bims-mitmed 2024-12-15 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2024–12–15
fifteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mitochondrial dynamics govern whole-body regeneration through stem cell pluripotency and mitonuclear balance.
Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo.
Opa1 and MT-Nd6 mutations induce early mitochondrial changes in the retina and prelaminar optic nerve of hereditary optic neuropathy mouse models.
Astrocytic mitochondrial transfer to brain endothelial cells and pericytes in vivo increases with aging.
Identification of a novel pathogenic gene, NDUFA3, in Leigh Syndrome through whole exome sequencing.
Optimizing rare disorder trials: a phase 1a/1b randomized study of KL1333 in adults with mitochondrial disease.
Inhibition of the PI3K-AKT-MTORC1 axis reduces the burden of the m.3243A>G mtDNA mutation by promoting mitophagy and improving mitochondrial function.
Cryopreserved PBMCs can be used for the analysis of mitochondrial respiration and serve as a diagnostic tool for mitochondrial diseases.
Phosphorylation of Optineurin by protein kinase D regulates Parkin-dependent mitophagy.
Clinical features and treatment of stroke-like episodes in mitochondrial disease: a cohort-based study.
Reactive oxygen species control protein degradation at the mitochondrial import gate.
Altered calcium responses and antioxidant properties in Friedreich's ataxia-like cerebellar astrocytes.
Omaveloxolone approved for patients aged 16 years and older with Friedreich ataxia (FRDA): A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG).
Celastrol ameliorates lipopolysaccharide (LPS)-induced acute lung injury by improving mitochondrial function through AMPK/PGC-1α/Nrf1-dependent mechanism.
Urolithin A and nicotinamide riboside differentially regulate innate immune defenses and metabolism in human microglial cells.

Nat Commun. 2024 Dec 13. 15(1): 10681

Mitochondrial dynamics govern whole-body regeneration through stem cell pluripotency and mitonuclear balance.

Xue Pan, Yun Zhao, Yucong Li, Jiajia Chen, Wenya Zhang, Ling Yang, Yuanyi Zhou Xiong, Yuqing Ying, Hao Xu, Yuhong Zhang, Chong Gao, Yuhan Sun, Nan Li, Liangyi Chen, Zhixing Chen, Kai Lei.

Tissue regeneration is a complex process involving large changes in cell proliferation, fate determination, and differentiation. Mitochondrial dynamics and metabolism play a crucial role in development and wound repair, but their function in large-scale regeneration remains poorly understood. Planarians offer an excellent model to investigate this process due to their remarkable regenerative abilities. In this study, we examine mitochondrial dynamics during planarian regeneration. We find that knockdown of the mitochondrial fusion gene, opa1, impairs both tissue regeneration and stem cell pluripotency. Interestingly, the regeneration defects caused by opa1 knockdown are rescued by simultaneous knockdown of the mitochondrial fission gene, drp1, which partially restores mitochondrial dynamics. Furthermore, we discover that Mitolow stem cells exhibit an enrichment of pluripotency due to their fate choices at earlier stages. Transcriptomic analysis reveals the delicate mitonuclear balance in metabolism and mitochondrial proteins in regeneration, controlled by mitochondrial dynamics. These findings highlight the importance of maintaining mitochondrial dynamics in large-scale tissue regeneration and suggest the potential for manipulating these dynamics to enhance stem cell functionality and regenerative processes.

DOI: https://doi.org/10.1038/s41467-024-54720-1
Mol Ther Methods Clin Dev. 2024 Dec 12. 32(4): 101372

Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo.

David V Begelman, Bhavna Dixit, Carly Truong, Christina D King, Mark A Watson, Birgit Schilling, Martin D Brand, Amutha Boominathan.

