bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022‒08‒07
twenty-two papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico
  1. Rapamycin rescues mitochondrial dysfunction in cells carrying the m.8344A > G mutation in the mitochondrial tRNALys.
  2. Regulation of mitochondrial proteostasis by the proton gradient.
  3. Nrf2 as a regulator of mitochondrial function: Energy metabolism and beyond.
  4. Measuring Single-Cell Mitochondrial DNA Copy Number and Heteroplasmy using Digital Droplet Polymerase Chain Reaction.
  5. Structural insight and characterization of human Twinkle helicase in mitochondrial disease.
  6. Mitochondrial DNA maintenance defects: potential therapeutic strategies.
  7. The mystery of mitochondrial plasticity: TMBIM5 integrates metabolic state and proteostasis.
  8. Altered SYNJ2BP-mediated mitochondrial-ER contacts in motor neuron disease.
  9. Extended spinal cord involvement in adult-onset Leigh syndrome due to mitochondrial 10197G > A mutation.
  10. Glutamatergic Synapse Dysfunction in Drosophila Neuromuscular Junctions Can Be Rescued by Proteostasis Modulation.
  11. Selective Disruption of Drp1-Independent Mitophagy and Mitolysosome Trafficking by an Alzheimer's Disease Relevant Tau Modification in a Novel C. elegans Model.
  12. Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy.
  13. Metrics of progression and prognosis in untreated adults with thymidine kinase 2 deficiency: An observational study.
  14. mTORC2 protects the heart from high-fat diet-induced cardiomyopathy through mitochondrial fission in Drosophila.
  15. Noninvasive Ophthalmic Imaging Measures Retinal Degeneration and Vision Deficits in Ndufs4-/- Mouse Model of Mitochondrial Complex I Deficiency.
  16. Highly conserved shifts in ubiquitin-proteasome system (UPS) activity drive mitochondrial remodeling during quiescence.
  17. Mitochondrial remodeling and ischemic protection by G protein-coupled receptor 35 agonists.
  18. Mitophagy initiates retrograde mitochondrial-nuclear signaling to guide retinal pigment cell heterogeneity.
  19. Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations.
  20. Loss of mitochondrial enzyme GPT2 causes early neurodegeneration in locus coeruleus.
  21. The mitochondrial unfolded protein response: A multitasking giant in the fight against human diseases.
  22. Enhanced mitochondrial activity reshapes a gut microbiota profile that delays NASH progression.
  1. Mol Med. 2022 Aug 03. 28(1): 90
    Rapamycin rescues mitochondrial dysfunction in cells carrying the m.8344A > G mutation in the mitochondrial tRNALys.
    Mariantonietta Capristo, Valentina Del Dotto, Concetta Valentina Tropeano, Claudio Fiorini, Leonardo Caporali, Chiara La Morgia, Maria Lucia Valentino, Monica Montopoli, Valerio Carelli, Alessandra Maresca.
      BACKGROUND: Myoclonus, Epilepsy and Ragged-Red-Fibers (MERRF) is a mitochondrial encephalomyopathy due to heteroplasmic mutations in mitochondrial DNA (mtDNA) most frequently affecting the tRNALys gene at position m.8344A > G. Defective tRNALys severely impairs mitochondrial protein synthesis and respiratory chain when a high percentage of mutant heteroplasmy crosses the threshold for full-blown clinical phenotype. Therapy is currently limited to symptomatic management of myoclonic epilepsy, and supportive measures to counteract muscle weakness with co-factors/supplements.METHODS: We tested two therapeutic strategies to rescue mitochondrial function in cybrids and fibroblasts carrying different loads of the m.8344A > G mutation. The first strategy was aimed at inducing mitochondrial biogenesis directly, over-expressing the master regulator PGC-1α, or indirectly, through the treatment with nicotinic acid, a NAD+ precursor. The second was aimed at stimulating the removal of damaged mitochondria through prolonged rapamycin treatment.
    RESULTS: The first approach slightly increased mitochondrial protein expression and respiration in the wild type and intermediate-mutation load cells, but was ineffective in high-mutation load cell lines. This suggests that induction of mitochondrial biogenesis may not be sufficient to rescue mitochondrial dysfunction in MERRF cells with high-mutation load. The second approach, when administered chronically (4 weeks), induced a slight increase of mitochondrial respiration in fibroblasts with high-mutation load, and a significant improvement in fibroblasts with intermediate-mutation load, rescuing completely the bioenergetics defect. This effect was mediated by increased mitochondrial biogenesis, possibly related to the rapamycin-induced inhibition of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and the consequent activation of the Transcription Factor EB (TFEB).
    CONCLUSIONS: Overall, our results point to rapamycin-based therapy as a promising therapeutic option for MERRF.
    Keywords:  MERRF; Mitochondrial DNA; Mitochondrial biogenesis; Mitochondrial dysfunction; Niacin; PGC-1α; Rapamycin; mTORC1
    DOI:  https://doi.org/10.1186/s10020-022-00519-z
  2. EMBO J. 2022 Aug 01. e110476
    Regulation of mitochondrial proteostasis by the proton gradient.
