bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022‒09‒11
23 papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico
  1. Mitochondrial DNA in Uremia and New Targets to Treat Myocardial Hypertrophy in the Cardiorenal Syndrome.
  2. Progress in mesenchymal stem cell mitochondria transfer for the repair of tissue injury and treatment of disease.
  3. A Combination Therapy of Urolithin A+EGCG Has Stronger Protective Effects than Single Drug Urolithin A in a Humanized Amyloid Beta Knockin Mice for Late-Onset Alzheimer's Disease.
  4. Mitochondrial protein synthesis and the bioenergetic cost of neurodevelopment.
  5. STAT6 in mitochondrial outer membrane impairs mitochondrial fusion by inhibiting MFN2 dimerization.
  6. Co-occurrence of amyotrophic lateral sclerosis and Leber's hereditary optic neuropathy: is mitochondrial dysfunction a modifier?
  7. Targeted Mitochondrial Epigenetics: A New Direction in Alzheimer's Disease Treatment.
  8. cAMP/PKA Signaling Modulates Mitochondrial Supercomplex Organization.
  9. Mitochondrial fission mediated by Drp1-Fis1 pathway and neurodegenerative diseases.
  10. Mitochondrial dysfunction is a key pathological driver of early stage Parkinson's.
  11. Bioenergetic and Metabolic Impairments in Induced Pluripotent Stem Cell-Derived Cardiomyocytes Generated from Duchenne Muscular Dystrophy Patients.
  12. Mitochondrial fission factor (MFF) frameshift variant in Bullmastiffs with mitochondrial fission encephalopathy.
  13. Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression.
  14. Mitochondrial DNA polymorphisms in COX1 affect the lifespan of Caenorhabditis elegans through nuclear gene dct-15.
  15. Leber hereditary optic neuropathy: new and emerging therapies.
  16. Mitochondrial respiratory complexes: Significance in human mitochondrial disorders and cancers.
  17. Low Expression of Mitofusin 1 Gene Leads to Mitochondrial Dysfunction and Embryonic Genome Activation Failure in Ovine-Bovine Inter-Species Cloned Embryos.
  18. CNS gene therapy: present developments and emerging trends accelerating industry-academia pathways.
  19. A brown fat-selective mechanism of mitochondrial calcium import?
  20. Senolytic elimination of senescent macrophages restores muscle stem cell function in severely dystrophic muscle.
  21. Nicotinamide-riboside shifts the differentiation of human primary white adipocytes to beige adipocytes impacting substrate preference and uncoupling respiration through SIRT1 activation and mitochondria-derived reactive species production.
  22. LONP1 downregulation with ageing contributes to osteoarthritis via mitochondrial dysfunction.
  23. Embryos with DNA from three people develop normally in first safety study.
  1. JACC Basic Transl Sci. 2022 Aug;7(8): 841-843
    Mitochondrial DNA in Uremia and New Targets to Treat Myocardial Hypertrophy in the Cardiorenal Syndrome.
    George Bayliss.
      
    Keywords:  cardiorenal syndrome; mitochondrial DNA; myocardial hypertrophy; uremia
    DOI:  https://doi.org/10.1016/j.jacbts.2022.06.005
  2. Biomed Pharmacother. 2022 Sep;pii: S0753-3322(22)00871-X. [Epub ahead of print]153 113482
    Progress in mesenchymal stem cell mitochondria transfer for the repair of tissue injury and treatment of disease.
    Ling Zhang, Qian Liu, Haoran Hu, Lu Zhao, Keyang Zhu.
      Mesenchymal stem cells (MSCs) have therapeutic value in many diseases. Mitochondria transfer can promote wound healing and can potentially be applied to the repair of damaged tissue, but the specific mechanisms and regulatory factors involved remain unclear. In this review, we discuss the mechanistic basis of mitochondria transfer and factors that restore mitochondrial function in injured somatic cells.
    Keywords:  Mesenchymal stem cells; Mitochondrial transfer; Tissue damage
    DOI:  https://doi.org/10.1016/j.biopha.2022.113482
  3. Cells. 2022 Aug 27. pii: 2660. [Epub ahead of print]11(17):
    A Combination Therapy of Urolithin A+EGCG Has Stronger Protective Effects than Single Drug Urolithin A in a Humanized Amyloid Beta Knockin Mice for Late-Onset Alzheimer's Disease.
    Sudhir Kshirsagar, Rainier Vladlen Alvir, Jangampalli Adi Pradeepkiran, Ashly Hindle, Murali Vijayan, Bhagavathi Ramasubramaniam, Subodh Kumar, Arubala P Reddy, P Hemachandra Reddy.
