bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022–04–24
twenty-six papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. What Is the Role of Mitochondrial Fission in Neurologic Disease?
  2. Multisystem Mitochondrial Disease Associated With a Mare m.10000G>A Mitochondrial tRNA Gly (MT-TG) Variant.
  3. Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration.
  4. Mitochondrial Respiratory Chain Dysfunction-A Hallmark Pathology of Idiopathic Parkinson's Disease?
  5. Organization and expression of the mammalian mitochondrial genome.
  6. Editorial: Mitochondrial Dysfunction in Stroke.
  7. SGPL1 stimulates VPS39 recruitment to the mitochondria in MICU1 deficient cells.
  8. Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
  9. Multicentric Standardization of Protocols for the Diagnosis of Human Mitochondrial Respiratory Chain Defects.
  10. Barth Syndrome Cardiomyopathy: An Update.
  11. Automated quantitative high-throughput multiplex immunofluorescence pipeline to evaluate OXPHOS defects in formalin-fixed human prostate tissue.
  12. Improving Mitochondrial Function in Viral Infection: Targeting Cellular Metabolism.
  13. The PPR domain of mitochondrial RNA polymerase is an exoribonuclease required for mtDNA replication in Drosophila melanogaster.
  14. Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation.
  15. Mitochondrial fusion- and fission-related protein expression in the regulation of skeletal muscle mass.
  16. Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy.
  17. Reduction of mtDNA heteroplasmy in mitochondrial replacement therapy by inducing forced mitophagy.
  18. Mechanisms and Therapeutic Effects of Benzoquinone Ring Analogs in Primary CoQ Deficiencies.
  19. The pattern of retinal ganglion cell loss in Wolfram syndrome is distinct from mitochondrial optic neuropathies.
  20. The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a Paclitaxel-Induced Drosophila Model of Peripheral Neuropathy.
  21. Rutaecarpine Promotes Adipose Thermogenesis and Protects against HFD-Induced Obesity via AMPK/PGC-1α Pathway.
  22. Paeoniflorin Alleviates Skeletal Muscle Atrophy in Ovariectomized Mice through the ERα/NRF1 Mitochondrial Biogenesis Pathway.
  23. Metabolic pathways utilized by the porcine conceptus, uterus, and placenta.
  24. A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response.
  25. Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease.
  26. Supraphysiological activation of TAK1 promotes skeletal muscle growth and mitigates neurogenic atrophy.
  1. Neurology. 2022 Apr 19. 98(16): 662-668
    What Is the Role of Mitochondrial Fission in Neurologic Disease?
    Eduardo Benarroch.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000200233
  2. Front Neurol. 2022 ;13 795060
    Multisystem Mitochondrial Disease Associated With a Mare m.10000G>A Mitochondrial tRNA Gly (MT-TG) Variant.
    Haiyan Yang, Victor Wei Zhang, Liang Ai, Siyi Gan, Liwen Wu.
       Background: Mitochondrial diseases are clinically heterogeneous, can occur at any age, and can manifest with a wide range of clinical symptoms. They can involve any organ or tissue, characteristically involve multiple systems, typically affecting organs that are highly dependent on aerobic metabolism, and making a definitive molecular diagnosis of a mitochondrial disorder is challenging.
    Methods: Clinical data of the proband and his family members were gathered in a retrospective study. Whole-exome sequencing and full-length sequencing of the mitochondrial genome that were performed on peripheral blood, urine, and oral mucosa cells were applied for genetic analysis.
    Results: In this study, we reported a childhood-onset mitochondrial phenotype in a 13-year-old patient. Analysis of the next-generation sequencing data of the nuclear genome and the full-length sequencing of the mitochondrial genome revealed the rare m.10000G>A variant in MT-TG that was present at variable heteroplasmy levels across tissue types: 32.7% in the blood, 56.15% in urinary epithelial cells, and 27.3% in oral mucosa cells. No variant was found in the peripheral blood of his mother and sister. No pathogenic mutation of nDNA was found.
    Conclusion: Our results added evidence that the de novo m.10000G>A variation in the highly conserved sequence of MT-TG appears to suggest a childhood-onset mitochondrial phenotype in the 13-year-old patient, thus broadening the genotypic interpretation of mitochondrial DNA-related diseases.
    Keywords:  children; m.10000G>A; mitochondrial disease; mitochondrial tRNA Gly; neurology—clinical
    DOI:  https://doi.org/10.3389/fneur.2022.795060
  3. Neuron. 2022 Apr 15. pii: S0896-6273(22)00251-3. [Epub ahead of print]
    Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration.
    Xiu-Tang Cheng, Ning Huang, Zu-Hang Sheng.
      Mitochondria generate ATP essential for neuronal growth, function, and regeneration. Due to their polarized structures, neurons face exceptional challenges to deliver mitochondria to and maintain energy homeostasis throughout long axons and terminal branches where energy is in high demand. Chronic mitochondrial dysfunction accompanied by bioenergetic failure is a pathological hallmark of major neurodegenerative diseases. Brain injury triggers acute mitochondrial damage and a local energy crisis that accelerates neuron death. Thus, mitochondrial maintenance defects and axonal energy deficits emerge as central problems in neurodegenerative disorders and brain injury. Recent studies have started to uncover the intrinsic mechanisms that neurons adopt to maintain (or reprogram) axonal mitochondrial density and integrity, and their bioenergetic capacity, upon sensing energy stress. In this review, we discuss recent advances in how neurons maintain a healthy pool of axonal mitochondria, as well as potential therapeutic strategies that target bioenergetic restoration to power neuronal survival, function, and regeneration.
