bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022‒12‒04
38 papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico
  1. Leigh syndrome is the main clinical characteristic of PTCD3 deficiency.
  2. Primary Mitochondrial Disorders in the Neonate.
  3. Emerging mitochondrial-mediated mechanisms involved in oligodendrocyte development.
  4. The mitochondrial challenge: Disorders and prevention strategies.
  5. Mathematical modeling and analysis of mitochondrial retrograde signaling dynamics.
  6. Inhibition of cellular senescence hallmarks by mitochondrial transplantation in senescence-induced ARPE-19 cells.
  7. Mitochondrial copper in human genetic disorders.
  8. The Caenorhabditis elegans ARIP-4 DNA helicase couples mitochondrial surveillance to immune, detoxification, and antiviral pathways.
  9. Inhibition of glutaminolysis restores mitochondrial function in senescent stem cells.
  10. An ER phospholipid hydrolase drives ER-associated mitochondrial constriction for fission and fusion.
  11. Mitochondrial respiration and dynamics of in vivo neural stem cells.
  12. Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A MT-ND4 Mutation.
  13. Mitochondria: how eminent in ageing and neurodegenerative disorders?
  14. AFG3L2 Biallelic Mutation: Clinical Heterogeneity in Two Italian Patients.
  15. The loss of cardiac SIRT3 decreases metabolic flexibility and proteostasis in an age-dependent manner.
  16. The Depletion of NAMPT Disturbs Mitochondrial Homeostasis and Causes Neuronal Degeneration in Mouse Hippocampus.
  17. Stochastic survival of the densest and mitochondrial DNA clonal expansion in aging.
  18. Mitochondria and cell death-associated inflammation.
  19. Nicotinamide riboside kinases regulate skeletal muscle fiber-type specification and are rate-limiting for metabolic adaptations during regeneration.
  20. Mutation accumulation in mtDNA of cancers resembles mutagenesis in normal stem cells.
  21. Horizontal transfer of tRNA genes to mitochondrial plasmids facilitates gene loss from fungal mitochondrial DNA.
  22. Generation of a homozygous FIS1 knockout human embryonic stem cell line GIBHe015-B by CRISPR/Cas9 system.
  23. Engineering Extracellular Vesicles to Modulate Their Innate Mitochondrial Load.
  24. Genetically personalised organ-specific metabolic models in health and disease.
  25. Profiling of mitochondrial heteroplasmy in single human oocytes by next-generation sequencing.
  26. Clinical, neuroimaging and genetic findings in children with hereditary ataxia: single center study.
  27. Chronic treatment with the anti-diabetic drug metformin rescues impaired brain mitochondrial activity and selectively ameliorates defective cognitive flexibility in a female mouse model of Rett syndrome.
  28. Mitochondrial fragmentation and ROS signaling in wound response and repair.
  29. Nuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation.
  30. Generation of induced pluripotent stem cells from three individuals with Huntington's disease.
  31. Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism.
  32. Metabolon formation regulates branched-chain amino acid oxidation and homeostasis.
  33. Characterization of pregnancy outcome of women with an offspring with inborn errors of metabolism: A population-based study.
  34. The roles of a mitochondrial protein Miga in autophagy.
  35. Cell-based therapeutic strategies for treatment of spinocerebellar ataxias: an update.
  36. A retrograde approach for liver gene transfer.
  37. Mitochondrial energetics in skeletal muscle are associated with leg power and cardiorespiratory fitness in the Study of Muscle, Mobility, and Aging (SOMMA).
  38. Loss of FoxOs in muscle increases strength and mitochondrial function during aging.
  1. Brain Pathol. 2022 Nov 30. e13134
    Leigh syndrome is the main clinical characteristic of PTCD3 deficiency.
    Gerard Muñoz-Pujol, Juan D Ortigoza-Escobar, Abraham J Paredes-Fuentes, Cristina Jou, Olatz Ugarteburu, Laura Gort, Delia Yubero, Angels García-Cazorla, Mar O'Callaghan, Jaume Campistol, Jordi Muchart, Vicente A Yépez, Mirjana Gusic, Julien Gagneur, Holger Prokisch, Rafael Artuch, Antonia Ribes, Roser Urreizti, Frederic Tort.
      Mitochondrial translation defects are a continuously growing group of disorders showing a large variety of clinical symptoms including a wide range of neurological abnormalities. To date, mutations in PTCD3, encoding a component of the mitochondrial ribosome, have only been reported in a single individual with clinical evidence of Leigh syndrome. Here, we describe three additional PTCD3 individuals from two unrelated families, broadening the genetic and phenotypic spectrum of this disorder, and provide definitive evidence that PTCD3 deficiency is associated with Leigh syndrome. The patients presented in the first months of life with psychomotor delay, respiratory insufficiency and feeding difficulties. The neurologic phenotype included dystonia, optic atrophy, nystagmus and tonic-clonic seizures. Brain MRI showed optic nerve atrophy and thalamic changes, consistent with Leigh syndrome. WES and RNA-seq identified compound heterozygous variants in PTCD3 in both families: c.[1453-1G>C];[1918C>G] and c.[710del];[902C>T]. The functional consequences of the identified variants were determined by a comprehensive characterization of the mitochondrial function. PTCD3 protein levels were significantly reduced in patient fibroblasts and, consistent with a mitochondrial translation defect, a severe reduction in the steady state levels of complexes I and IV subunits was detected. Accordingly, the activity of these complexes was also low, and high-resolution respirometry showed a significant decrease in the mitochondrial respiratory capacity. Functional complementation studies demonstrated the pathogenic effect of the identified variants since the expression of wild-type PTCD3 in immortalized fibroblasts restored the steady-state levels of complexes I and IV subunits as well as the mitochondrial respiratory capacity. Additionally, minigene assays demonstrated that three of the identified variants were pathogenic by altering PTCD3 mRNA processing. The fourth variant was a frameshift leading to a truncated protein. In summary, we provide evidence of PTCD3 involvement in human disease confirming that PTCD3 deficiency is definitively associated with Leigh syndrome.
    Keywords:  Leigh syndrome; PTCD3; mitochondria; mitochondrial disorder; mitochondrial translation
    DOI:  https://doi.org/10.1111/bpa.13134
  2. Neoreviews. 2022 Dec 01. 23(12): e796-e812
    Primary Mitochondrial Disorders in the Neonate.
    Rodrigo Tzovenos Starosta, Marwan Shinawi.
      Primary mitochondrial disorders (PMDs) are a heterogeneous group of disorders characterized by functional or structural abnormalities in the mitochondria that lead to a disturbance of cellular energy, reactive oxygen species, and free radical production, as well as impairment of other intracellular metabolic functions, causing single- or multiorgan dysfunction. PMDs are caused by pathogenic variants in nuclear and mitochondrial genes, resulting in distinct modes of inheritance. Onset of disease is variable and can occur in the neonatal period, with a high morbidity and mortality. In this article, we review the most common methods used for the diagnosis of PMDs, as well as their prenatal and neonatal presentations. We highlight the shift in the diagnostic approach for PMDs since the introduction of nontargeted molecular tests into clinical practice, which has significantly reduced the use of invasive studies. We discuss common PMDs that can present in the neonate, including general, nonsyndromic presentations as well as specific syndromic disorders. We also review current treatment advances, including the use of mitochondrial "cocktails" based on limited scientific evidence and theoretical reasoning, as well as the impending arrival of personalized mitochondrial-specific treatments.
    DOI:  https://doi.org/10.1542/neo.23-12-e796
  3. J Neurosci Res. 2022 Dec 03.
    Emerging mitochondrial-mediated mechanisms involved in oligodendrocyte development.
    Melanie Gil, Vivian Gama.
      Oligodendrocytes are the myelinating glia of the central nervous system and are generated after oligodendrocyte progenitor cells (OPCs) transition into pre-oligodendrocytes and then into myelinating oligodendrocytes. Myelin is essential for proper signal transmission within the nervous system and axonal metabolic support. Although the intrinsic and extrinsic factors that support the differentiation, survival, integration, and subsequent myelination of appropriate axons have been well investigated, little is known about how mitochondria-related pathways such as mitochondrial dynamics, bioenergetics, and apoptosis finely tune these developmental events. Previous findings suggest that changes to mitochondrial morphology act as an upstream regulatory mechanism of neural stem cell (NSC) fate decisions. Whether a similar mechanism is engaged during OPC differentiation has yet to be elucidated. Maintenance of mitochondrial dynamics is vital for regulating cellular bioenergetics, functional mitochondrial networks, and the ability of cells to distribute mitochondria to subcellular locations, such as the growing processes of oligodendrocytes. Myelination is an energy-consuming event, thus, understanding the interplay between mitochondrial dynamics, metabolism, and apoptosis will provide further insight into mechanisms that mediate oligodendrocyte development in healthy and disease states. Here we will provide a concise overview of oligodendrocyte development and discuss the potential contribution of mitochondrial mitochondrial-mediated mechanisms to oligodendrocyte bioenergetics and development.
