bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024‒09‒15
25 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Human neural stem cell-derived artificial organelles to improve oxidative phosphorylation.
  2. Variant load of mitochondrial DNA in single human mesenchymal stem cells.
  3. 26th Annual Symposium of the United Mitochondrial Disease Foundation -Mitochondrial Medicine 2023 - Abstracts.
  4. A promising therapeutic: Exosome-mediated mitochondrial transplantation.
  5. Pregnancy in women with mitochondrial disease-A literature review and suggested guidance for preconception and pregnancy care.
  6. Mitochondrial tRNAGlu 14693A>G Mutation, an "Enhancer" to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy.
  7. The multifaceted effects of mitochondria in kidney diseases.
  8. Characterization of two iPSC lines from patients with maternally inherited leigh (MILS) and neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome carrying the MT-ATP6 m.8993 T>G mutation at different degrees of heteroplasmy.
  9. Role of Mitochondrial Dysfunctions in Neurodegenerative Disorders: Advances in Mitochondrial Biology.
  10. Neurodegenerative disorders, metabolic icebergs, and mitohormesis.
  11. Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.
  12. Disruption of Mitochondrial Quality Control in Inherited Metabolic Disorders.
  13. Mitophagy protects against ferroptosis.
  14. Heteroplasmy in action: tracking mtDNA segregation dynamics.
  15. Antisense Oligonucleotide STK-002 Increases OPA1 in Retina and Improves Mitochondrial Function in Autosomal Dominant Optic Atrophy Cells.
  16. Targeted protein degradation in the mitochondrial matrix and its application to chemical control of mitochondrial morphology.
  17. Human embryo models are getting more realistic - raising ethical questions.
  18. Exploring the Mechanisms and Therapeutic Approaches of Mitochondrial Dysfunction in Alzheimer's Disease: An Educational Literature Review.
  19. Human neural stem cell-derived extracellular vesicles protect against ischemic stroke by activating the PI3K/AKT/mTOR pathway.
  20. Spastin regulates ER-mitochondrial contact sites and mitochondrial homeostasis.
  21. DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.
  22. SUMOylation modulates mitochondrial dynamics in an in vitro rotenone model of Parkinson's disease.
  23. Endurance exercise-induced histone methylation modification involved in skeletal muscle fiber type transition and mitochondrial biogenesis.
  24. mTORC1 pathway activity biases cell fate choice.
  25. The mitochondrial stress signaling tunes immunity from a view of systemic tumor microenvironment and ecosystem.
  1. Nat Commun. 2024 Sep 08. 15(1): 7855
    Human neural stem cell-derived artificial organelles to improve oxidative phosphorylation.
    Jiayi Wang, Mengke Zhao, Meina Wang, Dong Fu, Lin Kang, Yu Xu, Liming Shen, Shilin Jin, Liang Wang, Jing Liu.
      Oxidative phosphorylation (OXPHOS) in the mitochondrial inner membrane is a therapeutic target in many diseases. Neural stem cells (NSCs) show progress in improving mitochondrial dysfunction in the central nervous system (CNS). However, translating neural stem cell-based therapies to the clinic is challenged by uncontrollable biological variability or heterogeneity, hindering uniform clinical safety and efficacy evaluations. We propose a systematic top-down design based on membrane self-assembly to develop neural stem cell-derived oxidative phosphorylating artificial organelles (SAOs) for targeting the central nervous system as an alternative to NSCs. We construct human conditionally immortal clone neural stem cells (iNSCs) as parent cells and use a streamlined closed operation system to prepare neural stem cell-derived highly homogenous oxidative phosphorylating artificial organelles. These artificial organelles act as biomimetic organelles to mimic respiration chain function and perform oxidative phosphorylation, thus improving ATP synthesis deficiency and rectifying excessive mitochondrial reactive oxygen species production. Conclusively, we provide a framework for a generalizable manufacturing procedure that opens promising prospects for disease treatment.
    DOI:  https://doi.org/10.1038/s41467-024-52171-2
  2. Sci Rep. 2024 09 09. 14(1): 20989
    Variant load of mitochondrial DNA in single human mesenchymal stem cells.
    Daniel Hipps, Angela Pyle, Anna L R Porter, Philip F Dobson, Helen Tuppen, Conor Lawless, Oliver M Russell, Doug M Turnbull, David J Deehan, Gavin Hudson.