    Maria Patron, Daryna Tarasenko, Hendrik Nolte, Lara Kroczek, Mausumi Ghosh, Yohsuke Ohba, Yvonne Lasarzewski, Zeinab Alsadat Ahmadi, Alfredo Cabrera-Orefice, Akinori Eyiama, Tim Kellermann, Elena I Rugarli, Ulrich Brandt, Michael Meinecke, Thomas Langer.
      Mitochondria adapt to different energetic demands reshaping their proteome. Mitochondrial proteases are emerging as key regulators of these adaptive processes. Here, we use a multiproteomic approach to demonstrate the regulation of the m-AAA protease AFG3L2 by the mitochondrial proton gradient, coupling mitochondrial protein turnover to the energetic status of mitochondria. We identify TMBIM5 (previously also known as GHITM or MICS1) as a Ca2+ /H+ exchanger in the mitochondrial inner membrane, which binds to and inhibits the m-AAA protease. TMBIM5 ensures cell survival and respiration, allowing Ca2+ efflux from mitochondria and limiting mitochondrial hyperpolarization. Persistent hyperpolarization, however, triggers degradation of TMBIM5 and activation of the m-AAA protease. The m-AAA protease broadly remodels the mitochondrial proteome and mediates the proteolytic breakdown of respiratory complex I to confine ROS production and oxidative damage in hyperpolarized mitochondria. TMBIM5 thus integrates mitochondrial Ca2+ signaling and the energetic status of mitochondria with protein turnover rates to reshape the mitochondrial proteome and adjust the cellular metabolism.
    Keywords:  AFG3L2; TMBIM5; mitochondrial calcium; proton gradient; respiratory chain
    DOI:  https://doi.org/10.15252/embj.2021110476
  3. Free Radic Biol Med. 2022 Jul 30. pii: S0891-5849(22)00496-8. [Epub ahead of print]
    Nrf2 as a regulator of mitochondrial function: Energy metabolism and beyond.
    Noemí Esteras, Andrey Y Abramov.
      Mitochondria are unique and essential organelles that mediate many vital cellular processes including energy metabolism and cell death. The transcription factor Nrf2 (NF-E2 p45-related factor 2) has emerged in the last few years as an important modulator of multiple aspects of mitochondrial function. Well-known for controlling cellular redox homeostasis, the cytoprotective effects of Nrf2 extend beyond its ability to regulate a diverse network of antioxidant and detoxification enzymes. Here, we review the role of Nrf2 in the regulation of mitochondrial function and structure. We focus on Nrf2 involvement in promoting mitochondrial quality control and regulation of basic aspects of mitochondrial function, including energy production, reactive oxygen species generation, calcium signalling, and cell death induction. Given the importance of mitochondria in the development of multiple diseases, these findings reinforce the pharmacological activation of Nrf2 as an attractive strategy to counteract mitochondrial dysfunction.
    Keywords:  Calcium; Dynamics; Energy; Fission; Fusion; Mitochondria; Mitochondrial biogenesis; Mitophagy; Nrf2; ROS; mPTP
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.07.013
  4. J Vis Exp. 2022 Jul 12.
    Measuring Single-Cell Mitochondrial DNA Copy Number and Heteroplasmy using Digital Droplet Polymerase Chain Reaction.
    Stephen P Burr, Patrick F Chinnery.
      The mammalian mitochondrial (mt)DNA is a small, circular, double-stranded, intra-mitochondrial DNA molecule, encoding 13 subunits of the electron transport chain. Unlike the diploid nuclear genome, most cells contain many more copies of mtDNA, ranging from less than 100 to over 200,000 copies depending on cell type. MtDNA copy number is increasingly used as a biomarker for a number of age-related degenerative conditions and diseases, and thus, accurate measurement of the mtDNA copy number is becoming a key tool in both research and diagnostic settings. Mutations in the mtDNA, often occurring as single nucleotide polymorphisms (SNPs) or deletions, can either exist in all copies of the mtDNA within the cell (termed homoplasmy) or as a mixture of mutated and WT mtDNA copies (termed heteroplasmy). Heteroplasmic mtDNA mutations are a major cause of clinical mitochondrial pathology, either in rare diseases or in a growing number of common late-onset diseases such as Parkinson's disease. Determining the level of heteroplasmy present in cells is a critical step in the diagnosis of rare mitochondrial diseases and in research aimed at understanding common late-onset disorders where mitochondria may play a role. MtDNA copy number and heteroplasmy have traditionally been measured by quantitative (q)PCR-based assays or deep sequencing. However, the recent introduction of ddPCR technology has provided an alternative method for measuring both parameters. It offers several advantages over existing methods, including the ability to measure absolute mtDNA copy number and sufficient sensitivity to make accurate measurements from single cells even at low copy numbers. Presented here is a detailed protocol describing the measurement of mtDNA copy number in single cells using ddPCR, referred to as droplet generation PCR henceforth, with the option for simultaneous measurement of heteroplasmy in cells with mtDNA deletions. The possibility of expanding this method to measure heteroplasmy in cells with mtDNA SNPs is also discussed.