    Keywords:  axonal transport; bioenergetic failure; brain injury; energy deficits; energy metabolism; energy recovery; ischemia; mitochondrial anchoring; mitochondrial quality control; neurodegeneration
    DOI:  https://doi.org/10.1016/j.neuron.2022.03.015
  4. Front Cell Dev Biol. 2022 ;10 874596
    Mitochondrial Respiratory Chain Dysfunction-A Hallmark Pathology of Idiopathic Parkinson's Disease?
    Irene H Flønes, Charalampos Tzoulis.
      Parkinson's disease (PD) is the most common age-dependent neurodegenerative synucleinopathy. Loss of dopaminergic neurons of the substantia nigra pars compacta, together with region- and cell-specific aggregations of α -synuclein are considered main pathological hallmarks of PD, but its etiopathogenesis remains largely unknown. Mitochondrial dysfunction, in particular quantitative and/or functional deficiencies of the mitochondrial respiratory chain (MRC), has been associated with the disease. However, after decades of research in this field, the pervasiveness and anatomical extent of MRC dysfunction in PD remain largely unknown. Moreover, it is not known whether the observed MRC defects are pathogenic, compensatory responses, or secondary epiphenomena. In this perspective, we give an overview of current evidence for MRC dysfunction in PD, highlight pertinent knowledge gaps, and propose potential strategies for future research.
    Keywords:  Parkinson's disease; mitochondria; mitochondrial complex I; neurodegeneration; oxidative phosphorylation
    DOI:  https://doi.org/10.3389/fcell.2022.874596
  5. Nat Rev Genet. 2022 Apr 22.
    Organization and expression of the mammalian mitochondrial genome.
    Oliver Rackham, Aleksandra Filipovska.
      The mitochondrial genome encodes core subunits of the respiratory chain that drives oxidative phosphorylation and is, therefore, essential for energy conversion. Advances in high-throughput sequencing technologies and cryoelectron microscopy have shed light on the structure and organization of the mitochondrial genome and revealed unique mechanisms of mitochondrial gene regulation. New animal models of impaired mitochondrial protein synthesis have shown how the coordinated regulation of the cytoplasmic and mitochondrial translation machineries ensures the correct assembly of the respiratory chain complexes. These new technologies and disease models are providing a deeper understanding of mitochondrial genome organization and expression and of the diseases caused by impaired energy conversion, including mitochondrial, neurodegenerative, cardiovascular and metabolic diseases. They also provide avenues for the development of treatments for these conditions.
    DOI:  https://doi.org/10.1038/s41576-022-00480-x
  6. Front Aging Neurosci. 2022 ;14 888952
    Editorial: Mitochondrial Dysfunction in Stroke.
    Feng Yan, Hailiang Tang, Lin Wang, Lei Huang, John Zhang.
      
    Keywords:  mitochondrial dynamics; mitochondrial dysfunction; mitochondrial transfer; mitophagy and apoptosis; stroke
    DOI:  https://doi.org/10.3389/fnagi.2022.888952
  7. Mol Metab. 2022 Apr 19. pii: S2212-8778(22)00072-2. [Epub ahead of print] 101503
    SGPL1 stimulates VPS39 recruitment to the mitochondria in MICU1 deficient cells.
    Joshua Jackson, Lena Wischhof, Enzo Scifo, Anna Pellizzer, Yiru Wang, Antonia Piazzesi, Debora Gentile, Sana Siddig, Miriam Stork, Chris E Hopkins, Kristian Händler, Joachim Weis, Andreas Roos, Joachim L Schultze, Pierluigi Nicotera, Dan Ehninger, Daniele Bano.
       OBJECTIVE: Mitochondrial "retrograde" signaling may stimulate organelle biogenesis as a compensatory adaptation to aberrant activity of the oxidative phosphorylation (OXPHOS) system. To maintain energy-consuming processes in OXPHOS deficient cells, alternative metabolic pathways are functionally coupled to the degradation, recycling and redistribution of biomolecules across distinct intracellular compartments. While transcriptional regulation of mitochondrial network expansion has been the focus of many studies, the molecular mechanisms promoting mitochondrial maintenance in energy-deprived cells remain poorly investigated.
    METHODS: We performed transcriptomics, quantitative proteomics and lifespan assays to identify pathways that are mechanistically linked to mitochondrial network expansion and homeostasis in Caenorhabditis elegans lacking the mitochondrial calcium uptake protein 1 (MICU-1/MICU1). To support our findings, we carried out biochemical and image analyses in mammalian cells and mouse-derived tissues.
    RESULTS: We report that micu-1(null) mutations impair the OXPHOS system and promote C. elegans longevity through a transcriptional program that is independent of the mitochondrial calcium uniporter MCU-1/MCU and the essential MCU regulator EMRE-1/EMRE. We identify sphingosine phosphate lyase SPL-1/SGPL1 and the ATFS-1-target HOPS complex subunit VPS-39/VPS39 as critical lifespan modulators of micu-1(null) mutant animals. Cross-species investigation indicates that SGPL1 upregulation stimulates VPS39 recruitment to the mitochondria, thereby enhancing mitochondria-lysosome contacts. Consistently, VPS39 downregulation compromises mitochondrial network maintenance and basal autophagic flux in MICU1 deficient cells. In mouse-derived muscles, we show that VPS39 recruitment to the mitochondria may represent a common signature associated with altered OXPHOS system.
    CONCLUSIONS: Our findings reveal a previously unrecognized SGPL1/VPS39 axis that stimulates intracellular organelle interactions and sustains autophagy and mitochondrial homeostasis in OXPHOS deficient cells.
    Keywords:  Caenorhabditis elegans; MICU1; VPS39; autophagy; longevity; mitochondria; sphingosine signaling
    DOI:  https://doi.org/10.1016/j.molmet.2022.101503
  8. Int J Mol Sci. 2022 Apr 08. pii: 4149. [Epub ahead of print]23(8):
    Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
    Liza Douiev, Chaya Miller, Guy Keller, Hadar Benyamini, Bassam Abu-Libdeh, Ann Saada.
