bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022–04–03
27 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Neuropathic Pain as Main Manifestation of POLG-Related Disease: A Case Report.
  2. An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model.
  3. Proteomic profiling shows mitochondrial nucleoids are autophagy cargo in neurons: implications for neuron maintenance and neurodegenerative disease.
  4. Mitochondrial ROS signalling requires uninterrupted electron flow and is lost during ageing in flies.
  5. Heteroplasmic mitochondrial DNA variants in cardiovascular diseases.
  6. Analysis of Mitochondrial Dysfunction by Microplate Reader in hiPSC-Derived Neuronal Cell Models of Neurodegenerative Disorders.
  7. Anesthetic Management of the Patient with Mitochondrial Disease: A Review of Current Best Evidence.
  8. Inositol hexakisphosphate kinase-2 non-catalytically regulates mitophagy by attenuating PINK1 signaling.
  9. Mitochondrial Protein Translocation Machinery: From TOM Structural Biogenesis to Functional Regulation.
  10. Mesenchymal stem cells (MSCs) in Leber's hereditary optic neuropathy (LHON): a potential therapeutic approach for future.
  11. Redox Activation of Mitochondrial DAMPs and the Metabolic Consequences for Development of Autoimmunity.
  12. Mitochondrial Quality Control: the Role in Cardiac Injury.
  13. Newborn Screening for Mitochondrial Carnitine-Acylcarnitine Cycle Disorders in Zhejiang Province, China.
  14. Regulatory networks controlling mitochondrial quality control in skeletal muscle.
  15. PGC-1α induced mitochondrial biogenesis in stromal cells underpins mitochondrial transfer to melanoma.
  16. Metformin in m.3243A>G carriers can be both detrimental and beneficial.
  17. Rewiring mitochondrial metabolism to counteract exhaustion of CAR-T cells.
  18. Dysregulated mitochondrial metabolism upon cigarette smoke exposure in various human bronchial epithelial cell models.
  19. Effects of Mitochondrial Dynamics in the Pathophysiology of Obesity.
  20. Novel Biallelic Variant in the BRAT1 Gene Caused Nonprogressive Cerebellar Ataxia Syndrome.
  21. Mitochondrial Haplogroup Classification of Ancient DNA Samples Using Haplotracker.
  22. The metabolic basis of epilepsy.
  23. Hyperphosphorylated Human Tau Accumulates at the Synapse, Localizing on Synaptic Mitochondrial Outer Membranes and Disrupting Respiration in a Mouse Model of Tauopathy.
  24. Mitochondrial DNA in NLRP3 inflammasome activation.
  25. Sirtuin 3 and mitochondrial permeability transition pore (mPTP): a systematic review.
  26. Role of exercise in estrogen deficiency-induced sarcopenia.
  27. Use of mitochondrial sequencing to detect gene doping in horses via gene editing and somatic cell nuclear transfer.
  1. Front Neurol. 2022 ;13 846110
    Neuropathic Pain as Main Manifestation of POLG-Related Disease: A Case Report.
    Melanie Lang-Orsini, Paloma Gonzalez-Perez.
      Mutations in nuclear-encoded genes that are involved in mitochondrial DNA replication and maintenance (e.g., POLG) have been associated with chronic progressive external ophthalmoplegia (CPEO) phenotype. These nuclear genome mutations may lead to multiple mitochondrial DNA deletions or mitochondrial DNA depletion. On the other hand, primary genetic defects of mitochondrial DNA (such as single large-scale deletion or point mutations) have also been associated with the CPEO phenotype. Chronic progressive external ophthalmoplegia (CPEO) may be a manifestation of specific syndromes that, when clinically recognized, prompt clinicians to investigate specific genetic defects. Thus, CPEO, as part of Kearns Sayre syndrome, suggests the presence of a large-scale deletion of mitochondrial DNA. However, in pure CPEO or CPEO plus phenotypes, it is more difficult to know whether causative genetic defects affect the nuclear or mitochondrial DNA. Here, we present a patient with a long-standing history of CPEO plus phenotype, in whom the sequencing of mitochondrial DNA from skeletal muscle was normal, and no other genetic defect was suspected at first. At the time of our evaluation, the presence of polyneuropathy and neuropathic pain prompted us to investigate nuclear genetic defects and, specifically, mutations in the POLG gene. Thus, the sequencing of the POLG gene revealed p.Thr251Ile and p.Pro587Leu mutations in one allele, and p.Ala467Thr mutation in another allele. Although one would expect that mutations in POLG lead to multiple mitochondrial DNA deletions or depletion (loss of copies), the absence of mitochondrial DNA abnormalities in tissue may be explained by heteroplasmy, a lack or no significant involvement of biopsied tissue, or a sampling bias. So, the absence of secondary mitochondrial DNA alterations should not discourage clinicians from further investigating mutations in nuclear-encoded genes. Lastly, mitochondrial point mutations and single mitochondrial DNA deletions very rarely cause CPEO associated with polyneuropathy and neuropathic pain, and POLG-related disease should be considered in this scenario, instead.
    Keywords:  CPEO; POLG; mitochondrial disease; neuropathic pain; polyneuropathy
    DOI:  https://doi.org/10.3389/fneur.2022.846110
  2. J Vis Exp. 2022 Mar 09.
    An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model.
    Andrea Cavaliere, Silvia Marchet, Ivano Di Meo, Valeria Tiranti.
      Deficiency of the mitochondrial respiratory chain complexes that carry out oxidative phosphorylation (OXPHOS) is the biochemical marker of human mitochondrial disorders. From a genetic point of view, the OXPHOS represents a unique example because it results from the complementation of two distinct genetic systems: nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Therefore, OXPHOS defects can be due to mutations affecting nuclear and mitochondrial encoded genes. The groundbreaking work by King and Attardi, published in 1989, showed that human cell lines depleted of mtDNA (named rho0) could be repopulated by exogenous mitochondria to obtain the so-called "transmitochondrial cybrids." Thanks to these cybrids containing mitochondria derived from patients with mitochondrial disorders (MDs) and nuclei from rho0 cells, it is possible to verify whether a defect is mtDNA- or nDNA-related. These cybrids are also a powerful tool to validate the pathogenicity of a mutation and study its impact at a biochemical level. This paper presents a detailed protocol describing cybrid generation, selection, and characterization.
