bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2022–06–19
twenty papers selected by
Catalina Vasilescu, University of Helsinki
  1. OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy.
  2. Case Report: Rare Homozygous RNASEH1 Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions.
  3. Leber's hereditary optic neuropathy plus dystonia caused by the mitochondrial ND1 gene m.4160 T > C mutation.
  4. Mesenchymal stem cells improve redox homeostasis and mitochondrial respiration in fibroblast cell lines with pathogenic MT-ND3 and MT-ND6 variants.
  5. Mitochondrial Function and Dynamics in Neural Stem Cells and Neurogenesis: Implications for Neurodegenerative Diseases.
  6. Ginsenoside Rb1 inhibits astrocyte activation and promotes transfer of astrocytic mitochondria to neurons against ischemic stroke.
  7. Role of Constitutive STAR in Mitochondrial Structure and Function in MA-10 Leydig Cells.
  8. Mitochondrial and anutophagy-lysosomal pathway polygenic risk scores predict Parkinson's disease.
  9. TMBIM5 loss of function alters mitochondrial matrix ion homeostasis and causes a skeletal myopathy.
  10. Modeling of mitochondrial bioenergetics and autophagy impairment in MELAS-mutant iPSC-derived retinal pigment epithelial cells.
  11. RhoA/ROCK Signaling Regulates Drp1-Mediated Mitochondrial Fission During Collective Cell Migration.
  12. R-Loops and Mitochondrial DNA Metabolism.
  13. The mitochondrial adenine nucleotide transporters in myogenesis.
  14. P53 regulates mitochondrial biogenesis via transcriptionally induction of mitochondrial ribosomal protein L12.
  15. A Patient with a Novel RARS2 Variant Exhibiting Liver Involvement as a New Clinical Feature and Review of the Literature.
  16. Compound heterozygous variants of the NARS2 gene in siblings with developmental delay, epilepsy, and neonatal diabetes syndrome.
  17. Current Knowledge on the Role of Cardiolipin Remodeling in the Context of Lipid Oxidation and Barth Syndrome.
  18. RNA-binding proteins direct myogenic cell fate decisions.
  19. Measuring biological age using omics data.
  20. The influence of age, sex, and exercise on autophagy, mitophagy, and lysosome biogenesis in skeletal muscle.
  1. J Clin Invest. 2022 Jun 14. pii: e157504. [Epub ahead of print]
    OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy.
    Mario K Shammas, Xiaoping Huang, Beverly P Wu, Evelyn Fessler, Insung Song, Nicholas P Randolph, Yan Li, Christopher Ke Bleck, Danielle A Springer, Carl Fratter, Ines A Barbosa, Andrew F Powers, Pedro M Quirós, Carlos Lopez-Otin, Lucas T Jae, Joanna Poulton, Derek P Narendra.
      Mitochondrial stress triggers a response in the cell's mitochondria and nucleus, but how these stress responses are coordinated in vivo is poorly understood. Here, we characterize a family with myopathy caused by a dominant p.G58R mutation in the mitochondrial protein CHCHD10. To understand the disease etiology, we developed a knock-in mouse model and found that mutant CHCHD10 aggregates in affected tissues, applying a toxic protein stress to the inner mitochondrial membrane. Unexpectedly, survival of CHCHD10 knock-in mice depended on a protective stress response mediated by OMA1. The OMA1 stress response acted both locally within mitochondria, causing mitochondrial fragmentation, and signaled outside the mitochondria, activating the integrated stress response through cleavage of DELE1. We additionally identified an isoform switch in the terminal complex of the electron transport chain as a component of this response. Our results demonstrate that OMA1 is critical for neonatal survival conditionally in the setting of inner mitochondrial membrane stress, coordinating local and global stress responses to reshape the mitochondrial network and proteome.
    Keywords:  Cell Biology; Cell stress; Genetics; Mitochondria; Proteases
    DOI:  https://doi.org/10.1172/JCI157504
  2. Front Genet. 2022 ;13 906667
    Case Report: Rare Homozygous RNASEH1 Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions.
    Arianna Manini, Leonardo Caporali, Megi Meneri, Simona Zanotti, Daniela Piga, Ignazio Giuseppe Arena, Stefania Corti, Antonio Toscano, Giacomo Pietro Comi, Olimpia Musumeci, Valerio Carelli, Dario Ronchi.