    Keywords:  astrocytes; glia; glycolysis; mitochondria; neural precursor cells; neurons; oligodendrocytes; oxidative phosphorylation
    DOI:  https://doi.org/10.1002/jnr.25151
  4. Biosystems. 2022 Nov 27. pii: S0303-2647(22)00200-3. [Epub ahead of print] 104819
    The mitochondrial challenge: Disorders and prevention strategies.
    Elena Korchivaya, Yulia Silaeva, Ilya Mazunin, Ilya Volodyaev.
      This short review provides basic knowledge on mitochondrial inheritance, its disorders, and potential ways to overcome them in human reproductive medicine. The latter are currently mostly associated with the so-called mitochondrial replacement (nuclear transfer) procedures, performed at different stages and with slight technical differences. Being promising but obviously highly invasive, these procedures require detailed investigation of their delayed effects on embryogenesis, pregnancy and future health. A special attention is paid to the newest available data on these issues, as well as to their limitations and possible further research directions.
    Keywords:  Maternal spindle transfer; Mitochondrial diseases; Mitochondrial inheritance; Mitochondrial replacement; Nuclear transfer; Polar body transfer; Pronuclear transfer; mtDNA
    DOI:  https://doi.org/10.1016/j.biosystems.2022.104819
  5. iScience. 2022 Dec 22. 25(12): 105502
    Mathematical modeling and analysis of mitochondrial retrograde signaling dynamics.
    Shao-Ting Chiu, Wen-Wei Tseng, An-Chi Wei.
      Mitochondria, semi-autonomous eukaryotic organelles, participate in energy production and metabolism, making mitochondrial quality control crucial. As most mitochondrial proteins are encoded by nuclear genes, maintaining mitochondrial function and quality depends on proper mitochondria-nucleus communication and designated mitochondrial retrograde signaling. Early studies focused on retrograde signaling participants and specific gene knockouts. However, mitochondrial signal modulation remains elusive. A mathematical model based on ordinary differential equations was proposed to simulate signal propagation to nucleus following mitochondrial damage in yeast. Mitochondrial retrograde signaling decisions were described using a Boolean model. Dynamics of retrograde signaling were analyzed and extended to evaluate the model response to noisy damage signals. Simulation revealed localized protein concentration dynamics, including waveforms, frequency response, and robustness under noise. Retrograde signaling is bistable with localized steady states, and increased damage compromises robustness. We elucidated mitochondrial retrograde signaling, thus providing a basis for drug design against yeast and fungi.
    Keywords:  Biological sciences; Cell biology; Systems biology
    DOI:  https://doi.org/10.1016/j.isci.2022.105502
  6. Neurobiol Aging. 2022 Nov 06. pii: S0197-4580(22)00231-7. [Epub ahead of print]121 157-165
    Inhibition of cellular senescence hallmarks by mitochondrial transplantation in senescence-induced ARPE-19 cells.
    Sung-Eun Noh, Seok Jae Lee, Tae Geol Lee, Kyu-Sang Park, Jeong Hun Kim.
      Retinal pigment epithelium (RPE) damage is a major factor in age-related macular degeneration (AMD). The RPE in AMD shows mitochondrial dysfunction suggesting an association of AMD with mitochondrial function. Therefore, exogenous mitochondrial transplantation for restoring and replacing dysfunctional mitochondria may be an effective therapeutic strategy for AMD. Here, we investigated the effects of extrinsic mitochondrial transplantation on senescence-induced ARPE-19 cells. We demonstrated mitochondrial dysfunction in replicative senescence-induced ARPE-19 cells after repeated passage. Imbalanced mitophagy and mitochondrial dynamics resulted in increased mitochondrial numbers and elevated levels of mitochondrial and intracellular reactive oxygen species. Exogenous mitochondrial transplantation improved mitochondrial dysfunction and alleviated cellular senescence hallmarks, such as increased cell size, increased senescence-associated β-galactosidase activity, augmented NF-κB activity, increased inflammatory cytokines, and upregulated the cyclin-dependent kinase inhibitors p21 and p16. Further, cellular senescence properties were improved by exogenous mitochondrial transplantation in oxidative stress-induced senescent ARPE-19 cells. These results indicate that exogenous mitochondrial transplantation modulates cellular senescence and may be considered a novel therapeutic strategy for AMD.
    Keywords:  Age-related macular degeneration; Exogenous mitochondrial transplantation; Oxidative stress; Retinal pigment epithelium; Senescence
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2022.11.003
  7. Trends Endocrinol Metab. 2022 Nov 23. pii: S1043-2760(22)00199-0. [Epub ahead of print]
    Mitochondrial copper in human genetic disorders.
    Natalie M Garza, Abhinav B Swaminathan, Krishna P Maremanda, Mohammad Zulkifli, Vishal M Gohil.
      Copper is an essential micronutrient that serves as a cofactor for enzymes involved in diverse physiological processes, including mitochondrial energy generation. Copper enters cells through a dedicated copper transporter and is distributed to intracellular cuproenzymes by copper chaperones. Mitochondria are critical copper-utilizing organelles that harbor an essential cuproenzyme cytochrome c oxidase, which powers energy production. Mutations in copper transporters and chaperones that perturb mitochondrial copper homeostasis result in fatal genetic disorders. Recent studies have uncovered the therapeutic potential of elesclomol, a copper ionophore, for the treatment of copper deficiency disorders such as Menkes disease. Here we review the role of copper in mitochondrial energy metabolism in the context of human diseases and highlight the recent developments in copper therapeutics.
    Keywords:  Menkes disease; Wilson disease; copper; elesclomol; mitochondria; mitochondrial disease
    DOI:  https://doi.org/10.1016/j.tem.2022.11.001
  8. Proc Natl Acad Sci U S A. 2022 Dec 06. 119(49): e2215966119
    The Caenorhabditis elegans ARIP-4 DNA helicase couples mitochondrial surveillance to immune, detoxification, and antiviral pathways.
    Kai Mao, Peter Breen, Gary Ruvkun.
      Surveillance of Caenorhabditis elegans mitochondrial status is coupled to defense responses such as drug detoxification, immunity, antiviral RNA interference (RNAi), and regulation of life span. A cytochrome p540 detoxification gene, cyp-14A4, is specifically activated by mitochondrial dysfunction. The nuclear hormone receptor NHR-45 and the transcriptional Mediator component MDT-15/MED15 are required for the transcriptional activation of cyp-14A4 by mitochondrial mutations, gene inactivations, or toxins. A genetic screen for mutations that fail to activate this cytochrome p450 gene upon drug or mutation-induced mitochondrial dysfunction identified a DNA helicase ARIP-4 that functions in concert with the NHR-45 transcriptional regulatory cascade. In response to mitochondrial dysfunction, ARIP-4 and NHR-45 protein interaction is enhanced, and they relocalize from the nuclear periphery to the interior of intestinal nuclei. NHR-45/ARIP-4 also regulates the transcriptional activation of the eol-1 gene that encodes a decapping enzyme required for enhanced RNAi and transgene silencing of mitochondrial mutants. In the absence of arip-4, animals were more susceptible to the mitochondrial inhibitor antimycin. Thus, ARIP-4 serves as a transcriptional coactivator of NHR-45 to promote this defense response. A null mutation in arip-4 extends the life span and health span of both wild type and a mitochondrial mutant, suggesting that the activation of detoxification pathways is deleterious to health when the mitochondrial dysfunction is caused by mutation that cannot be cytochrome p450-detoxified. Thus, arip-4 acts in a pathway that couples mitochondrial surveillance to the activation of downstream immunity, detoxification, and RNAi responses.
    Keywords:  RNAi; detoxification; healthspan; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2215966119
  9. Cell Rep. 2022 Nov 29. pii: S2211-1247(22)01622-9. [Epub ahead of print]41(9): 111744
    Inhibition of glutaminolysis restores mitochondrial function in senescent stem cells.