    DOI:  https://doi.org/10.3791/63452
  3. Autophagy. 2022 Mar 29. 1-3
    Proteomic profiling shows mitochondrial nucleoids are autophagy cargo in neurons: implications for neuron maintenance and neurodegenerative disease.
    Juliet Goldsmith, Erika L F Holzbaur.
      Neurons depend on macroautophagy/autophagy to maintain cellular homeostasis, and loss of autophagy leads to neurodegeneration. To better understand the role of basal autophagy in neurons, we enriched autophagic vesicles from healthy adult mouse brain and performed mass spectrometry to identify cargos cleared by autophagy. We found that synaptic and mitochondrial proteins comprise nearly half of the unique AV cargos identified in brain. Similarly, synaptic and mitochondrial proteins are major cargos for basal autophagy in neurons. Strikingly, we noted a specific enrichment of mitochondrial nucleoids within neuronal autophagosomes, which occurs through a mechanism distinct from damage-associated mitophagy. Here, we discuss the implications of these findings for our understanding of homeostatic mechanisms in neurons and how the age-dependent decline of autophagy in neurons may contribute to the onset or progression of neurodegenerative disease.
    Keywords:  DNM1L; SYN1; TFAM; macroautophagy; mitochondria; mitochondrial division; mitochondrial nucleoids; mitophagy; neurodegeneration; neuronal homeostasis
    DOI:  https://doi.org/10.1080/15548627.2022.2056865
  4. Geroscience. 2022 Mar 30.
    Mitochondrial ROS signalling requires uninterrupted electron flow and is lost during ageing in flies.
    Charlotte Graham, Rhoda Stefanatos, Angeline E H Yek, Ruth V Spriggs, Samantha H Y Loh, Alejandro Huerta Uribe, Tong Zhang, L Miguel Martins, Oliver D K Maddocks, Filippo Scialo, Alberto Sanz.
      Mitochondrial reactive oxygen species (mtROS) are cellular messengers essential for cellular homeostasis. In response to stress, reverse electron transport (RET) through respiratory complex I generates high levels of mtROS. Suppression of ROS production via RET (ROS-RET) reduces survival under stress, while activation of ROS-RET extends lifespan in basal conditions. Here, we demonstrate that ROS-RET signalling requires increased electron entry and uninterrupted electron flow through the electron transport chain (ETC). We find that in old fruit flies, ROS-RET is abolished when electron flux is decreased and that their mitochondria produce consistently high levels of mtROS. Finally, we demonstrate that in young flies, limiting electron exit, but not entry, from the ETC phenocopies mtROS generation observed in old individuals. Our results elucidate the mechanism by which ROS signalling is lost during ageing.
    Keywords:  Ageing; Complex I; Complex IV; Drosophila; Mitochondria; Reactive oxygen species; Reverse electron transport
    DOI:  https://doi.org/10.1007/s11357-022-00555-x
  5. PLoS Genet. 2022 Apr 01. 18(4): e1010068
    Heteroplasmic mitochondrial DNA variants in cardiovascular diseases.
    Claudia Calabrese, Angela Pyle, Helen Griffin, Jonathan Coxhead, Rafiqul Hussain, Peter S Braund, Linxin Li, Annette Burgess, Patricia B Munroe, Louis Little, Helen R Warren, Claudia Cabrera, Alistair Hall, Mark J Caulfield, Peter M Rothwell, Nilesh J Samani, Gavin Hudson, Patrick F Chinnery.
      Mitochondria are implicated in the pathogenesis of cardiovascular diseases (CVDs) but the reasons for this are not well understood. Maternally-inherited population variants of mitochondrial DNA (mtDNA) which affect all mtDNA molecules (homoplasmic) are associated with cardiometabolic traits and the risk of developing cardiovascular disease. However, it is not known whether mtDNA mutations only affecting a proportion of mtDNA molecules (heteroplasmic) also play a role. To address this question, we performed a high-depth (~1000-fold) mtDNA sequencing of blood DNA in 1,399 individuals with hypertension (HTN), 1,946 with ischemic heart disease (IHD), 2,146 with ischemic stroke (IS), and 723 healthy controls. We show that the per individual burden of heteroplasmic single nucleotide variants (mtSNVs) increases with age. The age-effect was stronger for low-level heteroplasmies (heteroplasmic fraction, HF, 5-10%), likely reflecting acquired somatic events based on trinucleotide mutational signatures. After correcting for age and other confounders, intermediate heteroplasmies (HF 10-95%) were more common in hypertension, particularly involving non-synonymous variants altering the amino acid sequence of essential respiratory chain proteins. These findings raise the possibility that heteroplasmic mtSNVs in the pathophysiology of hypertension.
    DOI:  https://doi.org/10.1371/journal.pgen.1010068
  6. Methods Mol Biol. 2022 Mar 29.
    Analysis of Mitochondrial Dysfunction by Microplate Reader in hiPSC-Derived Neuronal Cell Models of Neurodegenerative Disorders.
    Tatiana R Rosenstock, Congxin Sun, Georgina Wynne Hughes, Katherine Winter, Sovan Sarkar.
      Mitochondria are responsible for many vital pathways governing cellular homeostasis, including cellular energy management, heme biosynthesis, lipid metabolism, cellular proliferation and differentiation, cell cycle regulation, and cellular viability. Electron transport and ADP phosphorylation coupled with proton pumping through the mitochondrial complexes contribute to the preservation of mitochondrial membrane potential (ΔΨm). Importantly, mitochondrial polarization is essential for reactive oxygen species (ROS) production and cytosolic calcium (Ca2+) handling. Thus, changes in mitochondrial oxidative phosphorylation (OXPHOS), ΔΨm, and ATP/ADP may occur in parallel or stimulate each other. Brain cells like neurons are heavily reliant on mitochondrial OXPHOS for its high-energy demands, and hence improper mitochondrial function is detrimental for neuronal survival. Indeed, several neurodegenerative disorders are associated with mitochondrial dysfunction. Modeling this disease-relevant phenotype in neuronal cells differentiated from patient-derived human induced pluripotent stem cells (hiPSCs) provide an appropriate cellular platform for studying the disease pathology and drug discovery. In this review, we describe high-throughput analysis of crucial parameters related to mitochondrial function in hiPSC-derived neurons. These methodologies include measurement of ΔΨm, intracellular Ca2+, oxidative stress, and ATP/ADP levels using fluorescence probes via a microplate reader. Benefits of such an approach include analysis of mitochondrial parameters on a large population of cells, simultaneous analysis of different cell lines and experimental conditions, and for drug screening to identify compounds restoring mitochondrial function.
