bims-mitmed 2023-08-06 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2023–08–06
thirty-six papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Contact sites between endoplasmic reticulum sheets and mitochondria regulate mitochondrial DNA replication and segregation.
Application of super-resolution microscopy in mitochondria-dynamic diseases.
Optimized allotopic expression of mitochondrial ND6 transgene restored complex I and apoptosis deficiencies caused by LHON-linked ND6 14484T > C mutation.
Completion of mitochondrial division requires the intermembrane space protein Mdi1/Atg44.
Clinical and molecular characterization of novel FARS2 variants causing neonatal mitochondrial disease.
FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for Pink1 phosphorylation in vivo.
Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I.
Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome.
Genome-wide methylation profile of mitochondrial DNA across bovine preimplantation development.
Phospholipids can regulate complex I assembly independent of their role in maintaining mitochondrial membrane integrity.
Sex-specific preservation of neuromuscular function and metabolism following systemic transplantation of multipotent adult stem cells in a murine model of progeria.
Sustained oral spermidine supplementation rescues functional and structural defects in COL6-deficient myopathic mice.
The role of mtDAMPs in the trauma-induced systemic inflammatory response syndrome.
Generation of induced pluripotent stem cells, KCi004-A derived from a male with Parkinsońs disease and homozygous for the PINK1 variant c.1366C > T, p.Gln456.
Mitochondrial quality control in lung diseases: current research and future directions.
Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton.
Mitochondrial transplantation rescues neuronal cells from ferroptosis.
Central role of Tim17 in mitochondrial presequence protein translocation.
Nuclear transfer improves the developmental potential of embryos derived from cytoplasmic deficient oocytes.
Excitatory amino acid transporter 1 supports adult hippocampal neural stem cell self-renewal.
Mitochondrial epigenetics in aging and cardiovascular diseases.
High-fat diet causes mitochondrial damage and downregulation of mitofusin-2 and optic atrophy-1 in multiple organs.
Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegans.
Myonectin protects against skeletal muscle dysfunction in male mice through activation of AMPK/PGC1α pathway.
Neuropathological hallmarks in autopsied cases with mitochondrial diseases caused by the mitochondrial 3243A>G mutation.
Fifty years of research on mitochondrial fatty acid oxidation defects: the remaining challenges.
Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model.
The stability of the myelinating oligodendrocyte transcriptome is regulated by the nuclear lamina.
Increased cardiac PFK-2 protects against high-fat diet-induced cardiomyopathy and mediates beneficial systemic metabolic effects.
Maternal Exposure to Cetylpyridinium Chloride Impairs Oogenesis by Causing Mitochondria Disorder in Neonates.
Accumulation of TERT in mitochondria exerts two opposing effects on apoptosis.
Pancytopenia and haematopoietic precursor vacuolisation in an infant: Clues to Pearson syndrome.
Convergent and divergent mechanisms of peroxisomal and mitochondrial division.
Mitochondrial Lon protease promotes CD4+ T cell activation by activating the cGAS-STING-TBK1 axis in systemic lupus erythematosus.
O-GlcNAcylation of Raptor transduces glucose signals to mTORC1.
Three-dimensional molecular architecture of mouse organogenesis.

iScience. 2023 Jul 21. 26(7): 107180

Contact sites between endoplasmic reticulum sheets and mitochondria regulate mitochondrial DNA replication and segregation.

Hema Saranya Ilamathi, Sara Benhammouda, Amel Lounas, Khalid Al-Naemi, Justine Desrochers-Goyette, Matthew A Lines, François J Richard, Jackie Vogel, Marc Germain.

  Mitochondria are multifaceted organelles crucial for cellular homeostasis that contain their own genome. Mitochondrial DNA (mtDNA) replication is a spatially regulated process essential for the maintenance of mitochondrial function, its defect causing mitochondrial diseases. mtDNA replication occurs at endoplasmic reticulum (ER)-mitochondria contact sites and is affected by mitochondrial dynamics: The absence of mitochondrial fusion is associated with mtDNA depletion whereas loss of mitochondrial fission causes the aggregation of mtDNA within abnormal structures termed mitobulbs. Here, we show that contact sites between mitochondria and ER sheets, the ER structure associated with protein synthesis, regulate mtDNA replication and distribution within mitochondrial networks. DRP1 loss or mutation leads to modified ER sheets and alters the interaction between ER sheets and mitochondria, disrupting RRBP1-SYNJ2BP interaction. Importantly, mtDNA distribution and replication were rescued by promoting ER sheets-mitochondria contact sites. Our work identifies the role of ER sheet-mitochondria contact sites in regulating mtDNA replication and distribution.

Keywords:  Biochemistry; Biological sciences; Cell biology

DOI:  https://doi.org/10.1016/j.isci.2023.107180
Adv Drug Deliv Rev. 2023 Aug 01. pii: S0169-409X(23)00358-7. [Epub ahead of print] 115043

Application of super-resolution microscopy in mitochondria-dynamic diseases.

Weiwei Zou, Li Yang, Hedong Lu, Min Li, Dongmei Ji, Jesse Slone, Taosheng Huang.

  Limited by spatial and temporal resolution, traditional optical microscopy cannot image the delicate ultra-structure organelles and sub-organelles. The emergence of super-resolution microscopy makes it possible. In this review, we focus on mitochondria. We summarize the process of mitochondrial dynamics, the primary proteins that regulate mitochondrial morphology, the diseases related to mitochondrial dynamics.-, The purpose is to apply super-resolution microscopy developed during recent years to the mitochondrial research. By providing the right research tools, we will help to promote the application of this technique to the in-depth elucidation of the pathogenesis of diseases related to mitochondrial dynamics, assistdiagnosis and develop the therapeutic treatment .

Keywords:  Disease; Dynamics; Mitochondria; Sub-organelle structures; Super-resolution microscopy

DOI:  https://doi.org/10.1016/j.addr.2023.115043
J Biomed Sci. 2023 Aug 03. 30(1): 63

Optimized allotopic expression of mitochondrial ND6 transgene restored complex I and apoptosis deficiencies caused by LHON-linked ND6 14484T > C mutation.

Jing Wang, Yanchun Ji, Cheng Ai, Jia-Rong Chen, Dingyi Gan, Juanjuan Zhang, Jun Q Mo, Min-Xin Guan.

   BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease due to mutations in mitochondrial DNA. However, there is no effective treatment for this disease. LHON-linked ND6 14484T > C (p.M64V) mutation caused complex I deficiency, diminished ATP production, increased production of reactive oxygen species (ROS), elevated apoptosis, and impaired mitophagy. Here, we investigated if the allotopic expression of human mitochondrial ND6 transgene corrected the mitochondrial dysfunctions due to LHON-associated m.14484T > C mutation.
METHODS: Nucleus-versions of ND6 was generated by changing 6 non-universal codons with universal codons and added to mitochondrial targeting sequence of COX8. Stable transfectants were generated by transferring human ND6 cDNA expressed in a pCDH-puro vector into mutant cybrids carrying the m.14484T > C mutation and control cybrids. The effect of allotopic expression of ND6 on oxidative phosphorylation (OXPHOS) was evaluated using Blue Native gel electrophoresis and extracellular flux analyzer. Assessment of ROS production in cell lines was performed by flow cytometry with MitoSOX Red reagent. Analyses for apoptosis and mitophagy were undertaken via flow cytometry, TUNEL and immunofluorescence assays.
RESULTS: The transfer of human ND6 into the cybrids carrying the m.14484T > C mutation raised the levels of ND6, ND1 and ND4L but did not change the levels of other mitochondrial proteins. The overexpression of ND6 led to 20~23% increases in the assembly and activity of complex I, and ~ 53% and ~ 33% increases in the levels of mitochondrial ATP and ΔΨm in the mutant cybrids bearing m.14484T > C mutation. Furthermore, mutant cybrids with overexpression of ND6 exhibited marked reductions in the levels of mitochondrial ROS. Strikingly, ND6 overexpression markedly inhibited the apoptosis process and restored impaired mitophagy in the cells carrying m.14484T > C mutation. However, overexpression of ND6 did not affect the ND6 level and mitochondrial functions in the wild-type cybrids, indicating that this ND6 level appeared to be the maximum threshold level to maintain the normal cell function.
CONCLUSION: We demonstrated that allotopic expression of nucleus-versions of ND6 restored complex I, apoptosis and mitophagy deficiencies caused by the m.14484T > C mutation. The restoration of m.14484T > C mutation-induced mitochondrial dysfunctions by overexpression of ND6 is a step toward therapeutic interventions for LHON and mitochondrial diseases.