  Replicative errors, inefficient repair, and proximity to sites of reactive oxygen species production make mitochondrial DNA (mtDNA) susceptible to damage with time. We explore in vivo allotopic expression (re-engineering mitochondrial genes and expressing them from the nucleus) as an approach to rescue defects arising from mtDNA mutations. We used a mouse strain C57BL/6J(mtFVB) with a natural polymorphism (m.7778 G>T) in the mitochondrial ATP8 gene that encodes a protein subunit of the ATP synthase. We generated a transgenic mouse with an epitope-tagged recoded mitochondrial-targeted ATP8 gene expressed from the ROSA26 locus in the nucleus and used the C57BL/6J(mtFVB) strain to verify successful incorporation. The allotopically expressed ATP8 protein in transgenic mice was constitutively expressed across all tested tissues, successfully transported into the mitochondria, and incorporated into ATP synthase. The ATP synthase with transgene had similar activity to non-transgenic control, suggesting successful integration and function. Exogenous ATP8 protein had no negative impact on measured mitochondrial function, metabolism, or behavior. Successful allotopic expression of a mitochondrially encoded protein in vivo in a mammal is a step toward utilizing allotopic expression as a gene therapy in humans to repair physiological consequences of mtDNA defects that may accumulate in congenital mitochondrial diseases or with age.

Keywords:  ATP8 gene; allotopic expression; in vivo gene therapy; mitochondrial DNA mutation; mtDNA; safe harbor expression; transgenic mouse

DOI:  https://doi.org/10.1016/j.omtm.2024.101372
Brain Commun. 2024 ;6(6): fcae404

Opa1 and MT-Nd6 mutations induce early mitochondrial changes in the retina and prelaminar optic nerve of hereditary optic neuropathy mouse models.

Jacques Bureau, Florence Manero, Olivier Baris, Alexia Bodin, Christophe Verny, Arnaud Chevrollier, Guy Lenaers, Philippe Codron.

  Hereditary optic neuropathies, including dominant optic atrophy and Leber's hereditary optic neuropathy, are genetic disorders characterized by retinal ganglion cell degeneration leading to vision loss, mainly associated with mitochondrial dysfunction. In this study, we analysed mitochondrial distribution and ultrastructure in the retina and longitudinal optic nerve sections of pre-symptomatic hereditary optic neuropathies mouse models with Opa1 and Nd6 deficiency to identify early mitochondrial changes. Our results show significant mitochondrial fragmentation and increased mitophagy in Opa1+/- mice, indicating early mitochondrial changes prior to neuronal loss. Conversely, Nd6P25L mice exhibited mitochondrial hypertrophy, suggesting an adaptive response to compensate for altered energy metabolism. These pre-symptomatic mitochondrial changes were mainly observed in the unmyelinated portion of the retinal ganglion cell axons, where the transmission of the visual information requires high energy expenditure, constituting the specific point of vulnerability in hereditary optic neuropathies. These findings highlight early focal mitochondrial changes prior to neuronal loss in hereditary optic neuropathies and provide insight into pre-symptomatic therapeutic approaches.

Keywords:  Leber hereditary optic neuropathy; Opa1; dominant optic atrophy; hereditary optic neuropathy; mitochondria

DOI:  https://doi.org/10.1093/braincomms/fcae404
J Cereb Blood Flow Metab. 2024 Dec 12. 271678X241306054

Astrocytic mitochondrial transfer to brain endothelial cells and pericytes in vivo increases with aging.

Gopal V Velmurugan, Hemendra J Vekaria, Samir P Patel, Patrick G Sullivan, W Brad Hubbard.

  Intercellular mitochondrial transfer (IMT) is an intriguing biological phenomenon where mitochondria are transferred between different cells and notably, cell types. IMT is physiological, occurring in normal conditions, but also is utilized to deliver healthy mitochondria to cells in distress. Transferred mitochondria can be integrated to improve cellular metabolism, and mitochondrial function. Research on the mitochondrial transfer axis between astrocytes and brain capillaries in vivo is limited by the cellular heterogeneity of the neurovascular unit. To this end, we developed an inducible mouse model that expresses mitochondrial Dendra2 only in astrocytes and then isolated brain capillaries to remove all intact astrocytes. This method allows the visualization of in vivo astrocyte- endothelial cell (EC) and astrocyte-pericyte IMT. We demonstrate evidence of astrocyte-EC and astrocyte-pericyte mitochondrial transfer within brain capillaries. We also show that healthy aging enhances mitochondrial transfer from astrocytes to brain capillaries, revealing a potential link between brain aging and cellular mitochondrial dynamics. Finally, we observe that astrocyte-derived extracellular vesicles transfer mitochondria to brain microvascular endothelial cells, showing the potential route of in vivo IMT. These results represent a breakthrough in our understanding of IMT in the brain and a new target in brain aging and neurovascular metabolism.