    Keywords:  Fluorescent dyes; Human induced pluripotent stem cells; Microplate reader; Mitochondria; Mitochondrial calcium; Mitochondrial dysfunction; Mitochondrial membrane potential; Mitochondrial superoxide; Neurodegenerative disease; Neuronal differentiation; Reactive oxygen species; hiPSC-derived neurons
    DOI:  https://doi.org/10.1007/7651_2021_451
  7. AANA J. 2022 Apr;90(2): 148-154
    Anesthetic Management of the Patient with Mitochondrial Disease: A Review of Current Best Evidence.
    Kara M Brody.
      Anesthetic management of the patient with mitochondrial disease (MD) requires thoughtful preoperative planning and hypervigilant perioperative monitoring. MD affects 1 in 4,000 persons and is often an unfamiliar topic to the anesthesia provider. This review aims to inform the anesthetist on important considerations in perioperative management of MD. Patients with MD have impaired mitochondrial energy formation pathways affecting function of cardiac, central nervous, and musculoskeletal systems. All general anesthetics interfere with these mitochondrial bioenergetic pathways. MD patients exhibit hypersensitivity to volatile anesthetics. Propofol interferes with mitochondrial function via multiple pathways thus its use should be limited. MD is not at increased risk for malignant hyperthermia and should not be managed with prolonged propofol infusion. Succinylcholine is contraindicated due to hyperkalemia and myotonic risks. Nondepolarizing agents should be used with caution given unpredictable effects. No single anesthetic plan has been found to be safer than another in patients with MD. Intravenous and volatile anesthetics should be titrated incrementally while monitoring anesthetic depth clinically or via processed electroencephalogram (EEG). All MD patients should be optimized by minimizing fasting times, careful fluid selection to avoid lactate, and hypervigilant temperature management aimed at reducing the detrimental effects of catabolic stress during the perioperative period.
    Keywords:  Anesthesiology; mitochondrial disease; mitochondrial myopathy; perioperative management
  8. Proc Natl Acad Sci U S A. 2022 Apr 05. 119(14): e2121946119
    Inositol hexakisphosphate kinase-2 non-catalytically regulates mitophagy by attenuating PINK1 signaling.
    Latika Nagpal, Michael D Kornberg, Solomon H Snyder.
      SignificanceInositol pyrophosphates are versatile messenger molecules containing the energetic pyrophosphate bond. One of the principal enzymes generating the inositol pyrophosphate IP7 (5-diphosphoinositolpentakisphosphate) is inositol hexakisphosphate kinase 2 (IP6K2). Previous work has shown that IP6K2 is neuroprotective and maintains mitochondrial respiration. We now report that loss of IP6K2 leads to increased mitochondrial fission and mitophagy. Regulation of mitochondrial dynamics by IP6K2 depends on the protein PINK1 and, interestingly, is independent of IP6K2 enzymatic activity. These findings provide mechanistic insight into the regulation of mitochondrial function by IP6K2, which has implications for neuroprotection and mitochondrial physiology more generally.
    Keywords:  PINK1; inositol phosphate; mitochondrial biogenesis; mitophagy; neuroprotection
    DOI:  https://doi.org/10.1073/pnas.2121946119
  9. J Biol Chem. 2022 Mar 25. pii: S0021-9258(22)00310-6. [Epub ahead of print] 101870
    Mitochondrial Protein Translocation Machinery: From TOM Structural Biogenesis to Functional Regulation.
    Ulfat Mohd Hanif Sayyed, Radhakrishnan Mahalakshmi.
      The human mitochondrial outer membrane is biophysically unique as it is the only membrane possessing transmembrane β-barrel proteins (mitochondrial outer membrane proteins, mOMPs) in the cell. The most vital of the three mOMPs is the core protein of the translocase of the outer mitochondrial membrane (TOM) complex. Identified first as MOM38 in Neurospora in 1990, the structure of Tom40, the core 19-stranded β-barrel translocation channel, was solved in 2017, after nearly three decades. Remarkably, the past four years have witnessed an exponential increase in structural and functional studies of yeast and human TOM complexes. In addition to being conserved across all eukaryotes, the TOM complex is the sole ATP-independent import machinery for nearly all of the ∼1000-1500 known mitochondrial proteins. Recent cryo-EM structures have provided detailed insight into both possible assembly mechanisms of the TOM core complex and organizational dynamics of the import machinery, and now reveal novel regulatory interplay with other mOMPs. Functional characterization of the TOM complex using biochemical and structural approaches has also revealed mechanisms for substrate recognition and at least five defined import pathways for precursor proteins. In this review, we discuss the discovery, recently solved structures, molecular function, and regulation of the TOM complex and its constituents, along with the implications these advances have for human diseases.
    Keywords:  TOM complex; Tom40; dysregulation; mitochondrial outer membrane; protein import pathways; transmembrane β-barrels
    DOI:  https://doi.org/10.1016/j.jbc.2022.101870
  10. Int Ophthalmol. 2022 Mar 31.
    Mesenchymal stem cells (MSCs) in Leber's hereditary optic neuropathy (LHON): a potential therapeutic approach for future.
    Mohana Devi Subramaniam, Ruth Bright Chirayath, Mahalaxmi Iyer, Aswathy P Nair, Balachandar Vellingiri.