      Cytochrome c oxidase (COX), a multimeric protein complex, is the final electron acceptor in the mitochondrial electron transfer chain. Primary COX deficiency, caused by mutations in either mitochondrial DNA or nuclear-encoded genes, is a heterogenous group of mitochondrial diseases with a wide range of presentations, ranging from fatal infantile to subtler. We previously reported a patient with primary COX deficiency due to a pathogenic variant in COX4I1 (encoding the common isoform of COX subunit 4, COX4-1), who presented with bone marrow failure, genomic instability, and short stature, mimicking Fanconi anemia (FA). In the present study, we demonstrated that accumulative DNA damage coincided primarily with proliferative cells in the patient's fibroblasts and in COX4i1 knockdown cells. Expression analysis implicated a reduction in DNA damage response pathways, which was verified by demonstrating impaired recovery from genotoxic insult and decreased DNA repair. The premature senescence of the COX4-1-deficient cells prevented us from undertaking additional studies; nevertheless, taken together, our results indicate replicative stress and impaired nuclear DNA damage response in COX4-1 deficiency. Interestingly, our in vitro findings recapitulated the patient's presentation and present status.
    Keywords:  COX4i1; DNA damage; cytochrome c oxidase; mitochondria; mitochondrial respiratory chain; replicative stress
    DOI:  https://doi.org/10.3390/ijms23084149
  9. Antioxidants (Basel). 2022 Apr 08. pii: 741. [Epub ahead of print]11(4):
    Multicentric Standardization of Protocols for the Diagnosis of Human Mitochondrial Respiratory Chain Defects.
    Nuria Bujan, Constanza Morén, Francesc J García-García, Alberto Blázquez, Clara Carnicer, Ana Belén Cortés, Cristina González, Ester López-Gallardo, Ester Lozano, Sonia Moliner, Laura Gort, Ester Tobías, Aitor Delmiro, Miguel Ángel Martin, Miguel Ángel Fernández-Moreno, Eduardo Ruiz-Pesini, Elena Garcia-Arumí, Juan Carlos Rodríguez-Aguilera, Glòria Garrabou.
      The quantification of mitochondrial respiratory chain (MRC) enzymatic activities is essential for diagnosis of a wide range of mitochondrial diseases, ranging from inherited defects to secondary dysfunctions. MRC lesion is frequently linked to extended cell damage through the generation of proton leak or oxidative stress, threatening organ viability and patient health. However, the intrinsic challenge of a methodological setup and the high variability in measuring MRC enzymatic activities represents a major obstacle for comparative analysis amongst institutions. To improve experimental and statistical robustness, seven Spanish centers with extensive experience in mitochondrial research and diagnosis joined to standardize common protocols for spectrophotometric MRC enzymatic measurements using minimum amounts of sample. Herein, we present the detailed protocols, reference ranges, tips and troubleshooting methods for experimental and analytical setups in different sample preparations and tissues that will allow an international standardization of common protocols for the diagnosis of MRC defects. Methodological standardization is a crucial step to obtain comparable reference ranges and international standards for laboratory assays to set the path for further diagnosis and research in the field of mitochondrial diseases.
    Keywords:  diagnosis; enzyme activity; mitochondrial disease; mitochondrial respiratory chain; standardization
    DOI:  https://doi.org/10.3390/antiox11040741
  10. Genes (Basel). 2022 Apr 08. pii: 656. [Epub ahead of print]13(4):
    Barth Syndrome Cardiomyopathy: An Update.
    Jing Pang, Yutong Bao, Kalia Mitchell-Silbaugh, Jennifer Veevers, Xi Fang.
      Barth syndrome (BTHS) is an X-linked mitochondrial lipid disorder caused by mutations in the TAFAZZIN (TAZ) gene, which encodes a mitochondrial acyltransferase/transacylase required for cardiolipin (CL) biosynthesis. Cardiomyopathy is a major clinical feature of BTHS. During the past four decades, we have witnessed many landmark discoveries that have led to a greater understanding of clinical features of BTHS cardiomyopathy and their molecular basis, as well as the therapeutic targets for this disease. Recently published Taz knockout mouse models provide useful experimental models for studying BTHS cardiomyopathy and testing potential therapeutic approaches. This review aims to summarize key findings of the clinical features, molecular mechanisms, and potential therapeutic approaches for BTHS cardiomyopathy, with particular emphasis on the most recent studies.
    Keywords:  Barth syndrome; TAFAZZIN; cardiolipin; cardiomyopathy
    DOI:  https://doi.org/10.3390/genes13040656
  11. Sci Rep. 2022 Apr 22. 12(1): 6660
    Automated quantitative high-throughput multiplex immunofluorescence pipeline to evaluate OXPHOS defects in formalin-fixed human prostate tissue.
    Ashwin Sachdeva, Claire A Hart, Christopher D Carey, Amy E Vincent, Laura C Greaves, Rakesh Heer, Pedro Oliveira, Michael D Brown, Noel W Clarke, Doug M Turnbull.
