochondrial redox balance. In skeletal muscle, Lonp1 is crucial for cell development, as it mediates the activation of PINK1/Parkin pathway needed for proper myoblast differentiation. Skeletal muscle-specific ablation of Lonp1 in mice causes reduced muscle fiber size and strength due to the accumulation of mitochondrial-retained protein in muscle. Lonp1 expression and activity decline with age in different tissues, including skeletal muscle, and are associated with a functional decline and structural impairment of muscle fibers. Aerobic exercise increases unfolded protein response markers including Lonp1 in the skeletal muscle of aged animals and is associated with muscle functional recovery. Finally, mutations of Lonp1 cause a syndrome named CODAS (Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies) characterized by the impaired development of multiple organs and tissues, including myocytes. CODAS patients show hypotonia and ptosis, indicative of skeletal muscle reduced performance. Overall, this body of observations points Lonp1 as a crucial regulator of mitochondrial functions in the heart and in skeletal muscle.
    Keywords:  Lon protease; UPRmt; heart dysfunction; sarcopenia
    DOI:  https://doi.org/10.3390/antiox12030598
  44. Am J Med Genet A. 2023 Mar 25.
    Clinical exome sequencing findings in 1589 patients.
    Ozlem Gorukmez, Orhan Gorukmez, Ali Topak.
      Clinical exome sequencing (CES) is important for the diagnosis of Mendelian diseases, which are clinically and etiologically heterogeneous. Sharing of large amounts of CES data associated with clinical findings will increase the accuracy of variant interpretation. We performed a retrospective study to state the diagnostic yield of CES in 1589 patients with a wide phenotypic spectrum. CES was performed using the Sophia Clinical Exome Sequencing Kit with 4493 genes, followed by sequencing on a NextSeq 500 system. The diagnosis rate was 36.8% when only pathogenic and likely pathogenic variants were included. Consanguineous unions and positive family history were associated with a high diagnostic yield. The neurological disease group had the highest number of patients. The groups with high diagnosis rates were ear, eye, and muscle disease groups. Seven candidate genes (EFHC2, HSPB3, FAAH2, ITGB1, GYG2, CD177, and CSTF2T) that are not yet associated with human diseases were identified. Owing to the high diagnostic yield of CES compared with that of other genetic tests, it can be used as a standard diagnostic test in patients with rare genetic disorders that require a wide differential diagnosis, especially in laboratories with limited resources.
    Keywords:  Mendelian disorders; clinical exome sequencing; copy number variations; next-generation sequencing; rare diseases
    DOI:  https://doi.org/10.1002/ajmg.a.63190
  45. STAR Protoc. 2023 Mar 30. pii: S2666-1667(23)00163-6. [Epub ahead of print]4(2): 102205
    Protocol for mapping double-stranded DNA break sites across the genome with translocation capture sequencing.
    Joe R Delaney, Albert R La Spada.
      Translocation sequencing can be used to assess mechanisms of DNA repair and identify genome-wide double-strand breaks (DSBs) accessible to DNA repair machinery. Here, we present a protocol for mapping double-strand DNA break sites across the genome with translocation capture sequencing. Bait DSBs are introduced using a Cas9 nuclease and repaired by the host cell, connecting bait DSBs to other DSBs. Repair sites are detected by isolating bait site DNA, cleaving normal sequence to enrich off-site repair, and next-generation sequencing. For complete details on the use and execution of this protocol, please refer to Switonski et al. (2021).1.
    Keywords:  Cell Biology; Genomics; High-throughput Screening
    DOI:  https://doi.org/10.1016/j.xpro.2023.102205
  46. Nat Commun. 2023 Mar 28. 14(1): 1738
    Mitochondrial ATP synthase as a direct molecular target of chromium(III) to ameliorate hyperglycaemia stress.
    Haibo Wang, Ligang Hu, Hongyan Li, Yau-Tsz Lai, Xueying Wei, Xiaohan Xu, Zhenkun Cao, Huiming Cao, Qianya Wan, Yuen-Yan Chang, Aimin Xu, Qunfang Zhou, Guibin Jiang, Ming-Liang He, Hongzhe Sun.
      Chromium(III) is extensively used as a supplement for muscle development and the treatment of diabetes mellitus. However, its mode of action, essentiality, and physiological/pharmacological effects have been a subject of scientific debate for over half a century owing to the failure in identifying the molecular targets of Cr(III). Herein, by integrating fluorescence imaging with a proteomic approach, we visualized the Cr(III) proteome being mainly localized in the mitochondria, and subsequently identified and validated eight Cr(III)-binding proteins, which are predominately associated with ATP synthesis. We show that Cr(III) binds to ATP synthase at its beta subunit via the catalytic residues of Thr213/Glu242 and the nucleotide in the active site. Such a binding suppresses ATP synthase activity, leading to the activation of AMPK, improving glucose metabolism, and rescuing mitochondria from hyperglycaemia-induced fragmentation. The mode of action of Cr(III) in cells also holds true in type II diabetic male mice. Through this study, we resolve the long-standing question of how Cr(III) ameliorates hyperglycaemia stress at the molecular level, opening a new horizon for further exploration of the pharmacological effects of Cr(III).