    Debanik Choudhury, Na Rong, Izuagie Ikhapoh, Nika Rajabian, Georgios Tseropoulos, Yulun Wu, Pihu Mehrotra, Ramkumar Thiyagarajan, Aref Shahini, Kenneth L Seldeen, Bruce R Troen, Pedro Lei, Stelios T Andreadis.
      Mitochondrial dysfunction, a hallmark of aging, has been associated with the onset of aging phenotypes and age-related diseases. Here, we report that impaired mitochondrial function is associated with increased glutamine catabolism in senescent human mesenchymal stem cells (MSCs) and myofibroblasts derived from patients suffering from Hutchinson-Gilford progeria syndrome. Increased glutaminase (GLS1) activity accompanied by loss of urea transporter SLC14A1 induces urea accumulation, mitochondrial dysfunction, and DNA damage. Conversely, blocking GLS1 activity restores mitochondrial function and leads to amelioration of aging hallmarks. Interestingly, GLS1 expression is regulated through the JNK pathway, as demonstrated by chemical and genetic inhibition. In agreement with our in vitro findings, tissues isolated from aged or progeria mice display increased urea accumulation and GLS1 activity, concomitant with declined mitochondrial function. Inhibition of glutaminolysis in progeria mice improves mitochondrial respiratory chain activity, suggesting that targeting glutaminolysis may be a promising strategy for restoring age-associated loss of mitochondrial function.
    Keywords:  CP: Cell biology; GLS1; Hutchinson-Gilford progeria syndrome; JNK; SLC14A1; aging; glutamine; mitochondria; senescence; urea
    DOI:  https://doi.org/10.1016/j.celrep.2022.111744
  10. Elife. 2022 Nov 30. pii: e84279. [Epub ahead of print]11
    An ER phospholipid hydrolase drives ER-associated mitochondrial constriction for fission and fusion.
    Tricia T Nguyen, Gia K Voeltz.
      Mitochondria are dynamic organelles that undergo cycles of fission and fusion at a unified platform defined by endoplasmic reticulum (ER)-mitochondria membrane contact sites (MCSs). These MCSs or nodes co-localize fission and fusion machinery. We set out to identify how ER-associated mitochondrial nodes can regulate both fission and fusion machinery assembly. We have used a promiscuous biotin ligase linked to the fusion machinery, Mfn1, and proteomics to identify an ER membrane protein, ABHD16A, as a major regulator of node formation. In the absence of ABHD16A, fission and fusion machineries fail to recruit to ER-associated mitochondrial nodes and fission and fusion rates are significantly reduced. ABHD16A contains an acyltransferase motif and an α/β hydrolase domain and point mutations in critical residues of these regions fail to rescue the formation of ER-associated mitochondrial hot spots. These data suggest a mechanism whereby ABHD16A functions by altering phospholipid composition at ER-mitochondria MCSs. Our data present the first example of an ER membrane protein that regulates the recruitment of both fission and fusion machineries to mitochondria.
    Keywords:  cell biology; human
    DOI:  https://doi.org/10.7554/eLife.84279
  11. Development. 2022 Dec 01. pii: dev200870. [Epub ahead of print]149(23):
    Mitochondrial respiration and dynamics of in vivo neural stem cells.
    Stavroula Petridi, Dnyanesh Dubal, Richa Rikhy, Jelle van den Ameele.
      Neural stem cells (NSCs) in the developing and adult brain undergo many different transitions, tightly regulated by extrinsic and intrinsic factors. While the role of signalling pathways and transcription factors is well established, recent evidence has also highlighted mitochondria as central players in NSC behaviour and fate decisions. Many aspects of cellular metabolism and mitochondrial biology change during NSC transitions, interact with signalling pathways and affect the activity of chromatin-modifying enzymes. In this Spotlight, we explore recent in vivo findings, primarily from Drosophila and mammalian model systems, about the role that mitochondrial respiration and morphology play in NSC development and function.
    Keywords:  Mitochondria; Mitochondrial morphology; Neural stem cell; Notch; Oxidative phosphorylation; Reactive oxygen species
    DOI:  https://doi.org/10.1242/dev.200870
  12. Ophthalmol Ther. 2022 Nov 30.
    Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A MT-ND4 Mutation.
    the LHON Study Group
      INTRODUCTION: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174.METHODS: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies.
    RESULTS: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P < 0.01) with a maximal follow-up of 3.9 years after injection. Most treated eyes were on-chart as compared to less than half of natural history eyes at 48 months after vision loss (89.6% versus 48.1%; P < 0.01) and at last observation (76.1% versus 44.4%; P < 0.01). When we adjusted for covariates of interest (gender, age of onset, ethnicity, and duration of follow-up), the estimated mean gain was - 0.43 logMAR (+ 21.5 ETDRS letters equivalent) versus natural history at last observation (P < 0.0001). Treatment effect was consistent across all phase 3 clinical trials. Analyses from REFLECT suggest a larger treatment effect in patients receiving bilateral injection compared to unilateral injection.
    CONCLUSION: The efficacy of lenadogene nolparvovec in improving visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared to the spontaneous natural history decline. Bilateral injection of gene therapy may offer added benefits over unilateral injection.
    TRIAL REGISTRATION NUMBERS: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY).
    Keywords:  Gene therapy; LHON; Leber hereditary optic neuropathy; MT-ND4; Natural history; Visual acuity
    DOI:  https://doi.org/10.1007/s40123-022-00611-x
  13. Hum Cell. 2022 Nov 29.
    Mitochondria: how eminent in ageing and neurodegenerative disorders?
    Chia Bamshad, Nima Najafi-Ghalehlou, Zahra Pourmohammadi-Bejarpasi, Kazuo Tomita, Yoshikazu Kuwahara, Tomoaki Sato, Alireza Feizkhah, Amaneh Mohammadi Roushnadeh, Mehryar Habibi Roudkenar.
      Numerous factors are implicated in the onset and progression of ageing and neurodegenerative disorders, with defects in cell energy supply and free radicals regulation designated as being the main functions of mitochondria and highly accentuated in plentiful studies. Hence, analysing the role of mitochondria as one of the main factors implicated in these disorders could undoubtedly come in handy with respect to disease prevention and treatment. In this review, first, we will explore how mitochondria account for neurodegenerative disorders and ageing and later will draw the various pathways contributing to mitochondrial dysfunction in their distinct way. Also, we will discuss the deviation-countering mechanisms, particularly mitophagy, a subset of autophagy known as a much larger cellular defence mechanism and regulatory system, along with its potential therapeutic effects. Last but not least, we will be highlighting the mitochondrial transfer experiments with animal models of neurodegenerative disorders.
    Keywords:  Ageing; Free radicals; Mitochondria; Mitochondrial transfer; Mitophagy; Neurodegenerative disorders
    DOI:  https://doi.org/10.1007/s13577-022-00833-y
  14. Cerebellum. 2022 Nov 30.
    AFG3L2 Biallelic Mutation: Clinical Heterogeneity in Two Italian Patients.
    Fabiana Colucci, Marcella Neri, Fernanda Fortunato, Alessandra Ferlini, Rosalba Carrozzo, Alessandra Torraco, Eleonora Lamantea, Andrea Legati, Ginevra Tecilla, Maura Pugliatti, Mariachiara Sensi.
      AFG3-like matrix AAA peptidase subunit 2 gene (AFG3L2, OMIM * 604,581) biallelic mutations lead to autosomal recessive spastic ataxia-5 SPAX5, OMIM # 614,487), a rare hereditary form of ataxia. The clinical spectrum includes early-onset cerebellar ataxia, spasticity, and progressive myoclonic epilepsy (PME). In Italy, the epidemiology of the disease is probably underestimated. The advent of next generation sequencing (NGS) technologies has speeded up the diagnosis of hereditary diseases and increased the percentage of diagnosis of rare disorders, such as the rare hereditary ataxia groups. Here, we describe two patients from two different villages in the province of Ferrara, who manifested a different clinical ataxia-plus history, although carrying the same biallelic mutation in AFG3L2 (p.Met625Ile) identified through NGS analysis.
    Keywords:  AFG3L2 gene; Late-onset cerebellar ataxia; Recessive ataxia; SPAX5
    DOI:  https://doi.org/10.1007/s12311-022-01497-y
  15. Geroscience. 2022 Dec 03.
    The loss of cardiac SIRT3 decreases metabolic flexibility and proteostasis in an age-dependent manner.
    Ping Li, Maria F Newhardt, Satoshi Matsuzaki, Craig Eyster, Atul Pranay, Frederick F Peelor, Albert Batushansky, Caroline Kinter, Kumar Subramani, Sandeep Subrahmanian, Jasimuddin Ahamed, Pengchun Yu, Michael Kinter, Benjamin F Miller, Kenneth M Humphries.