      Advances in multiplex immunofluorescence (mIF) and digital image analysis has enabled simultaneous assessment of protein defects in electron transport chain components. However, current manual methodology is time consuming and labour intensive. Therefore, we developed an automated high-throughput mIF workflow for quantitative single-cell level assessment of formalin fixed paraffin embedded tissue (FFPE), leveraging tyramide signal amplification on a Ventana Ultra platform coupled with automated multispectral imaging on a Vectra 3 platform. Utilising this protocol, we assessed the mitochondrial oxidative phosphorylation (OXPHOS) protein alterations in a cohort of benign and malignant prostate samples. Mitochondrial OXPHOS plays a critical role in cell metabolism, and OXPHOS perturbation is implicated in carcinogenesis. Marked inter-patient, intra-patient and spatial cellular heterogeneity in OXPHOS protein abundance was observed. We noted frequent Complex IV loss in benign prostate tissue and Complex I loss in age matched prostate cancer tissues. Malignant regions within prostate cancer samples more frequently contained cells with low Complex I & IV and high mitochondrial mass in comparison to benign-adjacent regions. This methodology can now be applied more widely to study the frequency and distribution of OXPHOS alterations in formalin-fixed tissues, and their impact on long-term clinical outcomes.
    DOI:  https://doi.org/10.1038/s41598-022-10588-z
  12. Am J Respir Cell Mol Biol. 2022 Apr 20.
    Improving Mitochondrial Function in Viral Infection: Targeting Cellular Metabolism.
    Brydie R Huckestein, John F Alcorn.
      
    DOI:  https://doi.org/10.1165/rcmb.2022-0096ED
  13. Nat Cell Biol. 2022 Apr 21.
    The PPR domain of mitochondrial RNA polymerase is an exoribonuclease required for mtDNA replication in Drosophila melanogaster.
    Yi Liu, Zhe Chen, Zong-Heng Wang, Katherine M Delaney, Juanjie Tang, Mehdi Pirooznia, Duck-Yeon Lee, Ilker Tunc, Yuesheng Li, Hong Xu.
      Mitochondrial DNA (mtDNA) replication and transcription are of paramount importance to cellular energy metabolism. Mitochondrial RNA polymerase is thought to be the primase for mtDNA replication. However, it is unclear how this enzyme, which normally transcribes long polycistronic RNAs, can produce short RNA oligonucleotides to initiate mtDNA replication. We show that the PPR domain of Drosophila mitochondrial RNA polymerase (PolrMT) has 3'-to-5' exoribonuclease activity, which is indispensable for PolrMT to synthesize short RNA oligonucleotides and prime DNA replication in vitro. An exoribonuclease-deficient mutant, PolrMTE423P, partially restores mitochondrial transcription but fails to support mtDNA replication when expressed in PolrMT-mutant flies, indicating that the exoribonuclease activity is necessary for mtDNA replication. In addition, overexpression of PolrMTE423P in adult flies leads to severe neuromuscular defects and a marked increase in mtDNA transcript errors, suggesting that exoribonuclease activity may contribute to the proofreading of mtDNA transcription.
    DOI:  https://doi.org/10.1038/s41556-022-00887-y
  14. Mov Disord. 2022 Apr 23.
    Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation.
    Kobi Wasner, Semra Smajic, Jenny Ghelfi, Sylvie Delcambre, Cesar A Prada-Medina, Evelyn Knappe, Giuseppe Arena, Patrycja Mulica, Gideon Agyeah, Aleksandar Rakovic, Ibrahim Boussaad, Katja Badanjak, Jochen Ohnmacht, Jean-Jacques Gérardy, Masashi Takanashi, Joanne Trinh, Michel Mittelbronn, Nobutaka Hattori, Christine Klein, Paul Antony, Philip Seibler, Malte Spielmann, Sandro L Pereira, Anne Grünewald.
       BACKGROUND: Mutations in the E3 ubiquitin ligase parkin cause autosomal recessive Parkinson's disease (PD). Together with PTEN-induced kinase 1 (PINK1), parkin regulates the clearance of dysfunctional mitochondria. New mitochondria are generated through an interplay of nuclear- and mitochondrial-encoded proteins, and recent studies suggest that parkin influences this process at both levels. In addition, parkin was shown to prevent mitochondrial membrane permeability, impeding mitochondrial DNA (mtDNA) escape and subsequent neuroinflammation. However, parkin's regulatory roles independent of mitophagy are not well described in patient-derived neurons.
    OBJECTIVES: We sought to investigate parkin's role in preventing neuronal mtDNA dyshomeostasis, release, and glial activation at the endogenous level.
    METHODS: We generated induced pluripotent stem cell (iPSC)-derived midbrain neurons from PD patients with parkin (PRKN) mutations and healthy controls. Live-cell imaging, proteomic, mtDNA integrity, and gene expression analyses were employed to investigate mitochondrial biogenesis and genome maintenance. To assess neuroinflammation, we performed single-nuclei RNA sequencing in postmortem tissue and quantified interleukin expression in mtDNA/lipopolysaccharides (LPS)-treated iPSC-derived neuron-microglia co-cultures.
    RESULTS: Neurons from patients with PRKN mutations revealed deficits in the mitochondrial biogenesis pathway, resulting in mtDNA dyshomeostasis. Moreover, the energy sensor sirtuin 1, which controls mitochondrial biogenesis and clearance, was downregulated in parkin-deficient cells. Linking mtDNA disintegration to neuroinflammation, in postmortem midbrain with PRKN mutations, we confirmed mtDNA dyshomeostasis and detected an upregulation of microglia overexpressing proinflammatory cytokines. Finally, parkin-deficient neuron-microglia co-cultures elicited an enhanced immune response when exposed to mtDNA/LPS.
    CONCLUSIONS: Our findings suggest that parkin coregulates mitophagy, mitochondrial biogenesis, and mtDNA maintenance pathways, thereby protecting midbrain neurons from neuroinflammation and degeneration. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  Parkinson's disease; induced pluripotent stem cells; mitochondrial DNA; parkin; neuroinflammation
    DOI:  https://doi.org/10.1002/mds.29025
  15. Physiol Rep. 2022 Apr;10(8): e15281
    Mitochondrial fusion- and fission-related protein expression in the regulation of skeletal muscle mass.