    DOI:  https://doi.org/10.1038/s41467-023-37351-w
  47. Life (Basel). 2023 Mar 08. pii: 733. [Epub ahead of print]13(3):
    Theoretical Framework for the Study of Genetic Diseases Caused by Dominant Alleles.
    Michael F Roberts, Stephen E Bricher.
      We propose a theoretical basis for analyzing several features of genetic diseases caused by dominant alleles, including: disease prevalence, genotype penetrance, and the relationship between causal genotype frequency and disease frequency. In addition, we provide a theoretical framework for accurate diagnosis and clinical approaches for disease study, including two examples in which inaccurate and incomplete diagnoses affect the estimates of disease prevalence: First, the disease iceberg effect shows that disease prevalence is often underestimated due to errors introduced by inaccurate diagnosis; second, because lifetime risk of disease is cumulative, and therefore an increasing function of age, measurements of prevalence are inaccurate if people of all ages are not included. Finally, we discuss the aggregation of genetic diseases. We identify theoretical and computational deficiencies associated with using the sibling recurrence-risk ratio as a measure of familial aggregation. We develop an alternative concept of aggregation and propose an associated measure that does not experience the deficiencies. Throughout, we provide clinicians and researchers practical implications of our theoretical framework.
    Keywords:  accurate diagnosis; cumulative lifetime risk; disease iceberg effect; familial aggregation; genetic disease; penetrance; prevalence
    DOI:  https://doi.org/10.3390/life13030733
  48. Life Sci Alliance. 2023 Jun;pii: e202201753. [Epub ahead of print]6(6):
    Crystal structures of dimeric and heptameric mtHsp60 reveal the mechanism of chaperonin inactivation.
    Meng-Cheng Lai, Hao-Yu Cheng, Sin-Hong Lew, Yu-An Chen, Chien-Hung Yu, Han-You Lin, Shih-Ming Lin.
      Mitochondrial Hsp60 (mtHsp60) plays a crucial role in maintaining the proper folding of proteins in the mitochondria. mtHsp60 self-assembles into a ring-shaped heptamer, which can further form a double-ring tetradecamer in the presence of ATP and mtHsp10. However, mtHsp60 tends to dissociate in vitro, unlike its prokaryotic homologue, GroEL. The molecular structure of dissociated mtHsp60 and the mechanism behind its dissociation remain unclear. In this study, we demonstrated that Epinephelus coioides mtHsp60 (EcHsp60) can form a dimeric structure with inactive ATPase activity. The crystal structure of this dimer reveals symmetrical subunit interactions and a rearranged equatorial domain. The α4 helix of each subunit extends and interacts with its adjacent subunit, leading to the disruption of the ATP-binding pocket. Furthermore, an RLK motif in the apical domain contributes to stabilizing the dimeric complex. These structural and biochemical findings provide new insights into the conformational transitions and functional regulation of this ancient chaperonin.
    DOI:  https://doi.org/10.26508/lsa.202201753
  49. iScience. 2023 Apr 21. 26(4): 106328
    Mitochondria-associated membrane protein PACS2 maintains right cardiac function in hypobaric hypoxia.
    Jie Yang, Mengjia Sun, Renzheng Chen, Xiaowei Ye, Boji Wu, Zhen Liu, Jihang Zhang, Xubin Gao, Ran Cheng, Chunyan He, Jingyu He, Xuhong Wang, Lan Huang.
      Hypobaric hypoxia (HH) is the primary challenge at highland. Prolonged HH exposure impairs right cardiac function. Mitochondria-associated membrane (MAM) plays a principal role in regulating mitochondrial function under hypoxia, but the mechanism was unclear. In this study, proteomics analysis identified that PACS2, a key protein in MAM, and mitophagy were downregulated in HH. Metabolomics analysis indicated suppression of glucose and fatty acids aerobic oxidation in HH conditions. Cardiomyocyte Pacs2 deficiency disrupted MAM formation and endoplasmic reticulum (ER)-mitochondria calcium flux, further inhibiting mitophagy and energy metabolism in HH. Pacs2 overexpression reversed these effects. Cardiac-specific knockout of Pacs2 exacerbated mitophagy inhibition, cardiomyocyte injury, and right cardiac dysfunction induced by HH. Conditional knock-in of Pacs2 recovered HH-induced right cardiac impairment. Thus, PACS2 is essential for protecting cardiomyocytes through ER-mitochondria calcium flux, mitophagy, and mitochondrial energy metabolism. Our work provides insight into the mechanism of HH-induced cardiomyocyte injury and potential targets for maintaining the right cardiac function at the highland.
