bims-mitrat Biomed News
on Mitochondrial transplantation and transfer
Issue of 2024–05–12
seventeen papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute
  1. Mitochondrial transplantation: A promising therapy for mitochondrial disorders.
  2. [Research advances on mesenchymal stem cell-mediated mitochondrial transfer for improving lung injury and repair in acute respiratory distress syndrome].
  3. Extracellular vesicles deviced from hypoxia-3D-GMSCs rescue the mitochondrial dysfunction of aging-GMSCs.
  4. An interphase actin wave promotes mitochondrial content mixing and organelle homeostasis.
  5. Generation of allogenic and xenogeneic functional muscle stem cells for intramuscular transplantation.
  6. Extracellular Vesicles: A New Approach to Study the Brain's Neural System and Its Diseases.
  7. Mesenchymal Stem Cells and Extracellular Vesicles: Therapeutic Potential in Organ Transplantation.
  8. Extracellular Vesicles in Pathophysiology: A Prudent Target That Requires Careful Consideration.
  9. Intranasal administration of umbilical cord mesenchymal stem cell exosomes alleviates Parkinson's disease.
  10. The interplay between mitochondrial dysfunction and NLRP3 inflammasome in multiple sclerosis: Therapeutic implications and animal model studies.
  11. Biomarkers of chemotherapy-induced cardiotoxicity: toward precision prevention using extracellular vesicles.
  12. Metformin induction of heat shock factor 1 activation and the mitochondrial unfolded protein response alleviate cardiac remodeling in spontaneously hypertensive rats.
  13. Exosomes secreted by adipose mesenchymal stem cells overexpressing circPIP5K1C exert.
  14. Mitochondrial dysfunction in brain tissues and Extracellular Vesicles Fragile X-associated tremor/ataxia syndrome.
  15. Insights on Natural Products Against Amyotrophic Lateral Sclerosis (ALS).
  16. Connexin 43 modulates reverse electron transfer in cardiac mitochondria from inducible knock-out Cx43Cre-ER(T)/fl mice by altering the coenzyme Q pool.
  17. Skeletal muscle cystathionine γ-lyase deficiency promotes obesity and insulin resistance and results in hyperglycemia and skeletal muscle injury upon HFD in mice.
  1. Int J Pharm. 2024 May 02. pii: S0378-5173(24)00428-9. [Epub ahead of print] 124194
    Mitochondrial transplantation: A promising therapy for mitochondrial disorders.
    Qiangqiang Jiao, Li Xiang, Yuping Chen.
      As a vital energy source for cellular metabolism and tissue survival, the mitochondrion can undergo morphological or positional change and even shuttle between cells in response to various stimuli and energy demands. Multiple human diseases are originated from mitochondrial dysfunction, but the curative succusses by traditional treatments are limited. Mitochondrial transplantation therapy (MTT) is an innovative therapeutic approach that is to deliver the healthy mitochondria either derived from normal cells or reassembled through synthetic biology into the cells and tissues suffering from mitochondrial damages and finally replace their defective mitochondria and restore their function. MTT has already been under investigation in clinical trial for cardiac ischemia-reperfusion injury and given an encouraging performance in animal models of numerous fatal critical diseases including central nervous system disorders, cardiovascular diseases, inflammatory conditions, cancer, renal injury, and pulmonary damage. This review article summarizes the mechanisms and strategies of mitochondrial transfer and the MTT application for types of mitochondrial diseases, and discusses the potential challenge in MTT clinical application, aiming to exhibit the good therapeutic prospects of MTTs in clinics.
    Keywords:  Artificial mitochondria; Clinical trials; Mitochondrial medicine; Mitochondrial transplantation
    DOI:  https://doi.org/10.1016/j.ijpharm.2024.124194
  2. Zhonghua Nei Ke Za Zhi. 2024 May 01. 63(5): 503-506
    [Research advances on mesenchymal stem cell-mediated mitochondrial transfer for improving lung injury and repair in acute respiratory distress syndrome].