      Heteroplasmic mitochondrial DNA (mtDNA) variants accumulate as humans age, particularly in the stem-cell compartments, and are an important contributor to age-related disease. Mitochondrial dysfunction has been observed in osteoporosis and somatic mtDNA pathogenic variants have been observed in animal models of osteoporosis. However, this has never been assessed in the relevant human tissue. Mesenchymal stem cells (MSCs) are the progenitors to many cells of the musculoskeletal system and are critical to skeletal tissues and bone vitality. Investigating mtDNA in MSCs could provide novel insights into the role of mitochondrial dysfunction in osteoporosis. To determine if this is possible, we investigated the landscape of somatic mtDNA variation in MSCs through a combination of fluorescence-activated cell sorting and single-cell next-generation sequencing. Our data show that somatic heteroplasmic variants are present in individual patient-derived MSCs, can reach high heteroplasmic fractions and have the potential to be pathogenic. The identification of somatic heteroplasmic variants in MSCs of patients highlights the potential for mitochondrial dysfunction to contribute to the pathogenesis of osteoporosis.
    Keywords:  Bone disease; Mesenchymal stem cells; Osteoporosis; Somatic mtDNA variation
    DOI:  https://doi.org/10.1038/s41598-024-71822-4
  3. Ther Adv Rare Dis. 2023 Jan-Dec;4:4 26330040231199665
    26th Annual Symposium of the United Mitochondrial Disease Foundation -Mitochondrial Medicine 2023 - Abstracts.
      
    DOI:  https://doi.org/10.1177/26330040231199665
  4. Int Immunopharmacol. 2024 Sep 12. pii: S1567-5769(24)01625-4. [Epub ahead of print]142(Pt A): 113104
    A promising therapeutic: Exosome-mediated mitochondrial transplantation.
    Meiling Cao, Jiahui Zou, Mingyue Shi, Danyang Zhao, Chang Liu, Yanshan Liu, Lei Li, Hongkun Jiang.
      Mitochondrial dysfunction has been identified as a trigger for cellular autophagy dysfunction and programmed cell death. Emerging studies have revealed that, in pathological contexts, intercellular transfer of mitochondria takes place, facilitating the restoration of mitochondrial function, energy metabolism, and immune homeostasis. Extracellular vesicles, membranous structures released by cells, exhibit reduced immunogenicity and enhanced stability during the transfer of mitochondria. Thus, this review provides a concise overview of mitochondrial dysfunction related diseases and the mechanism of mitochondrial dysfunction in diseases progression, and the composition and functions of the extracellular vesicles, along with elucidating the principal mechanisms underlying intercellular mitochondrial transfer. In this article, we will focus on the advancements in both animal models and clinical trials concerning the therapeutic efficacy of extracellular vesicle-mediated mitochondrial transplantation across various systemic diseases in neurodegenerative diseases and cardiovascular diseases. Additionally, the review delves into the multifaceted roles of extracellular vesicle-transplanted mitochondria, encompassing anti-inflammatory actions, promotion of tissue repair, enhancement of cellular function, and modulation of metabolic and immune homeostasis within diverse pathological contexts, aiming to provide novel perspectives for extracellular vesicle transplantation of mitochondria in the treatment of various diseases.
    Keywords:  Extracellular vesicles; Mitochondria; Mitochondrial transfer; Mitochondrial transplantation; Organ damage; Therapy
    DOI:  https://doi.org/10.1016/j.intimp.2024.113104
  5. Aust N Z J Obstet Gynaecol. 2024 Sep 11.
    Pregnancy in women with mitochondrial disease-A literature review and suggested guidance for preconception and pregnancy care.
    Lisa Hui, Pema Hayman, Ali Buckland, Michael C Fahey, David A Mackey, Andrew J Mallett, Daniel R Schweitzer, Clare P Stuart, Wai Yan Yau, John Christodoulou.
      Mitochondrial donation to reduce the risk of primary mitochondrial disease transmission from mother to child is now permitted under Australian law as part of a clinical trial. The energy demands of pregnancy have the potential to worsen mitochondrial disease symptoms and severity in affected women. We conducted a systematic literature review on mitochondrial disease in pregnancy; five cohort studies and 19 case reports were included. For many women with mitochondrial disease, pregnancy does not have a negative effect on health status. However, serious adverse outcomes may occur. We provide suggested guidelines for preconception counselling and antenatal care.
    Keywords:  assisted reproductive techniques; genetics; mitochondrial disease; pregnancy; pregnancy complications
    DOI:  https://doi.org/10.1111/ajo.13874
  6. Adv Sci (Weinh). 2024 Sep 12. e2401856
    Mitochondrial tRNAGlu 14693A>G Mutation, an "Enhancer" to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy.
    Lihao Jin, Dingyi Gan, Wentao He, Na Wu, Shuchenlu Xiang, Yinsheng Wei, Gilbert Eriani, Yanchun Ji, Min-Xin Guan, Meng Wang.