Keywords:  Allotopic expression; Apoptosis; Complex I; Leber’s hereditary optic neuropathy; Mitochondrial DNA mutation; Mitophagy

DOI:  https://doi.org/10.1186/s12929-023-00951-1
J Cell Biol. 2023 Oct 02. pii: e202303147. [Epub ahead of print]222(10):

Completion of mitochondrial division requires the intermembrane space protein Mdi1/Atg44.

Olivia M Connor, Srujan K Matta, Jonathan R Friedman.

Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by a dynamin-related protein, Dnm1 (Drp1 in humans), that constricts and divides the mitochondria in a GTP hydrolysis-dependent manner. However, it is unclear whether factors inside mitochondria help coordinate the process and if Dnm1/Drp1 activity is sufficient to complete the fission of both mitochondrial membranes. Here, we identify an intermembrane space protein required for mitochondrial fission in yeast, which we propose to name Mdi1 (also named Atg44). Loss of Mdi1 causes mitochondrial hyperfusion due to defects in fission, but not the lack of Dnm1 recruitment to mitochondria. Mdi1 is conserved in fungal species, and its homologs contain an amphipathic α-helix, mutations of which disrupt mitochondrial morphology. One model is that Mdi1 distorts mitochondrial membranes to enable Dnm1 to robustly complete fission. Our work reveals that Dnm1 cannot efficiently divide mitochondria without the coordinated function of Mdi1 inside mitochondria.

DOI: https://doi.org/10.1083/jcb.202303147
Mol Genet Metab. 2023 Jul 24. pii: S1096-7192(23)00287-1. [Epub ahead of print]140(3): 107657

Clinical and molecular characterization of novel FARS2 variants causing neonatal mitochondrial disease.

Wenqian Chen, Preeya Rehsi, Kyle Thompson, Mildrid Yeo, Karen Stals, Langping He, Paul Schimmel, Zofia M A Chrzanowska-Lightowlers, Emma Wakeling, Robert W Taylor, Bernhard Kuhle.

  FARS2 encodes the mitochondrial phenylalanyl-tRNA synthetase (mtPheRS), which is essential for charging mitochondrial (mt-) tRNAPhe with phenylalanine for use in intramitochondrial translation. Many biallelic, pathogenic FARS2 variants have been described previously, which are mostly associated with two distinct clinical phenotypes; an early onset epileptic mitochondrial encephalomyopathy or a later onset spastic paraplegia. In this study, we report on a patient who presented at 3 weeks of age with tachypnoea and poor feeding, which progressed to severe metabolic decompensation with lactic acidosis and seizure activity followed by death at 9 weeks of age. Rapid trio whole exome sequencing identified compound heterozygous FARS2 variants including a pathogenic exon 2 deletion on one allele and a rare missense variant (c.593G > T, p.(Arg198Leu)) on the other allele, necessitating further work to aid variant classification. Assessment of patient fibroblasts demonstrated severely decreased steady-state levels of mtPheRS, but no obvious defect in any components of the oxidative phosphorylation system. To investigate the potential pathogenicity of the missense variant, we determined its high-resolution crystal structure, demonstrating a local structural destabilization in the catalytic domain. Moreover, the R198L mutation reduced the thermal stability and impaired the enzymatic activity of mtPheRS due to a lower binding affinity for tRNAPhe and a slower turnover rate. Together these data confirm the pathogenicity of this FARS2 variant in causing early-onset mitochondrial epilepsy.

Keywords:  FARS2; Functional assays; Mitochondrial disease; Mitochondrial phenylalanyl-tRNA synthetase; Variant classification

DOI:  https://doi.org/10.1016/j.ymgme.2023.107657
PLoS Biol. 2023 Aug 03. 21(8): e3002244

FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for Pink1 phosphorylation in vivo.

Alvaro Sanchez-Martinez, Aitor Martinez, Alexander J Whitworth.

Functional analyses of genes linked to heritable forms of Parkinson's disease (PD) have revealed fundamental insights into the biological processes underpinning pathogenic mechanisms. Mutations in PARK15/FBXO7 cause autosomal recessive PD and FBXO7 has been shown to regulate mitochondrial homeostasis. We investigated the extent to which FBXO7 and its Drosophila orthologue, ntc, share functional homology and explored its role in mitophagy in vivo. We show that ntc mutants partially phenocopy Pink1 and parkin mutants and ntc overexpression supresses parkin phenotypes. Furthermore, ntc can modulate basal mitophagy in a Pink1- and parkin-independent manner by promoting the ubiquitination of mitochondrial proteins, a mechanism that is opposed by the deubiquitinase USP30. This basal ubiquitination serves as the substrate for Pink1-mediated phosphorylation that triggers stress-induced mitophagy. We propose that FBXO7/ntc works in equilibrium with USP30 to provide a checkpoint for mitochondrial quality control in basal conditions in vivo and presents a new avenue for therapeutic approaches.

DOI: https://doi.org/10.1371/journal.pbio.3002244
Sci Adv. 2023 Aug 02. 9(31): eadi1359

Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I.

Daniel N Grba, Injae Chung, Hannah R Bridges, Ahmed-Noor A Agip, Judy Hirst.

Respiratory complex I, a key enzyme in mammalian metabolism, captures the energy released by reduction of ubiquinone by NADH to drive protons across the inner mitochondrial membrane, generating the proton-motive force for ATP synthesis. Despite remarkable advances in structural knowledge of this complicated membrane-bound enzyme, its mechanism of catalysis remains controversial. In particular, how ubiquinone reduction is coupled to proton pumping and the pathways and mechanisms of proton translocation are contested. We present a 2.4-Å resolution cryo-EM structure of complex I from mouse heart mitochondria in the closed, active (ready-to-go) resting state, with 2945 water molecules modeled. By analyzing the networks of charged and polar residues and water molecules present, we evaluate candidate pathways for proton transfer through the enzyme, for the chemical protons for ubiquinone reduction, and for the protons transported across the membrane. Last, we compare our data to the predictions of extant mechanistic models, and identify key questions to answer in future work to test them.

DOI: https://doi.org/10.1126/sciadv.adi1359
EMBO Mol Med. 2023 Aug 03. e17399

Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome.

Arpita Chowdhury, Angela Boshnakovska, Abhishek Aich, Aditi Methi, Ana Maria Vergel Leon, Ivan Silbern, Christian Lüchtenborg, Lukas Cyganek, Jan Prochazka, Radislav Sedlacek, Jiri Lindovsky, Dominic Wachs, Zuzana Nichtova, Dagmar Zudova, Gizela Koubkova, André Fischer, Henning Urlaub, Britta Brügger, Dörthe M Katschinski, Jan Dudek, Peter Rehling.

  Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patients. TAZG197V mice recapitulate disease-specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid-driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPSC cell-derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZG197V . Treatment of mutant cells with AMPK activator reestablishes fatty acid-driven OXPHOS and protects mice against cardiac dysfunction.

Keywords:  Barth syndrome; cardiolipin; cardiomyopathy; mitochondria; tafazzin

DOI:  https://doi.org/10.15252/emmm.202317399
Epigenetics. 2023 12;18(1): 2241010

Genome-wide methylation profile of mitochondrial DNA across bovine preimplantation development.