    Daiki Nakano, Shuichi Machida.
      Mitochondria in the skeletal muscle are essential for maintaining metabolic plasticity and function. Mitochondrial quality control encompasses the dynamics of the biogenesis and remodeling of mitochondria, characterized by the constant fission and fusion of mitochondria in response to metabolic stressors. However, the roles of mitochondrial fission or fusion in muscle hypertrophy and atrophy remain unclear. The aim of this study was to determine whether mitochondrial fusion and fission events are influenced by muscle hypertrophy or atrophy stimulation. Twenty-six male F344 rats were randomly assigned to a control group or were subjected to up to 14 days of either plantaris overload (via tenotomy of the gastrocnemius and soleus muscles; hypertrophy group) or hindlimb cast immobilization (atrophy group). After 14 days of treatment, plantaris muscle samples were collected to determine the expression levels of mitochondrial fusion- and fission-related proteins. Muscle weight and total muscle protein content increased following plantaris overload in the hypertrophy group, but decreased following immobilization for 14 days in the atrophy group. In the hypertrophied muscle, the level of activated dynamin-related protein 1 (Drp1), phosphorylated at Ser616, significantly increased by 25.8% (p = 0.014). Moreover, the protein expression level of mitochondrial fission factor significantly decreased by 36.5% in the hypertrophy group compared with that of the control group (p = 0.017). In contrast, total Drp1 level significantly decreased in the atrophied plantaris muscle (p = 0.011). Our data suggest that mitochondrial fission events may be influenced by both muscle hypertrophy and atrophy stimulation, and that mitochondrial fission- related protein Drp1 plays an important role in the regulation of skeletal muscle in response to mechanical stimulation.
    Keywords:  Drp1; atrophy; hypertrophy; mitochondrial quality control
    DOI:  https://doi.org/10.14814/phy2.15281
  16. Pharmaceutics. 2022 Mar 31. pii: 757. [Epub ahead of print]14(4):
    Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy.
    Rúben Faria, Milan Paul, Swati Biswas, Eric Vivès, Prisca Boisguérin, Ângela Sousa, Diana Costa.
      Together with the nucleus, the mitochondrion has its own genome. Mutations in mitochondrial DNA are responsible for a variety of disorders, including neurodegenerative diseases and cancer. Current therapeutic approaches are not effective. In this sense, mitochondrial gene therapy emerges as a valuable and promising therapeutic tool. To accomplish this goal, the design/development of a mitochondrial-specific gene delivery system is imperative. In this work, we explored the ability of novel polymer- and peptide-based systems for mitochondrial targeting, gene delivery, and protein expression, performing a comparison between them to reveal the most adequate system for mitochondrial gene therapy. Therefore, we synthesized a novel mitochondria-targeting polymer (polyethylenimine-dequalinium) to load and complex a mitochondrial-gene-based plasmid. The polymeric complexes exhibited physicochemical properties and cytotoxic profiles dependent on the nitrogen-to-phosphate-group ratio (N/P). A fluorescence confocal microscopy study revealed the mitochondrial targeting specificity of polymeric complexes. Moreover, transfection mediated by polymer and peptide delivery systems led to gene expression in mitochondria. Additionally, the mitochondrial protein was produced. A comparative study between polymeric and peptide/plasmid DNA complexes showed the great capacity of peptides to complex pDNA at lower N/P ratios, forming smaller particles bearing a positive charge, with repercussions on their capacity for cellular transfection, mitochondria targeting and, ultimately, gene delivery and protein expression. This report is a significant contribution to the implementation of mitochondrial gene therapy, instigating further research on the development of peptide-based delivery systems towards clinical translation.
    Keywords:  PEI-based complexes; cell-penetrating peptides; mitochondria targeting; mitochondrial DNA diseases; mitochondrial gene therapy; nanodelivery systems
    DOI:  https://doi.org/10.3390/pharmaceutics14040757
  17. Nat Biomed Eng. 2022 Apr 18.
    Reduction of mtDNA heteroplasmy in mitochondrial replacement therapy by inducing forced mitophagy.
    Xiao-Yan Fan, Lei Guo, Lei-Ning Chen, Shen Yin, Jiarong Wen, Sen Li, Jun-Yu Ma, Tao Jing, Man-Xi Jiang, Xiao-Hong Sun, Meilan Chen, Feng Wang, Zhen-Bo Wang, Chang-Fa Zhang, Xing-Hua Wang, Zhao-Jia Ge, Chun Hu, Lizhang Zeng, Wei Shen, Qing-Yuan Sun, Xiang-Hong Ou, Shi-Ming Luo.
      Mitochondrial replacement therapy (MRT) has been used to prevent maternal transmission of disease-causing mutations in mitochondrial DNA (mtDNA). However, because MRT requires nuclear transfer, it carries the risk of mtDNA carryover and hence of the reversion of mtDNA to pathogenic levels owing to selective replication and genetic drift. Here we show in HeLa cells, mouse embryos and human embryos that mtDNA heteroplasmy can be reduced by pre-labelling the mitochondrial outer membrane of a donor zygote via microinjection with an mRNA coding for a transmembrane peptide fused to an autophagy receptor, to induce the degradation of the labelled mitochondria via forced mitophagy. Forced mitophagy reduced mtDNA carryover in newly reconstructed embryos after MRT, and had negligible effects on the growth curve, reproduction, exercise capacity and other behavioural characteristics of the offspring mice. The induction of forced mitophagy to degrade undesired donor mtDNA may increase the clinical feasibility of MRT and could be extended to other nuclear transfer techniques.
    DOI:  https://doi.org/10.1038/s41551-022-00881-7
  18. Antioxidants (Basel). 2022 Mar 30. pii: 665. [Epub ahead of print]11(4):
    Mechanisms and Therapeutic Effects of Benzoquinone Ring Analogs in Primary CoQ Deficiencies.