      SIRT3 is a longevity factor that acts as the primary deacetylase in mitochondria. Although ubiquitously expressed, previous global SIRT3 knockout studies have shown primarily a cardiac-specific phenotype. Here, we sought to determine how specifically knocking out SIRT3 in cardiomyocytes (SIRTcKO mice) temporally affects cardiac function and metabolism. Mice displayed an age-dependent increase in cardiac pathology, with 10-month-old mice exhibiting significant loss of systolic function, hypertrophy, and fibrosis. While mitochondrial function was maintained at 10 months, proteomics and metabolic phenotyping indicated SIRT3 hearts had increased reliance on glucose as an energy substrate. Additionally, there was a significant increase in branched-chain amino acids in SIRT3cKO hearts without concurrent increases in mTOR activity. Heavy water labeling experiments demonstrated that, by 3 months of age, there was an increase in protein synthesis that promoted hypertrophic growth with a potential loss of proteostasis in SIRT3cKO hearts. Cumulatively, these data show that the cardiomyocyte-specific loss of SIRT3 results in severe pathology with an accelerated aging phenotype.
    Keywords:  Flexibility; Mitochondria; Proteostasis
    DOI:  https://doi.org/10.1007/s11357-022-00695-0
  16. Mol Neurobiol. 2022 Nov 28.
    The Depletion of NAMPT Disturbs Mitochondrial Homeostasis and Causes Neuronal Degeneration in Mouse Hippocampus.
    Chen Shen, Cong Chen, Tong Wang, Tong-Yao Gao, Min Zeng, Yun-Bi Lu, Wei-Ping Zhang.
      Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme in the salvaging synthesis pathway of the nicotinamide adenine dinucleotide (NAD). Both NAMPT and NAD progressively decline upon aging and neurodegenerative diseases. The depletion of NAMPT induces mitochondrial dysfunction in motor neurons and causes bioenergetic stress in neurons. However, the roles of NAMPT in hippocampus neurons need to be further studied. Using floxed Nampt (Namptflox/flox) mice, we knocked out Nampt specifically in the hippocampus CA1 neurons by injecting rAAV-hSyn-Cre-APRE-pA. The depletion of NAMPT in hippocampus neurons induced cognitive deficiency in mice. Nevertheless, no morphological change of hippocampus neurons was observed with immunofluorescent imaging. Under the transmission electron microscope, we observed mitochondrial swollen and mitochondrial number decreasing in the cell body and the neurites of hippocampus neurons. In addition, we found the intracellular Aβ (6E10) increased in the hippocampus CA1 region. The intensity of Aβ42 remained unchanged, but it tended to aggregate. The GFAP level, an astrocyte marker, and the Iba1 level, a microglia marker, significantly increased in the mouse hippocampus. In the primary cultured rat neurons, NAMPT inhibition by FK866 decreased the NAD level of neurons at > 10-9 M. FK866 dropped the mitochondrial membrane potential in the cell body of neurons at > 10-9 M and in the dendrite of neurons at > 10-8 M. FK866 decreased the number and shortened the length of branches of neurons at > 10-7 M. Together, likely due to the injury of mitochondria, the decline of NAMPT level can be a critical risk factor for neurodegeneration.
    Keywords:  Mitochondria homeostasis; NAD (nicotinamide adenine dinucleotide); NAMPT (nicotinamide phosphoribosyltransferase); Neurodegeneration
    DOI:  https://doi.org/10.1007/s12035-022-03142-5
  17. Proc Natl Acad Sci U S A. 2022 Dec 06. 119(49): e2122073119
    Stochastic survival of the densest and mitochondrial DNA clonal expansion in aging.
    Ferdinando Insalata, Hanne Hoitzing, Juvid Aryaman, Nick S Jones.
      The expansion of mitochondrial DNA molecules with deletions has been associated with aging, particularly in skeletal muscle fibers; its mechanism has remained unclear for three decades. Previous accounts have assigned a replicative advantage (RA) to mitochondrial DNA containing deletion mutations, but there is also evidence that cells can selectively remove defective mitochondrial DNA. Here we present a spatial model that, without an RA, but instead through a combination of enhanced density for mutants and noise, produces a wave of expanding mutations with speeds consistent with experimental data. A standard model based on RA yields waves that are too fast. We provide a formula that predicts that wave speed drops with copy number, consonant with experimental data. Crucially, our model yields traveling waves of mutants even if mutants are preferentially eliminated. Additionally, we predict that mutant loads observed in single-cell experiments can be produced by de novo mutation rates that are drastically lower than previously thought for neutral models. Given this exemplar of how spatial structure (multiple linked mtDNA populations), noise, and density affect muscle cell aging, we introduce the mechanism of stochastic survival of the densest (SSD), an alternative to RA, that may underpin other evolutionary phenomena.
    Keywords:  aging; biomathematics; evolution; mitochondria; stochastic
    DOI:  https://doi.org/10.1073/pnas.2122073119
  18. Cell Death Differ. 2022 Nov 29.
    Mitochondria and cell death-associated inflammation.
    Esmee Vringer, Stephen W G Tait.
      Mitochondria have recently emerged as key drivers of inflammation associated with cell death. Many of the pro-inflammatory pathways activated during cell death occur upon mitochondrial outer membrane permeabilization (MOMP), the pivotal commitment point to cell death during mitochondrial apoptosis. Permeabilised mitochondria trigger inflammation, in part, through the release of mitochondrial-derived damage-associated molecular patterns (DAMPs). Caspases, while dispensable for cell death during mitochondrial apoptosis, inhibit activation of pro-inflammatory pathways after MOMP. Some of these mitochondrial-activated inflammatory pathways can be traced back to the bacterial ancestry of mitochondria. For instance, mtDNA and bacterial DNA are highly similar thereby activating similar cell autonomous immune signalling pathways. The bacterial origin of mitochondria suggests that inflammatory pathways found in cytosol-invading bacteria may be relevant to mitochondrial-driven inflammation after MOMP. In this review, we discuss how mitochondria can initiate inflammation during cell death highlighting parallels with bacterial activation of inflammation. Moreover, we discuss the roles of mitochondrial inflammation during cell death and how these processes may potentially be harnessed therapeutically, for instance to improve cancer treatment.
    DOI:  https://doi.org/10.1038/s41418-022-01094-w
  19. Front Cell Dev Biol. 2022 ;10 1049653
    Nicotinamide riboside kinases regulate skeletal muscle fiber-type specification and are rate-limiting for metabolic adaptations during regeneration.
    Tanja Sonntag, Sara Ancel, Sonia Karaz, Paulina Cichosz, Guillaume Jacot, Maria Pilar Giner, José Luis Sanchez-Garcia, Alice Pannérec, Sofia Moco, Vincenzo Sorrentino, Carles Cantó, Jérôme N Feige.
      Nicotinamide riboside kinases (NRKs) control the conversion of dietary Nicotinamide Riboside (NR) to NAD+, but little is known about their contribution to endogenous NAD+ turnover and muscle plasticity during skeletal muscle growth and remodeling. Using NRK1/2 double KO (NRKdKO) mice, we investigated the influence of NRKs on NAD+ metabolism and muscle homeostasis, and on the response to neurogenic muscle atrophy and regeneration following muscle injury. Muscles from NRKdKO animals have altered nicotinamide (NAM) salvage and a decrease in mitochondrial content. In single myonuclei RNAseq of skeletal muscle, NRK2 mRNA expression is restricted to type IIx muscle fibers, and perturbed NAD+ turnover and mitochondrial metabolism shifts the fiber type composition of NRKdKO muscle to fast glycolytic IIB fibers. NRKdKO does not influence muscle atrophy during denervation but alters muscle repair after myofiber injury. During regeneration, muscle stem cells (MuSCs) from NRKdKO animals hyper-proliferate but fail to differentiate. NRKdKO also alters the recovery of NAD+ during muscle regeneration as well as mitochondrial adaptations and extracellular matrix remodeling required for tissue repair. These metabolic perturbations result in a transient delay of muscle regeneration which normalizes during myofiber maturation at late stages of regeneration via over-compensation of anabolic IGF1-Akt signaling. Altogether, we demonstrate that NAD+ synthesis controls mitochondrial metabolism and fiber type composition via NRK1/2 and is rate-limiting for myogenic commitment and mitochondrial maturation during skeletal muscle repair.