       BACKGROUND: Optic neuropathy has become a new typical syndromic multi-system disease that leads to optic atrophy. This review discusses potential treatments and advances of Leber's hereditary optic neuropathy (LHON), a sporadic genetic disorder. LHON is caused due to slight mutations in mitochondria leading to mitochondrial dysfunction, causing vision loss. There are no current significant treatments that have been proven to work for LHON.
    METHODS: However, extensive review was carried out on capable studies that have shown potential treatment sensory systems and are being evaluated currently. Some of these studies are in clinical trials, whereas other ones are still being planned. Here, we focus more on treatment based on mesenchymal stem cells-mediated mitochondrial transfer via various techniques. We discuss different mitochondrial transfer modes and possible ways to understand the mitochondria transfer technique's phenotypic characteristics.
    CONCLUSION: It is clearly understood that transfer of healthy mitochondria from MSC to target cell would regulate the range of reactive oxygen species and ATP'S, which are majorly responsible for mutation upon irregulating. Therefore, mitochondrial transfer is suggested and discussed in this review with various aspects. The graphical abstract represents different means of mitochondrial transport like (a) Tunnelling nanotubules, (b) Extracellular vesicles, (c) Cell fusion and (d) Gap junctions. In (a) Tunnelling nanotubules, the signalling pathways TNF- α/TNF αip2 and NFkB/TNF αep2 are responsible for forming tunnels. Also, Miro protein acts as cargo for the transport of mitochondria with myosin's help in the presence of RhoGTPases [35]. In (b) Extracellular vesicles, the RhoA ARF6 contributes to Actin/Cytoskeletal rearrangement leading to the shedding of microvesicles. Coming to (c) Cell fusion when there is a high amount of ATP, the cells tend to fuse when in close proximity leading to the transfer of mitochondria via EFF-1/HAP2 [48]. In (d) Gap Junctions, Connexin43 is responsible for the intracellular channel in the presence of more ATP [86].
    Keywords:  Gene therapy; Leber’s hereditary optic neuropathy; Mesenchymal stem cells; Micro-vesicles-mediated transfer; Mitochondrial transfer; Tunnelling nanotubes
    DOI:  https://doi.org/10.1007/s10792-022-02267-9
  11. Antioxid Redox Signal. 2022 Mar;36(7-9): 441-461
    Redox Activation of Mitochondrial DAMPs and the Metabolic Consequences for Development of Autoimmunity.
    Andreas Koenig, Iwona A Buskiewicz-Koenig.
      Significance: Reactive oxygen species (ROS) are well known to promote innate immune responses during and in the absence of microbial infections. However, excessive or prolonged exposure to ROS provokes innate immune signaling dysfunction and contributes to the pathogenesis of many autoimmune diseases. The relatively high basal expression of pattern recognition receptors (PRRs) in innate immune cells renders them prone to activation in response to minor intrinsic or extrinsic ROS misbalances in the absence of pathogens. Critical Issues: A prominent source of ROS are mitochondria, which are also major inter-organelle hubs for innate immunity activation, since most PRRs and downstream receptor molecules are directly located either at mitochondria or at mitochondria-associated membranes. Due to their ancestral bacterial origin, mitochondria can also act as quasi-intrinsic self-microbes that mimic a pathogen invasion and become a source of danger-associated molecular patterns (DAMPs) that triggers innate immunity from within. Recent Advances: The release of mitochondrial DAMPs correlates with mitochondrial metabolism changes and increased generation of ROS, which can lead to the oxidative modification of DAMPs. Recent studies suggest that ROS-modified mitochondrial DAMPs possess increased, persistent immunogenicity. Future Directions: Herein, we discuss how mitochondrial DAMP release and oxidation activates PRRs, changes cellular metabolism, and causes innate immune response dysfunction by promoting systemic inflammation, thereby contributing to the onset or progression of autoimmune diseases. The future goal is to understand what the tipping point for DAMPs is to become oxidized, and whether this is a road without return. Antioxid. Redox Signal. 36, 441-461.
    Keywords:  ATP; Carbamoyl phosphate synthetase-1 (CPS1); MAVS oligomerization; N-formyl peptides (NFPs); autoimmunity; cardiolipin (CL); cyclic GMP-AMP synthase (cGAS); cytochrome C; damage-associated molecular pattern (DAMP); innate immunity; metabolism; mitochondria; mitochondrial ROS (mtROS); mitochondrial TFAM; mitochondrial antiviral signaling (MAVS) protein; neutrophil extracellular trap (NET); oxidized ATP; oxidized cardiolipin; oxidized mitochondrial DNA (mtDNA); oxidized mitochondrial RNA (mtRNA); reactive oxygen species (ROS); redox; stimulator of interferon genes (STING); succinate; systemic lupus erythematosus (SLE); transcription factor A
    DOI:  https://doi.org/10.1089/ars.2021.0073
  12. Front Biosci (Landmark Ed). 2022 Mar 09. 27(3): 96
    Mitochondrial Quality Control: the Role in Cardiac Injury.
    Grażyna Sygitowicz, Dariusz Sitkiewicz.
      The heart is a highly energy-dependent organ, and most of its energy is provided by mitochondrial oxidative phosphorylation. Therefore, maintaining a well-functioning mitochondrial population is of paramount importance for cardiac homeostasis, since damaged mitochondria produce less adenosine triphosphate (ATP) and generate higher amounts of reactive oxygen species (ROS). Mitochondrial dysfunction is associated with the development of many diseases, including cardiovascular disorders. In this article, we review the role of mitochondria as key determinants of acute myocardial ischemic/reperfusion injury (IRI) and also diabetic cardiomyopathy. The structure and function of mitochondria are regulated by the mitochondrial quality control (MQC) system. Mitochondrial quality control mechanisms involve a series of adaptive responses that preserve mitochondrial structure and function as well as ensure cardiomyocyte survival and cardiac function after injury. This review summarizes the basic mechanisms of MQC, including mitochondrial dynamics (fusion and fission), mitophagy and mitochondrial biogenesis. Mitochondrial dynamics are mainly controlled by the level of fission and fusion proteins and also by their post-translational modifications. In addition, this review aims to provide a contemporary view of the importance of miRNA molecules in the regulation of mitochondrial dynamics at the post-transcriptional level. Thus, miRNAs play an important role not only in the pathogenesis and prognosis of cardiac diseases, but can also be an important therapeutic target.