      In the current study, for the first time, we study mitophagy enhancer urolithin A and a combination of urolithin A+green tea extract EGCG against human Aβ peptide-induced mitochondrial and synaptic, dendritic, inflammatory toxicities and behavioral changes in humanized homozygous amyloid beta knockin (hAbKI) mice of late-onset Alzheimer's disease (AD). Our findings reveal significantly increased positive effects of urolithin A and a combination treatment of urolithin A+EGCG in hAbKI mice for phenotypic behavioral changes including motor coordination, locomotion/exploratory activity, spatial learning and working memory. mRNA and protein levels of mitochondrial fusion, synaptic, mitophagy and autophagy genes were upregulated, and mitochondrial fission genes are downregulated in urolithin A and combine treatment in hAbKI mice; however, the effect is stronger in combined treatment. Immunofluorescence analysis of hippocampal brain sections shows similar findings of mRNA and protein levels. Mitochondrial dysfunction is significantly reduced in both treatment groups, but a stronger reduction is observed in combined treatment. Dendritic spines and lengths are significantly increased in both treatment groups, but the effect is stronger in combined treatment. The fragmented number of mitochondria is reduced, and mitochondrial length is increased, and mitophagosomal formations are increased in both the groups, but the effect is stronger in the combined treatment. The levels of amyloid beta (Aβ) 40 and Aβ42 are reduced in both treatments, however, the reduction is higher for combined treatment. These observations suggest that urolithin A is protective against human Aβ peptide-induced toxicities; however, combined treatment of urolithin A+EGCG is effective and stronger, indicating that combined therapy is promising to treat late-onset AD patients.
    Keywords:  Alzheimer’s disease; amyloid beta; green tea extract EGCG; humanized amyloid beta knockin mice; mitochondria; urolithin A
    DOI:  https://doi.org/10.3390/cells11172660
  4. iScience. 2022 Sep 16. 25(9): 104920
    Mitochondrial protein synthesis and the bioenergetic cost of neurodevelopment.
    Pernille Bülow, Anupam Patgiri, Victor Faundez.
      The human brain consumes five orders of magnitude more energy than the sun by unit of mass and time. This staggering bioenergetic cost serves mostly synaptic transmission and actin cytoskeleton dynamics. The peak of both brain bioenergetic demands and the age of onset for neurodevelopmental disorders is approximately 5 years of age. This correlation suggests that defects in the machinery that provides cellular energy would be causative and/or consequence of neurodevelopmental disorders. We explore this hypothesis from the perspective of the machinery required for the synthesis of the electron transport chain, an ATP-producing and NADH-consuming enzymatic cascade. The electron transport chain is constituted by nuclear- and mitochondrial-genome-encoded subunits. These subunits are synthesized by the 80S and the 55S ribosomes, which are segregated to the cytoplasm and the mitochondrial matrix, correspondingly. Mitochondrial protein synthesis by the 55S ribosome is the rate-limiting step in the synthesis of electron transport chain components, suggesting that mitochondrial protein synthesis is a bottleneck for tissues with high bionergetic demands. We discuss genetic defects in the human nuclear and mitochondrial genomes that affect these protein synthesis machineries and cause a phenotypic spectrum spanning autism spectrum disorders to neurodegeneration during neurodevelopment. We propose that dysregulated mitochondrial protein synthesis is a chief, yet understudied, causative mechanism of neurodevelopmental and behavioral disorders.
    Keywords:  Biological Sciences; Cell Biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2022.104920
  5. iScience. 2022 Sep 16. 25(9): 104923
    STAT6 in mitochondrial outer membrane impairs mitochondrial fusion by inhibiting MFN2 dimerization.
    Hyunmi Kim, Soo Jung Park, Ilo Jou.
      Although it is reported that mitochondria-localized nuclear transcription factors (TFs) regulate mitochondrial processes such as apoptosis and mitochondrial transcription/respiration, the functions and mechanisms of mitochondrial dynamics regulated by mitochondria-localized nuclear TFs are yet to be fully characterized. Here, we identify STAT6 as a mitochondrial protein that is localized in the outer membrane of mitochondria (OMM). STAT6 in OMM inhibits mitochondrial fusion by blocking MFN2 dimerization. This implies that STAT6 has a critical role in mitochondrial dynamics. Moreover, mitochondrial accumulation of STAT6 in response to hypoxic conditions reveals that STAT6 is a regulator of mitochondrial processes including fusion/fission mechanisms.