    S S Meng, J L Wang, Y Z Huang.
      
    DOI:  https://doi.org/10.3760/cma.j.cn112138-20231024-00242
  3. Biochem Biophys Res Commun. 2024 Apr 27. pii: S0006-291X(24)00557-6. [Epub ahead of print]717 150021
    Extracellular vesicles deviced from hypoxia-3D-GMSCs rescue the mitochondrial dysfunction of aging-GMSCs.
    Yujia Deng, Zhixiong Liu, Ming Lu.
      Mesenchymal stem cells (MSCs) are ubiquitous multipotent cells exhibiting significant therapeutic potential for various diseases. It is generally accepted that clinical application requires massive expansion of MSCs, which is often accompanied by the occurrence of replicative senescence. Additionally, senescent MSCs exhibit significantly reduced proliferation, differentiation, and therapeutic potential. The scale-up of MSCs production and cellular senescence are major challenges for translational applications. This study first collected extracellular vesicles (EVs) from gingival MSCs (GMSCs) under hypoxia preconditioning combined with 3D dynamic culture (obtained EVs designed as H-3D-EVs). Subsequently, we further explored the effects and mechanisms of H-3D-EVs on aging-GMSCs. The results showed that H-3D-EVs improved the proliferation ability and cell activity of aging-GMSCs, and ameliorated their senescence. mRNA sequencing reveals transcriptomic changes in aging-GMSCs. It was found that H-3D-EVs up-regulated genes related to mitochondrial dynamics, cell cycle, and DNA repair, while down-regulated aging-related genes. Furthermore, we verified that H-3D-EVs corrected the mitochondrial dysfunction of aging-GMSCs by improving mitochondrial dynamics. In summary, this study provides a promising strategy for improving the culture methods of GMSCs and avoiding its senescence in large-scale production.
    Keywords:  Gingival mesenchymal stem cell; Mitochondrial dynamics; Senescence
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150021
  4. Nat Commun. 2024 May 07. 15(1): 3793
    An interphase actin wave promotes mitochondrial content mixing and organelle homeostasis.
    Stephen M Coscia, Andrew S Moore, Cameron P Thompson, Christian F Tirrito, E Michael Ostap, Erika L F Holzbaur.
      Across the cell cycle, mitochondrial dynamics are regulated by a cycling wave of actin polymerization/depolymerization. In metaphase, this wave induces actin comet tails on mitochondria that propel these organelles to drive spatial mixing, resulting in their equitable inheritance by daughter cells. In contrast, during interphase the cycling actin wave promotes localized mitochondrial fission. Here, we identify the F-actin nucleator/elongator FMNL1 as a positive regulator of the wave. FMNL1-depleted cells exhibit decreased mitochondrial polarization, decreased mitochondrial oxygen consumption, and increased production of reactive oxygen species. Accompanying these changes is a loss of hetero-fusion of wave-fragmented mitochondria. Thus, we propose that the interphase actin wave maintains mitochondrial homeostasis by promoting mitochondrial content mixing. Finally, we investigate the mechanistic basis for the observation that the wave drives mitochondrial motility in metaphase but mitochondrial fission in interphase. Our data indicate that when the force of actin polymerization is resisted by mitochondrial tethering to microtubules, as in interphase, fission results.
    DOI:  https://doi.org/10.1038/s41467-024-48189-1
  5. J Clin Invest. 2024 May 07. pii: e166998. [Epub ahead of print]
    Generation of allogenic and xenogeneic functional muscle stem cells for intramuscular transplantation.
    Ajda Lenardič, Seraina A Domenig, Joel Zvick, Nicola Bundschuh, Monika Tarnowska-Sengül, Regula Furrer, Falko J Noé, Christine Ling Li Trautmann, Adhideb Ghosh, Giada Bacchin, Pjeter Gjonlleshaj, Xhem Qabrati, Evi Masschelein, Katrien De Bock, Christoph Handschin, Ori Bar-Nur.