    Keywords:  cardiac injury; fusion and fission; miRNAs; mitochondrial biogenesis; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.31083/j.fbl2703096
  13. Front Genet. 2022 ;13 823687
    Newborn Screening for Mitochondrial Carnitine-Acylcarnitine Cycle Disorders in Zhejiang Province, China.
    Duo Zhou, Yi Cheng, Xiaoshan Yin, Haixia Miao, Zhenzhen Hu, Jianbin Yang, Yu Zhang, Benqing Wu, Xinwen Huang.
      Background: Disorders of mitochondrial carnitine-acylcarnitine cycle is a heterogeneous group of hereditary diseases of mitochondrial β-oxidation of fatty acids tested in NBS program in Zhejiang province, China. Large-scale studies reporting disorders of mitochondrial carnitine-acylcarnitine cycle among Chinese population in NBS are limited. The aim of this study was to explain the incidence and biochemical, clinical, and genetic characteristics of disorders of mitochondrial carnitine-acylcarnitine cycle in NBS. Methods: From January 2009 to June 2021, 4,070,375 newborns were screened by tandem mass spectrometry. Newborns with elevated C0 levels and/or C0/(C16 + C18) ratios were identified as having CPT1D, whereas those with decreased C0 levels and/or C0/(C16 + C18) ratios and/or elevated C12-C18:1 level were identified as having CPT2D or CACTD. Suspected positive patients were further subjected to genetic analysis. All confirmed patients received biochemical and nutritional treatment, as well as follow-up sessions. Results: Overall, 20 patients (12 with CPT1D, 4 with CPT2D, and 4 with CACTD) with disorders of mitochondrial carnitine-acylcarnitine cycle were diagnosed by NBS. The overall incidence of these disorders was one in 203,518 newborns. In toal, 11 patients with CPT1D exhibited increased C0 levels and C0/(C16 + C18) ratios. In all patients of CPT2D, all long chain acyl-carnitines levels were elevated except for case 14 having normal C12 levels. In all patients with CACTD, all long chain acyl-carnitines levels were elevated except for case 17 having normal C12, C18, and C18:1 levels. Most patients with CPT1D were asymptomatic. Overall, two of 4 patients with CPT2D did not present any clinical symptom, but other two patients died. In 4 cases with CACTD, the disease was onset after birth, and 75% patients died. In total, 14 distinct mutations were identified in CPT1A gene, of which 11 were novel and c.1910C > A (p.S637T), c.740C > T (p.P247L), and c.1328T > C (p.L443P) were the most common mutations. Overall, 3 novel mutations were identified in CPT2 gene, and the most frequent mutation was c.1711C > A (p.P571T). The most common variant in SLC25A20 gene was c.199-10T > G. Conclusion: Disorders of mitochondrial carnitine-acylcarnitine cycle can be detected by NBS, and the combined incidence of these disorders in newborns was rare in Zhejiang province, China. Most patients presented typical acylcarnitine profiles. Most patients with CPT1D presented normal growth and development, whereas those with CPT2D/CACTD exhibited a high mortality rate. Several novel CPT1A and CPT2 variants were identified, which expanded the variant spectrum.
    Keywords:  carnitine palmitoyl transferase 2 deficiency; carnitine palmitoyltransferase 2 deficiency; carnitine-acylcarnitine translocase deficiency; mitochondrial carnitine-acylcarnitine cycle disorders; newborn screening
    DOI:  https://doi.org/10.3389/fgene.2022.823687
  14. Am J Physiol Cell Physiol. 2022 Mar 30.
    Regulatory networks controlling mitochondrial quality control in skeletal muscle.
    Mikhaela B Slavin, Jonathan M Memme, Ashley N Oliveira, Neushaw Moradi, David A Hood.
      The adaptive plasticity of mitochondria within skeletal muscle is regulated by signals converging on a myriad of regulatory networks that operate during conditions of increased (i.e. exercise) and decreased (inactivity, disuse) energy requirements. Notably, some of the initial signals that induce adaptive responses are common to both conditions, differing in their magnitude and temporal pattern, to produce vastly opposing mitochondrial phenotypes. In response to exercise, signaling to PGC-1α and other regulators ultimately produces an abundance of high quality mitochondria, leading to reduced mitophagy and a higher mitochondrial content. This is accompanied by the presence of an enhanced protein quality control system that consists of the protein import machinery as well chaperones and proteases termed the UPRmt. The UPRmt monitors intra-organelle proteostasis, and strives to maintain a mito-nuclear balance between nuclear- and mtDNA-derived gene products via retrograde signaling from the organelle to the nucleus. In addition, antioxidant capacity is improved, affording greater protection against oxidative stress. In contrast, chronic disuse conditions produce similar signaling but result in decrements in mitochondrial quality and content. Thus, the interactive cross-talk of the regulatory networks that control organelle turnover during wide variations in muscle use and disuse remain incompletely understood, despite our improving knowledge of the traditional regulators of organelle content and function. This brief review acknowledges existing regulatory networks and summarizes recent discoveries of novel biological pathways involved in determining organelle biogenesis, dynamics, mitophagy, protein quality control and antioxidant capacity, identifying ample protein targets for therapeutic intervention that determine muscle and mitochondrial health.
    DOI:  https://doi.org/10.1152/ajpcell.00065.2022
  15. Br J Cancer. 2022 Mar 26.
    PGC-1α induced mitochondrial biogenesis in stromal cells underpins mitochondrial transfer to melanoma.
    Prakrit R Kumar, Mona Saad, Charlotte Hellmich, Jayna J Mistry, Jamie A Moore, Shannon Conway, Christopher J Morris, Kristian M Bowles, Marc D Moncrieff, Stuart A Rushworth.
       INTRODUCTION: Progress in the knowledge of metabolic interactions between cancer and its microenvironment is ongoing and may lead to novel therapeutic approaches. Until recently, melanoma was considered a glycolytic tumour due to mutations in mitochondrial-DNA, however, these malignant cells can regain OXPHOS capacity via the transfer of mitochondrial-DNA, a process that supports their proliferation in-vitro and in-vivo. Here we study how melanoma cells acquire mitochondria and how this process is facilitated from the tumour microenvironment.