Keywords:  Mitochondrial transfer; aging; astrocyte EV-mito; brain capillaries; capillary isolation

DOI:  https://doi.org/10.1177/0271678X241306054
Neurogenetics. 2024 Nov 28. 26(1): 13

Identification of a novel pathogenic gene, NDUFA3, in Leigh Syndrome through whole exome sequencing.

Bao-Guang Li, Wen-Juan Wu, Li-Hui Wang, Xin Wang, Chong Liu, Ya-Kun Du, Bao-Chi Li, Jin-Tong Hu, Su-Zhen Sun.

   BACKGROUND: Leigh syndrome is a common mitochondrial disorder caused by gene mutations in the nucleus and mitochondria. When building mitochondrial complex I, the main subunit ND1 combines with the Q module to form a 273 kDa complex, which then adds Ndufa3, Ndufa8, and Ndufa13 to create an intermediate product of about 283 kDa called Q/Pp-a. Although Ndufa8 and Ndufa13 have been linked to mitochondrial diseases, the role of Ndufa3 in disease development is still not fully understood.
METHODS: A family suspected of having Leigh syndrome was examined. Subjects (two brothers and a sister) underwent brain imaging, and their clinical symptoms were evaluated. Also, whole exome sequencing and minigene testing were performed by examining peripheral blood samples (2 ml) collected from the proband, his parents, and brothers.
RESULTS: Three affected children showed early-onset symptoms, including abnormalities in muscle tone and delayed motor and language development. Symptoms were relatively mild. The second child of the second pregnancy experienced worsened muscle tone abnormalities after injury, slow wound healing, and sustained increased muscle tone up to a year after wound closure. His brain scans revealed lesions in the basal ganglia and brainstem, consistent with Leigh syndrome diagnosis. Genetic analysis identified compound heterozygous mutations in the Ndufa3 gene in all affected family members.
CONCLUSION: This is the first report of a family affected by Leigh syndrome associated with mutations in the Ndufa3 gene. Our analyses of clinical symptoms, radiological scans, and genetic investigations broaden our understanding of Ndufa3 gene mutations and their role in the development of Leigh syndrome.

Keywords:   Ndufa3 ; Leigh syndrome; Mitochondrial disease

DOI:  https://doi.org/10.1007/s10048-024-00782-8
Brain. 2024 Dec 09. pii: awae308. [Epub ahead of print]

Optimizing rare disorder trials: a phase 1a/1b randomized study of KL1333 in adults with mitochondrial disease.

Chiara Pizzamiglio, Renae J Stefanetti, Robert McFarland, Naomi Thomas, George Ransley, Matilda Hugerth, Alvar Grönberg, Sonia Simon Serrano, Eskil Elmér, Michael G Hanna, Magnus J Hansson, Gráinne S Gorman, Robert D S Pitceathly.

  Over the past two decades there has been increased interest in orphan drug development for rare diseases. However, hurdles to clinical trial design for these disorders remain. This phase 1a/1b study addressed several challenges, while evaluating the safety and tolerability of the novel oral molecule KL1333 in healthy volunteers and subjects with primary mitochondrial disease. KL1333 aims to normalize the NAD+:NADH ratio that is critical for ATP production. The trial incorporated innovative design elements with potential translatability to other rare diseases including patient involvement, adaptive design and exploratory objectives, all of which have subsequently informed the protocol of an ongoing phase 2, pivotal efficacy study of KL1333. Results indicate KL1333 is safe and well tolerated, with dose-dependent gastrointestinal side effects, and validate potential novel outcome measures in primary mitochondrial disease including the 30-s Sit to Stand, and the patient-reported fatigue scales. Importantly, the data from the trial support efficacy of KL1333 based on improvements in fatigue and functional strength and endurance. Furthermore, the study highlights the value in using phase 1 studies to capture data that helps optimize later phase efficacy trial design.