    DOI:  https://doi.org/10.3791/63870
  5. Proc Natl Acad Sci U S A. 2022 Aug 09. 119(32): e2207459119
    Structural insight and characterization of human Twinkle helicase in mitochondrial disease.
    Amanda A Riccio, Jonathan Bouvette, Lalith Perera, Matthew J Longley, Juno M Krahn, Jason G Williams, Robert Dutcher, Mario J Borgnia, William C Copeland.
      Twinkle is the mammalian helicase vital for replication and integrity of mitochondrial DNA. Over 90 Twinkle helicase disease variants have been linked to progressive external ophthalmoplegia and ataxia neuropathies among other mitochondrial diseases. Despite the biological and clinical importance, Twinkle represents the only remaining component of the human minimal mitochondrial replisome that has yet to be structurally characterized. Here, we present 3-dimensional structures of human Twinkle W315L. Employing cryo-electron microscopy (cryo-EM), we characterize the oligomeric assemblies of human full-length Twinkle W315L, define its multimeric interface, and map clinical variants associated with Twinkle in inherited mitochondrial disease. Cryo-EM, crosslinking-mass spectrometry, and molecular dynamics simulations provide insight into the dynamic movement and molecular consequences of the W315L clinical variant. Collectively, this ensemble of structures outlines a framework for studying Twinkle function in mitochondrial DNA replication and associated disease states.
    Keywords:  Twinkle helicase; cryo-electron microscopy; mitochondrial DNA; mitochondrial DNA replication; progressive external ophthalmoplegia
    DOI:  https://doi.org/10.1073/pnas.2207459119
  6. Mol Genet Metab. 2022 Jul 06. pii: S1096-7192(22)00363-8. [Epub ahead of print]137(1-2): 40-48
    Mitochondrial DNA maintenance defects: potential therapeutic strategies.
    Mohammed Almannai, Ayman W El-Hattab, Mahshid S Azamian, May Ali, Fernando Scaglia.
      Mitochondrial DNA (mtDNA) replication depends on the mitochondrial import of hundreds of nuclear encoded proteins that control the mitochondrial genome maintenance and integrity. Defects in these processes result in an expanding group of disorders called mtDNA maintenance defects that are characterized by mtDNA depletion and/or multiple mtDNA deletions with variable phenotypic manifestations. As it applies for mitochondrial disorders in general, current treatment options for mtDNA maintenance defects are limited. Lately, with the development of model organisms, improved understanding of the pathophysiology of these disorders, and a better knowledge of their natural history, the number of preclinical studies and existing and planned clinical trials has been increasing. In this review, we discuss recent preclinical studies and current and future clinical trials concerning potential therapeutic options for the different mtDNA maintenance defects.
    Keywords:  Clinical trials; Mitochondria; Nucleoside bypass therapy; Preclinical studies; mtDNA depletion; mtDNA replication
    DOI:  https://doi.org/10.1016/j.ymgme.2022.07.003
  7. EMBO J. 2022 Aug 01. e111834
    The mystery of mitochondrial plasticity: TMBIM5 integrates metabolic state and proteostasis.
    Mindong Ren, Michael Schlame.
      Recent work identifies TMBIM5 as inner mitochondrial membrane Ca2+ /H+ exchanger, linking hyperpolarisation regulation to proteome control and energy metabolism.
    DOI:  https://doi.org/10.15252/embj.2022111834
  8. Neurobiol Dis. 2022 Jul 27. pii: S0969-9961(22)00224-8. [Epub ahead of print] 105832
    Altered SYNJ2BP-mediated mitochondrial-ER contacts in motor neuron disease.
    Naemeh Pourshafie, Ester Masati, Amber Lopez, Eric Bunker, Allison Snyder, Nancy A Edwards, Audrey M Winkelsas, Kenneth H Fischbeck, Christopher Grunseich.
      Synaptojanin 2 binding protein (SYNJ2BP) is an outer mitochondrial membrane protein with a cytosolic PDZ domain that functions as a cellular signaling hub. Few studies have evaluated its role in disease. Here we use induced pluripotent stem cell (iPSC)-derived motor neurons and post-mortem tissue from patients with two hereditary motor neuron diseases, spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis type 4 (ALS4), and show that SYNJ2BP expression is increased in diseased motor neurons. Similarly, we show that SYNJ2BP expression increases in iPSC-derived motor neurons undergoing stress. Using proteomic analysis, we found that elevated SYNJ2BP alters the cellular distribution of mitochondria and increases mitochondrial-ER membrane contact sites. Furthermore, decreasing SYNJ2BP levels improves mitochondrial oxidative function in the diseased motor neurons. Together, our observations offer new insight into the molecular pathology of motor neuron disease and the role of SYNJ2BP in mitochondrial dysfunction.