    METHODS: Primary melanoma cells, and MSCs derived from patients were obtained. Genes' expression and DNA quantification was analysed using Real-time PCR. MSC migration, melanoma proliferation and tumour volume, in a xenograft subcutaneous mouse model, were monitored through bioluminescent live animal imaging.
    RESULTS: Human melanoma cells attract bone marrow-derived stromal cells (MSCs) to the primary tumour site where they stimulate mitochondrial biogenesis in the MSCs through upregulation of PGC1a. Mitochondria are transferred to the melanoma cells via direct contact with the MSCs. Moreover, inhibition of MSC-derived PGC1a was able to prevent mitochondrial transfer and improve NSG melanoma mouse tumour burden.
    CONCLUSION: MSC mitochondrial biogenesis stimulated by melanoma cells is prerequisite for mitochondrial transfer and subsequent tumour growth, where targeting this pathway may provide an effective novel therapeutic approach in melanoma.
    DOI:  https://doi.org/10.1038/s41416-022-01783-w
  16. J Diabetes Complications. 2022 Mar 23. pii: S1056-8727(22)00078-2. [Epub ahead of print] 108184
    Metformin in m.3243A>G carriers can be both detrimental and beneficial.
    Josef Finsterer.
      
    Keywords:  Diabetes; MELAS; Metformin; Mitochondrial; mtDNA
    DOI:  https://doi.org/10.1016/j.jdiacomp.2022.108184
  17. J Hematol Oncol. 2022 Mar 28. 15(1): 38
    Rewiring mitochondrial metabolism to counteract exhaustion of CAR-T cells.
    Yue Huang, Xiaohui Si, Mi Shao, Xinyi Teng, Gang Xiao, He Huang.
      Short persistence and early exhaustion of T cells are major limits to the efficacy and broad application of immunotherapy. Exhausted T and chimeric antigen receptor (CAR)-T cells upregulate expression of genes associated with terminated T cell differentiation, aerobic glycolysis and apoptosis. Among cell exhaustion characteristics, impaired mitochondrial function and dynamics are considered hallmarks. Here, we review the mitochondrial characteristics of exhausted T cells and particularly discuss different aspects of mitochondrial metabolism and plasticity. Furthermore, we propose a novel strategy of rewiring mitochondrial metabolism to emancipate T cells from exhaustion and of targeting mitochondrial plasticity to boost CAR-T cell therapy efficacy.
    Keywords:  CAR-T cell exhaustion; Metabolism; Mitochondria; Single-cell techniques
    DOI:  https://doi.org/10.1186/s13045-022-01255-x
  18. Dis Model Mech. 2022 Mar 01. pii: dmm049247. [Epub ahead of print]15(3):
    Dysregulated mitochondrial metabolism upon cigarette smoke exposure in various human bronchial epithelial cell models.
    Christy B M Tulen, Ying Wang, Daan Beentjes, Phyllis J J Jessen, Dennis K Ninaber, Niki L Reynaert, Frederik-Jan van Schooten, Antoon Opperhuizen, Pieter S Hiemstra, Alexander H V Remels.
      Exposure to cigarette smoke (CS) is the primary risk factor for developing chronic obstructive pulmonary disease. The impact of CS exposure on the molecular mechanisms involved in mitochondrial quality control in airway epithelial cells is incompletely understood. Undifferentiated or differentiated primary bronchial epithelial cells were acutely/chronically exposed to whole CS (WCS) or CS extract (CSE) in submerged or air-liquid interface conditions. Abundance of key regulators controlling mitochondrial biogenesis, mitophagy and mitochondrial dynamics was assessed. Acute exposure to WCS or CSE increased the abundance of components of autophagy and receptor-mediated mitophagy in all models. Although mitochondrial content and dynamics appeared to be unaltered in response to CS, changes in both the molecular control of mitochondrial biogenesis and a shift toward an increased glycolytic metabolism were observed in particular in differentiated cultures. These alterations persisted, at least in part, after chronic exposure to WCS during differentiation and upon subsequent discontinuation of WCS exposure. In conclusion, smoke exposure alters the regulation of mitochondrial metabolism in airway epithelial cells, but observed alterations may differ between various culture models used. This article has an associated First Person interview with the joint first authors of the paper.
    Keywords:  Autophagy; Cell model; Cigarette smoke; Culture methods; Human primary bronchial epithelial cells; Mitochondrial metabolism
    DOI:  https://doi.org/10.1242/dmm.049247
  19. Front Biosci (Landmark Ed). 2022 Mar 18. 27(3): 107
    Effects of Mitochondrial Dynamics in the Pathophysiology of Obesity.
    Jinling Wang, Xiufu Lin, Ningning Zhao, Guanping Dong, Wei Wu, Ke Huang, Junfen Fu.
      Obesity has become an urgent and serious public health challenge with an overwhelming increase over the decades worldwide. The rate of obese children and adolescents has recently accelerated, especially in China. Obesity is closely related to unbalanced cellular energy metabolism. Mitochondria, as the main organelles of energy metabolism, play an important role in the pathophysiology of obesity. Recent researches have revealed that mitochondrial dynamics with constant fission and fusion, can alter mitochondrial structure, organelle connections, ROS production, neuronal activity, and OXPHOS system as well as adipose tissue thermogenesis, which ultimately lead to obesity. In this review, we will update the latest findings about mitochondrial fission/fusion related GTPase proteins and discuss the effects of mitochondrial dynamics in the pathophysiology of obesity.
    Keywords:  Drp1; Mfn1; Mfn2; Opa1; fission; fusion; mitochondrial dynamics; obesity
    DOI:  https://doi.org/10.31083/j.fbl2703107
  20. Front Genet. 2022 ;13 821587
    Novel Biallelic Variant in the BRAT1 Gene Caused Nonprogressive Cerebellar Ataxia Syndrome.