      Mitochondrial DNA (mtDNA) maintenance disorders embrace a broad range of clinical syndromes distinguished by the evidence of mtDNA depletion and/or deletions in affected tissues. Among the nuclear genes associated with mtDNA maintenance disorders, RNASEH1 mutations produce a homogeneous phenotype, with progressive external ophthalmoplegia (PEO), ptosis, limb weakness, cerebellar ataxia, and dysphagia. The encoded enzyme, ribonuclease H1, is involved in mtDNA replication, whose impairment leads to an increase in replication intermediates resulting from mtDNA replication slowdown. Here, we describe two unrelated Italian probands (Patient 1 and Patient 2) affected by chronic PEO, ptosis, and muscle weakness. Cerebellar features and severe dysphagia requiring enteral feeding were observed in one patient. In both cases, muscle biopsy revealed diffuse mitochondrial abnormalities and multiple mtDNA deletions. A targeted next-generation sequencing analysis revealed the homozygous RNASEH1 mutations c.129-3C>G and c.424G>A in patients 1 and 2, respectively. The c.129-3C>G substitution has never been described as disease-related and resulted in the loss of exon 2 in Patient 1 muscle RNASEH1 transcript. Overall, we recommend implementing the use of high-throughput sequencing approaches in the clinical setting to reach genetic diagnosis in case of suspected presentations with impaired mtDNA homeostasis.
    Keywords:  CPEO; RNASEH1; mitochondrial DNA; mtDNA maintenance disorders; myopathy; ribonuclease H1
    DOI:  https://doi.org/10.3389/fgene.2022.906667
  3. Neurol Sci. 2022 Jun 14.
    Leber's hereditary optic neuropathy plus dystonia caused by the mitochondrial ND1 gene m.4160 T > C mutation.
    Hong Ren, Yan Lin, Ying Li, Xiufang Zhang, Wei Wang, Xuebi Xu, Kunqian Ji, Yuying Zhao, Chuanzhu Yan.
       BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a common mitochondrial disease. More than 30 variants in the mitochondrial DNA (mtDNA) have been previously described in LHON. However, the pathogenicity of some variants remains unclear. Herein, we report a 19-year-old boy presenting unique LHON plus dystonia syndrome with the rare m.4136A > G and m.4160 T > C variants and elucidate the molecular pathomechanisms of the m.4160 T > C mutation.
    METHODS: We performed clinical, molecular genetic analysis, and biochemical investigation in the patient's different tissues and cybrid cell lines.
    RESULTS: The optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) of the patient showed typical pathological changes-a significant decrease in the 17 thickness of the retinal nerve fiber layer (RNFL) and the ganglion cell complex (GCC). Brain magnetic resonance imaging (MRI) found noteworthy abnormal signals in the basal ganglia region. The genetic analysis revealed that the m.4160 T > C variant was heteroplasmic in the blood (80.2%), urine sediment (90.8%), and oral mucosal (81.7%) samples of the patient. In contrast, the m.4136A > G variant was homoplasmic in all available tissues. Biochemical and bioenergetic investigations showed decreased mitochondrial protein levels and mitochondrial respiration deficiency in cybrid cells harboring these variants.
    CONCLUSIONS: This research provided more comprehensive data to help gain insight into the pathogenicity of the m.4160 T > C variant and broaden our view on the LHON plus phenotype.
    Keywords:  Complex I; Dystonia; LHON; Mitochondrial DNA; Mutation; ND1 gene
    DOI:  https://doi.org/10.1007/s10072-022-06165-x
  4. Stem Cell Res Ther. 2022 Jun 17. 13(1): 256
    Mesenchymal stem cells improve redox homeostasis and mitochondrial respiration in fibroblast cell lines with pathogenic MT-ND3 and MT-ND6 variants.
    Tharsini Navaratnarajah, Marlen Bellmann, Annette Seibt, Ruchika Anand, Özer Degistirici, Roland Meisel, Ertan Mayatepek, Andreas Reichert, Fabian Baertling, Felix Distelmaier.
      The most frequent biochemical defect of inherited mitochondrial disease is isolated complex I deficiency. There is no cure for this disorder, and treatment is mainly supportive. In this study, we investigated the effects of human mesenchymal stem cells (MSCs) on skin fibroblast derived from three individuals with complex I deficiency carrying different pathogenic variants in mitochondrial DNA-encoded subunits (MT-ND3, MT-ND6). Complex I-deficient fibroblasts were transiently co-cultured with bone marrow-derived MSCs. Mitochondrial transfer was analysed by fluorescence labelling and validated by Sanger sequencing. Levels of reactive oxygen species (ROS) were measured using MitoSOX Red. Moreover, mitochondrial respiration was analysed by Seahorse XFe96 Extracellular Flux Analyzer. Levels of antioxidant proteins were investigated via immunoblotting. Co-culturing of complex I-deficient fibroblast with MSCs lowered cellular ROS levels. The effect on ROS production was more sustained compared to treatment of patient fibroblasts with culture medium derived from MSC cultures. Investigation of cellular antioxidant defence systems revealed an upregulation of SOD2 (superoxide dismutase 2, mitochondrial) and HO-1 (heme oxygenase 1) in patient-derived cell lines. This adaptive response was normalised upon MSC treatment. Moreover, Seahorse experiments revealed a significant improvement of mitochondrial respiration, indicating a mitigation of the oxidative phosphorylation defect. Experiments with repetitive MSC co-culture at two consecutive time points enhanced this effect. Our study indicates that MSC-based treatment approaches might constitute an interesting option for patients with mitochondrial DNA-encoded mitochondrial diseases. We suggest that this strategy may prove more promising for defects caused by mitochondrial DNA variants compared to nuclear-encoded defects.