      Satellite cells, the stem cells of skeletal muscle tissue, hold a remarkable regeneration capacity and therapeutic potential in regenerative medicine. However, low satellite cell yield from autologous or donor-derived muscles hinders the adoption of satellite cell transplantation for the treatment of muscle diseases, including Duchenne muscular dystrophy (DMD). To address this limitation, here we investigated whether satellite cells can be derived in allogeneic or xenogeneic animal hosts. First, injection of CRISPR/Cas9-corrected mouse DMD-induced pluripotent stem cells (iPSCs) into mouse blastocysts carrying an ablation system of host satellite cells gave rise to intraspecies chimeras exclusively carrying iPSC-derived satellite cells. Furthermore, injection of genetically corrected DMD-iPSCs into rat blastocysts resulted in the formation of interspecies rat-mouse chimeras harboring mouse satellite cells. Remarkably, iPSC-derived satellite cells or derivative myoblasts produced in intraspecies or interspecies chimeras restored dystrophin expression in DMD mice following intramuscular transplantation, and contributed to the satellite cell pool. Collectively, this study demonstrates the feasibility of producing therapeutically competent stem cells across divergent animal species, raising the possibility of generating human muscle stem cells in large animals for regenerative medicine purposes.
    Keywords:  Movement disorders; Muscle biology; Skeletal muscle; Stem cells; iPS cells
    DOI:  https://doi.org/10.1172/JCI166998
  6. Cell Biochem Biophys. 2024 May 10.
    Extracellular Vesicles: A New Approach to Study the Brain's Neural System and Its Diseases.
    Shahid Afridi, Pradakshina Sharma, Furqan Choudhary, Amber Rizwan, Anam Nizam, Adil Parvez, Humaira Farooqi.
      In normal and pathophysiological conditions our cells secrete vesicular bodies known as extracellular particles. Extracellular vesicles are lipid-bound extracellular particles. A majority of these extracellular vesicles are linked to cell-to-cell communication. Brain consists of tightly packed neural cells. Neural cell releases extracellular vesicles in cerebrospinal fluid. Extracellular vesicle mediated crosstalk maintains neural homeostasis in the central nervous system via transferring cargos between neural cells. In neurodegenerative diseases, small extracellular vesicle transfer misfolded proteins to healthy cells in the neural microenvironment. They can also cross blood-brain barrier (BBB) and stimulate peripheral immune response inside central nervous system. In today's world different approaches employ extracellular vesicle in various therapeutics. This review gives a brief knowledge about the biological relevance of extracellular vesicles in the central nervous system and relevant advances in the translational application of EV in brain disorders.
    Keywords:  Engineered EVs; Extracellular vesicle (EVs); Naïve EVs; Neural EVs; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s12013-024-01271-3
  7. Stem Cells Int. 2024 ;2024 2043550
    Mesenchymal Stem Cells and Extracellular Vesicles: Therapeutic Potential in Organ Transplantation.
    Wennuo Pan, Shaohan Li, Kunsheng Li, Pengyu Zhou.
      At present, organ transplantation remains the most appropriate therapy for patients with end-stage organ failure. However, the field of organ transplantation is still facing many challenges, including the shortage of organ donors, graft function damage caused by organ metastasis, and antibody-mediated immune rejection. It is therefore urgently necessary to find new and effective treatment. Stem cell therapy has been regarded as a "regenerative medicine technology." Mesenchymal stem cells (MSCs), as the most common source of cells for stem cell therapy, play an important role in regulating innate and adaptive immune responses and have been widely used in clinical trials for the treatment of autoimmune and inflammatory diseases. Increasing evidence has shown that MSCs mainly rely on paracrine pathways to exert immunomodulatory functions. In addition, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are the main components of paracrine substances of MSCs. Herein, an overview of the application of the function of MSCs and MSC-EVs in organ transplantation will focus on the progress reported in recent experimental and clinical findings and explore their uses for graft preconditioning and recipient immune tolerance regulation. Additionally, the limitations on the use of MSC and MSC-EVs are also discussed, covering the isolation of exosomes and preservation techniques. Finally, the opportunities and challenges for translating MSCs and MSC-EVs into clinical practice of organ transplantation are also evaluated.