Camila Bruna de Lima, Hélène Martin, Marcella Pecora Milazzotto, Marc-André Sirard.

  This study characterized variations in the methylation profile of mitochondrial DNA (mtDNA) during initial bovine embryo development and correlated the presence of methylation with mtDNA transcription. Bovine oocytes were obtained from abattoir ovaries and submitted to in vitro culture procedures. Oocytes and embryos were collected at various stages (immature oocyte, IM; mature oocyte, MII; zygote, ZY; 4-cells, 4C; 16-cells, 16C and blastocysts, BL). Total DNA (including mtDNA) was used for Whole Genome Enzymatic Methyl Sequencing and for quantification of mtDNA copy number. Extracted RNA was used for quantification of mitochondrial transcripts using Droplet Digital PCR. We selected ND6, CYTB, tRNA-Phe and tRNA-Gln based on their location in the mitochondrial genome, functionality and/or previous literature associating these regions with cytosine methylation. The number of mtDNA copies per oocyte/embryo was found to be similar, while methylation levels in mtDNA varied among stages. Higher total methylation levels were found mainly at 4C and 16C. In specific gene regions, higher methylation levels were also observed at 4C and 16C (ND6, CYTB and tRNA-Phe), as well as an inverse correlation with the quantity of transcripts for these regions. This is a first description of epigenetic changes occurring in mtDNA during early embryonic development. Our results indicate that methylation might regulate the mtDNA transcription at a local level, particularly around the time of embryonic genome activation.

Keywords:  embryos; metabolism; methylation; mtDNA; oocytes

DOI:  https://doi.org/10.1080/15592294.2023.2241010
Cell Rep. 2023 Jul 29. pii: S2211-1247(23)00857-4. [Epub ahead of print]42(8): 112846

Phospholipids can regulate complex I assembly independent of their role in maintaining mitochondrial membrane integrity.

Anjaneyulu Murari, Shauna-Kay Rhooms, Divya Vimal, Kaniz Fatima Binte Hossain, Sanjay Saini, Maximino Villanueva, Michael Schlame, Edward Owusu-Ansah.

  Several phospholipid (PL) molecules are intertwined with some mitochondrial complex I (CI) subunits in the membrane domain of CI, but their function is unclear. We report that when the Drosophila melanogaster ortholog of the intramitochondrial PL transporter, STARD7, is severely disrupted, assembly of the oxidative phosphorylation (OXPHOS) system is impaired, and the biogenesis of several CI subcomplexes is hampered. However, intriguingly, a restrained knockdown of STARD7 impairs the incorporation of NDUFS5 and NDUFA1 into the proximal part of the CI membrane domain without directly affecting the incorporation of subunits in the distal part of the membrane domain, OXPHOS complexes already assembled, or mitochondrial cristae integrity. Importantly, the restrained knockdown of STARD7 appears to induce a modest amount of cardiolipin remodeling, indicating that there could be some alteration in the composition of the mitochondrial phospholipidome. We conclude that PLs can regulate CI biogenesis independent of their role in maintaining mitochondrial membrane integrity.

Keywords:  CP: Molecular biology; Drosophila; NDUFA1; NDUFS5; OXPHOS; STARD7; complex I; mitochondria; phospholipid

DOI:  https://doi.org/10.1016/j.celrep.2023.112846
Geroscience. 2023 Aug 03.

Sex-specific preservation of neuromuscular function and metabolism following systemic transplantation of multipotent adult stem cells in a murine model of progeria.

Seth D Thompson, Kelsey L Barrett, Chelsea L Rugel, Robin Redmond, Alexia Rudofski, Jacob Kurian, Jodi L Curtin, Sudarshan Dayanidhi, Mitra Lavasani.

  Onset and rates of sarcopenia, a disease characterized by a loss of muscle mass and function with age, vary greatly between sexes. Currently, no clinical interventions successfully arrest age-related muscle impairments since the decline is frequently multifactorial. Previously, we found that systemic transplantation of our unique adult multipotent muscle-derived stem/progenitor cells (MDSPCs) isolated from young mice-but not old-extends the health-span in DNA damage mouse models of progeria, a disease of accelerated aging. Additionally, induced neovascularization in the muscles and brain-where no transplanted cells were detected-strongly suggests a systemic therapeutic mechanism, possibly activated through circulating secreted factors. Herein, we used ZMPSTE24-deficient mice, a lamin A defect progeria model, to investigate the ability of young MDSPCs to preserve neuromuscular tissue structure and function. We show that progeroid ZMPST24-deficient mice faithfully exhibit sarcopenia and age-related metabolic dysfunction. However, systemic transplantation of young MDSPCs into ZMPSTE24-deficient progeroid mice sustained healthy function and histopathology of muscular tissues throughout their 6-month life span in a sex-specific manner. Indeed, female-but not male-mice systemically transplanted with young MDSPCs demonstrated significant preservation of muscle endurance, muscle fiber size, mitochondrial respirometry, and neuromuscular junction morphometrics. These novel findings strongly suggest that young MDSPCs modulate the systemic environment of aged animals by secreted rejuvenating factors to maintain a healthy homeostasis in a sex-specific manner and that the female muscle microenvironment remains responsive to exogenous regenerative cues in older age. This work highlights the age- and sex-related differences in neuromuscular tissue degeneration and the future prospect of preserving health in older adults with systemic regenerative treatments.

Keywords:  Aging; Cell therapy; Metabolism; Muscle fatigue; Neuromuscular tissues; Progeria; Regeneration; Sex differences; Skeletal muscle

DOI:  https://doi.org/10.1007/s11357-023-00892-5
Autophagy. 2023 Aug 01. 1-9

Sustained oral spermidine supplementation rescues functional and structural defects in COL6-deficient myopathic mice.

Lisa Gambarotto, Samuele Metti, Matteo Corpetti, Martina Baraldo, Patrizia Sabatelli, Silvia Castagnaro, Matilde Cescon, Bert Blaauw, Paolo Bonaldo.

  COL6 (collagen type VI)-related myopathies (COL6-RM) are a distinct group of inherited muscle disorders caused by mutations of COL6 genes and characterized by early-onset muscle weakness, for which no cure is available yet. Key pathophysiological features of COL6-deficient muscles involve impaired macroautophagy/autophagy, mitochondrial dysfunction, neuromuscular junction fragmentation and myofiber apoptosis. Targeting autophagy by dietary means elicited beneficial effects in both col6a1 null (col6a1-/-) mice and COL6-RM patients. We previously demonstrated that one-month per os administration of the nutraceutical spermidine reactivates autophagy and ameliorates myofiber defects in col6a1-/- mice but does not elicit functional improvement. Here we show that a 100-day-long spermidine regimen is able to rescue muscle strength in col6a1-/- mice, with also a beneficial impact on mitochondria and neuromuscular junction integrity, without any noticeable side effects. Altogether, these data provide a rationale for the application of spermidine in prospective clinical trials for COL6-RM.Abbreviations: AChR: acetylcholine receptor; BTX: bungarotoxin; CNF: centrally nucleated fibers; Colch: colchicine; COL6: collagen type VI; COL6-RM: COL6-related myopathies; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NMJ: neuromuscular junction; Spd: spermidine; SQSTM1/p62: sequestosome 1; TA: tibialis anterior; TOMM20: translocase of outer mitochondrial membrane 20; TUNEL: terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling.

Keywords:  Autophagy; collagen VI; nutraceutical; skeletal muscle; spermidine

DOI:  https://doi.org/10.1080/15548627.2023.2241125
Front Immunol. 2023 ;14 1164187

The role of mtDAMPs in the trauma-induced systemic inflammatory response syndrome.

Jingjing Ye, Xiaodan Hu, Zhiwei Wang, Rui Li, Lebin Gan, Mengwei Zhang, Tianbing Wang.