    Keywords:  Motor neuron disease; Polyglutamine disease; Spinal and bulbar muscular atrophy
    DOI:  https://doi.org/10.1016/j.nbd.2022.105832
  9. Neurol Sci. 2022 Jul 31.
    Extended spinal cord involvement in adult-onset Leigh syndrome due to mitochondrial 10197G > A mutation.
    Yanping Wei, Min Qian, Yingmai Yang.
      
    DOI:  https://doi.org/10.1007/s10072-022-06305-3
  10. Front Mol Neurosci. 2022 ;15 842772
    Glutamatergic Synapse Dysfunction in Drosophila Neuromuscular Junctions Can Be Rescued by Proteostasis Modulation.
    Anushka Chakravorty, Ankit Sharma, Vasu Sheeba, Ravi Manjithaya.
      Glutamate is the major excitatory neurotransmitter in the nervous system, and the Drosophila glutamatergic neuromuscular junctions (NMJs) offer a tractable platform to understand excitatory synapse biology both in health and disease. Synaptopathies are neurodegenerative diseases that are associated with synaptic dysfunction and often display compromised proteostasis. One such rare, progressive neurodegenerative condition, Spinocerebellar Ataxia Type 3 (SCA3) or Machado-Joseph Disease (MJD), is characterized by cerebellar ataxia, Parkinsonism, and degeneration of motor neuron synapses. While the polyQ repeat mutant protein ataxin-3 is implicated in MJD, it is unclear how it leads to impaired synaptic function. In this study, we indicated that a Drosophila model of MJD recapitulates characteristics of neurodegenerative disorders marked by motor neuron dysfunction. Expression of 78 polyQ repeats of mutant ataxin-3 protein in Drosophila motor neurons resulted in behavioral defects, such as impaired locomotion in both larval and adult stages. Furthermore, defects in eclosion and lifespan were observed in adult flies. Detailed characterization of larval glutamatergic neuromuscular junctions (NMJs) revealed defects in morphological features along with compromised NMJ functioning. Autophagy, one of the key proteostasis pathways, is known to be impaired in the case of several synaptopathies. Our study reveals that overexpression of the autophagy-related protein Atg8a rescued behavioral defects. Thus, we present a model for glutamatergic synapse dysfunction that recapitulates synaptic and behavioral deficits and show that it is an amenable system for carrying out genetic and chemical biology screens to identify potential therapeutic targets for synaptopathies.
    Keywords:  Drosophila neuromuscular junctions; Spinocerebellar Ataxia Type 3; autophagy; glutamatergic synapse; synapse dysfunction; synaptopathy
    DOI:  https://doi.org/10.3389/fnmol.2022.842772
  11. Genetics. 2022 Aug 02. pii: iyac104. [Epub ahead of print]
    Selective Disruption of Drp1-Independent Mitophagy and Mitolysosome Trafficking by an Alzheimer's Disease Relevant Tau Modification in a Novel C. elegans Model.
    Sanjib Guha, Anson Cheng, Trae Carroll, Dennisha King, Shon A Koren, Sierra Swords, Keith Nehrke, Gail V W Johnson.
      Accumulation of inappropriately phosphorylated tau into neurofibrillary tangles (NFT) is a defining feature of Alzheimer's disease (AD), with Tau pT231 being an early harbinger of tau pathology. Previously, we demonstrated that expressing a single genomic copy of human phosphomimetic mutant tau (T231E) in C. elegans drove age-dependent neurodegeneration. A critical finding was that T231E, unlike wild type tau, completely and selectively suppressed oxidative stress-induced mitophagy. Here, we used dynamic imaging approaches to analyze T231E-associated changes in mitochondria and mitolysosome (ML) morphology, abundance, trafficking, and stress-induced mitophagy as a function of mitochondrial fission mediator Drp1, which has been demonstrated to interact with hyper phosphorylated tau and contribute to AD pathogenesis, as well as Pink1, a well-recognized mediator of mitochondrial quality control that works together with Parkin to support stress-induced mitophagy. T231E impacted both mitophagy and ML neurite trafficking with exquisite selectivity, sparing macroautophagy as well as lysosome and autolysosome trafficking. Both oxidative-stress induced mitophagy and the ability of T231E to suppress it were independent of drp-1, but at least partially dependent on pink-1. Organelle trafficking was more complicated, with drp-1 and pink-1 mutants exerting independent effects, but generally supported the idea that the mitophagy phenotype is of greater physiologic impact in T231E. Collectively, our results refine the mechanistic pathway through which T231E causes neurodegeneration, demonstrating pathologic selectivity for mutations that mimic tauopathy-associated post-translational modifications, physiologic selectivity for organelles that contain damaged mitochondria, and molecular selectivity for Drp1-independent, Pink1-dependent, perhaps adaptive, mitophagy.
    Keywords:   C. elegans ; Alzheimer’s disease; Drp1; Pink1; mitochondria; mitophagy; tau phosphorylation
    DOI:  https://doi.org/10.1093/genetics/iyac104
  12. Nat Commun. 2022 Aug 01. 13(1): 4444
    Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy.