    Keywords:  Biological sciences; Molecular biology; Molecular interaction; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2022.104923
  6. J Neurol. 2022 Sep 06.
    Co-occurrence of amyotrophic lateral sclerosis and Leber's hereditary optic neuropathy: is mitochondrial dysfunction a modifier?
    Giulia Amore, Veria Vacchiano, Chiara La Morgia, Maria L Valentino, Leonardo Caporali, Claudio Fiorini, Danara Ormanbekova, Fabrizio Salvi, Anna Bartoletti-Stella, Sabina Capellari, Rocco Liguori, Valerio Carelli.
      
    DOI:  https://doi.org/10.1007/s00415-022-11355-w
  7. Int J Mol Sci. 2022 Aug 26. pii: 9703. [Epub ahead of print]23(17):
    Targeted Mitochondrial Epigenetics: A New Direction in Alzheimer's Disease Treatment.
    Ying Song, Xin-Yi Zhu, Xiao-Min Zhang, He Xiong.
      Mitochondrial epigenetic alterations are closely related to Alzheimer's disease (AD), which is described in this review. Reports of the alteration of mitochondrial DNA (mtDNA) methylation in AD demonstrate that the disruption of the dynamic balance of mtDNA methylation and demethylation leads to damage to the mitochondrial electron transport chain and the obstruction of mitochondrial biogenesis, which is the most studied mitochondrial epigenetic change. Mitochondrial noncoding RNA modifications and the post-translational modification of mitochondrial nucleoproteins have been observed in neurodegenerative diseases and related diseases that increase the risk of AD. Although there are still relatively few mitochondrial noncoding RNA modifications and mitochondrial nuclear protein post-translational modifications reported in AD, we have reason to believe that these mitochondrial epigenetic modifications also play an important role in the AD process. This review provides a new research direction for the AD mechanism, starting from mitochondrial epigenetics. Further, this review summarizes therapeutic approaches to targeted mitochondrial epigenetics, which is the first systematic summary of therapeutic approaches in the field, including folic acid supplementation, mitochondrial-targeting antioxidants, and targeted ubiquitin-specific proteases, providing a reference for therapeutic targets for AD.
    Keywords:  Alzheimer’s disease; methylation; mitochondrial DNA; mitochondrial epigenetics; noncoding RNA; post-translational modification
    DOI:  https://doi.org/10.3390/ijms23179703
  8. Int J Mol Sci. 2022 Aug 25. pii: 9655. [Epub ahead of print]23(17):
    cAMP/PKA Signaling Modulates Mitochondrial Supercomplex Organization.
    Anna Signorile, Consiglia Pacelli, Luigi Leonardo Palese, Arcangela Santeramo, Emilio Roca, Tiziana Cocco, Domenico De Rasmo.
      The oxidative phosphorylation (OXPHOS) system couples the transfer of electrons to oxygen with pumping of protons across the inner mitochondrial membrane, ensuring the ATP production. Evidence suggests that respiratory chain complexes may also assemble into supramolecular structures, called supercomplexes (SCs). The SCs appear to increase the efficiency/capacity of OXPHOS and reduce the reactive oxygen species (ROS) production, especially that which is produced by complex I. Studies suggest a mutual regulation between complex I and SCs, while SCs organization is important for complex I assembly/stability, complex I is involved in the supercomplex formation. Complex I is a pacemaker of the OXPHOS system, and it has been shown that the PKA-dependent phosphorylation of some of its subunits increases the activity of the complex, reducing the ROS production. In this work, using in ex vivo and in vitro models, we show that the activation of cAMP/PKA cascade resulted in an increase in SCs formation associated with an enhanced capacity of electron flux and ATP production rate. This is also associated with the phosphorylation of the NDUFS4 subunit of complex I. This aspect highlights the key role of complex I in cellular energy production.
    Keywords:  NDUFS4; cAMP/PKA; complex I; mitochondria; mitochondrial supercomplexes
    DOI:  https://doi.org/10.3390/ijms23179655
  9. Rev Neurosci. 2022 Sep 06.
    Mitochondrial fission mediated by Drp1-Fis1 pathway and neurodegenerative diseases.
    Wenjia Shi, Cheng Tan, Can Liu, Dan Chen.
      In recent years, the role of mitochondrial dynamics in neurodegenerative diseases has becoming increasingly important. More and more evidences have shown that in pathological conditions, abnormal mitochondrial divisions, especially Drp1-Fis1-mediated divisions, play an important role in the occurrence and development of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, glaucoma, and other neurodegenerative diseases. This review highlights several new mechanisms of physiological fission of mitochondria and the difference/connection of physiological/pathological mitochondrial fission. In addition, we described the relationship between abnormal mitochondrial dynamics and neurodegenerative diseases in detail and emphatically summarized its detection indicators in basic experiments, trying to provide references for further mechanism exploration and therapeutic targets.