      Leber's hereditary optic neuropathy (LHON), a maternally inherited ocular disease, is predominantly caused by mitochondrial DNA (mtDNA) mutations. Mitochondrial tRNA variants are hypothesized to amplify the pathogenic impact of three primary mutations. However, the exact mechanisms remained unclear. In the present study, the synergistic effect of the tRNAGlu 14693A>G and ND6 14484T>C mutations in three Chinese families affected by LHON is investigated. The m.14693A>G mutation nearly abolishes the pseudouridinylation at position 55 of tRNAGlu, leading to structural abnormalities, decreased stability, aberrant mitochondrial protein synthesis, and increased autophagy. In contrast, the ND6 14484T>C mutation predominantly impairs complex I function, resulting in heightened apoptosis and virtually no induction of mitochondrial autophagy compared to control cell lines. The presence of dual mutations in the same cell lines exhibited a coexistence of both upregulated cellular stress responses to mitochondrial damage, indicating a scenario of autophagy and mutation dysregulation within these dual-mutant cell lines. The data proposes a novel hypothesis that mitochondrial tRNA gene mutations generally lead to increased mitochondrial autophagy, while mutations in genes encoding mitochondrial proteins typically induce apoptosis, shedding light on the intricate interplay between different genetic factors in the manifestation of LHON.
    Keywords:  apoptosis; leber's hereditary optic neuropathy; mitochondrial tRNA mutation; mitophagy; phenotypic expression
    DOI:  https://doi.org/10.1002/advs.202401856
  7. Mitochondrion. 2024 Sep 11. pii: S1567-7249(24)00115-6. [Epub ahead of print] 101957
    The multifaceted effects of mitochondria in kidney diseases.
    Jia-Le Xue, Jia-Ling Ji, Yan Zhou, Yao Zhang, Bi-Cheng Liu, Rui-Xia Ma, Zuo-Lin Li.
      Mitochondria serve as the primary site for aerobic respiration within cells, playing a crucial role in maintaining cellular homeostasis. To maintain homeostasis and meet the diverse demands of the cells, mitochondria have evolved intricate systems of quality control, mainly including mitochondrial dynamics, mitochondrial autophagy (mitophagy) and mitochondrial biogenesis. The kidney, characterized by its high energy requirements, is particularly abundant in mitochondria. Interestingly, the mitochondria display complex behaviors and functions. When the kidney is suffered from obstructive, ischemic, hypoxic, oxidative, or metabolic insults, the dysfunctional mitochondrial derived from the defects in the mitochondrial quality control system contribute to cellular inflammation, cellular senescence, and cell death, posing a threat to the kidney. However, in addition to causing injury to the kidney in several cases, mitochondria also exhibit protective effect on the kidney. In recent years, accumulating evidence indicated that mitochondria play a crucial role in adaptive repair following kidney diseases caused by various etiologies. In this article, we comprehensively reviewed the current understanding about the multifaceted effects of mitochondria on kidney diseases and their therapeutic potential.
    Keywords:  Kidney diseases; Mitochondria; Mitochondrial quality control system; Treatment strategy
    DOI:  https://doi.org/10.1016/j.mito.2024.101957
  8. Stem Cell Res. 2024 Sep 06. pii: S1873-5061(24)00245-9. [Epub ahead of print]81 103547
    Characterization of two iPSC lines from patients with maternally inherited leigh (MILS) and neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome carrying the MT-ATP6 m.8993 T>G mutation at different degrees of heteroplasmy.
    Anna Maria Haschke, Sebastian Diecke, Markus Schuelke.
      Human-derived experimental systems such as induced pluripotent stem cell (iPSC)-derived models are useful tools to study mechanisms and potential therapeutic approaches for mitochondrial disorders. Here, we generated two iPSC lines from fibroblasts of patients carrying mutations at MT-ATP6 (m.8993 T>G). One patient with 96 % heteroplasmy suffered from Neuropathy, Ataxia, and Retinitis pigmentosa (NARP) syndrome, while the other patient with a homoplasmic mutation suffered from Maternally Inherited Leigh Syndrome (MILS). For reprogramming, we delivered reprogramming factors using Sendai virus and evaluated the pluripotency characteristics of the derived iPSCs. The degree of heteroplasmy remained stable after reprogramming.
    DOI:  https://doi.org/10.1016/j.scr.2024.103547
  9. Mol Neurobiol. 2024 Sep 13.
    Role of Mitochondrial Dysfunctions in Neurodegenerative Disorders: Advances in Mitochondrial Biology.
    Divya Sri Kathiresan, Rubadevi Balasubramani, Kamalesh Marudhachalam, Piyush Jaiswal, Nivedha Ramesh, Suruthi Gunna Sureshbabu, Vinayaga Moorthi Puthamohan, Murali Vijayan.