    Annie Lee, Chandana Kondapalli, Daniel M Virga, Tommy L Lewis, So Yeon Koo, Archana Ashok, Georges Mairet-Coello, Sebastien Herzig, Marc Foretz, Benoit Viollet, Reuben Shaw, Andrew Sproul, Franck Polleux.
      During the early stages of Alzheimer's disease (AD) in both mouse models and human patients, soluble forms of Amyloid-β 1-42 oligomers (Aβ42o) trigger loss of excitatory synapses (synaptotoxicity) in cortical and hippocampal pyramidal neurons (PNs) prior to the formation of insoluble amyloid plaques. In a transgenic AD mouse model, we observed a spatially restricted structural remodeling of mitochondria in the apical tufts of CA1 PNs dendrites corresponding to the dendritic domain where the earliest synaptic loss is detected in vivo. We also observed AMPK over-activation as well as increased fragmentation and loss of mitochondrial biomass in Ngn2-induced neurons derived from a new APPSwe/Swe knockin human ES cell line. We demonstrate that Aβ42o-dependent over-activation of the CAMKK2-AMPK kinase dyad mediates synaptic loss through coordinated phosphorylation of MFF-dependent mitochondrial fission and ULK2-dependent mitophagy. Our results uncover a unifying stress-response pathway causally linking Aβ42o-dependent structural remodeling of dendritic mitochondria to synaptic loss.
    DOI:  https://doi.org/10.1038/s41467-022-32130-5
  13. Neuromuscul Disord. 2022 Jul 16. pii: S0960-8966(22)00601-0. [Epub ahead of print]
    Metrics of progression and prognosis in untreated adults with thymidine kinase 2 deficiency: An observational study.
    Cristina Domínguez-González, Ana Hernández-Voth, Carlos Pablo de Fuenmayor-Fernández de la Hoz, Laura Bermejo Guerrero, Germán Morís, Jorge García-García, Nuria Muelas, Juan Carlos León Hernández, Maria Rabasa, David Lora, Alberto Blázquez, Joaquín Arenas, Miguel Ángel Martin.
      This historical cohort study evaluated clinical characteristics of progression and prognosis in adults with thymidine kinase 2 deficiency (TK2d). Records were available for 17 untreated adults with TK2d (mean age of onset, 32 years), including longitudinal data from 6 patients (mean follow-up duration, 26.5 months). Pearson's correlation assessed associations between standard motor and respiratory assessments, clinical characteristics, and laboratory values. Longitudinal data were assessed by linear regression mixed models. Respiratory involvement progressed at an annual rate of 8.16% decrement in forced vital capacity (FVC). Most patients under noninvasive ventilation (NIV) remained ambulant (12/14, 86%), reduced FVC was not associated with concomitant decline in 6-minute walk test (6MWT), and 6MWT results were not correlated with FVC. Disease severity, assessed by age at NIV onset, correlated most strongly at diagnosis with: creatinine levels (r = 0.8036; P = 0.0009), followed by FVC (r = 0.7265; P = 0.0033), mtDNA levels in muscle (r = 0.7933; P = 0.0188), and age at disease onset (r = 0.7128; P = 0.0042). This population of adults with TK2d demonstrates rapid deterioration of respiratory muscles, which progresses independently of motor impairment. The results support FVC at diagnosis, mtDNA levels in muscle, and age at disease onset as prognostic indicators. Creatinine levels may also be potentially prognostic, as previously reported in other neuromuscular disorders.
    Keywords:  Clinical trials (observational study); Creatinine; Mitochondrial disease; Thymidine kinase 2 deficiency
    DOI:  https://doi.org/10.1016/j.nmd.2022.07.399
  14. Front Cell Dev Biol. 2022 ;10 866210
    mTORC2 protects the heart from high-fat diet-induced cardiomyopathy through mitochondrial fission in Drosophila.
    Peiduo Liu, Kai Chang, Guillermo Requejo, Hua Bai.
      High-fat diet (HFD)-induced obesity has become the major risk factor for the development of cardiovascular diseases, but the underlying mechanisms remain poorly understood. Here, we use Drosophila as a model to study the role of mTORC2 in HFD-induced mitochondrial fission and cardiac dysfunction. We find that knockdown of mTORC2 subunit rictor blocks HFD-induced mitochondrial fragmentation and Drp1 recruitment. Knockdown of rictor further impairs cardiac contractile function under HFD treatment. Surprisingly, knockdown of Akt, the major effector of mTORC2, did not affect HFD-induced mitochondrial fission. Similar to mTORC2 inhibition, knockdown of Drp1 blocks HFD-induced mitochondrial fragmentation and induces contractile defects. Furthermore, overexpression of Drp1 restored HFD-induced mitochondrial fragmentation in rictor knockdown flies. Thus, we uncover a novel function of mTORC2 in protecting the heart from HFD treatment through Drp1-dependent mitochondrial fission.