    Alba Pesini, Agustin Hidalgo-Gutierrez, Catarina M Quinzii.
      Coenzyme Q (CoQ) is a conserved polyprenylated lipid composed of a redox-active benzoquinone ring and a long polyisoprenyl tail that serves as a membrane anchor. CoQ biosynthesis involves multiple steps, including multiple modifications of the precursor ring 4-hydroxybenzoic acid. Mutations in the enzymes involved in CoQ biosynthesis pathway result in primary coenzyme Q deficiencies, mitochondrial disorders whose clinical heterogenicity reflects the multiple biological function of CoQ. Patients with these disorders do not always respond to CoQ supplementation, and CoQ analogs have not been successful as alternative approaches. Progress made in understanding the CoQ biosynthesis pathway and studies of supplementation with 4-hydroxybenzoic acid ring analogs have opened a new area in the field of primary CoQ deficiencies treatment. Here, we will review these studies, focusing on efficacy of the different 4-hydroxybenzoic acid ring analogs, models in which they have been tested, and their mechanisms of action. Understanding how these compounds ameliorate biochemical, molecular, and/or clinical phenotypes of CoQ deficiencies is important to develop the most rational treatment for CoQ deficient patients, depending on their molecular defects.
    Keywords:  4-hydroxybenzoic acid; analogs; coenzyme Q10; mitochondria; preclinical models
    DOI:  https://doi.org/10.3390/antiox11040665
  19. Am J Ophthalmol. 2022 Apr 19. pii: S0002-9394(22)00119-2. [Epub ahead of print]
    The pattern of retinal ganglion cell loss in Wolfram syndrome is distinct from mitochondrial optic neuropathies.
    Piero Barboni, Giulia Amore, Maria Lucia Cascavilla, Marco Battista, Giulio Frontino, Martina Romagnoli, Leonardo Caporali, Cristina Baldoli, Laura Ludovica Gramegna, Elisa Sessagesimi, Riccardo Bonfanti, Andrea Romagnoli, Roberta Scotti, Maria Brambati, Michele Carbonelli, Vincenzo Starace, Claudio Fiorini, Roberta Panebianco, Vincenzo Parisi, Caterina Tonon, Francesco Bandello, Valerio Carelli, Chiara La Morgia.
       PURPOSE: To describe the clinical phenotype of a cohort of Wolfram syndrome (WS) patients, focusing on the pattern of optic atrophy correlated with brain MRI measurements, as compared to OPA1-associated mitochondrial optic neuropathy.
    DESIGN: Retrospective, comparative cohort study METHODS: 25 WS patients and 33 age-matched patients affected by OPA1-related Dominant Optic Atrophy (DOA). Ophthalmological, neurological, endocrinological and MRI data from WS patients were retrospectively retrieved. Ophthalmological data were compared to OPA1-related DOA and further analyzed for age dependency dividing patients in age quartiles. In a subgroup of WS patients, we correlated the structural damage assessed by optical coherence tomography (OCT) with brain MRI morphological measurements. Visual acuity (VA), visual field mean defect (MD), retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness assessed by OCT, MRI morphological measurements of anterior and posterior visual pathways.
    RESULTS: In our cohort optic atrophy was present in 100% of WS patients. VA, MD and RNFL thickness loss were worse in WS patients with a faster decline since early age as compared to DOA patients, who displayed a more stable visual function over the years. Conversely, GCL sectors were overall thinner in DOA patients since early age compared to WS, in which GCL thickness started to decline later in life. The neuroradiological sub-analysis on 11 WS patients exhibited bilateral thinning of the anterior optic pathway, especially prechiasmatic optic nerves and optic tracts. Optic tract thinning was significantly correlated with the GCL thickness but not with RNFL parameters.
    CONCLUSIONS: Our results showed a generally more severe and diffuse degeneration of both anterior and posterior visual pathways in WS, with fast deterioration of visual function and structural OCT parameters since early age. The pattern observed at OCT suggests that retinal ganglion cells axonal degeneration (i.e. RNFL) precedes of about a decade the cellular body atrophy (i.e. GCL). This differs substantially from DOA, in which a more stable visual function is evident with predominant early loss of GCL, indirectly supporting the lack of a primary mitochondrial dysfunction in WS.
    Keywords:  Wolfram syndrome; ganglion cells; optic neuropathy
    DOI:  https://doi.org/10.1016/j.ajo.2022.03.019
  20. Biomedicines. 2022 Apr 07. pii: 863. [Epub ahead of print]10(4):
    The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a Paclitaxel-Induced Drosophila Model of Peripheral Neuropathy.
    Hye-Ji Jang, Young-Yeon Kim, Kang-Min Lee, Jung-Eun Shin, Jeanho Yun.
      Paclitaxel is a widely used anticancer drug that induces dose-limiting peripheral neuropathy. Mitochondrial dysfunction has been implicated in paclitaxel-induced neuronal damage and in the onset of peripheral neuropathy. We have previously shown that the expression of PINK1, a key mediator of mitochondrial quality control, ameliorated the paclitaxel-induced thermal hyperalgesia phenotype and restored mitochondrial homeostasis in Drosophila larvae. In this study, we show that the small-molecule PINK1 activator niclosamide exhibits therapeutic potential for paclitaxel-induced peripheral neuropathy. Specifically, niclosamide cotreatment significantly ameliorated the paclitaxel-induced thermal hyperalgesia phenotype in Drosophila larvae in a PINK1-dependent manner. Paclitaxel-induced alteration of the dendrite structure of class IV dendritic arborization (C4da) neurons was not reduced upon niclosamide treatment. In contrast, paclitaxel treatment-induced increases in both mitochondrial ROS and aberrant mitophagy levels in C4da neurons were significantly suppressed by niclosamide. In addition, niclosamide suppressed paclitaxel-induced mitochondrial dysfunction in human SH-SY5Y cells in a PINK1-dependent manner. These results suggest that niclosamide alleviates thermal hyperalgesia by attenuating paclitaxel-induced mitochondrial dysfunction. Taken together, our results suggest that niclosamide is a potential candidate for the treatment of paclitaxel-induced peripheral neuropathy with low toxicity in neurons and that targeting mitochondrial dysfunction is a promising strategy for the treatment of chemotherapy-induced peripheral neuropathy.