    Keywords:  Complex I; Gene therapy; Mesenchymal stem cells; Mitochondrial DNA; Mitochondrial transfer; ND3; ND6
    DOI:  https://doi.org/10.1186/s13287-022-02932-x
  5. Ageing Res Rev. 2022 Jun 14. pii: S1568-1637(22)00109-X. [Epub ahead of print] 101667
    Mitochondrial Function and Dynamics in Neural Stem Cells and Neurogenesis: Implications for Neurodegenerative Diseases.
    Patrícia Coelho, Lígia Fão, Sandra Mota, A Cristina Rego.
      Mitochondria have been largely described as the powerhouse of the cell and recent findings demonstrate that this organelle is fundamental for neurogenesis. The mechanisms underlying neural stem cells (NSCs) maintenance and differentiation are highly regulated by both intrinsic and extrinsic factors. Mitochondrial-mediated switch from glycolysis to oxidative phosphorylation, accompanied by mitochondrial remodeling and dynamics are vital to NSCs fate. Deregulation of mitochondrial proteins, mitochondrial DNA, function, fission/fusion and metabolism underly several neurodegenerative diseases; data show that these impairments are already present in early developmental stages and NSC fate decisions. However, little is known about mitochondrial role in neurogenesis. In this Review, we describe the recent evidence covering mitochondrial role in neurogenesis, its impact in selected neurodegenerative diseases, for which aging is the major risk factor, and the recent advances in stem cell-based therapies that may alleviate neurodegenerative disorders-related neuronal deregulation through improvement of mitochondrial function and dynamics.
    Keywords:  Mitochondria; Neural Stem Cells; Neurodegenerative Disorders; Neurogenesis
    DOI:  https://doi.org/10.1016/j.arr.2022.101667
  6. Redox Biol. 2022 Jun 08. pii: S2213-2317(22)00135-5. [Epub ahead of print]54 102363
    Ginsenoside Rb1 inhibits astrocyte activation and promotes transfer of astrocytic mitochondria to neurons against ischemic stroke.
    Xue-Chun Ni, Hong-Fei Wang, Yuan-Yuan Cai, Dai Yang, Raphael N Alolga, Baolin Liu, Jia Li, Feng-Qing Huang.
      Astrocytes activation in response to stroke results in altered mitochondrial exchange with neurons. Ginsenoside Rb1is a major ginsenoside of Panax ginseng particularly known for its neuroprotective potential. This work aimed to investigate if Rb1 could rescue neurons from ischemic insult via astrocyte inactivation and mitochondrial transfer. We prepared conditioned astrocytes-derived medium for co-culture with neurons and examined the role of Rb1 in mitochondrial transfer from astrocytes to neurons. The neuroprotective potential of Rb1 was further confirmed in vivo using a mouse model of brain ischemia. In response to oxygen-glucose deprivation and reperfusion (OGD/R), astrocytes were reactivated and produced reactive oxygen species (ROS), an action that was blocked by Rb1. Mechanistically, Rb1 inhibited NADH dehydrogenase in mitochondrial complex I to block reverse electron transport-derived ROS production from complex I, and thus inactivated astrocytes to protect the mitochondria. Mitochondrial signal, mitochondrial membrane potential and ATP production detected in conditioned astrocyte-derived medium indicated that Rb1 protected functional mitochondria and facilitated their transfer. When neurons were injured by OGD/R insult, co-culturing with conditioned medium increased mitochondrial membrane potential and oxygen consumption rate within the neurons, indicating the protection conferred on them by Rb1 via mitochondrial transfer from astrocytes. Using the ischemic mouse brain model, CD38 knockdown in the cerebral ventricles diminished the neuroprotective effects of Rb1, providing evidence in support of the role of astrocyte mitochondrial transfer. Transient inhibition of mitochondrial complex I by Rb1 reduced mitochondrial ROS production and consequently avoided astrocyte activation. Astrocyte mitochondrial transfer therefore seemed a means by which Rb1 could promote neuronal survival and function. Different from the neurocentric view, these findings suggest the astrocytes may be a promising target for pharmacological interventions in ischemic brain injury.
    Keywords:  Astrocyte reactivity; Ginsenoside Rb1; Mitochondrial transfer; Stroke
    DOI:  https://doi.org/10.1016/j.redox.2022.102363
  7. Endocrinology. 2022 Jun 15. pii: bqac091. [Epub ahead of print]
    Role of Constitutive STAR in Mitochondrial Structure and Function in MA-10 Leydig Cells.
    Melanie Galano, Vassilios Papadopoulos.