      Mitochondria, essential organelles responsible for cellular energy production, emerge as a key factor in the pathogenesis of neurodegenerative disorders. This review explores advancements in mitochondrial biology studies that highlight the pivotal connection between mitochondrial dysfunctions and neurological conditions such as Alzheimer's, Parkinson's, Huntington's, ischemic stroke, and vascular dementia. Mitochondrial DNA mutations, impaired dynamics, and disruptions in the ETC contribute to compromised energy production and heightened oxidative stress. These factors, in turn, lead to neuronal damage and cell death. Recent research has unveiled potential therapeutic strategies targeting mitochondrial dysfunction, including mitochondria targeted therapies and antioxidants. Furthermore, the identification of reliable biomarkers for assessing mitochondrial dysfunction opens new avenues for early diagnosis and monitoring of disease progression. By delving into these advancements, this review underscores the significance of understanding mitochondrial biology in unraveling the mechanisms underlying neurodegenerative disorders. It lays the groundwork for developing targeted treatments to combat these devastating neurological conditions.
    Keywords:  Biogenesis; Mitochondria; MtDNA dynamics; Neurodegeneration; Oxidative stress; Therapeutics
    DOI:  https://doi.org/10.1007/s12035-024-04469-x
  10. Transl Neurodegener. 2024 Sep 06. 13(1): 46
    Neurodegenerative disorders, metabolic icebergs, and mitohormesis.
    Matthew C L Phillips, Martin Picard.
      Neurodegenerative disorders are typically "split" based on their hallmark clinical, anatomical, and pathological features, but they can also be "lumped" by a shared feature of impaired mitochondrial biology. This leads us to present a scientific framework that conceptualizes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) as "metabolic icebergs" comprised of a tip, a bulk, and a base. The visible tip conveys the hallmark neurological symptoms, neurodegenerative regions, and neuronal protein aggregates for each disorder. The hidden bulk depicts impaired mitochondrial biology throughout the body, which is multifaceted and may be subdivided into impaired cellular metabolism, cell-specific mitotypes, and mitochondrial behaviours, functions, activities, and features. The underlying base encompasses environmental factors, especially modern industrial toxins, dietary lifestyles, and cognitive, physical, and psychosocial behaviours, but also accommodates genetic factors specific to familial forms of AD, PD, and ALS, as well as HD. Over years or decades, chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk, which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip. We propose that impaired mitochondrial biology can be repaired and recalibrated by activating "mitohormesis", which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases. Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of, or suffering with, neurodegenerative disorders.
    Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Hormesis; Huntington’s disease; Lumping; Mitochondria; Mitohormesis; Mitotypes; Parkinson’s disease; Splitting
    DOI:  https://doi.org/10.1186/s40035-024-00435-8
  11. EMBO J. 2024 Sep 11.
    Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.
    Hilda Delgado de la Herran, Denis Vecellio Reane, Yiming Cheng, Máté Katona, Fabian Hosp, Elisa Greotti, Jennifer Wettmarshausen, Maria Patron, Hermine Mohr, Natalia Prudente de Mello, Margarita Chudenkova, Matteo Gorza, Safal Walia, Michael Sheng-Fu Feng, Anja Leimpek, Dirk Mielenz, Natalia S Pellegata, Thomas Langer, György Hajnóczky, Matthias Mann, Marta Murgia, Fabiana Perocchi.
      The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon chronic loss or gain of mitochondrial calcium uptake. We identify 89 high-confidence interactors that link MCUC to several mitochondrial complexes and pathways, half of which are associated with human disease. As a proof-of-concept, we validate the mitochondrial intermembrane space protein EFHD1 as a binding partner of the MCUC subunits MCU, EMRE, and MCUB. We further show a MICU1-dependent inhibitory effect of EFHD1 on calcium uptake. Next, we systematically survey compensatory mechanisms and functional consequences of mitochondrial calcium dyshomeostasis by analyzing the MCU interactome upon EMRE, MCUB, MICU1, or MICU2 knockdown. While silencing EMRE reduces MCU interconnectivity, MCUB loss-of-function leads to a wider interaction network. Our study provides a comprehensive and high-confidence resource to gain insights into players and mechanisms regulating mitochondrial calcium signaling and their relevance in human diseases.
    Keywords:  Calcium Signaling; Mitochondria; Mitochondrial Calcium Uniporter; Organelle; Proteomics
    DOI:  https://doi.org/10.1038/s44318-024-00219-w
  12. Mol Neurobiol. 2024 Sep 09.
    Disruption of Mitochondrial Quality Control in Inherited Metabolic Disorders.
    Manuela Bianchin Marcuzzo, Josyane de Andrade Silveira, Emílio L Streck, Jerry Vockley, Guilhian Leipnitz.