    Keywords:  Akt; DRP1; Drosophila cardiomyopathy; mitochondrial dynamics; mitochondrial homeostasis; rictor; semi-automatic optical heartbeat analysis (SOHA)
    DOI:  https://doi.org/10.3389/fcell.2022.866210
  15. Transl Vis Sci Technol. 2022 Aug 01. 11(8): 5
    Noninvasive Ophthalmic Imaging Measures Retinal Degeneration and Vision Deficits in Ndufs4-/- Mouse Model of Mitochondrial Complex I Deficiency.
    Maria I Avrutsky, Jacqueline M Lawson, Jade E Smart, Claire W Chen, Carol M Troy.
      Purpose: To characterize postnatal ocular pathology in a Ndufs4-/- mouse model of complex I deficiency using noninvasive retinal imaging and visual testing.Methods: Ndufs4-/- mice and wild-type (WT) littermates were analyzed at 3, 5, and 7 weeks postnatal. Retinal morphology was visualized by optical coherence tomography (OCT). OCT images were analyzed for changes in retinal thickness and reflectivity profiles. Visual function was assessed by electroretinogram (ERG) and optomotor reflex (OMR).
    Results: Ndufs4-/- animals have normal OCT morphology at weaning and develop inner plexiform layer atrophy over weeks 5 to 7. Outer retinal layers show hyporeflectivity of the external limiting membrane (ELM) and photoreceptor ellipsoid zone (EZ). Retinal function is impaired at 3 weeks, with profound deficits in b-wave, a-wave, and oscillatory potential amplitudes. The b-wave and oscillatory potential implicit times are delayed, but the a-wave implicit time is unaffected. Ndufs4-/- animals have normal OMR at 3 weeks and present with increasing acuity and contrast OMR deficits at 5 and 7 weeks. Physiological thinning of inner retinal layers, attenuation of ELM reflectivity, and attenuation of ERG b- and a-wave amplitudes occur in WT C57BL/6 littermates between weeks 3 and 7.
    Conclusions: Noninvasive ocular imaging captures early-onset retinal degeneration in Ndufs4-/- mice and is a tractable approach for investigating retinal pathology subsequent to complex I deficiency.
    Translational Relevance: Ophthalmic imaging captures clinically relevant measures of retinal disease in a fast-progressing mouse model of complex I deficiency consistent with human Leigh syndrome.
    DOI:  https://doi.org/10.1167/tvst.11.8.5
  16. Nat Commun. 2022 Aug 01. 13(1): 4462
    Highly conserved shifts in ubiquitin-proteasome system (UPS) activity drive mitochondrial remodeling during quiescence.
    Sibiao Yue, Lei Wang, George N DeMartino, FangZhou Zhao, Yi Liu, Matthew H Sieber.
      Defects in cellular proteostasis and mitochondrial function drive many aspects of infertility, cancer, and other age-related diseases. All of these conditions rely on quiescent cells, such as oocytes and adult stem cells, that reduce their activity and remain dormant as part of their roles in tissue homeostasis, reproduction, and even cancer recurrence. Using a multi-organism approach, we show that dynamic shifts in the ubiquitin proteasome system drive mitochondrial remodeling during cellular quiescence. In contrast to the commonly held view that the ubiquitin-proteasome system (UPS) is primarily regulated by substrate ubiquitination, we find that increasing proteasome number and their recruitment to mitochondria support mitochondrial respiratory quiescence (MRQ). GSK3 triggers proteasome recruitment to the mitochondria by phosphorylating outer membrane proteins, such as VDAC, and suppressing mitochondrial fatty acid oxidation. This work defines a process that couples dynamic regulation of UPS activity to coordinated shifts in mitochondrial metabolism in fungi, Drosophila, and mammals during quiescence.
    DOI:  https://doi.org/10.1038/s41467-022-32206-2
  17. Science. 2022 Aug 05. 377(6606): 621-629
    Mitochondrial remodeling and ischemic protection by G protein-coupled receptor 35 agonists.
    Gregory A Wyant, Wenyu Yu, IIias P Doulamis, Rio S Nomoto, Mossab Y Saeed, Thomas Duignan, James D McCully, William G Kaelin.
      Kynurenic acid (KynA) is tissue protective in cardiac, cerebral, renal, and retinal ischemia models, but the mechanism is unknown. KynA can bind to multiple receptors, including the aryl hydrocarbon receptor, the a7 nicotinic acetylcholine receptor (a7nAChR), multiple ionotropic glutamate receptors, and the orphan G protein-coupled receptor GPR35. Here, we show that GPR35 activation was necessary and sufficient for ischemic protection by KynA. When bound by KynA, GPR35 activated Gi- and G12/13-coupled signaling and trafficked to the outer mitochondria membrane, where it bound, apparantly indirectly, to ATP synthase inhibitory factor subunit 1 (ATPIF1). Activated GPR35, in an ATPIF1-dependent and pertussis toxin-sensitive manner, induced ATP synthase dimerization, which prevented ATP loss upon ischemia. These findings provide a rationale for the development of specific GPR35 agonists for the treatment of ischemic diseases.