    DOI:  https://doi.org/10.1155/2024/2043550
  8. Cells. 2024 Apr 26. pii: 754. [Epub ahead of print]13(9):
    Extracellular Vesicles in Pathophysiology: A Prudent Target That Requires Careful Consideration.
    Sanjay Shahi, Taeyoung Kang, Pamali Fonseka.
      Extracellular vesicles (EVs) are membrane-bound particles released by cells to perform multitudes of biological functions. Owing to their significant implications in diseases, the pathophysiological role of EVs continues to be extensively studied, leading research to neglect the need to explore their role in normal physiology. Despite this, many identified physiological functions of EVs, including, but not limited to, tissue repair, early development and aging, are attributed to their modulatory role in various signaling pathways via intercellular communication. EVs are widely perceived as a potential therapeutic strategy for better prognosis, primarily through utilization as a mode of delivery vehicle. Moreover, disease-associated EVs serve as candidates for the targeted inhibition by pharmacological or genetic means. However, these attempts are often accompanied by major challenges, such as off-target effects, which may result in adverse phenotypes. This renders the clinical efficacy of EVs elusive, indicating that further understanding of the specific role of EVs in physiology may enhance their utility. This review highlights the essential role of EVs in maintaining cellular homeostasis under different physiological settings, and also discusses the various aspects that may potentially hinder the robust utility of EV-based therapeutics.
    Keywords:  delivery vehicles; exosomes; extracellular vesicles; normal physiology; pathophysiology; therapeutic target
    DOI:  https://doi.org/10.3390/cells13090754
  9. Neuroscience. 2024 May 03. pii: S0306-4522(24)00169-6. [Epub ahead of print]
    Intranasal administration of umbilical cord mesenchymal stem cell exosomes alleviates Parkinson's disease.
    Weixiao Huang, Tao Zhang, Xiaodi Li, Leilei Gong, Yu Zhang, Chengcheng Luan, Qi Shan, Xiaosong Gu, Lili Zhao.
      Parkinson's disease (PD) is a common and complex neurodegenerative disease. This disease is typically characterized by the formation of Lewy bodies in multiple brain regions and dopaminergic neuronal loss in the substantia nigra pars compacta, resulting in non-motor symptoms (e.g., olfactory deficits) and motor dysfunction in the late stages. There is yet no effective cure for Parkinson's disease. Considering the neuroprotective effects of exosomes, we investigated whether intranasal administration of umbilical cord mesenchymal stem cell exosomes could improve behavioral functions in PD mice. First, exosomes were endocytosed by the cells in vitro and in vivo, indicating that exosomes can cross the blood-brain barrier. Second, we found that both motor and non-motor functions of the PD models were effectively improved during intranasal exosomes treatment. Finally, the activity of olfactory bulb neurons was improved and the loss of dopaminergic neurons in the substantia nigra pars compacta was reversed. Moreover, exosomes attenuated microglia and astrocyte activation, leading to a low level of inflammation in the brain. In conclusion, our study provided a new reference for the clinical application of exosomes in the treatment of PD.
    Keywords:  Parkinson's disease; dopaminergic neurons; exosomes; inflammation; olfactory bulb
    DOI:  https://doi.org/10.1016/j.neuroscience.2024.04.010
  10. Biomed Pharmacother. 2024 May 06. pii: S0753-3322(24)00557-2. [Epub ahead of print]175 116673
    The interplay between mitochondrial dysfunction and NLRP3 inflammasome in multiple sclerosis: Therapeutic implications and animal model studies.
    Alireza Shadab, Mohammad Abbasi-Kolli, Mansoore Saharkhiz, Seyed Hamed Ahadi, Behrooz Shokouhi, Javid Sadri Nahand.