      Inherited metabolic disorders (IMDs) are genetic disorders often characterized by the accumulation of toxic metabolites in patient tissues and bodily fluids. Although the pathophysiologic effect of these metabolites and their direct effect on cellular function is not yet established for many of these disorders, animal and cellular studies have shown that mitochondrial bioenergetic dysfunction with impairment of citric acid cycle activity and respiratory chain, along with secondary damage induced by oxidative stress are prominent in some. Mitochondrial quality control, requiring the coordination of multiple mechanisms such as mitochondrial biogenesis, dynamics, and mitophagy, is responsible for the correction of such defects. For inborn errors of enzymes located in the mitochondria, secondary abnormalities in quality control this organelle could play a role in their pathophysiology. This review summarizes preclinical data (animal models and patient-derived cells) on mitochondrial quality control disturbances in selected IMDs.
    Keywords:  Biogenesis; Fission; Fusion; Inherited Metabolic Disorders; Mitochondrial Quality Control; Mitophagy
    DOI:  https://doi.org/10.1007/s12035-024-04467-z
  13. Nat Cell Biol. 2024 Sep;26(9): 1374
    Mitophagy protects against ferroptosis.
    Petra Gross.
      
    DOI:  https://doi.org/10.1038/s41556-024-01507-7
  14. EMBO J. 2024 Sep 10.
    Heteroplasmy in action: tracking mtDNA segregation dynamics.
    Nitish Dua, Anjana Badrinarayanan.
      
    DOI:  https://doi.org/10.1038/s44318-024-00226-x
  15. Nucleic Acid Ther. 2024 Sep 12.
    Antisense Oligonucleotide STK-002 Increases OPA1 in Retina and Improves Mitochondrial Function in Autosomal Dominant Optic Atrophy Cells.
    Aditya Venkatesh, Taylor McKenty, Syed Ali, Donna Sonntag, Shobha Ravipaty, Yanyan Cui, Deirdre Slate, Qian Lin, Anne Christiansen, Sarah Jacobson, Jacob Kach, Kian Huat Lim, Vaishnavi Srinivasan, Boris Zinshteyn, Isabel Aznarez, Laryssa A Huryn, Zhiyu Li, Robert B Hufnagel, Gene Liau, Karen Anderson, Jeff Hoger.
      Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy most frequently associated with OPA1 mutations. Most variants result in haploinsufficiency, and patient cells express roughly half of the normal levels of OPA1 protein. OPA1 is a mitochondrial GTPase that is essential for normal mitochondrial function. We identified and characterized STK-002, an antisense oligonucleotide (ASO) designed to prevent the incorporation of a naturally occurring alternatively spliced nonproductive exon in OPA1. STK-002 dose dependently reduced the inclusion of this exon, and increased OPA1 protein in human cells, including ADOA patient-derived fibroblasts. ADOA patient cells manifest reduced mitochondrial respiration, and treatment with STK-002 improved the parameters of mitochondrial respiratory function in these cells. Since STK-002 increases OPA1 through the wild-type allele, we assessed retinal OPA1 in wild-type cynomolgus monkeys and rabbits after intravitreal administration of STK-002 or a rabbit-specific surrogate. Increased OPA1 protein was produced in retinal tissue in both species at 4 weeks after ASO injection and persisted in monkeys at 8 weeks. STK-002 and enhanced OPA1 immunofluorescence were visualized in retinal ganglion cells of cynomolgus monkeys treated with the ASO. Cumulatively, these data support the progression of STK-002 toward the clinic as the first potential disease-modifying treatment for ADOA.
    Keywords:  ADOA; ASO; OPA1; exon splicing; haploinsufficiency; mRNA
    DOI:  https://doi.org/10.1089/nat.2024.0022
  16. Chem Sci. 2024 Aug 28.
    Targeted protein degradation in the mitochondrial matrix and its application to chemical control of mitochondrial morphology.
    Wakana Yamada, Shusuke Tomoshige, Sho Nakamura, Shinichi Sato, Minoru Ishikawa.
      Dysfunction of mitochondria is implicated in various diseases, including cancer and neurodegenerative disorders, but drug discovery targeting mitochondria and mitochondrial proteins has so far made limited progress. Targeted protein degradation (TPD) technologies represented by proteolysis targeting chimeras (PROTACs) are potentially applicable for this purpose, but most existing TPD approaches leverage the ubiquitin-proteasome system or lysosomes, which are absent in mitochondria, and TPD in mitochondria (mitoTPD) remains little explored. Herein, we describe the design and synthesis of a bifunctional molecule comprising TR79, an activator of the mitochondrial protease complex caseinolytic protease P (ClpP), linked to desthiobiotin. This compound successfully induced the degradation of monomeric streptavidin (mSA) and its fusion proteins localized to the mitochondrial matrix. Furthermore, in cells overexpressing mSA fused to short transmembrane protein 1 (mSA-STMP1), which enhances mitochondrial fission, our mitochondrial mSA degrader restored the mitochondrial morphology by reducing the level of mSA-STMP1. A preliminary structure-activity relationship study indicated that a longer linker length enhances the degradation activity towards mSA. These findings highlight the potential of mitoTPD as a tool for drug discovery targeting mitochondria and for research in mitochondrial biology, as well as the utility of mSA as a degradation tag for mitochondrial protein.