  Systemic inflammatory response syndrome (SIRS) is a non-specific exaggerated defense response caused by infectious or non-infectious stressors such as trauma, burn, surgery, ischemia and reperfusion, and malignancy, which can eventually lead to an uncontrolled inflammatory response. In addition to the early mortality due to the "first hits" after trauma, the trauma-induced SIRS and multiple organ dysfunction syndrome (MODS) are the main reasons for the poor prognosis of trauma patients as "second hits". Unlike infection-induced SIRS caused by pathogen-associated molecular patterns (PAMPs), trauma-induced SIRS is mainly mediated by damage-associated molecular patterns (DAMPs) including mitochondrial DAMPs (mtDAMPs). MtDAMPs released after trauma-induced mitochondrial injury, including mitochondrial DNA (mtDNA) and mitochondrial formyl peptides (mtFPs), can activate inflammatory response through multiple inflammatory signaling pathways. This review summarizes the role and mechanism of mtDAMPs in the occurrence and development of trauma-induced SIRS.

Keywords:  mtDAMPs; mtDNA; mtFPs; trauma; trauma-induced SIRS

DOI:  https://doi.org/10.3389/fimmu.2023.1164187
Stem Cell Res. 2023 Jul 26. pii: S1873-5061(23)00161-7. [Epub ahead of print]71 103175

Generation of induced pluripotent stem cells, KCi004-A derived from a male with Parkinsońs disease and homozygous for the PINK1 variant c.1366C > T, p.Gln456.

Lasse Jonsgaard Larsen, Lisbeth Birk Møller.

Disease causing variants in PINK1 lead to Parkinsońs disease (PD) with early age of onset and slow disease progression. Loss of mitochondrial function is a signal of bioenergetic stress, PINK1 accumulates on the outer mitochondrial membrane and initiates ubiquitination and degradation of damaged mitochondria by mitophagy. Here we describe the successful generation of an induced pluripotent stem cell line (iPSC) KCi004-A from a PD patient homozygous for the disease- causing variant c.1366C > T, p.Gln456* in PINK1. For the generation we transfect a fibroblast culture from the patient with a non-integrative self-replicating RNA vector.

DOI: https://doi.org/10.1016/j.scr.2023.103175
Front Physiol. 2023 ;14 1236651

Mitochondrial quality control in lung diseases: current research and future directions.

Jiliu Liu, Junyi Wang, Anying Xiong, Lei Zhang, Yi Zhang, Yao Liu, Ying Xiong, Guoping Li, Xiang He.

  Lung diseases are a major global health problem, affecting millions of people worldwide. Recent research has highlighted the critical role that mitochondrial quality control plays in respiratory-related diseases, including chronic obstructive pulmonary disease (COPD), lung cancer, and idiopathic pulmonary fibrosis (IPF). In this review, we summarize recent findings on the involvement of mitochondrial quality control in these diseases and discuss potential therapeutic strategies. Mitochondria are essential organelles for energy production and other cellular processes, and their dysfunction is associated with various diseases. The quality control of mitochondria involves a complex system of pathways, including mitophagy, mitochondrial biogenesis, fusion/fission dynamics, and regulation of gene expression. In COPD and lung cancer, mitochondrial quality control is often involved in disease development by influencing oxidative stress and apoptosis. In IPF, it appears to be involved in the disease process by participating in the cellular senescence process. Mitochondrial quality control is a promising target for therapeutic interventions in lung diseases. However, there are conflicting reports on different pathological processes, such as the role of mitochondrial autophagy in lung cancer, which pose difficulties in the study of targeted mitochondrial quality control drugs. Additionally, there seems to be a delicate balance between the mitochondrial quality control processes in the physiological state. Emerging evidence suggests that molecules such as PTEN-induced putative kinase 1 (PINK1), parkin RBR E3 ubiquitin protein ligase (PRKN), dynamin-related protein 1 (DRP1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), as well as the signaling pathways they affect, play an important role in respiratory-related diseases. Targeting these molecules and pathways could contribute to the development of effective treatments for lung diseases. In conclusion, the involvement of mitochondrial quality control in lung diseases presents a promising new avenue for disease treatment. Further research is needed to better understand the complex mechanisms involved in the pathogenesis of respiratory diseases and to develop targeted therapies that could improve clinical outcomes.

Keywords:  chronic obstructive pulmonary disease; idiopathic pulmonary fibrosis; lung cancer; mitochondrial quality control; therapeutic approaches

DOI:  https://doi.org/10.3389/fphys.2023.1236651
Nat Commun. 2023 07 31. 14(1): 4587

Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton.

Madison L Doolittle, Dominik Saul, Japneet Kaur, Jennifer L Rowsey, Stephanie J Vos, Kevin D Pavelko, Joshua N Farr, David G Monroe, Sundeep Khosla.

Senescence drives organismal aging, yet the deep characterization of senescent cells in vivo remains incomplete. Here, we apply mass cytometry by time-of-flight using carefully validated antibodies to analyze senescent cells at single-cell resolution. We use multiple criteria to identify senescent mesenchymal cells that are growth-arrested and resistant to apoptosis. These p16 + Ki67-BCL-2+ cells are highly enriched for senescence-associated secretory phenotype and DNA damage markers, are strongly associated with age, and their percentages are increased in late osteoblasts/osteocytes and CD24high osteolineage cells. Moreover, both late osteoblasts/osteocytes and CD24high osteolineage cells are robustly cleared by genetic and pharmacologic senolytic therapies in aged mice. Following isolation, CD24+ skeletal cells exhibit growth arrest, senescence-associated β-galactosidase positivity, and impaired osteogenesis in vitro. These studies thus provide an approach using multiplexed protein profiling to define senescent mesenchymal cells in vivo and identify specific skeletal cell populations cleared by senolytics.

DOI: https://doi.org/10.1038/s41467-023-40393-9
Free Radic Biol Med. 2023 Aug 01. pii: S0891-5849(23)00571-3. [Epub ahead of print]

Mitochondrial transplantation rescues neuronal cells from ferroptosis.

Tingting Chen, Nad'a Majerníková, Alejandro Marmolejo-Garza, Marina Trombetta-Lima, Angélica María Sabogal-Guáqueta, Yuequ Zhang, Ruth Ten Kate, Minte Zuidema, Patty P M F A Mulder, Wilfred den Dunnen, Reinoud Gosens, Elisabeth Verpoorte, Carsten Culmsee, Ulrich L M Eisel, Amalia M Dolga.

  Ferroptosis is a type of oxidative cell death that can occur in neurodegenerative diseases and involves damage to mitochondria. Previous studies demonstrated that preventing mitochondrial dysfunction can rescue cells from ferroptotic cell death. However, the complexity of mitochondrial dysfunction and the timing of therapeutic interventions make it difficult to develop an effective treatment strategy against ferroptosis in neurodegeneration conditions. In this study, we explored the use of mitochondrial transplantation as a novel therapeutic approach for preventing ferroptotic neuronal cell death. Our data showed that isolated exogenous mitochondria were incorporated into both healthy and ferroptotic immortalized hippocampal HT-22 cells and primary cortical neurons (PCN). The mitochondrial incorporation was accompanied by increased metabolic activity and cell survival through attenuating lipid peroxidation and mitochondrial superoxide production. Further, the function of mitochondrial complexes I, III and V activities contributed to the neuroprotective activity of exogenous mitochondria. Similarly, we have also showed the internalization of exogenous mitochondria in mouse PCN; these internalized mitochondria were found to effectively preserve the neuronal networks when challenged with ferroptotic stimuli. The administration of exogenous mitochondria into the axonal compartment of a two-compartment microfluidic device induced mitochondrial transportation to the cell body, which prevented fragmentation of the neuronal network in ferroptotic PCN. These findings suggest that mitochondria transplantation may be a promising therapeutic approach for protecting neuronal cells from ferroptotic cell death.