    Yiming Qi, Xueqi Ji, Hongke Ding, Ling Liu, Yan Zhang, Aihua Yin.
      Recessive mutations in BRAT1 cause lethal neonatal rigidity and multifocal seizure syndrome (RMFSL), a phenotype characterized by neonatal microcephaly, hypertonia, and refractory epilepsy with premature death. Recently, attenuated disease variants have been described, suggesting that a wider clinical spectrum of BRAT1-associated neurodegeneration exists than was previously thought. Here, we reported a 10-year-old girl with severe intellectual disability, rigidity, ataxia or dyspraxia, and cerebellar atrophy on brain MRI; two BRAT1 variants in the trans configuration [c.1014A > C (p.Pro338 = ); c.706delC (p.Leu236Cysfs*5)] were detected using whole-exome sequencing. RNA-seq confirmed significantly decreased BRAT1 transcript levels in the presence of the variant; further, it revealed an intron retention between exon 7 and exon 8 caused by the synonymous base substitute. Subsequent prenatal diagnosis for these two variants guided the parents to reproduce. We expand the phenotypic spectrum of BRAT1-associated disorders by first reporting the pathogenic synonymous variant of the BRAT1 gene, resulting in clinical severity that is mild compared to the severe phenotype seen in RMFSL. Making an accurate diagnosis and prognostic evaluation of BRAT1-associated neurodegeneration is important for reproductive consultation and disease management.
    Keywords:  BRAT1; intron retention; nonprogressive cerebellar ataxia syndrome; prenatal diagnosis; synonymous variant
    DOI:  https://doi.org/10.3389/fgene.2022.821587
  21. Biomed Res Int. 2022 ;2022 5344418
    Mitochondrial Haplogroup Classification of Ancient DNA Samples Using Haplotracker.
    Kijeong Kim, Dong-Han Kim, Kyung-Yong Kim.
      Mitochondrial DNA haplogroup classification is used to study maternal lineage of ancient human populations. The haplogrouping of ancient DNA is not easy because the DNA is usually found in small pieces in limited quantities. We have developed Haplotracker, a straightforward and efficient high-resolution haplogroup classification tool optimized specifically for ancient DNA samples. Haplotracker offers a user-friendly input interface for multiple mitochondrial DNA sequence fragments in a sample. It provides accurate haplogroup classification with full-length mitochondrial genome sequences and provides high-resolution haplogroup predictions for some fragmented control region sequences using a novel algorithm built on Phylotree mtDNA Build 17 (Phylotree) and our haplotype database (n = 118,869). Its performance for accuracy was demonstrated to be high through haplogroup classification using 8,216 Phylotree full-length and control region mitochondrial DNA sequences compared with HaploGrep 2, one of the most accurate current haplogroup classifiers. Haplotracker provides a novel haplogroup tracking solution for fragmented sequences to track subhaplogroups or verify the haplogroups efficiently. Using Haplotracker, we classified mitochondrial haplogroups to the final subhaplogroup level in nine ancient DNA samples extracted from human skeletal remains found in 2,000-year-old elite Xiongnu cemetery in Northeast Mongolia. Haplotracker can be freely accessed at https://haplotracker.cau.ac.kr.
    DOI:  https://doi.org/10.1155/2022/5344418
  22. Nat Rev Neurol. 2022 Mar 31.
    The metabolic basis of epilepsy.
    Jong M Rho, Detlev Boison.
      The brain is a highly energy-demanding organ and requires bioenergetic adaptability to balance normal activity with pathophysiological fuelling of spontaneous recurrent seizures, the hallmark feature of the epilepsies. Recurrent or prolonged seizures have long been known to permanently alter neuronal circuitry and to cause excitotoxic injury and aberrant inflammation. Furthermore, pathological changes in bioenergetics and metabolism are considered downstream consequences of epileptic seizures that begin at the synaptic level. However, as we highlight in this Review, evidence is also emerging that primary derangements in cellular or mitochondrial metabolism can result in seizure genesis and lead to spontaneous recurrent seizures. Basic and translational research indicates that the relationships between brain metabolism and epileptic seizures are complex and bidirectional, producing a vicious cycle that compounds the deleterious consequences of seizures. Metabolism-based treatments such as the high-fat, antiseizure ketogenic diet have become mainstream, and metabolic substrates and enzymes have become attractive molecular targets for seizure prevention and recovery. Moreover, given that metabolism is crucial for epigenetic as well as inflammatory changes, the idea that epileptogenesis can be both negatively and positively influenced by metabolic changes is rapidly gaining ground. Here, we review evidence that supports both pathophysiological and therapeutic roles for brain metabolism in epilepsy.
    DOI:  https://doi.org/10.1038/s41582-022-00651-8
  23. Front Mol Neurosci. 2022 ;15 852368
    Hyperphosphorylated Human Tau Accumulates at the Synapse, Localizing on Synaptic Mitochondrial Outer Membranes and Disrupting Respiration in a Mouse Model of Tauopathy.
    Andrew J Trease, Joseph W George, Nashanthea J Roland, Eliezer Z Lichter, Katy Emanuel, Steven Totusek, Howard S Fox, Kelly L Stauch.
      Neurogenerative disorders, such as Alzheimer's disease (AD), represent a growing public health challenge in aging societies. Tauopathies, a subset of neurodegenerative disorders that includes AD, are characterized by accumulation of fibrillar and hyperphosphorylated forms of microtubule-associated protein tau with coincident mitochondrial abnormalities and neuronal dysfunction. Although, in vitro, tau impairs axonal transport altering mitochondrial distribution, clear in vivo mechanisms associating tau and mitochondrial dysfunction remain obscure. Herein, we investigated the effects of human tau on brain mitochondria in vivo using transgenic htau mice at ages preceding and coinciding with onset of tauopathy. Subcellular proteomics combined with bioenergetic assessment revealed pathologic forms of tau preferentially associate with synaptic over non-synaptic mitochondria coinciding with changes in bioenergetics, reminiscent of an aged synaptic mitochondrial phenotype in wild-type mice. While mitochondrial content was unaltered, mitochondrial maximal respiration was impaired in synaptosomes from htau mice. Further, mitochondria-associated tau was determined to be outer membrane-associated using the trypsin protection assay and carbonate extraction. These findings reveal non-mutant human tau accumulation at the synapse has deleterious effects on mitochondria, which likely contributes to synaptic dysfunction observed in the context of tauopathy.