    DOI:  https://doi.org/10.1126/science.abm1638
  18. Autophagy. 2022 Aug 03.
    Mitophagy initiates retrograde mitochondrial-nuclear signaling to guide retinal pigment cell heterogeneity.
    Sayantan Datta, Marisol Cano, Ganesh Satyanarayana, Tongyun Liu, Lei Wang, Jie Wang, Jie Cheng, Kie Itoh, Anjali Sharma, Imran Bhutto, Kannan Rangaramanujam, Jiang Qian, Debasish Sinha, James T Handa.
      Age-related macular degeneration (AMD), the leading cause of blindness among the elderly, is without treatment for early disease. Degenerative retinal pigment epithelial (RPE) cell heterogeneity is a well-recognized but understudied pathogenic factor. Due to the daily phagocytosis of photoreceptor outer segments, unique photo-oxidative stress, and high metabolism for maintaining vision, the RPE has robust macroautophagy/autophagy, and mitochondrial and antioxidant networks. However, the autophagy subtype, mitophagy, in the RPE and AMD is understudied. Here, we found decreased PINK1 (PTEN induced kinase 1) in perifoveal RPE of early AMD eyes. PINK1-deficient RPE have impaired mitophagy and mitochondrial function that triggers death-resistant epithelial-mesenchymal transition (EMT). This reprogramming is mediated by novel retrograde mitochondrial-nuclear signaling (RMNS) through superoxide, NFE2L2 (NFE2 like bZIP transcription factor 2), TXNRD1 (thioredoxin reductase 1), and phosphoinositide 3-kinase (PI3K)-AKT (AKT serine/threonine kinase) that induced canonical transcription factors ZEB1 (zinc finger E-box binding homeobox 1) and SNAI1 (Snail family transcriptional repressor 1) and an EMT transcriptome. NFE2L2 deficiency disrupted RMNS that paradoxically normalized morphology but decreased function and viability. Thus, RPE heterogeneity is defined by the interaction of two cytoprotective pathways that is triggered by mitophagy function. By neutralizing the consequences of impaired mitophagy, an antioxidant dendrimer tropic for the RPE and mitochondria, EMT (a recognized AMD alteration) was abrogated to offer potential therapy for early AMD, a stage without treatment.
    Keywords:  NFE2L2; PINK1; age-related macular degeneration; dendrimer; epithelial mesenchymal transition; heterogeneity; mitophagy; retinal pigment epithelium; retrograde mitochondrial-nuclear signaling
    DOI:  https://doi.org/10.1080/15548627.2022.2109286
  19. Cell Mol Life Sci. 2022 Aug 02. 79(8): 463
    Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations.
    Angelique Cercillieux, Eleonora Ciarlo, Carles Canto.
      Alterations in cellular nicotinamide adenine dinucleotide (NAD+) levels have been observed in multiple lifestyle and age-related medical conditions. This has led to the hypothesis that dietary supplementation with NAD+ precursors, or vitamin B3s, could exert health benefits. Among the different molecules that can act as NAD+ precursors, Nicotinamide Riboside (NR) has gained most attention due to its success in alleviating and treating disease conditions at the pre-clinical level. However, the clinical outcomes for NR supplementation strategies have not yet met the expectations generated in mouse models. In this review we aim to provide a comprehensive view on NAD+ biology, what causes NAD+ deficits and the journey of NR from its discovery to its clinical development. We also discuss what are the current limitations in NR-based therapies and potential ways to overcome them. Overall, this review will not only provide tools to understand NAD+ biology and assess its changes in disease situations, but also to decide which NAD+ precursor could have the best therapeutic potential.
    Keywords:  Metabolic disease; NAD+; Nicotinamide; Nicotinamide riboside; Vitamin B3
    DOI:  https://doi.org/10.1007/s00018-022-04499-5
  20. Neurobiol Dis. 2022 Jul 28. pii: S0969-9961(22)00223-6. [Epub ahead of print] 105831
    Loss of mitochondrial enzyme GPT2 causes early neurodegeneration in locus coeruleus.
    Ozan Baytas, Julie A Kauer, Eric M Morrow.
      Locus coeruleus (LC) is among the first brain areas to degenerate in Alzheimer's disease and. Parkinson's disease; however, the underlying causes for the vulnerability of LC neurons are not well defined. Here we report a novel mechanism of degeneration of LC neurons caused by loss of the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2). GPT2 Deficiency is a newly-recognized childhood neurometabolic disorder. The GPT2 enzyme regulates cell growth through replenishment of tricarboxylic acid (TCA) cycle intermediates and modulation of amino acid metabolism. In Gpt2-null mice, we observe an early loss of tyrosine hydroxylase (TH) positive neurons in LC and reduced soma size at postnatal day 18. Gpt2-null LC shows selective positive Fluoro-Jade C staining. Neuron loss is accompanied by selective, prominent microgliosis and astrogliosis in LC. We observe reduced noradrenergic projections to and norepinephrine levels in hippocampus and spinal cord. Whole cell recordings in Gpt2-null LC slices show reduced soma size and abnormal action potentials with altered firing kinetics. Strikingly, we observe early decreases in phosphorylated S6 in Gpt2-null LC, preceding prominent p62 aggregation, increased LC3B-II to LC3B-I ratio, and neuronal loss. These data are consistent with a possible mechanism involving deficiency in protein synthesis and cell growth, associated subsequently with abnormal autophagy and neurodegeneration. As compared to the few genetic animal models with LC degeneration, loss of LC neurons in Gpt2-null mice is developmentally the earliest. Early neuron loss in LC in a model of human neurometabolic disease provides important clues regarding the metabolic vulnerability of LC and may lead to new therapeutic targets.