    Keywords:  NAD+; NRK; fiber type; mitochondria; muscle regeneration; muscle stem cell (satellite cell); nicotinamide riboside; skeletal muscle
    DOI:  https://doi.org/10.3389/fcell.2022.1049653
  20. iScience. 2022 Dec 22. 25(12): 105610
    Mutation accumulation in mtDNA of cancers resembles mutagenesis in normal stem cells.
    Freek Manders, Jip van Dinter, Ruben van Boxtel.
      Mitochondria are small organelles that play an essential role in the energy production of eukaryotic cells. Defects in their genomes are associated with diseases, such as aging and cancer. Here, we analyzed the mitochondrial genomes of 532 whole-genome sequencing samples from cancers and normal clonally expanded single cells. We show that the mitochondria of normal cells accumulate mutations with age and that most of the mitochondrial mutations found in cancer are the result of healthy mutation accumulation. We also show that the normal HSPCs of patients with leukemia have an increased mitochondrial mutation load. Finally, we show that secondary pediatric cancers and chemotherapy treatments do not impact the mitochondrial mutation load and mtDNA copy numbers of most cells, suggesting that damage to the mitochondrial genome is not a major driver for carcinogenesis. Overall, these findings may contribute to our understanding of mitochondrial genomes and their role in cancer.
    Keywords:  Cancer; Genomics; Stem cells research
    DOI:  https://doi.org/10.1016/j.isci.2022.105610
  21. Curr Genet. 2022 Nov 30.
    Horizontal transfer of tRNA genes to mitochondrial plasmids facilitates gene loss from fungal mitochondrial DNA.
    Mathijs Nieuwenhuis, Jeroen Groeneveld, Duur K Aanen.
      Fungal and plant mitochondria are known to exchange DNA with retroviral plasmids. Transfer of plasmid DNA to the organellar genome is best known and occurs through wholesale insertion of the plasmid. Less well known is the transfer of organellar DNA to plasmids, in particular tRNA genes. Presently, it is unknown whether fungal plasmids can adopt mitochondrial functions such as tRNA production through horizontal gene transfer. In this paper, we studied the exchange of DNA between fungal linear plasmids and fungal mtDNA, mainly focusing on the basidiomycete family Lyophyllaceae. We report at least six independent transfers of complete tRNA genes to fungal plasmids. Furthermore, we discovered two independent cases of loss of a tRNA gene from a fungal mitochondrial genome following transfer of such a gene to a linear mitochondrial plasmid. We propose that loss of a tRNA gene from mtDNA following its transfer to a plasmid creates a mutualistic dependency of the host mtDNA on the plasmid. We also find that tRNA genes transferred to plasmids encode codons that occur at the lowest frequency in the host mitochondrial genomes, possibly due to a higher number of unused transcripts. We discuss the potential consequences of mtDNA transfer to plasmids for both the host mtDNA and the plasmid.
    Keywords:  Fungi; Horizontal gene transfer; Lyophyllaceae; Mitochondrial plasmids; Phylogenetics; mtDNA
    DOI:  https://doi.org/10.1007/s00294-022-01259-7
  22. Stem Cell Res. 2022 Nov 22. pii: S1873-5061(22)00329-4. [Epub ahead of print]65 102980
    Generation of a homozygous FIS1 knockout human embryonic stem cell line GIBHe015-B by CRISPR/Cas9 system.
    Mingquan Wang, Jun Tang, Tiancheng Zhou, Yuchan Mai, Yanling Zhu.
      The mitochondrial fission protein 1 (FIS1) is essential for mitochondrial division or fission and has been determined to mediate mitochondrial and peroxisomal fission. Other studies also found that FIS1 functions as an essential component of the mitophagy and apoptosis pathways in mammalian cells, suggesting that FIS1 has multiple important roles. Here, we generated homozygous FIS1 knockout human embryonic stem cells (hESCs) using the CRISPR/Cas9 system. This cell line exhibits normal karyotype, pluripotency, and trilineage differentiation potential, which could provide a useful cellular resource for exploring the functions of FIS1 and their implications in human health and diseases.
    DOI:  https://doi.org/10.1016/j.scr.2022.102980
  23. Cell Mol Bioeng. 2022 Oct;15(5): 367-389
    Engineering Extracellular Vesicles to Modulate Their Innate Mitochondrial Load.
    Kandarp M Dave, Duncan X Dobbins, Maura N Farinelli, Abigail Sullivan, Jadranka Milosevic, Donna B Stolz, Jeongyun Kim, Siyang Zheng, Devika S Manickam.
      Introduction: Extracellular vesicles (EVs) are promising carriers for the delivery of biotherapeutic cargo such as RNA and proteins. We have previously demonstrated that the innate EV mitochondria in microvesicles (MVs), but not exosomes (EXOs) can be transferred to recipient BECs and mouse brain slice neurons. Here, we sought to determine if the innate EV mitochondrial load can be further increased via increasing mitochondrial biogenesis in the donor cells. We hypothesized that mitochondria-enriched EVs ("mito-EVs") may increase the recipient BEC ATP levels to a greater extent than naïve MVs.Methods: We treated NIH/3T3, a fibroblast cell line and hCMEC/D3, a human brain endothelial cell (BEC) line using resveratrol to activate peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), the central mediator of mitochondrial biogenesis. Naïve EVs and mito-EVs isolated from the non-activated and activated donor cells were characterized using transmission electron microscopy, dynamic light scattering and nanoparticle tracking analysis. The effect of mito-EVs on resulting ATP levels in the recipient BECs were determined using Cell Titer Glo ATP assay. The uptake of Mitotracker Red-stained EVs into recipient BECs and their colocalization with recipient BEC mitochondria were studied using flow cytometry and fluorescence microscopy.
    Results: Resveratrol treatment increased PGC-1α expression in the donor cells. Mito-MVs but not mito-EXOs showed increased expression of mitochondrial markers ATP5A and TOMM20 compared to naïve MVs. TEM images showed that a greater number of mito-MVs contained mitochondria compared to naïve MVs. Mito-MVs but not mito-EXOs showed a larger particle diameter compared to their naïve EV counterparts from the non-activated cells suggesting increased mitochondria incorporation. Mito-EVs were generated at higher particle concentrations compared to naïve EVs from non-activated cells. Mito-EVs increased the cellular ATP levels and transferred their mitochondrial load into the recipient BECs. Mito-MV mitochondria also colocalized with recipient BEC mitochondria.
    Conclusions: Our results suggest that the pharmacological modulation of mitochondrial biogenesis in the donor cells can change the mitochondrial load in the secreted MVs. Outcomes of physicochemical characterization studies and biological assays confirmed the superior effects of mito-MVs compared to naïve MVs-suggesting their potential to improve mitochondrial function in neurovascular and neurodegenerative diseases.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-022-00738-8.
    Keywords:  ATP; Brain endothelial cells; EVs; Exosomes; Metabolic function; Microvesicles; Mitochondria; PGC-1α
    DOI:  https://doi.org/10.1007/s12195-022-00738-8
  24. Nat Commun. 2022 Nov 29. 13(1): 7356
    Genetically personalised organ-specific metabolic models in health and disease.
    Carles Foguet, Yu Xu, Scott C Ritchie, Samuel A Lambert, Elodie Persyn, Artika P Nath, Emma E Davenport, David J Roberts, Dirk S Paul, Emanuele Di Angelantonio, John Danesh, Adam S Butterworth, Christopher Yau, Michael Inouye.
      Understanding how genetic variants influence disease risk and complex traits (variant-to-function) is one of the major challenges in human genetics. Here we present a model-driven framework to leverage human genome-scale metabolic networks to define how genetic variants affect biochemical reaction fluxes across major human tissues, including skeletal muscle, adipose, liver, brain and heart. As proof of concept, we build personalised organ-specific metabolic flux models for 524,615 individuals of the INTERVAL and UK Biobank cohorts and perform a fluxome-wide association study (FWAS) to identify 4312 associations between personalised flux values and the concentration of metabolites in blood. Furthermore, we apply FWAS to identify 92 metabolic fluxes associated with the risk of developing coronary artery disease, many of which are linked to processes previously described to play in role in the disease. Our work demonstrates that genetically personalised metabolic models can elucidate the downstream effects of genetic variants on biochemical reactions involved in common human diseases.
    DOI:  https://doi.org/10.1038/s41467-022-35017-7
  25. Mol Reprod Dev. 2022 Nov 29.
    Profiling of mitochondrial heteroplasmy in single human oocytes by next-generation sequencing.