    Keywords:  Cardiovascular medicine; Metabolomics; Molecular biology; Physiology; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2023.106328
  50. Redox Biol. 2023 Mar 21. pii: S2213-2317(23)00088-5. [Epub ahead of print]62 102687
    Pathologically high intraocular pressure induces mitochondrial dysfunction through Drp1 and leads to retinal ganglion cell PANoptosis in glaucoma.
    Zhou Zeng, Mengling You, Cong Fan, Rong Rong, Haibo Li, Xiaobo Xia.
      Glaucoma is a common neurodegenerative disease characterized by progressive retinal ganglion cell (RGC) loss and visual field defects. Pathologically high intraocular pressure (ph-IOP) is an important risk factor for glaucoma, and it triggers molecularly distinct cascades that control RGC death and axonal degeneration. Dynamin-related protein 1 (Drp1)-mediated abnormalities in mitochondrial dynamics are involved in glaucoma pathogenesis; however, little is known about the precise pathways that regulate RGC injury and death. Here, we aimed to investigate the role of the ERK1/2-Drp1-reactive oxygen species (ROS) axis in RGC death and the relationship between Drp1-mediated mitochondrial dynamics and PANoptosis in ph-IOP injury. Our results suggest that inhibiting the ERK1/2-Drp1-ROS pathway is a potential therapeutic strategy for treating ph-IOP-induced injuries. Furthermore, inhibiting Drp1 can regulate RGC PANoptosis by modulating caspase3-dependent, nucleotide-binding oligomerization domain-like receptor-containing pyrin domain 3(NLRP3)-dependent, and receptor-interacting protein (RIP)-dependent pathways in the ph-IOP model. Overall, our findings provide new insights into possible protective interventions that could regulate mitochondrial dynamics to improve RGC survival.
    Keywords:  Dynamin-related protein 1; Glaucoma; Mitochondrial dynamics; PANoptosis; Retinal ganglion cell
    DOI:  https://doi.org/10.1016/j.redox.2023.102687
  51. Eur J Pediatr. 2023 Mar 31.
    Rapid exome sequencing as a first-tier test in neonates with suspected genetic disorder: results of a prospective multicenter clinical utility study in the Netherlands.
    RADICON-NL consortium
      The introduction of rapid exome sequencing (rES) for critically ill neonates admitted to the neonatal intensive care unit has made it possible to impact clinical decision-making. Unbiased prospective studies to quantify the impact of rES over routine genetic testing are, however, scarce. We performed a clinical utility study to compare rES to conventional genetic diagnostic workup for critically ill neonates with suspected genetic disorders. In a multicenter prospective parallel cohort study involving five Dutch NICUs, we performed rES in parallel to routine genetic testing for 60 neonates with a suspected genetic disorder and monitored diagnostic yield and the time to diagnosis. To assess the economic impact of rES, healthcare resource use was collected for all neonates. rES detected more conclusive genetic diagnoses than routine genetic testing (20% vs. 10%, respectively), in a significantly shorter time to diagnosis (15 days (95% CI 10-20) vs. 59 days (95% CI 23-98, p < 0.001)). Moreover, rES reduced genetic diagnostic costs by 1.5% (€85 per neonate).
    CONCLUSION:  Our findings demonstrate the clinical utility of rES for critically ill neonates based on increased diagnostic yield, shorter time to diagnosis, and net healthcare savings. Our observations warrant the widespread implementation of rES as first-tier genetic test in critically ill neonates with disorders of suspected genetic origin.
    WHAT IS KNOWN: • Rapid exome sequencing (rES) enables diagnosing rare genetic disorders in a fast and reliable manner, but retrospective studies with neonates admitted to the neonatal intensive care unit (NICU) indicated that genetic disorders are likely underdiagnosed as rES is not routinely used. • Scenario modeling for implementation of rES for neonates with presumed genetic disorders indicated an expected increase in costs associated with genetic testing.
    WHAT IS NEW: • This unique prospective national clinical utility study of rES in a NICU setting shows that rES obtained more and faster diagnoses than conventional genetic tests. • Implementation of rES as replacement for all other genetic tests does not increase healthcare costs but in fact leads to a reduction in healthcare costs.
    Keywords:  Clinical utility; Diagnostic workflow; Economic evaluation; Neonates; Rapid exome sequencing
    DOI:  https://doi.org/10.1007/s00431-023-04909-1
  52. Front Mol Biosci. 2023 ;10 1168941
    Editorial: Methods in Metabolomics 2022.
    Joerg Buescher, Luciana Hannibal.
      
    Keywords:  MS-imaging; mass spectrometry; metabolite; metabolomics; method optimization
    DOI:  https://doi.org/10.3389/fmolb.2023.1168941
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