Keywords:  KL1333; clinical trial; phase 1 trial; primary mitochondrial disease; rare diseases

DOI:  https://doi.org/10.1093/brain/awae308
Autophagy. 2024 Dec 12. 1-16

Inhibition of the PI3K-AKT-MTORC1 axis reduces the burden of the m.3243A>G mtDNA mutation by promoting mitophagy and improving mitochondrial function.

Chih-Yao Chung, Kritarth Singh, Preethi Sheshadri, Gabriel E Valdebenito, Anitta R Chacko, María Alicia Costa Besada, Xiao Fei Liang, Lida Kabir, Robert D S Pitceathly, Gyorgy Szabadkai, Michael R Duchen.

  Mitochondrial DNA (mtDNA) encodes genes essential for oxidative phosphorylation. The m.3243A>G mutation causes severe disease, including myopathy, lactic acidosis and stroke-like episodes (MELAS) and is the most common pathogenic mtDNA mutation in humans. We have previously shown that the mutation is associated with constitutive activation of the PI3K-AKT-MTORC1 axis. Inhibition of this pathway in patient fibroblasts reduced the mutant load, rescued mitochondrial bioenergetic function and reduced glucose dependence. We have now investigated the mechanisms that select against the mutant mtDNA under these conditions. Basal macroautophagy/autophagy and lysosomal degradation of mitochondria were suppressed in the mutant cells. Pharmacological inhibition of any step of the PI3K-AKT-MTORC1 pathway activated mitophagy and progressively reduced m.3243A>G mutant load over weeks. Inhibition of autophagy with bafilomycin A1 or chloroquine prevented the reduction in mutant load, suggesting that mitophagy was necessary to remove the mutant mtDNA. Inhibition of the pathway was associated with metabolic remodeling - mitochondrial membrane potential and respiratory rate improved even before a measurable fall in mutant load and proved crucial for mitophagy. Thus, maladaptive activation of the PI3K-AKT-MTORC1 axis and impaired autophagy play a major role in shaping the presentation and progression of disease caused by the m.3243A>G mutation. Our findings highlight a potential therapeutic target for this otherwise intractable disease.Abbreviation: ΔΨm: mitochondrial membrane potential; 2DG: 2-deoxy-D-glucose; ANOVA: analysis of variance; ARMS-qPCR: amplification-refractory mutation system quantitative polymerase chain reaction; Baf A1: bafilomycin A1; BSA: bovine serum albumin; CQ: chloroquine; Cybrid: cytoplasmic hybrid; CYCS: cytochrome c, somatic; DCA: dichloroacetic acid; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethylsulfoxide; EGFP: enhanced green fluorescent protein; LC3B-I: carboxy terminus cleaved microtubule-associated protein 1 light chain 3 beta; LC3B-II: lipidated microtubule-associated protein 1 light chain 3 beta; LY: LY290042; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MELAS: mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; MFC: mitochondrial fragmentation count; mt-Keima: mitochondrial-targeted mKeima; mtDNA: mitochondrial DNA/mitochondrial genome; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OA: oligomycin+antimycin A; OxPhos: oxidative phosphorylation; DPBS: Dulbecco's phosphate-buffered saline; PPARGC1A/PGC-1α: PPARG coactivator 1 alpha; PPARGC1B/PGC-1β: PPARG coactivator 1 beta; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced kinase 1; qPCR: quantitative polymerase chain reaction; RNA-seq: RNA sequencing; RP: rapamycin; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; WT: wild-type.

Keywords:  PI3K-AKT-MTORC1; m.3243A>G; mitochondria; mitophagy; mtDNA mutations; nutrient signaling

DOI:  https://doi.org/10.1080/15548627.2024.2437908
Anal Biochem. 2024 Dec 05. pii: S0003-2697(24)00289-6. [Epub ahead of print] 115745

Cryopreserved PBMCs can be used for the analysis of mitochondrial respiration and serve as a diagnostic tool for mitochondrial diseases.

Zuzana Korandová, Petr Pecina, Alena Pecinová, Eliška Koňaříková, Markéta Tesařová, Josef Houštěk, Hana Hansíková, Hana Ptáčková, Jiří Zeman, Tomáš Honzík, Tomáš Mráček.