    DOI:  https://doi.org/10.1039/d4sc03145h
  17. Nature. 2024 Sep;633(8029): 268-271
    Human embryo models are getting more realistic - raising ethical questions.
    Smriti Mallapaty.
      
    Keywords:  Cell biology; Developmental biology; Stem cells
    DOI:  https://doi.org/10.1038/d41586-024-02915-3
  18. Mol Neurobiol. 2024 Sep 10.
    Exploring the Mechanisms and Therapeutic Approaches of Mitochondrial Dysfunction in Alzheimer's Disease: An Educational Literature Review.
    Mostafa Hossam El Din Moawad, Ibrahim Serag, Ibraheem M Alkhawaldeh, Abdallah Abbas, Abdulrahman Sharaf, Sumaya Alsalah, Mohammed Ahmed Sadeq, Mahmoud Mohamed Mohamed Shalaby, Mahmoud Tarek Hefnawy, Mohamed Abouzid, Mostafa Meshref.
      Alzheimer's disease (AD) presents a significant challenge to global health. It is characterized by progressive cognitive deterioration and increased rates of morbidity and mortality among older adults. Among the various pathophysiologies of AD, mitochondrial dysfunction, encompassing conditions such as increased reactive oxygen production, dysregulated calcium homeostasis, and impaired mitochondrial dynamics, plays a pivotal role. This review comprehensively investigates the mechanisms of mitochondrial dysfunction in AD, focusing on aspects such as glucose metabolism impairment, mitochondrial bioenergetics, calcium signaling, protein tau and amyloid-beta-associated synapse dysfunction, mitophagy, aging, inflammation, mitochondrial DNA, mitochondria-localized microRNAs, genetics, hormones, and the electron transport chain and Krebs cycle. While lecanemab is the only FDA-approved medication to treat AD, we explore various therapeutic modalities for mitigating mitochondrial dysfunction in AD, including antioxidant drugs, antidiabetic agents, acetylcholinesterase inhibitors (FDA-approved to manage symptoms), nutritional supplements, natural products, phenylpropanoids, vaccines, exercise, and other potential treatments.
    Keywords:  Alzheimer’s Disease; Mitochondrial Dysfunction; Therapeutic Modalities
    DOI:  https://doi.org/10.1007/s12035-024-04468-y
  19. Neural Regen Res. 2024 Sep 06.
    Human neural stem cell-derived extracellular vesicles protect against ischemic stroke by activating the PI3K/AKT/mTOR pathway.
    Jiayi Wang, Mengke Zhao, Dong Fu, Meina Wang, Chao Han, Zhongyue Lv, Liang Wang, Jing Liu.
      Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells, and can thus be used as substitutes for stem cells in stem cell therapy, thereby mitigating the risks of stem cell therapy and advancing the frontiers of stem cell-derived treatments. This lays a foundation for the development of potentially potent new treatment modalities for ischemic stroke. However, the precise mechanisms underlying the efficacy and safety of human neural stem cell-derived extracellular vesicles remain unclear, presenting challenges for clinical translation. To promote the translation of therapy based on human neural stem cell-derived extracellular vesicles from the bench to the bedside, we conducted a comprehensive preclinical study to evaluate the efficacy and safety of human neural stem cell-derived extracellular vesicles in the treatment of ischemic stroke. We found that administration of human neural stem cell-derived extracellular vesicles to an ischemic stroke rat model reduced the volume of cerebral infarction and promoted functional recovery by alleviating neuronal apoptosis. The human neural stem cell-derived extracellular vesicles reduced neuronal apoptosis by enhancing phosphorylation of phosphoinositide 3-kinase, mammalian target of rapamycin, and protein kinase B, and these effects were reversed by treatment with a phosphoinositide 3-kinase inhibitor. These findings suggest that human neural stem cell-derived extracellular vesicles play a neuroprotective role in ischemic stroke through activation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway. Finally, we showed that human neural stem cell-derived extracellular vesicles have a good in vivo safety profile. Therefore, human neural stem cell-derived extracellular vesicles are a promising potential agent for the treatment of ischemic stroke.
    DOI:  https://doi.org/10.4103/NRR.NRR-D-23-01144
  20. iScience. 2024 Sep 20. 27(9): 110683
    Spastin regulates ER-mitochondrial contact sites and mitochondrial homeostasis.