      Multiple sclerosis (MS) is a complex autoimmune disorder that impacts the central nervous system (CNS), resulting in inflammation, demyelination, and neurodegeneration. The NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome, a multiprotein complex of the innate immune system, serves an essential role in the pathogenesis of MS by regulating the production of pro-inflammatory cytokines (IL-1β & IL-18) and the induction of pyroptotic cell death. Mitochondrial dysfunction is one of the main potential factors that can trigger NLRP3 inflammasome activation and lead to inflammation and axonal damage in MS. This highlights the importance of understanding how mitochondrial dynamics modulate NLRP3 inflammasome activity and contribute to the inflammatory and neurodegenerative features of MS. The lack of a comprehensive understanding of the pathogenesis of MS and the urge for the introduction of new therapeutic strategies led us to review the therapeutic potential of targeting the interplay between mitochondrial dysfunction and the NLRP3 inflammasome in MS. This paper also evaluates the natural and synthetic compounds that can improve mitochondrial function and/or inhibit the NLRP3 inflammasome, thereby providing neuroprotection. Moreover, it summarizes the evidence from animal models of MS that demonstrate the beneficial effects of these compounds on reducing inflammation, demyelination, and neurodegeneration. Finally, this review advocates for a deeper investigation into the molecular crosstalk between mitochondrial dynamics and the NLRP3 inflammasome as a means to refine therapeutic targets for MS.
    Keywords:  Inflammation; Mitochondrial dynamics; Mitochondrial dysfunctions; Multiple Sclerosis; NLRP3 inflammasome; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.biopha.2024.116673
  11. Front Oncol. 2024 ;14 1393930
    Biomarkers of chemotherapy-induced cardiotoxicity: toward precision prevention using extracellular vesicles.
    Brian B Silver, Anna Kreutz, Madeleine Weick, Kevin Gerrish, Erik J Tokar.
      Detrimental side effects of drugs like doxorubicin, which can cause cardiotoxicity, pose barriers for preventing cancer progression, or treating cancer early through molecular interception. Extracellular vesicles (EVs) are valued for their potential as biomarkers of human health, chemical and molecular carcinogenesis, and therapeutics to treat disease at the cellular level. EVs are released both during normal growth and in response to toxicity and cellular death, playing key roles in cellular communication. Consequently, EVs may hold promise as precision biomarkers and therapeutics to prevent or offset damaging off-target effects of chemotherapeutics. EVs have promise as biomarkers of impending cardiotoxicity induced by chemotherapies and as cardioprotective therapeutic agents. However, EVs can also mediate cardiotoxic cues, depending on the identity and past events of their parent cells. Understanding how EVs mediate signaling is critical toward implementing EVs as therapeutic agents to mitigate cardiotoxic effects of chemotherapies. For example, it remains unclear how mixtures of EV populations from cells exposed to toxins or undergoing different stages of cell death contribute to signaling across cardiac tissues. Here, we present our perspective on the outlook of EVs as future clinical tools to mitigate chemotherapy-induced cardiotoxicity, both as biomarkers of impending cardiotoxicity and as cardioprotective agents. Also, we discuss how heterogeneous mixtures of EVs and transient exposures to toxicants may add complexity to predicting outcomes of exogenously applied EVs. Elucidating how EV cargo and signaling properties change during dynamic cellular events may aid precision prevention of cardiotoxicity in anticancer treatments and development of safer chemotherapeutics.
    Keywords:  cancer; cardioprotection; cardiotoxicity; chemotherapy; doxorubicin; extracellular vesicles; precision prevention
    DOI:  https://doi.org/10.3389/fonc.2024.1393930
  12. FASEB J. 2024 May 15. 38(9): e23654
    Metformin induction of heat shock factor 1 activation and the mitochondrial unfolded protein response alleviate cardiac remodeling in spontaneously hypertensive rats.
    Man Xu, Li-Peng Li, Xi He, Xing-Zhu Lu, Xue-Yuan Bi, Qi Li, Xiao-Rong Xue.