Keywords:  Ferroptosis; HT-22 cells; Mitochondrial transplantation; Oxidative stress; Primary cortical neurons

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.07.034
Nature. 2023 Aug 01.

Central role of Tim17 in mitochondrial presequence protein translocation.

Laura F Fielden, Jakob D Busch, Sandra G Merkt, Iniyan Ganesan, Conny Steiert, Hanna B Hasselblatt, Jon V Busto, Christophe Wirth, Nicole Zufall, Sibylle Jungbluth, Katja Noll, Julia M Dung, Ludmila Butenko, Karina von der Malsburg, Hans-Georg Koch, Carola Hunte, Martin van der Laan, Nils Wiedemann.

The presequence translocase of the mitochondrial inner membrane (TIM23) represents the major route for the import of nuclear-encoded proteins into mitochondria1,2. About 60% of more than 1,000 different mitochondrial proteins are synthesised with amino-terminal targeting signals, termed presequences, which form positively charged amphiphilic α-helices3,4. TIM23 sorts the presequence proteins into the inner membrane or matrix. Various views including regulatory and coupling functions have been reported on the essential TIM23 subunit Tim175-7. We mapped the interaction of Tim17 with matrix-targeted and inner membrane-sorted preproteins during translocation in the native membrane environment. We show that Tim17 contains conserved negative charges close to the intermembrane space side of the bilayer, which are essential to initiate presequence protein translocation along a distinct transmembrane cavity of Tim17 for both classes of preproteins. The amphiphilic character of mitochondrial presequences directly matches this Tim17-dependent translocation mechanism. This mechanism permits direct lateral release of transmembrane segments of inner membrane-sorted precursors into the inner membrane.

DOI: https://doi.org/10.1038/s41586-023-06477-8
iScience. 2023 Aug 18. 26(8): 107299

Nuclear transfer improves the developmental potential of embryos derived from cytoplasmic deficient oocytes.

Zhaodi Liao, Yuzhuo Li, Chunyang Li, Xinyan Bian, Qiang Sun.

  Embryo development after fertilization is largely determined by the oocyte quality, which is in turn dependent on the competence of both the cytoplasm and nucleus. Here, to improve the efficiency of embryo development from developmentally incompetent oocytes, we performed spindle-chromosome complex transfer (ST) between in vitro matured (IVM) and in vivo matured (IVO) oocytes of the non-human primate rhesus monkey. We observed that the blastocyst rate of embryos derived from transferring the spindle-chromosome complex (SCC) of IVM oocytes into enucleated IVO oocytes was comparable with that of embryos derived from IVO oocytes. After transferring the reconstructed embryos into the uterus of surrogate mothers, two live rhesus monkeys were obtained, indicating that the nuclei of IVM oocytes support both the pre-and post-implantation embryo development of non-human primates.

Keywords:  Cell biology; Female reproductive endocrinology; Reproductive medicine

DOI:  https://doi.org/10.1016/j.isci.2023.107299
iScience. 2023 Jul 21. 26(7): 107068

Excitatory amino acid transporter 1 supports adult hippocampal neural stem cell self-renewal.

Joshua D Rieskamp, Ileanexis Rosado-Burgos, Jacob E Christofi, Eliza Ansar, Dalia Einstein, Ashley E Walters, Valentina Valentini, John P Bruno, Elizabeth D Kirby.

  Within the adult mammalian dentate gyrus (DG) of the hippocampus, glutamate stimulates neural stem cell (NSC) self-renewing proliferation, providing a link between adult neurogenesis and local circuit activity. Here, we show that glutamate-induced self-renewal of adult DG NSCs requires glutamate transport via excitatory amino acid transporter 1 (EAAT1) to stimulate lipogenesis. Loss of EAAT1 prevented glutamate-induced self-renewing proliferation of NSCs in vitro and in vivo, with little role evident for canonical glutamate receptors. Transcriptomics and further pathway manipulation revealed that glutamate simulation of NSCs relied on EAAT1 transport-stimulated lipogenesis. Our findings demonstrate a critical, direct role for EAAT1 in stimulating NSCs to support neurogenesis in adulthood, thereby providing insights into a non-canonical mechanism by which NSCs sense and respond to their niche.

Keywords:  Biochemistry; Cell biology; Molecular biology; Neurology

DOI:  https://doi.org/10.1016/j.isci.2023.107068
Front Cardiovasc Med. 2023 ;10 1204483

Mitochondrial epigenetics in aging and cardiovascular diseases.

Alessia Mongelli, Alessandro Mengozzi, Martin Geiger, Era Gorica, Shafeeq Ahmed Mohammed, Francesco Paneni, Frank Ruschitzka, Sarah Costantino.

  Mitochondria are cellular organelles which generate adenosine triphosphate (ATP) molecules for the maintenance of cellular energy through the oxidative phosphorylation. They also regulate a variety of cellular processes including apoptosis and metabolism. Of interest, the inner part of mitochondria-the mitochondrial matrix-contains a circular molecule of DNA (mtDNA) characterised by its own transcriptional machinery. As with genomic DNA, mtDNA may also undergo nucleotide mutations that have been shown to be responsible for mitochondrial dysfunction. During physiological aging, the mitochondrial membrane potential declines and associates with enhanced mitophagy to avoid the accumulation of damaged organelles. Moreover, if the dysfunctional mitochondria are not properly cleared, this could lead to cellular dysfunction and subsequent development of several comorbidities such as cardiovascular diseases (CVDs), diabetes, respiratory and cardiovascular diseases as well as inflammatory disorders and psychiatric diseases. As reported for genomic DNA, mtDNA is also amenable to chemical modifications, namely DNA methylation. Changes in mtDNA methylation have shown to be associated with altered transcriptional programs and mitochondrial dysfunction during aging. In addition, other epigenetic signals have been observed in mitochondria, in particular the interaction between mtDNA methylation and non-coding RNAs. Mitoepigenetic modifications are also involved in the pathogenesis of CVDs where oxygen chain disruption, mitochondrial fission, and ROS formation alter cardiac energy metabolism leading to hypertrophy, hypertension, heart failure and ischemia/reperfusion injury. In the present review, we summarize current evidence on the growing importance of epigenetic changes as modulator of mitochondrial function in aging. A better understanding of the mitochondrial epigenetic landscape may pave the way for personalized therapies to prevent age-related diseases.

Keywords:  aging; cardiovascular diseases; methylation; mitochondria; mitoepigenetics; mtDNA; ncRNAs

DOI:  https://doi.org/10.3389/fcvm.2023.1204483
J Clin Biochem Nutr. 2023 Jul;73(1): 61-76

High-fat diet causes mitochondrial damage and downregulation of mitofusin-2 and optic atrophy-1 in multiple organs.

Peng Zheng, Wenjing Ma, Yilu Gu, Hengfang Wu, Zhiping Bian, Nannan Liu, Di Yang, Xiangjian Chen.

  High-fat consumption promotes the development of obesity, which is associated with various chronic illnesses. Mitochondria are the energy factories of eukaryotic cells, maintaining self-stability through a fine-tuned quality-control network. In the present study, we evaluated high-fat diet (HFD)-induced changes in mitochondrial ultrastructure and dynamics protein expression in multiple organs. C57BL/6J male mice were fed HFD or normal diet (ND) for 24 weeks. Compared with ND-fed mice, HFD-fed mice exhibited increased body weight, cardiomyocyte enlargement, pulmonary fibrosis, hepatic steatosis, renal and splenic structural abnormalities. The cellular apoptosis of the heart, liver, and kidney increased. Cellular lipid droplet deposition and mitochondrial deformations were observed. The proteins related to mitochondrial biogenesis (TFAM), fission (DRP1), autophagy (LC3 and LC3-II: LC3-I ratio), and mitophagy (PINK1) presented different changes in different organs. The mitochondrial fusion regulators mitofusin-2 (MFN2) and optic atrophy-1 (OPA1) were consistently downregulated in multiple organs, even the spleen. TOMM20 and ATP5A protein were enhanced in the heart, skeletal muscle, and spleen, and attenuated in the kidney. These results indicated that high-fat feeding caused pathological changes in multiple organs, accompanied by mitochondrial ultrastructural damage, and MFN2 and OPA1 downregulation. The mitochondrial fusion proteins may become promising targets and/or markers for treating metabolic disease.