      The steroidogenic acute regulatory protein (STAR) is critical for the transport of cholesterol into the mitochondria for hormone-induced steroidogenesis. Steroidogenic cells express STAR under control conditions (constitutive STAR). Upon hormonal stimulation, STAR localizes to the outer mitochondrial membrane (OMM) where it facilitates cholesterol transport and where it is processed to its mature form. Here, we show that knockout of STAR in MA-10 mouse tumor Leydig cells (STARKO1) causes defects in mitochondrial structure and function under basal conditions. We also show that overexpression of STAR in STARKO1 cells exacerbates, rather than recovers, mitochondrial structure and function, which further disrupts the processing of STAR at the OMM. Our findings suggest that constitutive STAR is necessary for proper mitochondrial structure and function and that mitochondrial dysfunction leads to defective STAR processing at the OMM.
    Keywords:  Leydig cells; STAR; mitochondrial respiration; mitochondrial structure; steroidogenesis
    DOI:  https://doi.org/10.1210/endocr/bqac091
  8. Mol Cell Neurosci. 2022 Jun 13. pii: S1044-7431(22)00057-4. [Epub ahead of print] 103751
    Mitochondrial and anutophagy-lysosomal pathway polygenic risk scores predict Parkinson's disease.
    Mohammad Dehestani, Hui Liu, Ashwin Ashok Kumar Sreelatha, Claudia Schulte, Vikas Bansal, Thomas Gasser.
      Polygenic Risk Scores (PRS), which allow assessing an individuals' genetic risk for a complex disease, are calculated as the weighted number of genetic risk alleles in an individual's genome, with the risk alleles and their weights typically derived from the results of genome-wide association studies (GWAS). Among a wide range of applications, PRS can be used to identify at-risk individuals and select them for further clinical follow-up. Pathway PRS are genetic scores based on single nucleotide polymorphisms (SNPs) assigned to genes involved in major disease pathways. The aim of this study is to assess the predictive utility of PRS models constructed based on SNPs corresponding to two cardinal pathways in Parkinson's disease (PD) including mitochondrial PRS (Mito PRS) and autophagy-lysosomal PRS (ALP PRS). PRS models were constructed using the clumping-and-thresholding method in a German population as prediction dataset that included 371 cases and 249 controls, using SNPs discovered by the most recent PD-GWAS. We showed that these pathway PRS significantly predict the PD status. Furthermore, we demonstrated that Mito PRS are significantly associated with later age of onset in PD patients. Our results may add to the accumulating evidence for the contribution of mitochondrial and autophagy-lysosomal pathways to PD risk and facilitate biologically relevant risk stratification of PD patients.
    Keywords:  Autophagy; Lysosomal pathway; Mitochondrial pathway; Parkinson's disease; Polygenic risk scores
    DOI:  https://doi.org/10.1016/j.mcn.2022.103751
  9. Life Sci Alliance. 2022 Oct;pii: e202201478. [Epub ahead of print]5(10):
    TMBIM5 loss of function alters mitochondrial matrix ion homeostasis and causes a skeletal myopathy.
    Li Zhang, Felicia Dietsche, Bruno Seitaj, Liliana Rojas-Charry, Nadina Latchman, Dhanendra Tomar, Rob Ci Wüst, Alexander Nickel, Katrin Bm Frauenknecht, Benedikt Schoser, Sven Schumann, Michael J Schmeisser, Johannes Vom Berg, Thorsten Buch, Stefanie Finger, Philip Wenzel, Christoph Maack, John W Elrod, Jan B Parys, Geert Bultynck, Axel Methner.
      Ion fluxes across the inner mitochondrial membrane control mitochondrial volume, energy production, and apoptosis. TMBIM5, a highly conserved protein with homology to putative pH-dependent ion channels, is involved in the maintenance of mitochondrial cristae architecture, ATP production, and apoptosis. Here, we demonstrate that overexpressed TMBIM5 can mediate mitochondrial calcium uptake. Under steady-state conditions, loss of TMBIM5 results in increased potassium and reduced proton levels in the mitochondrial matrix caused by attenuated exchange of these ions. To identify the in vivo consequences of TMBIM5 dysfunction, we generated mice carrying a mutation in the channel pore. These mutant mice display increased embryonic or perinatal lethality and a skeletal myopathy which strongly correlates with tissue-specific disruption of cristae architecture, early opening of the mitochondrial permeability transition pore, reduced calcium uptake capability, and mitochondrial swelling. Our results demonstrate that TMBIM5 is an essential and important part of the mitochondrial ion transport system machinery with particular importance for embryonic development and muscle function.
    DOI:  https://doi.org/10.26508/lsa.202201478
  10. Stem Cell Res Ther. 2022 Jun 17. 13(1): 260
    Modeling of mitochondrial bioenergetics and autophagy impairment in MELAS-mutant iPSC-derived retinal pigment epithelial cells.
    Sujoy Bhattacharya, Jinggang Yin, Weihong Huo, Edward Chaum.