      Heart failure and cardiac remodeling are both characterized by mitochondrial dysfunction. Healthy mitochondria are required for adequate contractile activity and appropriate regulation of cell survival. In the mammalian heart, enhancement of the mitochondrial unfolded protein response (UPRmt) is cardioprotective under pressure overload conditions. We explored the UPRmt and the underlying regulatory mechanism in terms of hypertension-induced cardiac remodeling and the cardioprotective effect of metformin. Male spontaneously hypertensive rats and angiotensin II-treated neonatal rat cardiomyocytes were used to induce cardiac hypertrophy. The results showed that hypertension induced the formation of aberrant mitochondria, characterized by a reduced mtDNA/nDNA ratio and swelling, as well as lower levels of mitochondrial complexes I to V and inhibition of the expression of one protein subunit of each of complexes I to IV. Such changes eventually enlarged cardiomyocytes and increased cardiac fibrosis. Metformin treatment increased the mtDNA/nDNA ratio and regulated the UPRmt, as indicated by increased expression of activating transcription factor 5, Lon protease 1, and heat shock protein 60, and decreased expression of C/EBP homologous protein. Thus, metformin improved mitochondrial ultrastructure and function in spontaneously hypertensive rats. In vitro analyses revealed that metformin reduced the high levels of angiotensin II-induced mitochondrial reactive oxygen species in such animals and stimulated nuclear translocation of heat shock factor 1 (HSF1). Moreover, HSF1 small-interfering RNA reduced the metformin-mediated improvements in mitochondrial morphology and the UPRmt by suppressing hypertrophic signals and cardiomyocyte apoptosis. These results suggest that HSF1/UPRmt signaling contributes to the beneficial effects of metformin. Metformin-mediated targeting of mitochondrial protein homeostasis and modulation of HSF1 levels have potential therapeutic implications in terms of cardiac remodeling.
    Keywords:  cardiac remodeling; heat shock factor 1; hypertension; metformin; mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1096/fj.202400070R
  13. Biochim Biophys Acta Mol Basis Dis. 2024 May 06. pii: S0925-4439(24)00212-6. [Epub ahead of print] 167223
    Exosomes secreted by adipose mesenchymal stem cells overexpressing circPIP5K1C exert.
    Xin Gu, Li Liang, Chao Lu, Jiangyi Wang, Bao Hua, Wengfeng Li, Yuanshen Mao, Qing Yang, Bin Xu.
       BACKGROUND: Erectile dysfunction (ED) seriously affects men's normal life, and obstructive sleep apnoea (OSA) has been diagnosed as a causative factor. Currently, exosomes secreted by adipose mesenchymal stem cells (ADSC) have been used in the non-clinical experimental treatment of ED disease with prominent efficacy due to the advantages of high stability and no immune exclusion.
    METHODS: In this study, chronic intermittent hypoxia (CIH) exposure was used to induce ED-corresponding phenotypes in Sprague Dawley (SD) rats as well as in cavernous smooth muscle cells (CCSMCs). ED symptoms were treated using exosomes secreted by ADSCs overexpressing circPIP5K1C (EXO-circ) injected into the rat corpus cavernosum.
    RESULTS: EXO-circ has the effect of ameliorating ED induced by CIH exposure in rats, the mechanism of which is to promote the expression of the downstream target gene SMURF1 after adsorption of miR-153-3p through the sponge so that SMURF1 and PFKFB3 occur protein-protein binding and ubiquitination degradation of PFKFB3 appears to inhibit the occurrence of spongiotic smooth muscle cells glycolysis, and to restore the function of the smooth muscle.
    CONCLUSIONS: These findings show that EXO-circ have a promising therapeutic potential in OSA-induced ED.
    Keywords:  Chronic intermittent hypoxia; Erectile dysfunction; Exosomes
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167223
  14. Ann Clin Transl Neurol. 2024 May 08.
    Mitochondrial dysfunction in brain tissues and Extracellular Vesicles Fragile X-associated tremor/ataxia syndrome.