Keywords:  high-fat diet; hyperlipidemia; mitochondria; mitofusin-2; optic atrophy-1

DOI:  https://doi.org/10.3164/jcbn.22-73
Proc Natl Acad Sci U S A. 2023 Aug 08. 120(32): e2216141120

Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegans.

Adriana Raluca Vintila, Luke Slade, Michael Cooke, Craig R G Willis, Roberta Torregrossa, Mizanur Rahman, Taslim Anupom, Siva A Vanapalli, Christopher J Gaffney, Nima Gharahdaghi, Csaba Szabo, Nathaniel J Szewczyk, Matthew Whiteman, Timothy Etheridge.

  Living longer without simultaneously extending years spent in good health ("health span") is an increasing societal burden, demanding new therapeutic strategies. Hydrogen sulfide (H2S) can correct disease-related mitochondrial metabolic deficiencies, and supraphysiological H2S concentrations can pro health span. However, the efficacy and mechanisms of mitochondrion-targeted sulfide delivery molecules (mtH2S) administered across the adult life course are unknown. Using a Caenorhabditis elegans aging model, we compared untargeted H2S (NaGYY4137, 100 µM and 100 nM) and mtH2S (AP39, 100 nM) donor effects on life span, neuromuscular health span, and mitochondrial integrity. H2S donors were administered from birth or in young/middle-aged animals (day 0, 2, or 4 postadulthood). RNAi pharmacogenetic interventions and transcriptomics/network analysis explored molecular events governing mtH2S donor-mediated health span. Developmentally administered mtH2S (100 nM) improved life/health span vs. equivalent untargeted H2S doses. mtH2S preserved aging mitochondrial structure, content (citrate synthase activity) and neuromuscular strength. Knockdown of H2S metabolism enzymes and FoxO/daf-16 prevented the positive health span effects of mtH2S, whereas DCAF11/wdr-23 - Nrf2/skn-1 oxidative stress protection pathways were dispensable. Health span, but not life span, increased with all adult-onset mtH2S treatments. Adult mtH2S treatment also rejuvenated aging transcriptomes by minimizing expression declines of mitochondria and cytoskeletal components, and peroxisome metabolism hub components, under mechanistic control by the elt-6/elt-3 transcription factor circuit. H2S health span extension likely acts at the mitochondrial level, the mechanisms of which dissociate from life span across adult vs. developmental treatment timings. The small mtH2S doses required for health span extension, combined with efficacy in adult animals, suggest mtH2S is a potential healthy aging therapeutic.

Keywords:  H2S; health span; longevity; mitochondria; transcriptomics

DOI:  https://doi.org/10.1073/pnas.2216141120
Nat Commun. 2023 Aug 04. 14(1): 4675

Myonectin protects against skeletal muscle dysfunction in male mice through activation of AMPK/PGC1α pathway.

Yuta Ozaki, Koji Ohashi, Naoya Otaka, Hiroshi Kawanishi, Tomonobu Takikawa, Lixin Fang, Kunihiko Takahara, Minako Tatsumi, Sohta Ishihama, Mikito Takefuji, Katsuhiro Kato, Yuuki Shimizu, Yasuko K Bando, Aiko Inoue, Masafumi Kuzuya, Shinji Miura, Toyoaki Murohara, Noriyuki Ouchi.

To maintain and restore skeletal muscle mass and function is essential for healthy aging. We have found that myonectin acts as a cardioprotective myokine. Here, we investigate the effect of myonectin on skeletal muscle atrophy in various male mouse models of muscle dysfunction. Disruption of myonectin exacerbates skeletal muscle atrophy in age-associated, sciatic denervation-induced or dexamethasone (DEX)-induced muscle atrophy models. Myonectin deficiency also contributes to exacerbated mitochondrial dysfunction and reduces expression of mitochondrial biogenesis-associated genes including PGC1α in denervated muscle. Myonectin supplementation attenuates denervation-induced muscle atrophy via activation of AMPK. Myonectin also reverses DEX-induced atrophy of cultured myotubes through the AMPK/PGC1α signaling. Furthermore, myonectin treatment suppresses muscle atrophy in senescence-accelerated mouse prone (SAMP) 8 mouse model of accelerated aging or mdx mouse model of Duchenne muscular dystrophy. These data indicate that myonectin can ameliorate skeletal muscle dysfunction through AMPK/PGC1α-dependent mechanisms, suggesting that myonectin could represent a therapeutic target of muscle atrophy.

DOI: https://doi.org/10.1038/s41467-023-40435-2
Brain Pathol. 2023 Aug 03. e13199

Neuropathological hallmarks in autopsied cases with mitochondrial diseases caused by the mitochondrial 3243A>G mutation.

Hiroaki Miyahara, Chisato Tamai, Masanori Inoue, Kazuhito Sekiguchi, Daisuke Tahara, Nao Tahara, Kazuhiro Takeda, Shusei Arafuka, Hideyuki Moriyoshi, Ryuichi Koizumi, Akio Akagi, Yuichi Riku, Jun Sone, Mari Yoshida, Kenji Ihara, Yasushi Iwasaki.

  The mitochondrial (m.) 3243A>G mutation is known to be associated with various mitochondrial diseases including mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Their clinical symptoms have been estimated to occur with an increased mitochondrial DNA (mtDNA) heteroplasmy and reduced activity of oxidative phosphorylation (OXPHOS) complexes, but their trends in the central nervous system remain unknown. Six autopsied mutant cases and three disease control cases without the mutation were enrolled in this study. The mutant cases had a disease duration of 1-27 years. Five of six mutant cases were compatible with MELAS. In the mutant cases, cortical lesions including a laminar necrosis were frequently observed in the parietal, lateral temporal, and occipital lobes; less frequently in the frontal lobe including precentral gyrus; and not at all in the medial temporal lobe. The mtDNA heteroplasmy in brain tissue samples of the mutant cases was strikingly high, ranging from 53.8% to 85.2%. The medial temporal lobe was preserved despite an inhospitable environment having high levels of mtDNA heteroplasmy and lactic acid. OXPHOS complex I was widely decreased in the mutant cases. The swelling of smooth muscle cells in the vessels on the leptomeninges, with immunoreactivity (IR) against mitochondria antibody, and a decreased nuclear/cytoplasmic ratio of choroidal epithelial cells were observed in all mutant cases but in none without the mutation. Common neuropathological findings such as cortical laminar necrosis and basal ganglia calcification were not always observed in the mutant cases. A high level of mtDNA heteroplasmy was observed throughout the brain in spite of heterogeneous cortical lesions. A lack of medial temporal lesion, mitochondrial vasculopathy in vessels on the leptomeninges, and an increased cytoplasmic size of epithelial cells in the choroid plexus could be neuropathological hallmarks helpful in the diagnosis of mitochondrial diseases.

Keywords:  MELAS; choroidal epithelial cell swelling; mitochondrial 3243A>G mutation; mitochondrial vasculopathy; mtDNA heteroplasmy; stroke-like episodes

DOI:  https://doi.org/10.1111/bpa.13199
J Inherit Metab Dis. 2023 Aug 02.

Fifty years of research on mitochondrial fatty acid oxidation defects: the remaining challenges.

Christine Vianey-Saban, Nathalie Guffon, Alain Fouilhoux, Cécile Acquaviva.