       BACKGROUND: Mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage in the retinal pigment epithelium (RPE) have been implicated in the pathogenesis of age-related macular degeneration (AMD). However, a deeper understanding is required to determine the contribution of mitochondrial dysfunction and impaired mitochondrial autophagy (mitophagy) to RPE damage and AMD pathobiology. In this study, we model the impact of a prototypical systemic mitochondrial defect, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), in RPE health and homeostasis as an in vitro model for impaired mitochondrial bioenergetics.
    METHODS: We used induced pluripotent stem cells (iPSCs) derived from skin biopsies of MELAS patients (m.3243A > G tRNA leu mutation) with different levels of mtDNA heteroplasmy and differentiated them into RPE cells. Mitochondrial depletion of ARPE-19 cells (p0 cells) was also performed using 50 ng/mL ethidium bromide (EtBr) and 50 mg/ml uridine. Cell fusion of the human platelets with the p0 cells performed using polyethylene glycol (PEG)/suspension essential medium (SMEM) mixture to generate platelet/RPE "cybrids." Confocal microscopy, FLowSight Imaging cytometry, and Seahorse XF Mito Stress test were used to analyze mitochondrial function. Western Blotting was used to analyze expression of autophagy and mitophagy proteins.
    RESULTS: We found that MELAS iPSC-derived RPE cells exhibited key characteristics of native RPE. We observed heteroplasmy-dependent impairment of mitochondrial bioenergetics and reliance on glycolysis for generating energy in the MELAS iPSC-derived RPE. The degree of heteroplasmy was directly associated with increased activation of signal transducer and activator of transcription 3 (STAT3), reduced adenosine monophosphate-activated protein kinase α (AMPKα) activation, and decreased autophagic activity. In addition, impaired autophagy was associated with aberrant lysosomal function, and failure of mitochondrial recycling. The mitochondria-depleted p0 cells replicated the effects on autophagy impairment and aberrant STAT3/AMPKα signaling and showed reduced mitochondrial respiration, demonstrating phenotypic similarities between p0 and MELAS iPSC-derived RPE cells.
    CONCLUSIONS: Our studies demonstrate that the MELAS iPSC-derived disease models are powerful tools for dissecting the molecular mechanisms by which mitochondrial DNA alterations influence RPE function in aging and macular degeneration, and for testing novel therapeutics in patients harboring the MELAS genotype.
    Keywords:  AMPKα; Age-related macular degeneration; Autophagy flux; MELAS; Mitochondrial heteroplasmy; Mitophagy; PGC-1α; Prom1/CD133; Regenerative medicine; iPSC-derived retinal pigment epithelium
    DOI:  https://doi.org/10.1186/s13287-022-02937-6
  11. Front Cell Dev Biol. 2022 ;10 882581
    RhoA/ROCK Signaling Regulates Drp1-Mediated Mitochondrial Fission During Collective Cell Migration.
    Chen Qu, Wen Yang, Yating Kan, Hui Zuo, Mengqi Wu, Qing Zhang, Heng Wang, Dou Wang, Jiong Chen.
      Collective migration plays critical roles in developmental, physiological and pathological processes, and requires a dynamic actomyosin network for cell shape change, cell adhesion and cell-cell communication. The dynamic network of mitochondria in individual cells is regulated by mitochondrial fission and fusion, and is required for cellular processes including cell metabolism, apoptosis and cell division. But whether mitochondrial dynamics interplays with and regulates actomyosin dynamics during collective migration is not clear. Here, we demonstrate that proper regulation of mitochondrial dynamics is critical for collective migration of Drosophila border cells during oogenesis, and misregulation of fission or fusion results in reduction of ATP levels. Specifically, Drp1 is genetically required for border cell migration, and Drp1-mediated mitochondrial fission promotes formation of leading protrusion, likely through its regulation of ATP levels. Reduction of ATP levels by drug treatment also affects protrusion formation as well as actomyosin dynamics. Importantly, we find that RhoA/ROCK signaling, which is essential for actin and myosin dynamics during border cell migration, could exert its effect on mitochondrial fission through regulating Drp1's recruitment to mitochondria. These findings suggest that RhoA/ROCK signaling may couple or coordinate actomyosin dynamics with mitochondrial dynamics to achieve optimal actomyosin function, leading to protrusive and migratory behavior.
    Keywords:  DRP1; Drosophila border cells; RhoA/ROCK signaling; actomyosin dynamics; collective migration; mitochondrial dynamics
    DOI:  https://doi.org/10.3389/fcell.2022.882581
  12. Methods Mol Biol. 2022 ;2528 173-202
    R-Loops and Mitochondrial DNA Metabolism.
    Ian J Holt.