    Keywords:  PINK1; mitochondrial dysfunction; niclosamide; paclitaxel; peripheral neuropathy
    DOI:  https://doi.org/10.3390/biomedicines10040863
  21. Pharmaceuticals (Basel). 2022 Apr 13. pii: 469. [Epub ahead of print]15(4):
    Rutaecarpine Promotes Adipose Thermogenesis and Protects against HFD-Induced Obesity via AMPK/PGC-1α Pathway.
    Dandan Chen, Yanan Duan, Shuxiang Yu, Xinwen Zhang, Ni Li, Jingya Li.
      Pharmacological activation of adaptive thermogenesis to increase energy expenditure is considered to be a novel strategy for obesity. Peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α), which serves as an inducible co-activator in energy expenditure, is highly expressed in brown adipose tissues (BAT). In this study, we found a PGC-1α transcriptional activator, natural compound rutaecarpine (Rut), which promoted brown adipocytes mitochondrial biogenesis and thermogenesis in vitro. Chronic Rut treatment reduced the body weight gain and mitigated insulin sensitivity through brown and beige adipocyte thermogenesis. Mechanistic study showed that Rut activated the energy metabolic pathway AMP-activated protein kinase (AMPK)/PGC-1α axis, and deficiency of AMPK abolished the beneficial metabolic phenotype of the Rut treatment in vitro and in vivo. In summary, a PGC-1α transcriptional activator Rut was found to activate brown and beige adipose thermogenesis to resist diet-induced obesity through AMPK pathway. Our findings serve as a further understanding of the natural compound in adipose tissue and provides a possible strategy to combat obesity and related metabolic disorders.
    Keywords:  AMP-activated protein kinase; adipocytes; browning; obesity; peroxisome-proliferator-activated receptor γ co-activator-1α; rutaecarpine; thermogenesis
    DOI:  https://doi.org/10.3390/ph15040469
  22. Pharmaceuticals (Basel). 2022 Mar 23. pii: 390. [Epub ahead of print]15(4):
    Paeoniflorin Alleviates Skeletal Muscle Atrophy in Ovariectomized Mice through the ERα/NRF1 Mitochondrial Biogenesis Pathway.
    Ki-Sun Park, Hyungjun Kim, Hye Jin Kim, Kang-In Lee, Seo-Young Lee, Jieun Kim.
      Muscle atrophy in postmenopausal women is caused by estrogen deficiency and a variety of inflammatory factors, including tumor necrosis factor alpha (TNFα). Paeoniflorin (PNF), a natural compound with anti-inflammatory properties, improves estradiol synthesis. Here, we demonstrate that PNF inhibits the progression of TNFα-induced skeletal muscle atrophy after menopause by restoring mitochondrial biosynthesis. Differentiated myoblasts damaged by TNFα were restored by PNF, as evident by the increase in the expression of myogenin (MyoG) and myosin heavy chain 3 (Myh3)-the markers of muscle differentiation. Moreover, diameter of atrophied myotubes was restored by PNF treatment. TNFα-repressed nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) (a major regulator of mitochondrial biosynthesis) were restored by PNF, via regulation by estrogen receptor alpha (ERα), an upregulator of NRF1. This mechanism was confirmed in ovariectomized (OVX) mice with a ~40% reduction in the cross-sectional area of the anterior tibialis muscle. OVX mice administered PNF (100, 300 mg/kg/day) for 12 weeks recovered more than ~20%. Behavioral, rotarod, and inverted screen tests showed that PNF enhances reduced muscle function in OVX mice. ERα restored expression of mitofusin 1 (MFN1) and mitofusin 2 (MFN2) (mitochondrial fusion markers) and dynamin-related protein (DRP1) and fission 1 (FIS1) (mitochondrial fission markers). Therefore, PNF can prevent muscle atrophy in postmenopausal women by inhibiting dysfunctional mitochondrial biogenesis.
    Keywords:  anti-inflammation; estrogen insufficiency; mitochondrial biogenesis; muscle atrophy; muscle differentiation; paeoniflorin; post-menopausal women
    DOI:  https://doi.org/10.3390/ph15040390
  23. Mol Reprod Dev. 2022 Apr 22.
    Metabolic pathways utilized by the porcine conceptus, uterus, and placenta.
    Gregory A Johnson, Heewon Seo, Fuller W Bazer, Guoyao Wu, Avery C Kramer, Bryan A McLendon, Joe W Cain.