  Since the identification of the first disorder of mitochondrial fatty acid oxidation (FAOD) in 1973, more than twenty defects have been identified. Although there are some differences, most FAOD have similar clinical signs, which are mainly due to energy depletion and toxicity of accumulated metabolites. However, some of them have an unusual clinical phenotype or specific clinical signs. This manuscript focuses on what we have learnt so far on the pathophysiology of these disorders which present with clinical signs that are not typical of categorical FAOD. It also highlights that some disorders have not yet been identified and tries to make assumptions to explain why. It also deals with new treatments under consideration in FAOD, including triheptanoin and similar anaplerotic substrates, ketone body treatments, RNA and gene therapy approaches. Finally, it suggests challenges for the diagnosis of FAOD in the coming years, both for symptomatic patients and for those diagnosed through newborn screening. The ultimate goal would be to identify all the patients born with FAOD and ensure for them the best possible quality of life. TAKE HOME MESSAGE: Tentative hypotheses to improve the diagnosis and the treatment of fatty acid oxidation defects. This article is protected by copyright. All rights reserved.

Keywords:  inborn errors of riboflavin metabolism; mitochondrial fatty acid oxidation disorders

DOI:  https://doi.org/10.1002/jimd.12664
Cell Death Dis. 2023 Aug 03. 14(8): 496

Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model.

Volha Liaudanskaya, Nicholas J Fiore, Yang Zhang, Yuka Milton, Marilyn F Kelly, Marly Coe, Ariana Barreiro, Victoria K Rose, Matthew R Shapiro, Adam S Mullis, Anna Shevzov-Zebrun, Mathew Blurton-Jones, Michael J Whalen, Aviva J Symes, Irene Georgakoudi, Thomas J F Nieland, David L Kaplan.

Traumatic Brain injury-induced disturbances in mitochondrial fission-and-fusion dynamics have been linked to the onset and propagation of neuroinflammation and neurodegeneration. However, cell-type-specific contributions and crosstalk between neurons, microglia, and astrocytes in mitochondria-driven neurodegeneration after brain injury remain undefined. We developed a human three-dimensional in vitro triculture tissue model of a contusion injury composed of neurons, microglia, and astrocytes and examined the contributions of mitochondrial dysregulation to neuroinflammation and progression of injury-induced neurodegeneration. Pharmacological studies presented here suggest that fragmented mitochondria released by microglia are a key contributor to secondary neuronal damage progression after contusion injury, a pathway that requires astrocyte-microglia crosstalk. Controlling mitochondrial dysfunction thus offers an exciting option for developing therapies for TBI patients.

DOI: https://doi.org/10.1038/s41419-023-05980-0
Cell Rep. 2023 Jul 27. pii: S2211-1247(23)00859-8. [Epub ahead of print]42(8): 112848

The stability of the myelinating oligodendrocyte transcriptome is regulated by the nuclear lamina.

Mathilde Pruvost, Julia Patzig, Camila Yattah, Ipek Selcen, Marylens Hernandez, Hye-Jin Park, Sarah Moyon, Shibo Liu, Malia S Morioka, Lindsay Shopland, Osama Al-Dalahmah, Jaroslav Bendl, John F Fullard, Panos Roussos, James Goldman, Ye He, Jeffrey L Dupree, Patrizia Casaccia.

  Oligodendrocytes are specialized cells that insulate and support axons with their myelin membrane, allowing proper brain function. Here, we identify lamin A/C (LMNA/C) as essential for transcriptional and functional stability of myelinating oligodendrocytes. We show that LMNA/C levels increase with differentiation of progenitors and that loss of Lmna in differentiated oligodendrocytes profoundly alters their chromatin accessibility and transcriptional signature. Lmna deletion in myelinating glia is compatible with normal developmental myelination. However, altered chromatin accessibility is detected in fully differentiated oligodendrocytes together with increased expression of progenitor genes and decreased levels of lipid-related transcription factors and inner mitochondrial membrane transcripts. These changes are accompanied by altered brain metabolism, lower levels of myelin-related lipids, and altered mitochondrial structure in oligodendrocytes, thereby resulting in myelin thinning and the development of a progressively worsening motor phenotype. Overall, our data identify LMNA/C as essential for maintaining the transcriptional and functional stability of myelinating oligodendrocytes.

Keywords:  CP: Neuroscience; brain; chromatin; epigenetics; myelin; nucleus; progenitors

DOI:  https://doi.org/10.1016/j.celrep.2023.112848
iScience. 2023 Jul 21. 26(7): 107131

Increased cardiac PFK-2 protects against high-fat diet-induced cardiomyopathy and mediates beneficial systemic metabolic effects.

Maria F Mendez Garcia, Satoshi Matsuzaki, Albert Batushansky, Ryan Newhardt, Caroline Kinter, Yan Jin, Shivani N Mann, Michael B Stout, Haiwei Gu, Ying Ann Chiao, Michael Kinter, Kenneth M Humphries.

  A healthy heart adapts to changes in nutrient availability and energy demands. In metabolic diseases like type 2 diabetes (T2D), increased reliance on fatty acids for energy production contributes to mitochondrial dysfunction and cardiomyopathy. A principal regulator of cardiac metabolism is 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2), which is a central driver of glycolysis. We hypothesized that increasing PFK-2 activity could mitigate cardiac dysfunction induced by high-fat diet (HFD). Wild type (WT) and cardiac-specific transgenic mice expressing PFK-2 (GlycoHi) were fed a low fat or HFD for 16 weeks to induce metabolic dysfunction. Metabolic phenotypes were determined by measuring mitochondrial bioenergetics and performing targeted quantitative proteomic and metabolomic analysis. Increasing cardiac PFK-2 had beneficial effects on cardiac and mitochondrial function. Unexpectedly, GlycoHi mice also exhibited sex-dependent systemic protection from HFD, including increased glucose homeostasis. These findings support improving glycolysis via PFK-2 activity can mitigate mitochondrial and functional changes that occur with metabolic syndrome.

Keywords:  Metabolomics; Molecular biology; Physiology; Proteomics

DOI:  https://doi.org/10.1016/j.isci.2023.107131
Environ Toxicol Pharmacol. 2023 Aug 02. pii: S1382-6689(23)00181-3. [Epub ahead of print] 104239

Maternal Exposure to Cetylpyridinium Chloride Impairs Oogenesis by Causing Mitochondria Disorder in Neonates.

Ronglu Liu, Xinyi Mu, Rufei Gao, Yanqing Geng, Yan Zhang, Xuemei Chen, Xin Yin, Hong Wang, Fangfang Li, Junlin He.

  Cetylpyridinium Chloride (CPC) is a common disinfectant with potential mitochondrial toxicity. However, the effects of CPC on female reproduction remains unclear. In the present study, pregnant mice were exposed to environmentally relevant doses of CPC for 3 days, the effects were evaluated in the female offspring. Maternal exposure to CPC caused loss of oocytes in neonatal ovaries. TEM analysis of neonatal ovaries showed CPC caused aberrant mitochondrial morphology including vacuolated and disorganized structure, reduced functional cristae. In addition, CPC decreased mitochondrial membrane potential in neonatal oocytes. Seahorse analysis showed that CPC hampered mitochondrial reserve, manifested as reduced spare respiratory capacity. Furthermore, CPC damaged mitochondrial function and impaired developmental competence of MII oocytes, suggesting a persisting impact into adulthood. In summary, this is the first known demonstration that maternal exposure to CPC caused mitochondrial disorders in neonatal ovaries and had long-term effects on fertility of the female offspring.

Keywords:  Cetylpyridinium chloride; MII oocyte; mitochondrial dysfunction; neonatal ovary; quaternary ammonium compounds

DOI:  https://doi.org/10.1016/j.etap.2023.104239
FEBS Open Bio. 2023 Jul 31.

Accumulation of TERT in mitochondria exerts two opposing effects on apoptosis.

Hiroshi Ebata, Tomohiro Shima, Ryo Iizuka, Sotaro Uemura.