    Keywords:  Drp1; Fis1; mitochondrial dynamics; neurodegenerative diseases; pathological fission; physiological fission
    DOI:  https://doi.org/10.1515/revneuro-2022-0056
  10. Acta Neuropathol Commun. 2022 Sep 08. 10(1): 134
    Mitochondrial dysfunction is a key pathological driver of early stage Parkinson's.
    Christina E Toomey, Wendy E Heywood, James R Evans, Joanne Lachica, Sarah N Pressey, Sandrine C Foti, Mesfer Al Shahrani, Karishma D'Sa, Iain P Hargreaves, Simon Heales, Michael Orford, Claire Troakes, Johannes Attems, Ellen Gelpi, Miklos Palkovits, Tammaryn Lashley, Steve M Gentleman, Tamas Revesz, Kevin Mills, Sonia Gandhi.
      BACKGROUND: The molecular drivers of early sporadic Parkinson's disease (PD) remain unclear, and the presence of widespread end stage pathology in late disease masks the distinction between primary or causal disease-specific events and late secondary consequences in stressed or dying cells. However, early and mid-stage Parkinson's brains (Braak stages 3 and 4) exhibit alpha-synuclein inclusions and neuronal loss along a regional gradient of severity, from unaffected-mild-moderate-severe. Here, we exploited this spatial pathological gradient to investigate the molecular drivers of sporadic PD.METHODS: We combined high precision tissue sampling with unbiased large-scale profiling of protein expression across 9 brain regions in Braak stage 3 and 4 PD brains, and controls, and verified these results using targeted proteomic and functional analyses.
    RESULTS: We demonstrate that the spatio-temporal pathology gradient in early-mid PD brains is mirrored by a biochemical gradient of a changing proteome. Importantly, we identify two key events that occur early in the disease, prior to the occurrence of alpha-synuclein inclusions and neuronal loss: (i) a metabolic switch in the utilisation of energy substrates and energy production in the brain, and (ii) perturbation of the mitochondrial redox state. These changes may contribute to the regional vulnerability of developing alpha-synuclein pathology. Later in the disease, mitochondrial function is affected more severely, whilst mitochondrial metabolism, fatty acid oxidation, and mitochondrial respiration are affected across all brain regions.
    CONCLUSIONS: Our study provides an in-depth regional profile of the proteome at different stages of PD, and highlights that mitochondrial dysfunction is detectable prior to neuronal loss, and alpha-synuclein fibril deposition, suggesting that mitochondrial dysfunction is one of the key drivers of early disease.
    Keywords:  Brain; Mitochondria; Neurodegeneration; Parkinson’s; Progression; Proteomics
    DOI:  https://doi.org/10.1186/s40478-022-01424-6
  11. Int J Mol Sci. 2022 Aug 29. pii: 9808. [Epub ahead of print]23(17):
    Bioenergetic and Metabolic Impairments in Induced Pluripotent Stem Cell-Derived Cardiomyocytes Generated from Duchenne Muscular Dystrophy Patients.
    Lubna Willi, Ifat Abramovich, Jonatan Fernandez-Garcia, Bella Agranovich, Margarita Shulman, Helena Milman, Polina Baskin, Binyamin Eisen, Daniel E Michele, Michael Arad, Ofer Binah, Eyal Gottlieb.
      Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene and dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality in DMD patients. We tested the hypothesis that DCM is caused by metabolic impairments by employing induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from four DMD patients; an adult male, an adult female, a 7-year-old (7y) male and a 13-year-old (13y) male, all compared to two healthy volunteers. To test the hypothesis, we measured the bioenergetics, metabolomics, electrophysiology, mitochondrial morphology and mitochondrial activity of CMs, using respirometry, LC-MS, patch clamp, electron microscopy (EM) and confocal microscopy methods. We found that: (1) adult DMD CMs exhibited impaired energy metabolism and abnormal mitochondrial structure and function. (2) The 7y CMs demonstrated arrhythmia-free spontaneous firing along with "healthy-like" metabolic status, normal mitochondrial morphology and activity. In contrast, the 13y CMs were mildly arrhythmogenic and showed adult DMD-like bioenergetics deficiencies. (3) In DMD adult CMs, mitochondrial activities were attenuated by 45-48%, whereas the 7y CM activity was similar to that of healthy CMs. (4) In DMD CMs, but not in 7y CMs, there was a 75% decrease in the mitochondrial ATP production rate compared to healthy iPSC-CMs. In summary, DMD iPSC-CMs exhibit bioenergetic and metabolic impairments that are associated with rhythm disturbances corresponding to the patient's phenotype, thereby constituting novel targets for alleviating cardiomyopathy in DMD patients.