  Mitochondrial diseases are severe, inherited metabolic disorders that affect the paediatric population. They affect the functioning of mitochondrial oxidative phosphorylation (OXPHOS) apparatus either directly or indirectly. Since mutations in mtDNA are responsible for only 25% of paediatric cases and next-generation sequencing does not always provide a conclusive diagnosis, the biochemical approach still represents a valuable tool in diagnostics. Mitochondrial defects can be identified in tissue biopsies (muscle or skin). However, they also often manifest in peripheral blood cells. We developed a protocol for isolation and cryopreservation of peripheral blood mononuclear cells (PBMCs) from 5 ml of children's blood using Ficoll centrifugation which can be utilised for subsequent functional measurements on thawed samples. Furthermore, we evaluated the diagnostic utility of the optimised high-resolution oxygraphy protocol using digitonin-permeabilized cryopreserved PBMCs on 47 samples from patients with confirmed or suspected mitochondrial disease. Overall, the diagnosis was confirmed in 72% of cases, while the analysis of cryopreserved PBMCs provided a false negative outcome in 13% of cases. Our study demonstrates a sensitive, fast, and non-invasive approach for the diagnostics of various types of mitochondrial disorders, especially those of nuclear genetic origin manifesting in paediatric patients.

Keywords:  OXPHOS; PBMC; cryopreservation; diagnostics; glycolysis; mitochondrial diseases; oxidative phosphorylation; peripheral blood mononuclear cells; respirometry

DOI:  https://doi.org/10.1016/j.ab.2024.115745
iScience. 2024 Dec 20. 27(12): 111384

Phosphorylation of Optineurin by protein kinase D regulates Parkin-dependent mitophagy.

Robert Weil, Emmanuel Laplantine, Messaouda Attailia, Anne Oudin, Shannel Curic, Aya Yokota, Elie Banide, Pierre Génin.

  Degradation of damaged mitochondria, a process called mitophagy, plays a role in mitochondrial quality control and its dysfunction has been linked to neurodegenerative pathologies. The PINK1 kinase and the ubiquitin ligase Parkin-mediated mitophagy represents the most common pathway in which specific receptors, including Optineurin (Optn), target ubiquitin-labeled mitochondria to autophagosomes. Here, we show that Protein Kinases D (PKD) are activated and recruited to damaged mitochondria. Subsequently, PKD phosphorylate Optn to promote a complex with Parkin leading to enhancement of its ubiquitin ligase activity. Paradoxically, inhibiting PKD activity enhances the interaction between Optn and LC3, promotes the recruitment of Parkin to mitochondria, and increases the mitophagic function of Optn. This enhancement of mitophagy is characterized by increased production of mitochondrial ROS and a reduction in mitochondrial mass. The PKD kinases may therefore regulate Optn-dependent mitophagy by amplifying the Parkin-mediated degradation signals to improve the cell response against oxidative stress damage.

Keywords:  Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.111384
J Neurol. 2024 Dec 12. 272(1): 47

Clinical features and treatment of stroke-like episodes in mitochondrial disease: a cohort-based study.

Nora Mickelsson, Jussi Hirvonen, Mika H Martikainen.

   BACKGROUND: Stroke-like episode (SLE) is a subacute evolving brain syndrome in patients with primary mitochondrial diseases. Despite previous research, the understanding of the clinical spectrum, treatment, and outcomes of mitochondrial SLEs is far from complete. In this single centre study, we report the clinical symptoms and radiological findings as well as the medical treatment and outcomes of SLEs in patients with mitochondrial disease.
METHODS: This retrospective, observational study during years 2000-2023 was based on a cohort of patients diagnosed with mitochondrial disease at Turku University Hospital (TUH; Turku, Finland) in the region of Southwest Finland. Data were obtained from the hospital electronic medical record system.
RESULTS: The investigated cohort consisted of 76 patients (37 men, 39 women) with a diagnosis of mitochondrial disease. Among these, 12 patients had a history of at least one SLE; the total number of SLEs was 20. The most common genetic aetiology among patients with SLEs was m.3243A > G (N = 7). The mean age at first SLE was 40 years (range: 5-66 years), and the mean interval between episodes was 4.8 years (range: 4 months-10 years). The duration of episodes varied between 1 and 193 days (median 14 days, mean 37 days); 10 patients needed intensive care unit (ICU) treatment. The mean survival time between the first SLE and death was 3.6 years (range: 0-16 years).
CONCLUSION: Our study highlights the importance of early recognition and prompt management of SLE symptoms, especially epileptic seizures, in this life-threatening entity.