    Amelie Raby, Sonia Missiroli, Peggy Sanatine, Dominique Langui, Julien Pansiot, Nissai Beaude, Lucie Vezzana, Rachelle Saleh, Martina Marinello, Mireille Laforge, Paolo Pinton, Ana Buj-Bello, Andrea Burgo.
      Mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) emerged to play critical roles in numerous cellular processes, and their dysregulation has been associated to neurodegenerative disorders. Mutations in the SPG4 gene coding for spastin are among the main causes of hereditary spastic paraplegia (HSP). Spastin binds and severs microtubules, and the long isoform of this protein, namely M1, spans the outer leaflet of ER membrane where it interacts with other ER-HSP proteins. Here, we showed that overexpressed M1 spastin localizes in ER-mitochondria intersections and that endogenous spastin accumulates in MERCs. We demonstrated in different cellular models that downregulation of spastin enhances the number of MERCs, alters mitochondrial morphology, and impairs ER and mitochondrial calcium homeostasis. These effects are associated with reduced mitochondrial membrane potential, oxygen species levels, and oxidative metabolism. These findings extend our knowledge on the role of spastin in the ER and suggest MERCs deregulation as potential causes of SPG4-HSP disease.
    Keywords:  Biological sciences; Molecular biology; Molecular interaction
    DOI:  https://doi.org/10.1016/j.isci.2024.110683
  21. Elife. 2024 Sep 10. pii: RP91002. [Epub ahead of print]12
    DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.
    Ran-Der Hwang, YuNing Lu, Qing Tang, Goran Periz, Giho Park, Xiangning Li, Qiwang Xiang, Yang Liu, Tao Zhang, Jiou Wang.
      Proteotoxic stress impairs cellular homeostasis and underlies the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The proteasomal and autophagic degradation of proteins are two major pathways for protein quality control in the cell. Here, we report a genome-wide CRISPR screen uncovering a major regulator of cytotoxicity resulting from the inhibition of the proteasome. Dihydrolipoamide branched chain transacylase E2 (DBT) was found to be a robust suppressor, the loss of which protects against proteasome inhibition-associated cell death through promoting clearance of ubiquitinated proteins. Loss of DBT altered the metabolic and energetic status of the cell and resulted in activation of autophagy in an AMP-activated protein kinase (AMPK)-dependent mechanism in the presence of proteasomal inhibition. Loss of DBT protected against proteotoxicity induced by ALS-linked mutant TDP-43 in Drosophila and mammalian neurons. DBT is upregulated in the tissues of ALS patients. These results demonstrate that DBT is a master switch in the metabolic control of protein quality control with implications in neurodegenerative diseases.
    Keywords:  ES cell; cell culture; fruit flies; human; neuroscience
    DOI:  https://doi.org/10.7554/eLife.91002
  22. Mol Cell Neurosci. 2024 Sep 10. pii: S1044-7431(24)00054-X. [Epub ahead of print]131 103969
    SUMOylation modulates mitochondrial dynamics in an in vitro rotenone model of Parkinson's disease.
    Ericks Sousa Soares, Letícia Yoshitome Queiroz, Ellen Gerhardt, Rui Daniel S Prediger, Tiago Fleming Outeiro, Helena Iturvides Cimarosti.
      SUMOylation is a post-translational modification essential for various biological processes. SUMO proteins bind to target substrates in a three-step enzymatic pathway, which is rapidly reversible by the action of specific proteases, known as SENPs. Studies have shown that SUMOylation is dysregulated in several human disorders, including neurodegenerative diseases that are characterized by the progressive loss of neurons, mitochondrial dysfunction, deficits in autophagy, and oxidative stress. Considering the potential neuroprotective roles of SUMOylation, the aim of this study was to investigate the effects of SENP3 knockdown in H4 neuroglioma cells exposed to rotenone, an in vitro model of cytotoxicity that mimics dopaminergic loss in Parkinson's disease (PD). The current data show that SENP3 knockdown increases SUMO-2/3 conjugates, which is accompanied by reduced levels of the mitochondrial fission protein Drp1 and increased levels of the mitochondrial fusion protein OPA1. Of high interest, SENP3 knockdown prevented rotenone-induced superoxide production and cellular death. Taken together, these findings highlight the importance of SUMOylation in maintaining mitochondrial homeostasis and the neuroprotective potential of this modification in PD.
    Keywords:  Mitochondria; Parkinson's disease; SENP3 knockdown; SUMOylation
    DOI:  https://doi.org/10.1016/j.mcn.2024.103969
  23. Sci Rep. 2024 09 10. 14(1): 21154
    Endurance exercise-induced histone methylation modification involved in skeletal muscle fiber type transition and mitochondrial biogenesis.
    Jialin Li, Sheng Zhang, Can Li, Xiaoxia Zhang, Yuhui Shan, Ziyi Zhang, Hai Bo, Yong Zhang.