      R-loops forming inadvertently during transcription can threaten genome stability, but R-loops are also formed intentionally, as a means of regulating transcription and other aspects of DNA metabolism. The study of R-loops in mitochondria is in its infancy, and yet there is already clear evidence that they are predominantly located in the major regulatory region of the mammalian mitochondrial genome. Here, we describe how mitochondrial R-loops have been characterized to date, with the emphasis on the problems of their being extremely labile, and how to minimize their loss during extraction. The oft-overlooked issues of RNA-DNA hybrids not being synonymous with R-loops, and adventitious RNA hybridization to DNA, are tackled head on; and possible new approaches are described and placed in the context of future research lines that could reveal the detailed roles of R-loops in the metabolism of mitochondrial DNA.
    Keywords:  Mitochondrial DNA; Mitochondrial DNA replication; Mitochondrial transcription; R-loop; RNA–DNA hybrid
    DOI:  https://doi.org/10.1007/978-1-0716-2477-7_12
  13. Free Radic Biol Med. 2022 Jun 14. pii: S0891-5849(22)00213-1. [Epub ahead of print]
    The mitochondrial adenine nucleotide transporters in myogenesis.
    Adrian Flierl, Samuel Schriner, Saege Hancock, Pinar Coskun, Douglas C Wallace.
      Adenine Nucleotide Translocator isoforms (ANTs) exchange ADP/ATP across the inner mitochondrial membrane, are also voltage-activated proton channels and regulate mitophagy and apoptosis. The ANT1 isoform predominates in heart and muscle while ANT2 is systemic. Here, we report the creation of Ant mutant mouse myoblast cell lines with normal Ant1 and Ant2 genes, deficient in either Ant1 or Ant2, and deficient in both the Ant1 and Ant2 genes. These cell lines are immortal under permissive conditions (IFN-γ + serum at 32 °C) permitting expansion but return to normal myoblasts that can be differentiated into myotubes at 37 °C. With this system we were able to complement our Ant1 mutant studies by demonstrating that ANT2 is important for myoblast to myotube differentiation and myotube mitochondrial respiration. ANT2 is also important in, the regulation of mitochondrial biogenesis and antioxidant defenses. in association with increased oxidative stress response and modulation for Ca++ sequestration and activation of the mitochondrial permeability transition (mtPTP) pore during cell differentiation.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.05.022
  14. Exp Cell Res. 2022 Jun 09. pii: S0014-4827(22)00242-7. [Epub ahead of print] 113249
    P53 regulates mitochondrial biogenesis via transcriptionally induction of mitochondrial ribosomal protein L12.
    Yitong Han, Yi Liu, Junhui Zhen, Shaoshuai Hou, Bo Zhang, ZhengGuo Cui, Qiang Wan, Hong Feng.
      The well-documented tumor suppressor p53 is also a major stress response factor for its diverse regulation on cellular energetics. However, the effect of p53 on mitochondrial biogenesis, which plays a predominant role in response to the elevated energy demands, appears to be pleiotropic in various conditions and has not reached agreement. Mitochondrial ribosomal protein L12 (MRPL12), reported as a bi-functional protein for its roles in both mitochondrial ribosomes and transcriptional complexes, is a core regulatory component in mitochondrial biogenesis. Here we proved that MRPL12 is transcriptionally regulated by p53. Furthermore, the p53/MRPL12 regulation of mitochondria is part of the signaling pathway that maintains the basal mitochondrial content and positively coordinates the mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) in response to metabolic perturbation. Since p53 serves as the'Guardian of the Genome', our findings may revealed a new mechanism underlying the conditions when more ATP is warranted to maintain the genome integrity and cell survival. Therefore the pharmacological intervention or metabolic modulation (e.g., through fasting or exercise) of the p53/MRPL12 pathway promises to be a therapeutic approach that can safeguard health.
    Keywords:  MRPL12(2); Mitochondrial DNA(3); Mitochondrial transcription(4); Oxidative phosphorylation(5); p53(1)
    DOI:  https://doi.org/10.1016/j.yexcr.2022.113249
  15. Mol Syndromol. 2022 May;13(3): 226-234
    A Patient with a Novel RARS2 Variant Exhibiting Liver Involvement as a New Clinical Feature and Review of the Literature.
    Selin Sevinç, Aslı İnci, Fatih S Ezgü, Fatma T Eminoğlu.