    Pamela J Yao, Apostolos Manolopoulos, Erden Eren, Susan Michelle Rivera, David R Hessl, Randi Hagerman, Veronica Martinez-Cerdeno, Flora Tassone, Dimitrios Kapogiannis.
       OBJECTIVE: Mitochondrial impairments have been implicated in the pathogenesis of Fragile X-associated tremor/ataxia syndrome (FXTAS) based on analysis of mitochondria in peripheral tissues and cultured cells. We sought to assess whether mitochondrial abnormalities present in postmortem brain tissues of patients with FXTAS are also present in plasma neuron-derived extracellular vesicles (NDEVs) from living carriers of fragile X messenger ribonucleoprotein1 (FMR1) gene premutations at an early asymptomatic stage of the disease continuum.
    METHODS: We utilized postmortem frozen cerebellar and frontal cortex samples from a cohort of eight patients with FXTAS and nine controls and measured the quantity and activity of the mitochondrial proteins complex IV and complex V. In addition, we evaluated the same measures in isolated plasma NDEVs by selective immunoaffinity capture targeting L1CAM from a separate cohort of eight FMR1 premutation carriers and four age-matched controls.
    RESULTS: Lower complex IV and V quantity and activity were observed in the cerebellum of FXTAS patients compared to controls, without any differences in total mitochondrial content. No patient-control differences were observed in the frontal cortex. In NDEVs, FMR1 premutation carriers compared to controls had lower activity of Complex IV and Complex V, but higher Complex V quantity.
    INTERPRETATION: Quantitative and functional abnormalities in mitochondrial electron transport chain complexes IV and V seen in the cerebellum of patients with FXTAS are also manifest in plasma NDEVs of FMR1 premutation carriers. Plasma NDEVs may provide further insights into mitochondrial pathologies in this syndrome and could potentially lead to the development of biomarkers for predicting symptomatic FXTAS among premutation carriers and disease monitoring.
    DOI:  https://doi.org/10.1002/acn3.52040
  15. Curr Neuropharmacol. 2024 ;22(7): 1169-1188
    Insights on Natural Products Against Amyotrophic Lateral Sclerosis (ALS).
    Kadja Luana Chagas Monteiro, Marcone Gomes Dos Santos Alcântara, Thiago Mendonça de Aquino, Edeildo Ferreira da Silva-Júnior.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes the death of motor neurons and consequent muscle paralysis. Despite many efforts to address it, current therapy targeting ALS remains limited, increasing the interest in complementary therapies. Over the years, several herbal preparations and medicinal plants have been studied to prevent and treat this disease, which has received remarkable attention due to their blood-brain barrier penetration properties and low toxicity. Thus, this review presents the therapeutic potential of a variety of medicinal herbs and their relationship with ALS and their physiopathological pathways.
    Keywords:  ALS; Central nervous system; heat shock proteins; medicinal herbs.; mtDNA; reactive oxygen species
    DOI:  https://doi.org/10.2174/1570159X22666231016153606
  16. Basic Res Cardiol. 2024 May 09.
    Connexin 43 modulates reverse electron transfer in cardiac mitochondria from inducible knock-out Cx43Cre-ER(T)/fl mice by altering the coenzyme Q pool.
    Marta Consegal, Elisabet Miró-Casas, Ignasi Barba, Marisol Ruiz-Meana, Javier Inserte, Begoña Benito, Cristina Rodríguez, Freddy G Ganse, Laura Rubio-Unguetti, Carmen Llorens-Cebrià, Ignacio Ferreira-González, Antonio Rodríguez-Sinovas.