    Keywords:  DMD; bioenergetics; electrophysiology; iPSC-CMs; metabolism
    DOI:  https://doi.org/10.3390/ijms23179808
  12. Anim Genet. 2022 Sep 09.
    Mitochondrial fission factor (MFF) frameshift variant in Bullmastiffs with mitochondrial fission encephalopathy.
    Matthias Christen, Rodrigo Gutierrez-Quintana, Helene Vandenberghe, Adriana Kaczmarska, Jacques Penderis, Roberto José-López, Angie Rupp, Ian R Griffiths, Vidhya Jagannathan, Tosso Leeb.
      Familial cerebellar ataxia with hydrocephalus in Bullmastiffs was described almost 40 years ago as a monogenic autosomal recessive trait. We investigated two young Bullmastiffs showing similar clinical signs. They developed progressive gait and behavioural abnormalities with an onset at around 6 months of age. Neurological assessment was consistent with a multifocal brain disease. Magnetic resonance imaging of the brain showed intra-axial bilateral symmetrical focal lesions localised to the cerebellar nuclei. Based on the juvenile age, nature of neurological deficits and imaging findings, an inherited disorder of the brain was suspected. We sequenced the genome of one affected Bullmastiff. The data were compared with 782 control genomes of dogs from diverse breeds. This search revealed a private homozygous frameshift variant in the MFF gene in the affected dog, XM_038574000.1:c.471_475delinsCGCTCT, that is predicted to truncate 55% of the wild type MFF open reading frame, XP_038429928.1: p.(Glu158Alafs*14). Human patients with pathogenic MFF variants suffer from 'encephalopathy due to defective mitochondrial and peroxisomal fission 2'. Archived samples from two additional affected Bullmastiffs related to the originally described cases were obtained. Genotypes in a cohort of four affected and 70 unaffected Bullmastiffs showed perfect segregation with the disease phenotype. The available data together with information from previous disease reports allow classification of the investigated MFF frameshift variant as pathogenic and probably causative defect of the observed neurological phenotype. In analogy to the human phenotype, we propose to rename this disease 'mitochondrial fission encephalopathy (MFE)'.
    Keywords:   Canis lupus familiaris ; animal model; dog; mitochondrion; neurology; precision medicine; veterinary medicine
    DOI:  https://doi.org/10.1111/age.13263
  13. Nat Commun. 2022 Sep 03. 13(1): 5202
    Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression.
    Jin Zhou, Jeremy Pang, Madhulika Tripathi, Jia Pei Ho, Anissa Anindya Widjaja, Shamini Guna Shekeran, Stuart Alexander Cook, Ayako Suzuki, Anna Mae Diehl, Enrico Petretto, Brijesh Kumar Singh, Paul Michael Yen.
      Spermidine is a natural polyamine that has health benefits and extends life span in several species. Deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH) are key enzymes that utilize spermidine to catalyze the post-translational hypusination of the translation factor EIF5A (EIF5AH). Here, we have found that hepatic DOHH mRNA expression is decreased in patients and mice with non-alcoholic steatohepatitis (NASH), and hepatic cells treated with fatty acids. The mouse and cell culture models of NASH have concomitant decreases in Eif5aH and mitochondrial protein synthesis which leads to lower mitochondrial activity and fatty acid β-oxidation. Spermidine treatment restores EIF5AH, partially restores protein synthesis and mitochondrial function in NASH, and prevents NASH progression in vivo. Thus, the disrupted DHPS-DOHH-EIF5AH pathway during NASH represents a therapeutic target to increase hepatic protein synthesis and mitochondrial fatty acid oxidation (FAO) and prevent NASH progression.
    DOI:  https://doi.org/10.1038/s41467-022-32788-x
  14. Gene. 2022 Sep 02. pii: S0378-1119(22)00595-9. [Epub ahead of print] 146776
    Mitochondrial DNA polymorphisms in COX1 affect the lifespan of Caenorhabditis elegans through nuclear gene dct-15.
    Yao Zhu, Ying Li, Yuechen Wang, Liang Wang, Peng Shi, Xinze Du, Yingchun Zhang, Yuanjian Song, Zuobin Zhu.