Keywords:  Epilepsy; Genetics; Mitochondrial DNA; Mitochondrial diseases; Stroke-like episode

DOI:  https://doi.org/10.1007/s00415-024-12745-y
Mol Cell. 2024 Dec 05. pii: S1097-2765(24)00909-2. [Epub ahead of print]84(23): 4612-4628.e13

Reactive oxygen species control protein degradation at the mitochondrial import gate.

Rachael McMinimy, Andrew G Manford, Christine L Gee, Srividya Chandrasekhar, Gergey Alzaem Mousa, Joelle Chuang, Lilian Phu, Karen Y Shih, Christopher M Rose, John Kuriyan, Baris Bingol, Michael Rapé.

  While reactive oxygen species (ROS) have long been known to drive aging and neurodegeneration, their persistent depletion below basal levels also disrupts organismal function. Cells counteract loss of basal ROS via the reductive stress response, but the identity and biochemical activity of ROS sensed by this pathway remain unknown. Here, we show that the central enzyme of the reductive stress response, the E3 ligase Cullin 2-FEM1 homolog B (CUL2FEM1B), specifically acts at mitochondrial TOM complexes, where it senses ROS produced by complex III of the electron transport chain (ETC). ROS depletion during times of low ETC activity triggers the localized degradation of CUL2FEM1B substrates, which sustains mitochondrial import and ensures the biogenesis of the rate-limiting ETC complex IV. As complex III yields most ROS when the ETC outpaces metabolic demands or oxygen availability, basal ROS are sentinels of mitochondrial activity that help cells adjust their ETC to changing environments, as required for cell differentiation and survival.

Keywords:  FEM1B; TOM complex; electron transport chain; mitochondria; proteasome; reductive stress response; ubiquitin

DOI:  https://doi.org/10.1016/j.molcel.2024.11.004
J Cell Sci. 2024 Dec 09. pii: jcs.263446. [Epub ahead of print]

Altered calcium responses and antioxidant properties in Friedreich's ataxia-like cerebellar astrocytes.

Chiara Marullo, Laura Croci, Iris Giupponi, Claudia Rivoletti, Sofia Zuffetti, Barbara Bettegazzi, Ottavio Cremona, Paola Giunti, Alessandro Ambrosi, Filippo Casoni, Gian Giacomo Consalez, Franca Codazzi.

  Friedreich's ataxia (FRDA) is a neurodegenerative disorder characterized by severe neurological signs, affecting the peripheral and central nervous system, caused by reduced frataxin protein (FXN) levels. While several studies highlight cellular dysfunctions in neurons, there is limited information on the effects of FXN depletion in astrocytes and on the potential non-cell autonomous mechanisms affecting neurons in FRDA. In this study, we generated a model of FRDA cerebellar astrocytes to unveil phenotypic alterations that might contribute to cerebellar atrophy. We treated primary cerebellar astrocytes with an RNA interference-based approach, to achieve a reduction of FXN comparable to that observed in patients. These FRDA-like astrocytes display some typical features of the disease, such as an increase of oxidative stress and a depletion of glutathione content. Moreover, FRDA-like astrocytes exhibit decreased calcium responses to purinergic stimuli. Our findings shed light on cellular changes caused by FXN downregulation in cerebellar astrocytes, likely impairing their complex interaction with neurons. The potentially impaired ability to provide neuronal cells with glutathione or to release neuromodulators in a calcium-dependent manner could affect neuronal function, contributing to neurodegeneration.

Keywords:  Calcium signalling; Cerebellar astrocytes; Friedreich's ataxia; Mitochondria; Oxidative stress

DOI:  https://doi.org/10.1242/jcs.263446
Genet Med Open. 2023 ;1(1): 100832

Omaveloxolone approved for patients aged 16 years and older with Friedreich ataxia (FRDA): A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG).