      Succinate accumulates during myocardial ischemia and is rapidly oxidized during reperfusion, leading to reactive oxygen species (ROS) production through reverse electron transfer (RET) from mitochondrial complex II to complex I, and favoring cell death. Given that connexin 43 (Cx43) modulates mitochondrial ROS production, we investigated whether Cx43 influences RET using inducible knock-out Cx43Cre-ER(T)/fl mice. Oxygen consumption, ROS production, membrane potential and coenzyme Q (CoQ) pool were analyzed in subsarcolemmal (SSM, expressing Cx43) and interfibrillar (IFM) cardiac mitochondria isolated from wild-type Cx43fl/fl mice and Cx43Cre-ER(T)/fl knock-out animals treated with 4-hydroxytamoxifen (4OHT). In addition, infarct size was assessed in isolated hearts from these animals submitted to ischemia-reperfusion (IR), and treated or not with malonate, a complex II inhibitor attenuating RET. Succinate-dependent ROS production and RET were significantly lower in SSM, but not IFM, from Cx43-deficient animals. Mitochondrial membrane potential, a RET driver, was similar between groups, whereas CoQ pool (2.165 ± 0.338 vs. 4.18 ± 0.55 nmol/mg protein, p < 0.05) and its reduction state were significantly lower in Cx43-deficient animals. Isolated hearts from Cx43Cre-ER(T)/fl mice treated with 4OHT had a smaller infarct size after IR compared to Cx43fl/fl, despite similar concentration of succinate at the end of ischemia, and no additional protection by malonate. Cx43 deficiency attenuates ROS production by RET in SSM, but not IFM, and was associated with a decrease in CoQ levels and a change in its redox state. These results may partially explain the reduced infarct size observed in these animals and their lack of protection by malonate.
    Keywords:  Coenzyme Q; Complex II; Mitochondria; Reactive oxygen species; Reverse electron transfer; Succinate dehydrogenase
    DOI:  https://doi.org/10.1007/s00395-024-01052-2
  17. Redox Rep. 2024 Dec;29(1): 2347139
    Skeletal muscle cystathionine γ-lyase deficiency promotes obesity and insulin resistance and results in hyperglycemia and skeletal muscle injury upon HFD in mice.
    Jiani Lu, Zhengshan Tang, Miaomiao Xu, Jianqiang Lu, Fengmei Wang, Xin Ni, Changnan Wang, Bo Yu.
       OBJECTIVES: The objective of this study was to investigate whether skeletal muscle cystathionine γ-lyase (CTH) contributes to high-fat diet (HFD)-induced metabolic disorders using skeletal muscle Cth knockout (CthΔskm) mice.
    METHODS: The CthΔskm mice and littermate Cth-floxed (Cthf/f) mice were fed with either HFD or chow diet for 13 weeks. Metabolomics and transcriptome analysis were used to assess the impact of CTH deficiency in skeletal muscle.
    RESULTS: Metabolomics coupled with transcriptome showed that CthΔskm mice displayed impaired energy metabolism and some signaling pathways linked to insulin resistance (IR) in skeletal muscle although the mice had normal insulin sensitivity. HFD led to reduced CTH expression and impaired energy metabolism in skeletal muscle in Cthf/f mice. CTH deficiency and HFD had some common pathways enriched in the aspects of amino acid metabolism, carbon metabolism, and fatty acid metabolism. CthΔskm+HFD mice exhibited increased body weight gain, fasting blood glucose, plasma insulin, and IR, and reduced glucose transporter 4 and CD36 expression in skeletal muscle compared to Cthf/f+HFD mice. Impaired mitochondria and irregular arrangement in myofilament occurred in CthΔskm+HFD mice. Omics analysis showed differential pathways enriched between CthΔskm mice and Cthf/f mice upon HFD. More severity in impaired energy metabolism, reduced AMPK signaling, and increased oxidative stress and ferroptosis occurred in CthΔskm+HFD mice compared to Cthf/f+HFD mice.
    DISCUSSION: Our results indicate that skeletal muscle CTH expression dysregulation contributes to metabolism disorders upon HFD.
    Keywords:  Cystathionine γ-lyase; ferroptosis; high-fat diet; insulin resistance; oxidative stress; skeletal muscle
    DOI:  https://doi.org/10.1080/13510002.2024.2347139
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