    Keywords:  Autophagy; GPT2; Locus coeruleus; Neurodegeneration; Neurogenetics; Neurometabolism; Proteostasis; Selective vulnerability
    DOI:  https://doi.org/10.1016/j.nbd.2022.105831
  21. Ageing Res Rev. 2022 Jul 28. pii: S1568-1637(22)00144-1. [Epub ahead of print]81 101702
    The mitochondrial unfolded protein response: A multitasking giant in the fight against human diseases.
    Zixin Zhou, Yumei Fan, Ruikai Zong, Ke Tan.
      Mitochondria, which serve as the energy factories of cells, are involved in cell differentiation, calcium homeostasis, amino acid and fatty acid metabolism and apoptosis. In response to environmental stresses, mitochondrial homeostasis is regulated at both the organelle and molecular levels to effectively maintain the number and function of mitochondria. The mitochondrial unfolded protein response (UPRmt) is an adaptive intracellular stress mechanism that responds to stress signals by promoting the transcription of genes encoding mitochondrial chaperones and proteases. The mechanism of the UPRmt in Caenorhabditis elegans (C. elegans) has been clarified over time, and the main regulatory factors include ATFS-1, UBL-5 and DVE-1. In mammals, the activation of the UPRmt involves eIF2α phosphorylation and the uORF-regulated expression of CHOP, ATF4 and ATF5. Several additional factors, such as SIRT3 and HSF1, are also involved in regulating the UPRmt. A deep and comprehensive exploration of the UPRmt can provide new directions and strategies for the treatment of human diseases, including aging, neurodegenerative diseases, cardiovascular diseases and diabetes. In this review, we mainly discuss the function of UPRmt, describe the regulatory mechanisms of UPRmt in C. elegans and mammals, and summarize the relationship between UPRmt and various human diseases.
    Keywords:  ATFS-1; Aging; Mitochondria stress; Mitochondrial unfolded protein response; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.arr.2022.101702
  22. Hepatology. 2022 Aug 03.
    Enhanced mitochondrial activity reshapes a gut microbiota profile that delays NASH progression.
    María Juárez-Fernández, Naroa Goikoetxea-Usandizaga, David Porras, María Victoria García-Mediavilla, Miren Bravo, Marina Serrano-Maciá, Jorge Simón, Teresa C Delgado, Sofía Lachiondo-Ortega, Susana Martínez-Flórez, Óscar Lorenzo, Mercedes Rincón, Marta Varela-Rey, Leticia Abecia, Héctor Rodríguez, Juan Anguita, Esther Nistal, María Luz Martínez-Chantar, Sonia Sánchez-Campos.
      OBJECTIVE: Recent studies suggest that mitochondrial dysfunction promotes progression to non-alcoholic steatohepatitis (NASH) by aggravating the gut-liver status. However, the underlying mechanism remains unclear. Herein, we hypothesized that enhanced mitochondrial activity might reshape a specific microbiota signature that, when transferred to germ-free (GF) mice, could delay NASH progression. Design WT and methylation-controlled J protein knock-out (MCJ-KO) mice were fed for 6 weeks with either control or a choline-deficient, L-amino acid-defined, high-fat diet (CDA-HFD). One mouse of each group acted as a donor of caecal microbiota to GF mice, who also underwent the CDA-HFD model for 3 weeks. Hepatic injury, intestinal barrier, gut microbiome and the associated faecal metabolome were then studied.RESULTS: Following 6 weeks of CDA-HFD, the absence of MCJ, an inhibitor of mitochondrial complex I activity, reduced hepatic injury and improved gut-liver axis in an aggressive NASH dietary model. This effect was transferred to GF mice through caecal microbiota transplantation. We suggest that the specific microbiota profile of MCJ-KO, characterised by an increase in the faecal relative abundance of Dorea and Oscillospira genera and a reduction in AF12, Allboaculum and [Ruminococcus], exerted protective actions through enhancing short-chain fatty acids, NAD+ metabolism and sirtuin activity, subsequently increasing fatty acid oxidation in GF mice. Importantly, we identified Dorea genus as one of the main modulators of this microbiota-dependent protective phenotype.
    CONCLUSION: Overall, we provide evidence for the relevance of mitochondria-microbiota interplay during NASH, and that targeting it could be a valuable therapeutic approach.
    DOI:  https://doi.org/10.1002/hep.32705
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