      Conceptus elongation and early placentation involve growth and remodeling that requires proliferation and migration of cells. This demands conceptuses expend energy before establishment of a placenta connection and when they are dependent upon components of histotroph secreted or transported into the uterine lumen from the uterus. Glucose and fructose, as well as many amino acids (including arginine, aspartate, glutamine, glutamate, glycine, methionine, and serine), increase in the uterine lumen during the peri-implantation period. Glucose and fructose enter cells via their transporters, SLC2A, SLC2A3, and SLC2A8, and amino acids enter the cells via specific transporters that are expressed by the conceptus trophectoderm. However, porcine conceptuses develop rapidly through extensive cellular proliferation and migration as they elongate and attach to the uterine wall resulting in increased metabolic demands. Therefore, coordination of multiple metabolic biosynthetic pathways is an essential aspect of conceptus development. Oxidative metabolism primarily occurs through the tricarboxylic acid (TCA) cycle and the electron transport chain, but proliferating and migrating cells, like the trophectoderm of pigs, enhance aerobic glycolysis. The glycolytic intermediates from glucose can then be shunted into the pentose phosphate pathway and one-carbon metabolism for the de novo synthesis of nucleotides. A result of aerobic glycolysis is limited availability of pyruvate for maintaining the TCA cycle, and trophectoderm cells likely replenish TCA cycle metabolites primarily through glutaminolysis to convert glutamine into TCA cycle intermediates. The synthesis of ATP, nucleotides, amino acids, and fatty acids through these biosynthetic pathways is essential to support elongation, migration, hormone synthesis, implantation, and early placental development of conceptuses.
    Keywords:  conceptus; fructose; glucose; metabolism; pig; uterus
    DOI:  https://doi.org/10.1002/mrd.23570
  24. Elife. 2022 Apr 22. pii: e71634. [Epub ahead of print]11
    A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response.
    James P Held, Gaomin Feng, Benjamin R Saunders, Claudia V Pereria, Kristopher Burkewitz, Maulik R Patel.
      The mitochondrial unfolded protein response (UPRmt) has emerged as a predominant mechanism that preserves mitochondrial function. Consequently, multiple pathways likely exist to modulate UPRmt. We discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is key to UPRmt regulation in Caenorhabditis elegans. We find that nuclear HOE-1 is necessary and sufficient to robustly activate UPRmt. We show that HOE-1 acts via transcription factors ATFS-1 and DVE-1 that are crucial for UPRmt. Mechanistically, we show that HOE-1 likely mediates its effects via tRNAs, as blocking tRNA export prevents HOE-1-induced UPRmt. Interestingly, we find that HOE-1 does not act via the integrated stress response, which can be activated by uncharged tRNAs, pointing towards its reliance on a new mechanism. Finally, we show that the subcellular localization of HOE-1 is responsive to mitochondrial stress and is subject to negative regulation via ATFS-1. Together, we have discovered a novel RNA-based cellular pathway that modulates UPRmt.
    Keywords:  C. elegans; cell biology
    DOI:  https://doi.org/10.7554/eLife.71634
  25. Cells. 2022 Apr 16. pii: 1363. [Epub ahead of print]11(8):
    Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease.
    Eirini Taouktsi, Eleni Kyriakou, Stefanos Smyrniotis, Fivos Borbolis, Labrina Bondi, Socratis Avgeris, Efstathios Trigazis, Stamatis Rigas, Gerassimos E Voutsinas, Popi Syntichaki.
      Cells engage complex surveillance mechanisms to maintain mitochondrial function and protein homeostasis. LonP1 protease is a key component of mitochondrial quality control and has been implicated in human malignancies and other pathological disorders. Here, we employed two experimental systems, the worm Caenorhabditis elegans and human cancer cells, to investigate and compare the effects of LONP-1/LonP1 deficiency at the molecular, cellular, and organismal levels. Deletion of the lonp-1 gene in worms disturbed mitochondrial function, provoked reactive oxygen species accumulation, and impaired normal processes, such as growth, behavior, and lifespan. The viability of lonp-1 mutants was dependent on the activity of the ATFS-1 transcription factor, and loss of LONP-1 evoked retrograde signaling that involved both the mitochondrial and cytoplasmic unfolded protein response (UPRmt and UPRcyt) pathways and ensuing diverse organismal stress responses. Exposure of worms to triterpenoid CDDO-Me, an inhibitor of human LonP1, stimulated only UPRcyt responses. In cancer cells, CDDO-Me induced key components of the integrated stress response (ISR), the UPRmt and UPRcyt pathways, and the redox machinery. However, genetic knockdown of LonP1 revealed a genotype-specific cellular response and induced apoptosis similar to CDDO-Me treatment. Overall, the mitochondrial dysfunction ensued by disruption of LonP1 elicits adaptive cytoprotective mechanisms that can inhibit cancer cell survival but diversely modulate organismal stress response and aging.
    Keywords:  C. elegans; CDDO-Me; LonP1; aging; cancer; mitochondria
    DOI:  https://doi.org/10.3390/cells11081363
  26. Nat Commun. 2022 Apr 22. 13(1): 2201
    Supraphysiological activation of TAK1 promotes skeletal muscle growth and mitigates neurogenic atrophy.
    Anirban Roy, Ashok Kumar.
      Skeletal muscle mass is regulated through coordinated activation of multiple signaling pathways. TAK1 signalosome has been found to be activated in various conditions of muscle atrophy and hypertrophy. However, the role and mechanisms by which TAK1 regulates skeletal muscle mass remain less understood. Here, we demonstrate that supraphysiological activation of TAK1 in skeletal muscle of adult mice stimulates translational machinery, protein synthesis, and myofiber growth. TAK1 causes phosphorylation of elongation initiation factor 4E (eIF4E) independent of mTOR. Inactivation of TAK1 disrupts neuromuscular junction morphology and causes deregulation of Smad signaling. Using genetic approaches, we demonstrate that TAK1 prevents excessive loss of muscle mass during denervation. TAK1 favors the nuclear translocation of Smad4 and cytoplasmic retention of Smad6. TAK1 is also required for the phosphorylation of eIF4E in denervated skeletal muscle. Collectively, our results demonstrate that TAK1 supports skeletal muscle growth and prevents neurogenic muscle atrophy in adult mice.
    DOI:  https://doi.org/10.1038/s41467-022-29752-0
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