      Pontocerebellar hypoplasia (PCH) is a heterogeneous neurodevelopmental disorder that is characterized by decreased brainstem and cerebellum volume. Pontocerebellar hypoplasia type 6 (PCH6) is a mitochondrial disease associated with autosomal recessive inheritance that results from mutations in the RARS2 gene. In this case report, we describe a new clinical presentation with a novel RARS2 pathogenic variant. We report here on 2 siblings who presented with neonatal lactic acidosis, microcephaly, growth retardation, persistent seizures, and cholestasis with a previously undefined RARS2 pathogenic variant. In our literature review, we evaluated the clinical features and pathogenic variants of 34 patients reported in 16 publications since the initial identification of RARS2 pathogenic variants in PCH6 in 2007. Both siblings were detected with c.1564G>A (p.Val522Ile), a novel homozygous pathogenic variant of the RARS2 gene. Imaging revealed advanced cerebral atrophy and cerebellar hypoplasia, while the basal ganglia and pons were preserved. At follow-up, the elevations in liver function test results and cholestasis had regressed while the LDH and GGT elevations persisted. Both siblings showed microcephaly on follow-up and started to suffer seizures. Severe developmental delay and nutritional problems were observed, and both died in infancy. RARS2 pathogenic variant is a mitochondrial disease that causes severe mental, motor, and developmental retardation, as well as short life expectancy. Our patients are the first cases with liver involvement in PCH6 and a novel homozygous RARS2 pathogenic variant to be reported in the literature. This additional phenotype can be considered as making a valid contribution to the literature.
    Keywords:  Liver involvement; Mitochondrial arginyl tRNA; Pontocerebellar hypoplasia type 6; RARS2
    DOI:  https://doi.org/10.1159/000519604
  16. Am J Med Genet A. 2022 Jun 15.
    Compound heterozygous variants of the NARS2 gene in siblings with developmental delay, epilepsy, and neonatal diabetes syndrome.
    Hideaki Yagasaki, Fumikazu Sano, Hiromune Narusawa, Daisuke Watanabe, Yoshimi Kaga, Koji Kobayashi, Yoshihiro Asano, Miho Nagata, Ayumi Yonei, Takeshi Inukai.
      Neonatal diabetes mellitus (NDM) with developmental delay and epilepsy is classified as developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. The majority of DEND syndrome are due to severely damaging variants of K-ATP channels, and few mitochondria-related genes have been reported. We report here two Japanese siblings who were clinically diagnosed with DEND syndrome in whom NARS2 compound heterozygous variants were detected. Patient 1 was a 3-year-old girl and presented with diabetes ketoacidosis at 3 months old. Patient 2 was a 1-year-old boy who presented with severe hyperglycemia and started insulin therapy at 3 days old. After the first episodes, they both presented with severe developmental delay, hearing loss and treatment-resistant epilepsy accompanied by progressive brain atrophy. Whole-exome sequencing revealed compound heterozygous NARS2 p.R159C and p.L217V variants, and the GATA4 p.P407Q variant in both patients. They were treated by mitochondrial supportive therapy of vitamin B1, L-carnitine, and coenzyme Q10. Patient 2 was withdrawn from insulin therapy at 6 months old. This is the first report of NDM in which variants of the NARS2 gene coding mitochondrial protein were detected. Genetic analysis including mitochondrial genes should be considered in patients with neonatal onset diabetes associated with neurogenic symptoms.
    Keywords:  DEND syndrome; NARS2; epilepsy; mitochondria; neonatal diabetes mellitus
    DOI:  https://doi.org/10.1002/ajmg.a.62873
  17. Front Mol Biosci. 2022 ;9 915301
    Current Knowledge on the Role of Cardiolipin Remodeling in the Context of Lipid Oxidation and Barth Syndrome.
    Zhuqing Liang, Michael W Schmidtke, Miriam L Greenberg.
      Barth syndrome (BTHS, OMIM 302060) is a genetic disorder caused by variants of the TAFAZZIN gene (G 4.5, OMIM 300394). This debilitating disorder is characterized by cardio- and skeletal myopathy, exercise intolerance, and neutropenia. TAFAZZIN is a transacylase that catalyzes the second step in the cardiolipin (CL) remodeling pathway, preferentially converting saturated CL species into unsaturated CLs that are susceptible to oxidation. As a hallmark mitochondrial membrane lipid, CL has been shown to be essential in a myriad of pathways, including oxidative phosphorylation, the electron transport chain, intermediary metabolism, and intrinsic apoptosis. The pathological severity of BTHS varies substantially from one patient to another, even in individuals bearing the same TAFAZZIN variant. The physiological modifier(s) leading to this disparity, along with the exact molecular mechanism linking CL to the various pathologies, remain largely unknown. Elevated levels of reactive oxygen species (ROS) have been identified in numerous BTHS models, ranging from yeast to human cell lines, suggesting that cellular ROS accumulation may participate in the pathogenesis of BTHS. Although the exact mechanism of how oxidative stress leads to pathogenesis is unknown, it is likely that CL oxidation plays an important role. In this review, we outline what is known about CL oxidation and provide a new perspective linking the functional relevance of CL remodeling and oxidation to ROS mitigation in the context of BTHS.
    Keywords:  apoptosis; barth syndrome; cardiolipin; cardiolipin remodeling; oxidation
    DOI:  https://doi.org/10.3389/fmolb.2022.915301
  18. Elife. 2022 06 13. pii: e75844. [Epub ahead of print]11
    RNA-binding proteins direct myogenic cell fate decisions.