    Valentina Russo, Massimo Ancora, Valentina Gatta, Massimiliano Orsini, Giuseppe Prencipe, Alessia Peserico, Alessia Colosimo, Mohammad El Khatib, Annunziata Mauro, Chiara Di Berardino, Silvia Scialabba, Gian Mario Tiboni, Maurilia Marcacci, Cesare Cammà, Barbara Barboni.
      Mitochondrial DNA (mtDNA) plays a crucial role in the development of a competent oocyte. Indeed, mtDNA alterations may predispose to chromosome nondisjunction, resulting in infertility due to a reduced vitality and quality of oocytes and embryos. In this methods paper, the multiple displacement amplification approach was applied in combination with next-generation sequencing (NGS) to amplify and sequence, in single-end, the entire mtDNA of single human oocytes to directly construct genomic NGS libraries, and subsequently, to highlight and quantify the mutations they presented. The bioinformatic workflow was carried out with a specific ad hoc developed in-house software. This approach proved to be sensitive and specific, also highlighting the mutations present in heteroplasmy, showing deletion, insertion or substitution mutations in the genes involved in the respiratory chain, even if the found variants were benign or of uncertain meaning. The analysis of mtDNA mutations in the oocyte could provide a better understanding of specific genetic abnormalities and of their possible effect on oocyte developmental competence. This study shows how this approach, based on a massive parallel sequencing of clonally amplified DNA molecules, allows to sequence the entire mitochondrial genome of single oocytes in a short time and with a single analytical run and to verify mtDNA mutations.
    Keywords:  heteroplasmic mutations; human oocyte; mitochondrial DNA; next-generation sequencing
    DOI:  https://doi.org/10.1002/mrd.23655
  26. Mol Biol Rep. 2022 Dec 03.
    Clinical, neuroimaging and genetic findings in children with hereditary ataxia: single center study.
    Yasar Bildirici, Ayca Kocaaga, Sevgi Yimenicioglu.
      BACKGROUND: The genetics of hereditary ataxia (HA) are complex and multigenic. The diversity of genes that cause ataxia varies considerably between populations. We aimed to investigate the clinical, neuroimaging, and genetic findings of HA in children from a tertiary center in Turkey.METHODS: The clinical and neuroimaging evaluations of patients, laboratory investigations, and molecular genetic evaluations of those with ataxia were performed at the pediatrics, pediatric neurology, and genetics outpatient clinics between October 2020 and October 2021. With repeated expansions in the ATXN 1, 2, 3, 7, and 8 genes for spinocerebellar ataxia (SCA) and FXN genes for Friedreich's ataxia (FA), whole-exome sequencing (WES) was used to analyze every patient.
    RESULTS: 25 patients from 24 families had ataxia and an unsteady gait as their main symptoms. The patients had a mean age of 8.5 ± 3.78 years, and the symptoms had begun at a mean age of 2 ± 0.62 years; five of these were males and three were females. A genetic cause of ataxia was found in 8/25 patients (32%). Seven of the eight gene mutations detected in the patients were novel mutations. Spinocerebellar ataxia was found in 16% of cases (n = 4), L-2-Hydroxyglutaric aciduria was found in 12% of cases (n = 3), and ataxia-telangiectasia was found in 4% of cases (n = 1).
    CONCLUSION: Our research adds to the body of knowledge by describing the clinical and genetic traits of HA patients in our area and by finding unusual gene changes linked to ataxia.
    Keywords:  Ataxia; Novel mutation; Pathogenic; Spinocerebellar ataxia; Whole exome sequencing
    DOI:  https://doi.org/10.1007/s11033-022-08148-9
  27. Neuropharmacology. 2022 Nov 25. pii: S0028-3908(22)00409-9. [Epub ahead of print] 109350
    Chronic treatment with the anti-diabetic drug metformin rescues impaired brain mitochondrial activity and selectively ameliorates defective cognitive flexibility in a female mouse model of Rett syndrome.
    Chiara Urbinati, Chiara Lanzillotta, Livia Cosentino, Daniela Valenti, Maria Cristina Quattrini, Livia Di Crescenzo, Francesca Prestia, Donatella Pietraforte, Marzia Perluigi, Fabio Di Domenico, Rosa Anna Vacca, Bianca De Filippis.
      Metformin is the most common anti-diabetic drug and a promising therapy for disorders beyond diabetes, including Rett syndrome (RTT), a rare neurologic disease characterized by severe intellectual disability. A 10-day-long treatment rescued aberrant mitochondrial activity and restrained oxidative stress in a female RTT mouse model. However, this treatment regimen did not improve the phenotype of RTT mice. In the present study, we demonstrate that a 4-month-long treatment with metformin (150 mg/Kg/day, delivered in drinking bottles) provides a selective normalization of cognitive flexibility defects in RTT female mice at an advanced stage of disease, but it does not affect their impaired general health status and abnormal motor skills. The 4-month-long treatment also rescues the reduced activity of mitochondrial respiratory chain complex activities, the defective brain ATP production and levels as well as the increased production of reactive oxidizing species in the whole blood of RTT mice. A significant boost of PGC-1α-dependent pathways related to mitochondrial biogenesis and antioxidant defense occurs in the brain of RTT mice that received the metformin treatment. Further studies will have to verify whether these effects may underlie its long-lasting beneficial effects on brain energy metabolism.
    Keywords:  Cognition; Metformin; Mitochondria; Oxidative stress status; Rett syndrome
    DOI:  https://doi.org/10.1016/j.neuropharm.2022.109350
  28. Cell Regen. 2022 Dec 01. 11(1): 38
    Mitochondrial fragmentation and ROS signaling in wound response and repair.
    Shiqi Xu, Shiyao Li, Mikael Bjorklund, Suhong Xu.
      Mitochondria are organelles that serve numerous critical cellular functions, including energy production, Ca2+ homeostasis, redox signaling, and metabolism. These functions are intimately linked to mitochondrial morphology, which is highly dynamic and capable of rapid and transient changes to alter cellular functions in response to environmental cues and cellular demands. Mitochondrial morphology and activity are critical for various physiological processes, including wound healing. In mammals, wound healing is a complex process that requires coordinated function of multiple cell types and progresses in partially overlapping but distinct stages: hemostasis and inflammation, cell proliferation and migration, and tissue remodeling. The repair process at the single-cell level forms the basis for wound healing and regeneration in tissues. Recent findings reveal that mitochondria fulfill the intensive energy demand for wound repair and aid wound closure by cytoskeleton remodeling via morphological changes and mitochondrial reactive oxygen species (mtROS) signaling. In this review, we will mainly elucidate how wounding induces changes in mitochondrial morphology and activity and how these changes, in turn, contribute to cellular wound response and repair.
    Keywords:  FZO-1; MFN-1/2; MIRO-1; Membrane repair; Mitochondrial dynamic; Mitochondrial fragmentation; Plasma membrane; Reactive oxygen species
    DOI:  https://doi.org/10.1186/s13619-022-00141-8
  29. Nat Commun. 2022 Dec 02. 13(1): 7414
    Nuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation.
    Wei Li, Qi Long, Hao Wu, Yanshuang Zhou, Lifan Duan, Hao Yuan, Yingzhe Ding, Yile Huang, Yi Wu, Jinyu Huang, Delong Liu, Baodan Chen, Jian Zhang, Juntao Qi, Shiwei Du, Linpeng Li, Yang Liu, Zifeng Ruan, Zihuang Liu, Zichao Liu, Yifan Zhao, Jianghuan Lu, Junwei Wang, Wai-Yee Chan, Xingguo Liu.
      Pluripotent stem cells hold great promise in regenerative medicine and developmental biology studies. Mitochondrial metabolites, including tricarboxylic acid (TCA) cycle intermediates, have been reported to play critical roles in pluripotency. Here we show that TCA cycle enzymes including Pdha1, Pcb, Aco2, Cs, Idh3a, Ogdh, Sdha and Mdh2 are translocated to the nucleus during somatic cell reprogramming, primed-to-naive transition and totipotency acquisition. The nuclear-localized TCA cycle enzymes Pdha1, Pcb, Aco2, Cs, Idh3a promote somatic cell reprogramming and primed-to-naive transition. In addition, nuclear-localized TCA cycle enzymes, particularly nuclear-targeted Pdha1, facilitate the 2-cell program in pluripotent stem cells. Mechanistically, nuclear Pdha1 increases the acetyl-CoA and metabolite pool in the nucleus, leading to chromatin remodeling at pluripotency genes by enhancing histone H3 acetylation. Our results reveal an important role of mitochondrial TCA cycle enzymes in the epigenetic regulation of pluripotency that constitutes a mitochondria-to-nucleus retrograde signaling mode in different states of pluripotent acquisition.