ACMG Therapeutics Committee5∗documents@acmg.net



Keywords:  Friedreich ataxia; Neuromuscular medicine; Omaveloxolone; Orphan drug; Precision medicine

DOI:  https://doi.org/10.1016/j.gimo.2023.100832
Free Radic Biol Med. 2024 Dec 04. pii: S0891-5849(24)01121-3. [Epub ahead of print]227 210-220

Celastrol ameliorates lipopolysaccharide (LPS)-induced acute lung injury by improving mitochondrial function through AMPK/PGC-1α/Nrf1-dependent mechanism.

Xinyu Deng, Jing He, Wenpeng Deng, Wang Deng, Xingyu Zhu, Hao Luo, Daoxin Wang.

  Acute lung injury (ALI) is a devastating clinical syndrome without effective therapy. Celastrol, as a natural anti-inflammatory compound, has showed therapeutic potential against inflammatory diseases. In this study, we have investigated the potential effect of Celastrol on lipopolysaccharide (LPS)-induced ALI. C57BL/6J mice, Nrf1-knockout mice and A549 (human alveolar epithelial cell line) cells were used to investigate the protective role of Celastrol in LPS-induced ALI. Our data showed that administration of Celastrol significantly alleviated lung pathologic injury and increased the survival rate, which was associated with the improvement of mitochondrial function in the injured lung. Moreover, Celastrol enhanced phosphorylation of AMP-activated protein kinase (AMPK) and expression of peroxisome proliferator-activated receptor coactivator protein-1α (PGC-1α), thereby increasing the nuclear translocation of nuclear respiratory factor 1 (Nrf1) and subsequent up-regulation of its downstream mitochondria electron transport chain complex I (NDUF) gene expression, which induced an increase in mitochondrial complex Ⅰ activity. The beneficial effects of Celastrol on regulation of Nrf1 were abolished by inhibition of AMPK and PGC-1α. Finally, in Nrf1 deficient mice, the protective effects of Celastrol on LPS-induced ALI were largely vanished. Our data indicated that Celastrol can prevent LPS-induced ALI by improving mitochondrial function through AMPK/PGC-1α/Nrf1-dependent mechanism, suggesting that Celastrol may represent a novel therapeutic potential for LPS-induced ALI.

Keywords:  Acute lung injury; Acute respiratory distress syndrome; Celastrol; Mitochondrial function; Nuclear respiratory factor 1

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.017
Front Aging Neurosci. 2024 ;16 1503336

Urolithin A and nicotinamide riboside differentially regulate innate immune defenses and metabolism in human microglial cells.

Helena Borland Madsen, Claudia Navarro, Emilie Gasparini, Jae-Hyeon Park, Zhiquan Li, Deborah L Croteau, Vilhelm A Bohr.

   Introduction: During aging, many cellular processes, such as autophagic clearance, DNA repair, mitochondrial health, metabolism, nicotinamide adenine dinucleotide (NAD+) levels, and immunological responses, become compromised. Urolithin A (UA) and Nicotinamide Riboside (NR) are two naturally occurring compounds known for their anti-inflammatory and mitochondrial protective properties, yet the effects of these natural substances on microglia cells have not been thoroughly investigated. As both UA and NR are considered safe dietary supplements, it is equally important to understand their function in normal cells and in disease states.
Methods: This study investigates the effects of UA and NR on immune signaling, mitochondrial function, and microglial activity in a human microglial cell line (HMC3).
Results: Both UA and NR were shown to reduce DNA damage-induced cellular senescence. However, they differentially regulated gene expression related to neuroinflammation, with UA enhancing cGAS-STING pathway activation and NR displaying broader anti-inflammatory effects. Furthermore, UA and NR differently influenced mitochondrial dynamics, with both compounds improving mitochondrial respiration but exhibiting distinct effects on production of reactive oxygen species and glycolytic function.
Discussion: These findings underscore the potential of UA and NR as therapeutic agents in managing neuroinflammation and mitochondrial dysfunction in neurodegenerative diseases.

Keywords:  aging; innate immune signaling; microglia; mitochondrial health; nicotinamide riboside; urolithin A

DOI:  https://doi.org/10.3389/fnagi.2024.1503336