    Joshua R Wheeler, Oscar N Whitney, Thomas O Vogler, Eric D Nguyen, Bradley Pawlikowski, Evan Lester, Alicia Cutler, Tiffany Elston, Nicole Dalla Betta, Kevin R Parker, Kathryn E Yost, Hannes Vogel, Thomas A Rando, Howard Y Chang, Aaron M Johnson, Roy Parker, Bradley B Olwin.
      RNA-binding proteins (RBPs), essential for skeletal muscle regeneration, cause muscle degeneration and neuromuscular disease when mutated. Why mutations in these ubiquitously expressed RBPs orchestrate complex tissue regeneration and direct cell fate decisions in skeletal muscle remains poorly understood. Single-cell RNA-sequencing of regenerating Mus musculus skeletal muscle reveals that RBP expression, including the expression of many neuromuscular disease-associated RBPs, is temporally regulated in skeletal muscle stem cells and correlates with specific stages of myogenic differentiation. By combining machine learning with RBP engagement scoring, we discovered that the neuromuscular disease-associated RBP Hnrnpa2b1 is a differentiation-specifying regulator of myogenesis that controls myogenic cell fate transitions during terminal differentiation in mice. The timing of RBP expression specifies cell fate transitions by providing post-transcriptional regulation of messenger RNAs that coordinate stem cell fate decisions during tissue regeneration.
    Keywords:  RNA splicing; RNA-binding protein; mouse; post-transcriptional regulation; regeneration; regenerative medicine; skeletal muscle; splicing network; stem cells
    DOI:  https://doi.org/10.7554/eLife.75844
  19. Nat Rev Genet. 2022 Jun 17.
    Measuring biological age using omics data.
    Jarod Rutledge, Hamilton Oh, Tony Wyss-Coray.
      Age is the key risk factor for diseases and disabilities of the elderly. Efforts to tackle age-related diseases and increase healthspan have suggested targeting the ageing process itself to 'rejuvenate' physiological functioning. However, achieving this aim requires measures of biological age and rates of ageing at the molecular level. Spurred by recent advances in high-throughput omics technologies, a new generation of tools to measure biological ageing now enables the quantitative characterization of ageing at molecular resolution. Epigenomic, transcriptomic, proteomic and metabolomic data can be harnessed with machine learning to build 'ageing clocks' with demonstrated capacity to identify new biomarkers of biological ageing.
    DOI:  https://doi.org/10.1038/s41576-022-00511-7
  20. Skelet Muscle. 2022 Jun 11. 12(1): 13
    The influence of age, sex, and exercise on autophagy, mitophagy, and lysosome biogenesis in skeletal muscle.
    Matthew Triolo, Ashley N Oliveira, Rita Kumari, David A Hood.
       BACKGROUND: Aging decreases skeletal muscle mass and quality. Maintenance of healthy muscle is regulated by a balance between protein and organellar synthesis and their degradation. The autophagy-lysosome system is responsible for the selective degradation of protein aggregates and organelles, such as mitochondria (i.e., mitophagy). Little data exist on the independent and combined influence of age, biological sex, and exercise on the autophagy system and lysosome biogenesis. The purpose of this study was to characterize sex differences in autophagy and lysosome biogenesis in young and aged muscle and to determine if acute exercise influences these processes.
    METHODS: Young (4-6 months) and aged (22-24 months) male and female mice were assigned to a sedentary or an acute exercise group. Mitochondrial content, the autophagy-lysosome system, and mitophagy were measured via protein analysis. A TFEB-promoter-construct was utilized to examine Tfeb transcription, and nuclear-cytosolic fractions allowed us to examine TFEB localization in sedentary and exercised muscle with age and sex.
    RESULTS: Our results indicate that female mice, both young and old, had more mitochondrial protein than age-matched males. However, mitochondria in the muscle of females had a reduced respiratory capacity. Mitochondrial content was only reduced with age in the male cohort. Young female mice had a greater abundance of autophagy, mitophagy, and lysosome proteins than young males; however, increases were evident with age irrespective of sex. Young sedentary female mice had indices of greater autophagosomal turnover than male counterparts. Exhaustive exercise was able to stimulate autophagic clearance solely in young male mice. Similarly, nuclear TFEB protein was enhanced to a greater extent in young male, compared to young female mice following exercise, but no changes were observed in aged mice. Finally, TFEB-promoter activity was upregulated following exercise in both young and aged muscle.
    CONCLUSIONS: The present study demonstrates that biological sex influences mitochondrial homeostasis, the autophagy-lysosome system, and mitophagy in skeletal muscle with age. Furthermore, our data suggest that young male mice have a more profound ability to activate these processes with exercise than in the other groups. Ultimately, this may contribute to a greater remodeling of muscle in response to exercise training in males.
    Keywords:  Aging; Autophagy; Lysosomes; Mitophagy; Muscle; Sex differences; TFEB
    DOI:  https://doi.org/10.1186/s13395-022-00296-7
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