      Mutations in the mitochondrial DNA (mtDNA) are closely related to age and age-related complex diseases, but the exact regulatory mechanism of mtDNA natural variation or polymorphism and ageing remains unclear. Recently, nuclear genes that regulate mitochondrial functions and thereby influence ageing have been widely studied. In this study, the relationship between the retrograde communication from the mitochondria to the nucleus and its ultimate effect on ageing has been elucidated. This study found that the natural variations in COX1 of the mitochondria in the Caenorhabditis elegans population do not correlate with multiple phenotypes, except for a mild correlation with lifespan. After excluding the differences in the nuclear genome, the correlation between natural mitochondrial variation and lifespan increased significantly. Moreover, mtDNA variation downregulated the nuclear dct-15 gene expression, which consequently reduced the lifespan, development rate and motility of C. elegans. dct-15 mutations decreased mitochondria copy number but increased ATP content and mitochondrial ultrastructure. Thus, the results indicated that dct-15 interacted with the mitochondrial DNA polymorphisms in COX1 and is associated with ageing. Finally, bioinformatic analyses revealed that mtDNA variation regulated the structural constituent of the cuticle via dct-15 and suggested that the structural constituent of the cuticle could have an important role in the development and ageing processes. These results provide insights into the mtDNA mechanism that can alter the nuclear gene and thereby regulate ageing and ageing-related diseases.
    DOI:  https://doi.org/10.1016/j.gene.2022.146776
  15. Curr Opin Ophthalmol. 2022 Aug 25.
    Leber hereditary optic neuropathy: new and emerging therapies.
    Pamela Davila-Siliezar, Michael Carter, Dan Milea, Andrew G Lee.
      PURPOSE OF REVIEW: To review recent therapeutic advances in Leber hereditary optic neuropathy (LHON).RECENT FINDINGS: Idebenone, a synthetic analog of ubiquinone (Coenzyme Q10) is an antioxidant and component of the mitochondrial electron transport chain. Since the initial approval of the drug in 2015 in Europe, recent trials have evaluated its role as prolonged treatment in LHON. Gene therapy has recently emerged as a promising alternative for the treatment of LHON. Among several investigations, RESCUE and REVERSE are two phase 3 clinical trials of gene therapy in patients with LHON in early stages. Results in these trials have shown a bilateral visual acuity improvement with unilateral intravitreal injections at 96 weeks and sustained visual improvement after 3 years of treatment. The most recent REFLECT phase 3 clinical trial in LHON has shown significant improvement of vision after bilateral intravitreal injections compared with the group that received unilateral injections.
    SUMMARY: Historically, LHON has been considered an untreatable disease, but recent developments show that new pharmacological and gene therapy approaches may lead to visual recovery. Further studies are needed to support these data.
    DOI:  https://doi.org/10.1097/ICU.0000000000000891
  16. J Cell Physiol. 2022 Sep 08.
    Mitochondrial respiratory complexes: Significance in human mitochondrial disorders and cancers.
    Kunwar Somesh Vikramdeo, Sarabjeet Kour Sudan, Ajay P Singh, Seema Singh, Santanu Dasgupta.
      Mitochondria are pivotal organelles that govern cellular energy production through the oxidative phosphorylation system utilizing five respiratory complexes. In addition, mitochondria also contribute to various critical signaling pathways including apoptosis, damage-associated molecular patterns, calcium homeostasis, lipid, and amino acid biosynthesis. Among these diverse functions, the energy generation program oversee by mitochondria represents an immaculate orchestration and functional coordination between the mitochondria and nuclear encoded molecules. Perturbation in this program through respiratory complexes' alteration results in the manifestation of various mitochondrial disorders and malignancy, which is alarmingly becoming evident in the recent literature. Considering the clinical relevance and importance of this emerging medical problem, this review sheds light on the timing and nature of molecular alterations in various respiratory complexes and their functional consequences observed in various mitochondrial disorders and human cancers. Finally, we discussed how this wealth of information could be exploited and tailored to develop respiratory complex targeted personalized therapeutics and biomarkers for better management of various incurable human mitochondrial disorders and cancers.
    Keywords:  ATP; cancer; genetic disorders; mitochondria; oxidative phosphorylation (OXPHOS); respiratory complexes
    DOI:  https://doi.org/10.1002/jcp.30869
  17. Int J Mol Sci. 2022 Sep 04. pii: 10145. [Epub ahead of print]23(17):
    Low Expression of Mitofusin 1 Gene Leads to Mitochondrial Dysfunction and Embryonic Genome Activation Failure in Ovine-Bovine Inter-Species Cloned Embryos.
    Shanshan Wu, Xiaoyu Zhao, Meiling Wu, Lei Yang, Xuefei Liu, Danyi Li, Han Xu, Yuefang Zhao, Xiaohu Su, Zhuying Wei, Chunling Bai, Guanghua Su, Guangpeng Li.