    DOI:  https://doi.org/10.1038/s41467-022-35199-0
  30. Stem Cell Res. 2022 Nov 17. pii: S1873-5061(22)00325-7. [Epub ahead of print]65 102976
    Generation of induced pluripotent stem cells from three individuals with Huntington's disease.
    Duncan C Miller, Pawel Lisowski, Selene Lickfett, Barbara Mlody, Miriam Bünning, Carolin Genehr, Claas Ulrich, Erich E Wanker, Sebastian Diecke, Josef Priller, Alessandro Prigione.
      Huntington's disease (HD) is a neurodegenerative disorder caused by abnormal glutamine (Q) expansion in the huntingtin protein due to elongated CAG repeats in the gene HTT. We used non-integrative episomal plasmids to generate induced pluripotent stem cells (iPSCs) from three individuals affected by HD: CH1 (58Q), and two twin brothers CH3 (44Q) and CH4 (44Q). The iPSC lines exhibited one healthy HTT allele and one with elongated CAG repeats, as confirmed by PCR and sequencing. All iPSC lines expressed pluripotency markers, exhibited a normal karyotype, and generated cells of the three germ layers in vitro.
    DOI:  https://doi.org/10.1016/j.scr.2022.102976
  31. Nat Commun. 2022 Nov 28. 13(1): 7338
    Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism.
    Claudio Bussi, Tiaan Heunis, Enrica Pellegrino, Elliott M Bernard, Nourdine Bah, Mariana Silva Dos Santos, Pierre Santucci, Beren Aylan, Angela Rodgers, Antony Fearns, Julia Mitschke, Christopher Moore, James I MacRae, Maria Greco, Thomas Reinheckel, Matthias Trost, Maximiliano G Gutierrez.
      Transient lysosomal damage after infection with cytosolic pathogens or silica crystals uptake results in protease leakage. Whether limited leakage of lysosomal contents into the cytosol affects the function of cytoplasmic organelles is unknown. Here, we show that sterile and non-sterile lysosomal damage triggers a cell death independent proteolytic remodelling of the mitochondrial proteome in macrophages. Mitochondrial metabolic reprogramming required leakage of lysosomal cathepsins and was independent of mitophagy, mitoproteases and proteasome degradation. In an in vivo mouse model of endomembrane damage, live lung macrophages that internalised crystals displayed impaired mitochondrial function. Single-cell RNA-sequencing revealed that lysosomal damage skewed metabolic and immune responses in alveolar macrophages subsets with increased lysosomal content. Functionally, drug modulation of macrophage metabolism impacted host responses to Mycobacterium tuberculosis infection in an endomembrane damage dependent way. This work uncovers an inter-organelle communication pathway, providing a general mechanism by which macrophages undergo mitochondrial metabolic reprograming after endomembrane damage.
    DOI:  https://doi.org/10.1038/s41467-022-34632-8
  32. Nat Metab. 2022 Nov 28.
    Metabolon formation regulates branched-chain amino acid oxidation and homeostasis.
    McKenzie Patrick, Zhimin Gu, Gen Zhang, R Max Wynn, Pranita Kaphle, Hui Cao, Hieu Vu, Feng Cai, Xiaofei Gao, Yuannyu Zhang, Mingyi Chen, Min Ni, David T Chuang, Ralph J DeBerardinis, Jian Xu.
      The branched-chain aminotransferase isozymes BCAT1 and BCAT2, segregated into distinct subcellular compartments and tissues, initiate the catabolism of branched-chain amino acids (BCAAs). However, whether and how BCAT isozymes cooperate with downstream enzymes to control BCAA homeostasis in an intact organism remains largely unknown. Here, we analyse system-wide metabolomic changes in BCAT1- and BCAT2-deficient mouse models. Loss of BCAT2 but not BCAT1 leads to accumulation of BCAAs and branched-chain α-keto acids (BCKAs), causing morbidity and mortality that can be ameliorated by dietary BCAA restriction. Through proximity labelling, isotope tracing and enzymatic assays, we provide evidence for the formation of a mitochondrial BCAA metabolon involving BCAT2 and branched-chain α-keto acid dehydrogenase. Disabling the metabolon contributes to BCAT2 deficiency-induced phenotypes, which can be reversed by BCAT1-mediated BCKA reamination. These findings establish a role for metabolon formation in BCAA metabolism in vivo and suggest a new strategy to modulate this pathway in diseases involving dysfunctional BCAA metabolism.
    DOI:  https://doi.org/10.1038/s42255-022-00689-4
  33. Front Genet. 2022 ;13 1030361
    Characterization of pregnancy outcome of women with an offspring with inborn errors of metabolism: A population-based study.
    Tali Epstein Weiss, Offer Erez, Itai Hazan, Amit-Shira Babiev, Orna Staretz Chacham.
      Introduction: Inborn errors of metabolism (IEM) are scarce, and their diagnosis is often made after birth. This has led to the perception that most fetuses affected by these disorders do not become clinically apparent during pregnancy. Our aim was to determine the obstetrical characteristics of women with an offspring affected by IEM. Methods: This population-based retrospective cohort study included all women who delivered at the Soroka University Medical Center (SUMC) from 1988 to 2017 who met the inclusion criteria. Mothers who had an offspring with IEM were included in the study group, and those who had offsprings without IEM comprised the comparison group. Results: A total of 388,813 pregnancies were included in the study, and 184 of them were complicated by a fetus with IEM. The number of Bedouin women was higher in the IEM-affected infant group than in the comparison group (90.8% vs. 53.3%, p < 0.001); women who had a fetus with IEM had a higher rate of polyhydramnios (7.1% vs. 3.2%, p = 0.005), HELLP syndrome (3.3% vs. 1.1%, p = 0.014), and preterm birth (20.7% vs. 10.1%, p < 0.001); neonates with IEM had lower mean birth weight (p < 0.001), lower Apgar scores at 1' and 5' minutes (p < 0.001), and a higher rate of fetal growth restriction (FGR) (p < 0.001), postpartum death <28 days (p < 0.001), and neonatal death (p < 0.001) than those in the comparison group. Pregnancies with IEM fetuses were independently associated with preterm birth (OR 2.00; CI 1.4-3), polyhydramnios (OR 2.08; CI 1.17-3.71), and FGR (OR 2.24; CI 1.2-4.19). Each family of metabolic diseases is independently associated with specific pregnancy complications (i.e., mitochondrial diseases are associated with HELLP syndrome (OR 5.6; CI 1.8-17), and lysosomal storage disease are associated with nonimmune hydrops fetalis (OR 26.4; CI 3.39-206). Conclusion: This study reports for the first time, an independent association of IEM with specific complications of pregnancy. This observation has clinical implications, as the identification of specific pregnancy complications in a population at risk for IEM can assist in the prenatal diagnosis of an affected fetus.
    Keywords:  HELLP syndrome; fetal growth restriction; inborn errors of metabolism; neonatal death; nonimmune hydrops fetalis; polyhydramnios; pregnancy characteristics; preterm birth
    DOI:  https://doi.org/10.3389/fgene.2022.1030361
  34. Autophagy. 2022 Nov 30.
    The roles of a mitochondrial protein Miga in autophagy.
    Lingna Xu, Liquan Wang, Chao Tong.
      Miga is an evolutionarily conserved protein that localizes to the outer membrane of mitochondria and mediates endoplasmic reticulum (ER)-mitochondrial contacts through interaction with VAP proteins in the ER. We recently reported that Miga is required for autophagosome-lysosome fusion during macroautophagy/autophagy. Miga binds to Atg14 and Uvrag, two alternative subunits of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex. Miga regulates phosphatidylinositol-3-phosphate (PtdIns3P) levels through its interaction with Uvrag and its ER-mitochondrial contact site (ERMCS) tethering activity. Miga stabilizes Atg14, which maintains steady levels of the SNARE protein, Syx17. We propose that Miga establishes a direct link between mitochondria and autophagy to maintain cellular homeostasis.
    Keywords:  Drosophila; autophagy; endoplasmic reticulum-mitochondrial contacts; mitochondrion; phosphatidylinositol-3 kinase
    DOI:  https://doi.org/10.1080/15548627.2022.2153569
  35. Neural Regen Res. 2023 Jun;18(6): 1203-1212
    Cell-based therapeutic strategies for treatment of spinocerebellar ataxias: an update.