  Telomerase reverse transcriptase (TERT) is a protein that catalyzes the reverse transcription of telomere elongation. TERT is also expected to play a noncanonical role beyond telomere lengthening since it localizes not only in the nucleus but also in mitochondria, where telomeres do not exist. Several studies have reported that mitochondrial TERT regulates apoptosis induced by oxidative stress. However, there is still some controversy as to whether mitochondrial TERT promotes or inhibits apoptosis, mainly due to the lack of information on changes in TERT distribution in individual cells over time. Here, we simultaneously detected apoptosis and TERT localization after oxidative stress in individual HeLa cells by live-cell tracking. Single-cell tracking revealed that the stress-induced accumulation of TERT in mitochondria caused apoptosis, but that accumulation increased over time until cell death. The results suggest a new model in which mitochondrial TERT has two opposing effects at different stages of apoptosis: it predetermines apoptosis at the first stage of cell-fate determination, but also delays apoptosis at the second stage. As such, our data support a model that integrates the two opposing hypotheses on mitochondrial TERT's effect on apoptosis. Furthermore, detailed statistical analysis of TERT mutations, which have been predicted to inhibit TERT transport to mitochondria, revealed that these mutations suppress apoptosis independent of mitochondrial localization of TERT. Together, these results imply that the non-canonical functions of TERT affect a wide range of mitochondria-dependent and mitochondria-independent apoptosis pathways.

Keywords:  Apoptosis; Live-cell Imaging; Mitochondria; Oxidative Stress; TERT

DOI:  https://doi.org/10.1002/2211-5463.13682
Br J Haematol. 2023 Jul 30.

Pancytopenia and haematopoietic precursor vacuolisation in an infant: Clues to Pearson syndrome.

Jordan H Driskill, Miguel Dario Cantu, Jessica Garcia, Kathryn E Dickerson, Weina Chen.

DOI: https://doi.org/10.1111/bjh.18987
J Cell Biol. 2023 09 04. pii: e202304076. [Epub ahead of print]222(9):

Convergent and divergent mechanisms of peroxisomal and mitochondrial division.

Suresh Subramani, Nandini Shukla, Jean-Claude Farre.

Organelle division and segregation are important in cellular homeostasis. Peroxisomes (POs) and mitochondria share a core division machinery and mechanism of membrane scission. The division of each organelle is interdependent not only on the other but also on other organelles, reflecting the dynamic communication between subcellular compartments, even as they coordinate the exchange of metabolites and signals. We highlight common and unique mechanisms involved in the fission of these organelles under the premise that much can be gleaned regarding the division of one organelle based on information available for the other.

DOI: https://doi.org/10.1083/jcb.202304076
Int Immunopharmacol. 2023 Jul 31. pii: S1567-5769(23)00842-1. [Epub ahead of print]123 110519

Mitochondrial Lon protease promotes CD4+ T cell activation by activating the cGAS-STING-TBK1 axis in systemic lupus erythematosus.

Xiangyang Huang, Yi Liu, Guanghui Ling, Xin Cao.

  Systemic lupus erythematosus (SLE) is an autoimmune disease in which autoreactive CD4+ T cells play an essential role. We extracted CD4+ T cells from SLE-prone Fcgr2b-/- mice to elaborate the mechanism of mitochondrial Lon protease in CD4+ T cell activation in SLE. Transcriptome sequencing was performed in SLE-prone Fcgr2b-/- mice, and the stimulator of interferon gene (STING) related to SLE was obtained. It was demonstrated that STING expression was elevated in CD4+ T cells in SLE-prone Fcgr2b-/- mice. The downstream genes and pathways of STING were predicted by GO and KEGG approaches. The data indicated that STING regulated IFN signaling to promote CD4+ T cell activation in SLE-prone Fcgr2b-/- mice. Next, the interaction of cGAS, STING, TBK1, and IFN-I was verified by Co-IP assay. Moreover, the roles of cGAS, STING, and TBK1 in activating CD4+ T cells from SLE-prone Fcgr2b-/- mice were evaluated using gain- or loss-of-function experiments. Mechanistically, cGAS upregulated the IFN-I signaling pathway by directly interacting with STING and TBK1, contributing to CD4+ T cell activation. Besides, cytosolic mtDNA could activate CD4+ T cell activation in SLE-prone Fcgr2b-/- mice by upregulating the cGAS-STING-TBK1 axis. The function of mitochondrial Lon protease in oxidative damage and mtDNA release in CD4+ T cells of SLE-prone Fcgr2b-/- mice were explored. Mitochondrial Lon protease enhanced mtDNA release into the cytoplasm under oxidative stress. Collectively, our work indicates that mitochondrial Lon protease enhances CD4+ T cell activation by inducing mtDNA leakage and offers new candidate targets for developing diagnostic and therapeutic strategies.

Keywords:  CD4(+) T cells; Mitochondrial Lon protease; Systemic lupus erythematosus; Type I interferon; cGAS-STING-TBK1; mtDNA

DOI:  https://doi.org/10.1016/j.intimp.2023.110519
Mol Cell. 2023 Jul 28. pii: S1097-2765(23)00526-9. [Epub ahead of print]

O-GlcNAcylation of Raptor transduces glucose signals to mTORC1.

Chenchen Xu, Xiaoqing Pan, Dong Wang, Yuanyuan Guan, Wenyu Yang, Xing Chen, Ying Liu.

  The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient levels. Dysregulation of mTORC1 results in a broad spectrum of diseases. Glucose is the primary energy supply of cells, and therefore, glucose levels must be accurately conveyed to mTORC1 through highly responsive signaling mechanisms to control mTORC1 activity. Here, we report that glucose-induced mTORC1 activation is regulated by O-GlcNAcylation of Raptor, a core component of mTORC1, in HEK293T cells. Mechanistically, O-GlcNAcylation of Raptor at threonine 700 facilitates the interactions between Raptor and Rag GTPases and promotes the translocation of mTOR to the lysosomal surface, consequently activating mTORC1. In addition, we show that AMPK-mediated phosphorylation of Raptor suppresses Raptor O-GlcNAcylation and inhibits Raptor-Rags interactions. Our findings reveal an exquisitely controlled mechanism, which suggests how glucose coordinately regulates cellular anabolism and catabolism.

Keywords:  O-GlcNAcylation; Raptor; glucose sensing; mTOR

DOI:  https://doi.org/10.1016/j.molcel.2023.07.011
Nat Commun. 2023 07 31. 14(1): 4599

Three-dimensional molecular architecture of mouse organogenesis.

Fangfang Qu, Wenjia Li, Jian Xu, Ruifang Zhang, Jincan Ke, Xiaodie Ren, Xiaogao Meng, Lexin Qin, Jingna Zhang, Fangru Lu, Xin Zhou, Xi Luo, Zhen Zhang, Minhan Wang, Guangming Wu, Duanqing Pei, Jiekai Chen, Guizhong Cui, Shengbao Suo, Guangdun Peng.

Mammalian embryos exhibit sophisticated cellular patterning that is intricately orchestrated at both molecular and cellular level. It has recently become apparent that cells within the animal body display significant heterogeneity, both in terms of their cellular properties and spatial distributions. However, current spatial transcriptomic profiling either lacks three-dimensional representation or is limited in its ability to capture the complexity of embryonic tissues and organs. Here, we present a spatial transcriptomic atlas of all major organs at embryonic day 13.5 in the mouse embryo, and provide a three-dimensional rendering of molecular regulation for embryonic patterning with stacked sections. By integrating the spatial atlas with corresponding single-cell transcriptomic data, we offer a detailed molecular annotation of the dynamic nature of organ development, spatial cellular interactions, embryonic axes, and divergence of cell fates that underlie mammalian development, which would pave the way for precise organ engineering and stem cell-based regenerative medicine.

DOI: https://doi.org/10.1038/s41467-023-40155-7