      Inter-species somatic cell nuclear transfer (iSCNT) is significant in the study of biological problems such as embryonic genome activation and the mitochondrial function of embryos. Here, we used iSCNT as a model to determine whether abnormal embryo genome activation was caused by mitochondrial dysfunction. First, we found the ovine-bovine iSCNT embryos were developmentally blocked at the 8-cell stage. The reactive oxygen species level, mitochondrial membrane potential, and ATP level in ovine-bovine cloned embryos were significantly different from both bovine-bovine and IVF 8-cell stage embryos. RNA sequencing and q-PCR analysis revealed that mitochondrial transport, mitochondrial translational initiation, mitochondrial large ribosomal subunit, and mitochondrial outer membrane genes were abnormally expressed in the ovine-bovine embryos, and the mitochondrial outer membrane and mitochondrial ribosome large subunit genes, mitochondrial fusion gene 1, and ATPase Na+/K+ transporting subunit beta 3 gene were expressed at lower levels in the ovine-bovine cloned embryos. Furthermore, we found that overexpression and knockdown of Mfn1 significantly affected mitochondrial fusion and subsequent biological functions such as production of ATP, mitochondrial membrane potential, reactive oxygen species and gene expressions in cloned embryos. These findings enhance our understanding of the mechanism by which the Mfn1 gene regulates embryonic development and embryonic genome activation events.
    Keywords:  embryonic genome activation; interspecies somatic cell nuclear transfer; mitochondrial fusion; transcriptomic sequencing
    DOI:  https://doi.org/10.3390/ijms231710145
  18. Hum Gene Ther. 2022 Sep 07.
    CNS gene therapy: present developments and emerging trends accelerating industry-academia pathways.
    Margareta Rybarikova, Amanda Almacellas Barbanoj, Stephanie Schorge, Nicole Déglon.
      The recent success of first central nervous system gene therapies has reinvigorated the growing community of gene therapy researchers and strengthened the field's market position. We are witnessing an increase of clinical trials with long-term efficiency mainly for neurometabolic, neurodegenerative and neurodevelopmental diseases caused by loss-of-function mutations. The ever-expanding knowledge and accessibility to the most advanced tools allow enrichment of applications to more complex diseases. This gradually contributes towards sealing the gap between top diseases impacting current global health and those towards which gene therapy development is currently aimed. Here, we highlight innovative therapeutic approaches that have reached the clinics and outline the latest improvements of vector design and targeting. Finally, we address the pressing challenges faced by clinical trials and the direction they are heading.
    DOI:  https://doi.org/10.1089/hum.2022.177
  19. Cell Metab. 2022 Sep 06. pii: S1550-4131(22)00354-0. [Epub ahead of print]34(9): 1231-1233
    A brown fat-selective mechanism of mitochondrial calcium import?
    Janane F Rahbani, Lawrence Kazak.
      In this issue of Cell Metabolism, Xue et al. propose that the mitochondrial calcium uniporter (MCU) binds uncoupling protein 1 (UCP1) via the MCU regulator (EMRE) to form a protein complex that the authors term the "thermoporter." Through gain- and loss-of-function experiments, the authors infer that the thermoporter promotes calcium influx into the mitochondrial matrix to enhance NADH production, which supports thermogenesis in brown adipose tissue (BAT).
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.011
  20. Aging (Albany NY). 2022 Sep 08. 14(undefined):
    Senolytic elimination of senescent macrophages restores muscle stem cell function in severely dystrophic muscle.
    Lei Liu, Xianlin Yue, Zewei Sun, William S Hambright, Qi Feng, Yan Cui, Johnny Huard, Paul D Robbins, Zhihui Wang, Xiaodong Mu.
      The aging of the immune system, or immunosenescence, was recently verified to have a causal role in driving the aging of solid organs, while the senolytic elimination of senescent immune cells was found to effectively delay systemic aging. Our recent study also showed that immune cells in severely dystrophic muscles develop senescence-like phenotypes, including the increased expression of senescence-associated secretory phenotype (SASP) factors and senescence markers. Here we further investigated whether the specific clearance of senescent immune cells in dystrophic muscle may effectively improve the function of muscle stem cells and the phenotypes of dystrophic muscle. We observed increased percentage of senescent cells in macrophages from mdx/utro(-/-) mice (a murine model for muscular dystrophy disease, dystrophin-/-; utrophin-/-), while the treatment of mdx/utro(-/-) macrophages with senolytic drug fisetin resulted in reduced number of senescent cells. We administrated fisetin to mdx/utro(-/-) mice for 4 weeks, and observed obviously reduced number of senescent immune cells, restored number of muscle cells, and improve muscle phenotypes. In conclusion, our results reveal that senescent immune cells, such as macrophages, are greatly involved in the development of muscle dystrophy by impacting the function of muscle stem cells, and the senolytic ablation of these senescent cells with fisetin can be an effective therapeutic strategy for improving function of muscle stem cells and phenotypes of dystrophic muscles.