      Skeletal muscle is a highly heterogeneous tissue, and its contractile proteins are composed of different isoforms, forming various types of muscle fiber, each of which has its own metabolic characteristics. It has been demonstrated that endurance exercise induces the transition of muscle fibers from fast-twitch to slow-twitch muscle fiber type. Herein, we discover a novel epigenetic mechanism for muscle contractile property tightly coupled to its metabolic capacity during muscle fiber type transition with exercise training. Our results show that an 8-week endurance exercise induces histone methylation remodeling of PGC-1α and myosin heavy chain (MHC) isoforms in the rat gastrocnemius muscle, accompanied by increased mitochondrial biogenesis and an elevated ratio of slow-twitch to fast-twitch fibers. Furthermore, to verify the roles of reactive oxygen species (ROS) and AMPK in exercise-regulated epigenetic modifications and muscle fiber type transitions, mouse C2C12 myotubes were used. It was shown that rotenone activates ROS/AMPK pathway and histone methylation enzymes, which then promote mitochondrial biogenesis and MHC slow isoform expression. Mitoquinone (MitoQ) partially blocking rotenone-treated model confirms the role of ROS in coupling mitochondrial biogenesis with muscle fiber type. In conclusion, endurance exercise couples mitochondrial biogenesis with MHC slow isoform by remodeling histone methylation, which in turn promotes the transition of fast-twitch to slow-twitch muscle fibers. The ROS/AMPK pathway may be involved in the regulation of histone methylation enzymes by endurance exercise.
    Keywords:  AMPK; Endurance exercise; Histone methylation; Mitochondrial biogenesis; ROS; Skeletal muscle fiber type
    DOI:  https://doi.org/10.1038/s41598-024-72088-6
  24. Sci Rep. 2024 09 06. 14(1): 20832
    mTORC1 pathway activity biases cell fate choice.
    Yuntao Wang, Monika Papayova, Eleanor Warren, Catherine J Pears.
      Pluripotent stem cells can differentiate into distinct cell types but the intracellular pathways controlling cell fate choice are not well understood. The social amoeba Dictyostelium discoideum is a simplified system to study choice preference as proliferating amoebae enter a developmental cycle upon starvation and differentiate into two major cell types, stalk and spores, organised in a multicellular fruiting body. Factors such as acidic vesicle pH predispose amoebae to one fate. Here we show that the mechanistic target of rapamycin complex 1 (mTORC1) pathway has a role in cell fate bias in Dictyostelium. Inhibiting the mTORC1 pathway activity by disruption of Rheb (activator Ras homolog enriched in brain), or treatment with the mTORC1 inhibitor rapamycin prior to development, biases cells to a spore cell fate. Conversely activation of the pathway favours stalk cell differentiation. The Set1 histone methyltransferase, responsible for histone H3 lysine4 methylation, in Dictyostelium cells regulates transcription at the onset of development. Disruption of Set1 leads to high mTORC1 pathway activity and stalk cell predisposition. The ability of the mTORC1 pathway to regulate cell fate bias of cells undergoing differentiation offers a potential target to increase the efficiency of stem cell differentiation into a particular cell type.
    Keywords:   Dictyostelium discoideum ; Cell fate choice; Rapamycin; Set1; mTORC1
    DOI:  https://doi.org/10.1038/s41598-024-71298-2
  25. iScience. 2024 Sep 20. 27(9): 110710
    The mitochondrial stress signaling tunes immunity from a view of systemic tumor microenvironment and ecosystem.
    Cheng-Liang Kuo, Ying-Chen Lin, Yu Kang Lo, Yu-Zhi Lu, Ananth Ponneri Babuharisankar, Hui-Wen Lien, Han-Yu Chou, Alan Yueh-Luen Lee.
      Mitochondria play important roles in cell fate, calcium signaling, mitophagy, and the signaling through reactive oxygen species (ROS). Recently, mitochondria are considered as a signaling organelle in the cell and communicate with other organelles to constitute the mitochondrial information processing system (MIPS) that transduce input-to-output biological information. The success in immunotherapy, a concept of systemic therapy, has been proved to be dependent on paracrine interactions within the tumor microenvironment (TME) and distant organs including microbiota and immune components. We will adopt a broader view from the concept of TME to tumor micro- and macroenvironment (TM 2 E) or tumor-organ ecosystem (TOE). In this review, we will discuss the role of mitochondrial signaling by mitochondrial ROS, calcium flux, metabolites, mtDNA, vesicle transportation, and mitochondria-derived peptide in the TME and TOE, in particular immune regulation and effective cancer immunotherapy.
    Keywords:  Cancer; Immune response; Microenvironment
    DOI:  https://doi.org/10.1016/j.isci.2024.110710
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