    Joana Sofia Correia, Sara Duarte-Silva, António José Salgado, Patrícia Maciel.
      Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion, which encodes a long glutamine tract (polyglutamine) in the respective wild-type protein causing misfolding and protein aggregation. Clinical features of polyglutamine spinocerebellar ataxias include neuronal aggregation, mitochondrial dysfunction, decreased proteasomal activity, and autophagy impairment. Mutant polyglutamine protein aggregates accumulate within neurons and cause neural dysfunction and death in specific regions of the central nervous system. Spinocerebellar ataxias are mostly characterized by progressive ataxia, speech and swallowing problems, loss of coordination and gait deficits. Over the past decade, efforts have been made to ameliorate disease symptoms in patients, yet no cure is available. Previous studies have been proposing the use of stem cells as promising tools for central nervous system tissue regeneration. So far, pre-clinical trials have shown improvement in various models of neurodegenerative diseases following stem cell transplantation, including animal models of spinocerebellar ataxia types 1, 2, and 3. However, contrasting results can be found in the literature, depending on the animal model, cell type, and route of administration used. Nonetheless, clinical trials using cellular implants into degenerated brain regions have already been applied, with the expectation that these cells would be able to differentiate into the specific neuronal subtypes and re-populate these regions, reconstructing the affected neural network. Meanwhile, the question of how feasible it is to continue such treatments remains unanswered, with long-lasting effects being still unknown. To establish the value of these advanced therapeutic tools, it is important to predict the actions of the transplanted cells as well as to understand which cell type can induce the best outcomes for each disease. Further studies are needed to determine the best route of administration, without neglecting the possible risks of repetitive transplantation that these approaches so far appear to demand. Despite the challenges ahead of us, cell-transplantation therapies are reported to have transient but beneficial outcomes in spinocerebellar ataxias, which encourages efforts towards their improvement in the future.
    Keywords:  cell transplantation; engraftment; induced pluripotent stem cells; mesenchymal stem cells; neural progenitor cells; neuroprotection; polyglutamine spinocerebellar ataxias; secretome; spinocerebellar ataxia; stem cell therapy
    DOI:  https://doi.org/10.4103/1673-5374.355981
  36. Mol Ther Methods Clin Dev. 2022 Dec 08. 27 488-490
    A retrograde approach for liver gene transfer.
    Nicola Brunetti-Pierri, Paul Gissen.
      
    Keywords:  gene therapy; hydrodynamic injections; hydrodynamic retrograde intrabiliary injection; nonviral vectors; ornithine transcarbamylase deficiency
    DOI:  https://doi.org/10.1016/j.omtm.2022.11.002
  37. J Gerontol A Biol Sci Med Sci. 2022 Dec 03. pii: glac238. [Epub ahead of print]
    Mitochondrial energetics in skeletal muscle are associated with leg power and cardiorespiratory fitness in the Study of Muscle, Mobility, and Aging (SOMMA).
    Theresa Mau, Li-Yung Lui, Giovanna Distefano, Philip A Kramer, Sofhia V Ramos, Frederico G S Toledo, Adam J Santanasto, Eric G Shankland, David J Marcinek, Michael J Jurczak, Ian Sipula, Fiona M Bello, Kate A Duchowny, Anthony J A Molina, Lauren M Sparks, Bret H Goodpaster, Russell T Hepple, Stephen B Kritchevsky, Anne B Newman, Peggy M Cawthon, Steven R Cummings, Paul M Coen.
      BACKGROUND: Mitochondrial energetics are an important property of aging muscle, as generation of energy is pivotal to the execution of muscle contraction. However, its association with functional outcomes, including leg power and cardiorespiratory fitness is largely understudied.METHODS: In the Study of Muscle, Mobility, and Aging (SOMMA), we collected vastus lateralis biopsies from older adults (n=879,70-94 years,59.2% women). Maximal state 3 respiration (Max OXPHOS) was assessed in permeabilized fiber bundles by high-resolution respirometry. Capacity for maximal adenosine triphosphate production (ATPmax) was measured in vivo by 31P magnetic resonance spectroscopy. Leg extension power was measured with a Keiser press system, and VO2 peak was determined using a standardized cardiopulmonary exercise test. Gender-stratified multivariate linear regression models were adjusted for age, race, technician/site, adiposity, and physical activity with beta-coefficients expressed per 1 SD increment in the independent variable.
    RESULTS: Max OXPHOS was associated with leg power for both women (β=0.12Watts/kg,p<0.001) and men (β=0.11Watts/kg,p<0.050). ATPmax was associated with leg power for men (β=0.09Watts/kg p<0.05) but was not significant for women (β=0.03Watts/kg,p=0.11). Max OXPHOS and ATPmax were associated with VO2 peak in women and men (Max OXPHOS, βwomen=1.03mL/kg/min, βmen=1.32 mL/kg/min; ATPmax βwomen=0.87mL/kg/min, βmen=1.50mL/kg/min;all p<0.001).
    CONCLUSIONS: Higher muscle mitochondrial energetics measures were associated with both better cardiorespiratory fitness and greater leg power in older adults. Muscle mitochondrial energetics explained a greater degree of variance in VO2 peak compared to leg power.
    Keywords:  Muscle; cardiorespiratory fitness; mitochondria; power
    DOI:  https://doi.org/10.1093/gerona/glac238
  38. J Cachexia Sarcopenia Muscle. 2022 Nov 28.
    Loss of FoxOs in muscle increases strength and mitochondrial function during aging.
    Christie M Penniman, Gourav Bhardwaj, Colette J Nowers, Chandler U Brown, Taylor L Junck, Cierra K Boyer, Jayashree Jena, Jordan D Fuqua, Vitor A Lira, Brian T O'Neill.
      BACKGROUND: Muscle mitochondrial decline is associated with aging-related muscle weakness and insulin resistance. FoxO transcription factors are targets of insulin action and deletion of FoxOs improves mitochondrial function in diabetes. However, disruptions in proteostasis and autophagy are hallmarks of aging and the effect of chronic inhibition of FoxOs in aged muscle is unknown. This study investigated the role of FoxOs in regulating muscle strength and mitochondrial function with age.METHODS: We measured muscle strength, cross-sectional area, muscle fibre-type, markers of protein synthesis/degradation, central nuclei, glucose/insulin tolerance, and mitochondrial bioenergetics in 4.5-month (Young) and 22-24-month-old (Aged) muscle-specific FoxO1/3/4 triple KO (TKO) and littermate control (Ctrl) mice.
    RESULTS: Lean mass was increased in Aged TKO compared with both Aged Ctrl and younger groups by 26-33% (P < 0.01). Muscle strength, measured by max force of tibialis anterior (TA) contraction, was 20% lower in Aged Ctrl compared with Young Ctrls (P < 0.01) but was not decreased in Aged TKOs. Increased muscle strength in Young and Aged TKO was associated with 18-48% increased muscle weights compared with Ctrls (P < 0.01). Muscle cross-sectional analysis of TA, soleus, and plantaris revealed increases in fibre size distribution and a 2.5-10-fold increase in central nuclei in Young and Aged TKO mice, without histologic signs of muscle damage. Age-dependent increases in Gadd45a and Ube4a expression as well accumulation of K48 polyubiquitinated proteins were observed in quad and TA but were prevented by FoxO deletion. Young and Aged TKO muscle showed minimal changes in autophagy flux and no accumulation of autophagosomes compared with Ctrl groups. Increased strength in Young and Aged TKO was associated with a 10-20% increase in muscle mitochondrial respiration using glutamate/malate/succinate compared with controls (P < 0.05). OXPHOS subunit expression and complex I activity were decreased 16-34% in Aged Ctrl compared with Young Ctrl but were prevented in Aged TKO. Both Aged Ctrl and Aged TKO showed impaired glucose tolerance by 33% compared to young groups (P < 0.05) indicating improved strength and mitochondrial respiration are not due to improved glycemia.
    CONCLUSIONS: FoxO deletion increases muscle strength even during aging. Deletion of FoxOs maintains muscle strength in part by mild suppression of atrophic pathways, including inhibition of Gadd45a and Ube4a expression, without accumulation of autophagosomes in muscle. Deletion of FoxOs also improved mitochondrial function by maintenance of OXPHOS in both young and aged TKO.
    Keywords:  Aging; FoxO; Glucose tolerance; Insulin resistance; Mitochondrial function; Muscle hypertrophy
    DOI:  https://doi.org/10.1002/jcsm.13124
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