    Keywords:  cellular senescence; immunosenescence; muscular dystrophy; senolytics; stem cells
    DOI:  https://doi.org/10.18632/aging.204275
  21. Front Cell Dev Biol. 2022 ;10 979330
    Nicotinamide-riboside shifts the differentiation of human primary white adipocytes to beige adipocytes impacting substrate preference and uncoupling respiration through SIRT1 activation and mitochondria-derived reactive species production.
    Lilla Nagy, Boglárka Rauch, Tamás Szerafin, Karen Uray, Attila Tóth, Péter Bai.
      Beige adipocytes play key roles in organismal energy and metabolic balance. In this study, we assessed whether the supplementation of human white adipocytes, differentiated from human adipose tissue-derived stem cells, with nicotinamide riboside (NR), a potent NAD + precursor, can shift differentiation to beige adipocytes (beiging). NR induced mitochondrial biogenesis and the expression of beige markers (TBX1 and UCP1) in white adipocytes demonstrating that NR can declutch beiging. NR did not induce PARP activity but supported SIRT1 induction, which plays a key role in beiging. NR induced etomoxir-resistant respiration, suggesting increases in the oxidation of carbohydrates, carbohydrate breakdown products, or amino acids. Furthermore, NR boosted oligomycin-resistant respiration corresponding to uncoupled respiration. Enhanced etomoxir and oligomycin-resistant respiration were dependent on mitochondrial reactive-species production. Taken together, NR supplementation can induce beiging and uncoupled respiration, which are beneficial for combatting metabolic diseases.
    Keywords:  adipocyte differentiation; beige adipocyte; mitochondrial oxidation; nicotinamide riboside; uncoupled respiration
    DOI:  https://doi.org/10.3389/fcell.2022.979330
  22. Free Radic Biol Med. 2022 Sep 02. pii: S0891-5849(22)00566-4. [Epub ahead of print]
    LONP1 downregulation with ageing contributes to osteoarthritis via mitochondrial dysfunction.
    Yuzhe He, Qianhai Ding, Wenliang Chen, Changjian Lin, Lujie Ge, Chenting Ying, Kai Xu, Zhipeng Wu, Langhai Xu, Jisheng Ran, Weiping Chen, Lidong Wu.
      Osteoarthritis (OA) is an age-related disorder and an important cause of disability that is characterized by a senescence-associated secretory phenotype and matrix degradation leading to a gradual loss of articular cartilage integrity. Mitochondria, as widespread organelles, are involved in regulation of complex biological processes such as energy synthesis and cell metabolism, which also have bidirectional communication with the nucleus to help maintain cellular homeostasis and regulate adaptation to a broad range of stressors. In light of the evidence that OA is strongly associated with mitochondrial dysfunction. In addition, mitochondria are considered to be the culprits of cell senescence, and mitochondrial function changes during ageing are considered to have a controlling role in cell fate. Mitochondrial dysfunction is also observed in age-related OA, however, the internal mechanism by which mitochondrial function changes with ageing to lead to the development of OA has not been elucidated. In this study, we found that the expression of Lon protease 1 (LONP1), a mitochondrial protease, was decreased in human OA cartilage and in ageing rat chondrocytes. Furthermore, LONP1 knockdown accelerated the progression and severity of osteoarthritis, which was associated with aspects of mitochondrial dysfunction including oxidative stress, metabolic changes and mitophagy, leading to downstream MAPK pathway activation. Antioxidant therapy with resveratrol suppressed oxidative stress and MAPK pathway activation induced by LONP1 knockdown to mitigate OA progression. Therefore, our findings demonstrate that LONP1 is a central regulator of mitochondrial function in chondrocytes and reveal that downregulation of LONP1 with ageing contributes to osteoarthritis.
    Keywords:  Ageing; LONP1; Mitochondria; Osteoarthritis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.08.038
  23. Nature. 2022 Sep 06.
    Embryos with DNA from three people develop normally in first safety study.
    Yvaine Ye.
      
    Keywords:  Diseases; Government
    DOI:  https://doi.org/10.1038/d41586-022-02792-8
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