    Keywords:  Alzheimer’s disease; aging; bioenergetics; phosphorylation; proteomics; synaptic mitochondria; tau; tauopathy
    DOI:  https://doi.org/10.3389/fnmol.2022.852368
  24. Int Immunopharmacol. 2022 Mar 26. pii: S1567-5769(22)00203-X. [Epub ahead of print]108 108719
    Mitochondrial DNA in NLRP3 inflammasome activation.
    Yanbing Qiu, Yumei Huang, Meilin Chen, Yuqin Yang, Xiaoxu Li, Wenling Zhang.
      As an intracellular polyprotein complex, the NLRP3 inflammasome is activated by NLRP3 perceiving pathogen-related molecular patterns, damage-related molecular patterns(DAMPs), which will result in the secretion of the caspase1-dependent pro-inflammatory cytokines IL1β and IL18, and the cleavage of GSDMD-mediated pyroptosis. Therefore, inflammasome signaling is tightly regulated. Intracellular and extracellular mitochondria DNA (mtDNA) play different roles in activating the NLRP3 inflammasome. Intracellular mtDNA is easily oxidized and transferred to the cytoplasm, and directly binds to NLRP3 to activate NLRP3 inflammasome, the extracellular mtDNA is involved in the priming and activation of NLRP3 inflammasome as a DAMP; which is related to the occurrence and development of plentiful diseases. In this paper, we will discuss how mitochondrial DNA activates the NLRP3 inflammasome and how the process of activating NLRP3 inflammasome by mtDNA interacts with other NLRP3 inflammasome activation models.
    Keywords:  Activation; Mitochondrial DNA; NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.intimp.2022.108719
  25. Mitochondrion. 2022 Mar 25. pii: S1567-7249(22)00024-1. [Epub ahead of print]
    Sirtuin 3 and mitochondrial permeability transition pore (mPTP): a systematic review.
    Yaping Yang, Weiping Wang, Ye Tian, Jiong Shi.
      Mitochondrial permeability transition pore (mPTP) is a channel that opens at the inner mitochondrial membrane under conditions of stress. Sirtuin 3 (Sirt3) is a mitochondrial deacetylase known to play a major role in stress resistance and a regulatory role in cell death. This systematic review aims to elucidate the role of Sirt3 in mPTP inhibition. Electronic databases, including PubMed, EMBASE, Web of Science and Cochrane Library were searched up to May 2020. Original studies that investigated the relationship between Sirt3 and mPTP were included. Two reviewers independently extracted data on study characteristics, methods and outcomes. A total of 194 articles were found. Twenty-nine articles, which met criteria were included in the systematic review. Twenty-three studies provided evidence of the inhibitory effect of Sirt3 on the mPTP aperture. This review summarizes up-to-date evidence of the protective and inhibitory role of Sirt3 through deacetylating Cyclophilin D (CypD) on the mPTP aperture. Furthermore, we discuss the implications of this effect in disease.
    Keywords:  Cyclophilin D; Sirtuin3; deacetylase; mPTP; mitochondria
    DOI:  https://doi.org/10.1016/j.mito.2022.03.004
  26. J Exerc Rehabil. 2022 Feb;18(1): 2-9
    Role of exercise in estrogen deficiency-induced sarcopenia.
    Eun-Jeong Cho, Youngju Choi, Su-Jeen Jung, Hyo-Bum Kwak.
      A decline in estrogen levels during menopause is associated with the loss of muscle mass and function, and it can accelerate sarcopenia. However, with the growing number of postmenopausal women due to the increase in life expectancy, the effects of estrogen on skeletal muscle are not completely understood. This article reviews the relationship between estrogen deficiency and skeletal muscle, its potential mechanisms, including those involving mitochondria, and the effects of exercise on estrogen deficiency-induced skeletal muscle impairment. In particular, mitochondrial dysfunction induced by estrogen deficiency accelerates sarcopenia via mitochondrial dynamics, mitophagy, and mitochondrial-mediated apoptosis. It is well known that exercise training is essential for health, including for the improvement of sarcopenia. This review highlights the importance of exercise training (aerobic and resistance exercise) as a therapeutic intervention against estrogen deficiency-induced sarcopenia.
    Keywords:  Estrogen; Exercise training; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.12965/jer.2244004.002
  27. Drug Test Anal. 2022 Mar 31.
    Use of mitochondrial sequencing to detect gene doping in horses via gene editing and somatic cell nuclear transfer.
    Jillian Maniego, Bogusia Pesko, Jocelyn Habershon-Butcher, Pamela Hincks, Polly Taylor, Teruaki Tozaki, Aoi Ohnuma, Graham Stewart, Christopher Proudman, Edward Ryder.
      Gene editing and subsequent cloning techniques offer great potential not only in genetic disease correction in domestic animals, but also in livestock production by enhancement of desirable traits. The existence of the technology, however, leaves it open to potential misuse in performance-led sports such as horseracing and other equestrian events. Recent advances in equine gene editing, regarding the generation of gene-edited embryos using CRISPR/Cas9 technology and somatic cell nuclear transfer, has highlighted the need to develop tools to detect potential prohibited use of the technology. One possible method involves the characterisation of the mitochondrial genome (which is not routinely preserved during cloning) and comparing it to the sequence of the registered dam. We present here our approach to whole-mitochondrial sequencing using tiled long-range PCR and next-generation sequencing. To determine whether the background mutation rate in the mitochondrial genome could potentially confound results, we sequenced ten sets of dam and foal duos. We found variation between duos but none within duos, indicating that this method is feasible for future screening systems. Analysis of WGS data from over one hundred Thoroughbred horses revealed wide variation in the mitochondria sequence within the breed, further displaying the utility of this approach.
    Keywords:  Gene doping; SNCT; equine; genetics; mitochondrial DNA
    DOI:  https://doi.org/10.1002/dta.3267
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