bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023–04–09
24 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.
  2. MitoSwap - Mitophagy partnered with compensatory mitochondrial biogenesis during stem cell differentiation.
  3. The mitochondrial ATP synthase as an ATP consumer-a surprising therapeutic target.
  4. Mitochondria in Health, Disease, and Ageing.
  5. NAD+ repletion with niacin counteracts cancer cachexia.
  6. Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.
  7. MELAS: Phenotype Classification into Classic-versus-Atypical Presentations.
  8. Mitochondrial fumarate implicated in inflammation.
  9. Mitochondrial DNA as inflammatory DAMP: a warning of an aging immune system?
  10. The mitochondrial ribosomal protein mRpL4 regulates Notch signaling.
  11. Natural products for kidney disease treatment: Focus on targeting mitochondrial dysfunction.
  12. Protein translocation in mitochondria: Sorting out the Toms, Tims, Pams, Sams and Mia.
  13. Exogenous L-lactate administration in rat hippocampus increases expression of key regulators of mitochondrial biogenesis and antioxidant defense.
  14. Cryopreserved placental biopsies maintain mitochondrial activity for high-resolution respirometry.
  15. Acute, next-generation AMPK activation initiates a disease-resistant gene expression program in dystrophic skeletal muscle.
  16. Transient inhibition of mitochondrial function by chrysin and apigenin prolong longevity via mitohormesis in C. elegans.
  17. Quantitative haplotype-resolved analysis of mitochondrial DNA heteroplasmy in Human single oocytes, blastoids, and pluripotent stem cells.
  18. Metabolic set points of mammalian neurodevelopment.
  19. Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich's Ataxia.
  20. Sequencing through hyperexpanded Friedreich's ataxia-GAA repeats by nanopore technology: implications in genotype-phenotype correlation.
  21. Autosomal Recessive Cerebellar Ataxias in Europe: Frequency, Onset, and Severity in 677 Patients.
  22. CLPP inhibition triggers apoptosis in human ovarian granulosa cells via COX5A abnormality-Mediated mitochondrial dysfunction.
  23. Stem-cell derived 'embryos' implanted in monkeys.
  24. Skeletal muscle aging and sarcopenia: Perspectives from mechanical studies of single permeabilized muscle fibers.
  1. EMBO Mol Med. 2023 Apr 04. e16775
    Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.
    Genomics England Research Consortium
      Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.
    Keywords:  Bloom syndrome; TOP3A; mitochondrial disease; mtDNA
    DOI:  https://doi.org/10.15252/emmm.202216775
  2. Autophagy Rep. 2022 ;1(1): 210-213
    MitoSwap - Mitophagy partnered with compensatory mitochondrial biogenesis during stem cell differentiation.
    Priyanka Gajwani, Jalees Rehman.
      Differentiating stem cells must adapt their mitochondrial metabolism to fit the needs of the mature differentiated cell. In a recent study, we observed that during differentiation to an endothelial phenotype, pluripotent stem cell mitochondria are removed by mitophagy, triggering compensatory mitochondrial biogenesis to replenish the mitochondrial pool. We identified the mitochondrial phosphatase PGAM5 as the link between mitophagy and transcription of the mitochondrial biogenesis regulator PPARGC1A/PGC1α in the nucleus. Swapping of mitochondria through the coupled processes of mitophagy and mitochondrial biogenesis lead to enhanced metabolic reprogramming in the differentiated cell.
    Keywords:  CTNNB1/β-catenin; PINK1; PPARGC1A/PGC1α; differentiation; endothelium; mitochondrial biogenesis; mitofusin 2; mitophagy; stem cells
    DOI:  https://doi.org/10.1080/27694127.2022.2071549
  3. EMBO J. 2023 Apr 06. e114141
    The mitochondrial ATP synthase as an ATP consumer-a surprising therapeutic target.
    Gabriel E Valdebenito, Anitta R Chacko, Michael R Duchen.
      The mitochondrial F1 Fo -ATP synthase uses a rotary mechanism to synthesise ATP. This mechanism can, however, also operate in reverse, pumping protons at the expense of ATP, with significant potential implications for mitochondrial and age-related diseases. In a recent study, Acin-Perez et al (2023) use an elegant assay to screen compounds for the capacity to selectively inhibit ATP hydrolysis without affecting ATP synthesis. They show that (+)-epicatechin is one such compound and has significant benefits for cell and tissue function in disease models. These findings signpost a novel therapeutic approach for mitochondrial disease.
    DOI:  https://doi.org/10.15252/embj.2023114141
  4. Physiol Rev. 2023 Apr 06.
    Mitochondria in Health, Disease, and Ageing.
    John S Harrington, Stefan W Ryter, Maria Plataki, David R Price, Augustine M K Choi.
      Mitochondria are well-known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. While oxidative phosphorylation may be their most important function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell-death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.
    Keywords:  Apoptosis; Inflammation; Mitochondria; Mitochondrial Dysfunction; Mitophagy
    DOI:  https://doi.org/10.1152/physrev.00058.2021
  5. Nat Commun. 2023 Apr 03. 14(1): 1849
    NAD+ repletion with niacin counteracts cancer cachexia.
    Marc Beltrà, Noora Pöllänen, Claudia Fornelli, Kialiina Tonttila, Myriam Y Hsu, Sandra Zampieri, Lucia Moletta, Samantha Corrà, Paolo E Porporato, Riikka Kivelä, Carlo Viscomi, Marco Sandri, Juha J Hulmi, Roberta Sartori, Eija Pirinen, Fabio Penna.
      Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD+) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirm that depletion of NAD+ and downregulation of Nrk2, an NAD+ biosynthetic enzyme, are common features of severe cachexia in different mouse models. Testing NAD+ repletion therapy in cachectic mice reveals that NAD+ precursor, vitamin B3 niacin, efficiently corrects tissue NAD+ levels, improves mitochondrial metabolism and ameliorates cancer- and chemotherapy-induced cachexia. In a clinical setting, we show that muscle NRK2 is downregulated in cancer patients. The low expression of NRK2 correlates with metabolic abnormalities underscoring the significance of NAD+ in the pathophysiology of human cancer cachexia. Overall, our results propose NAD+ metabolism as a therapy target for cachectic cancer patients.
    DOI:  https://doi.org/10.1038/s41467-023-37595-6
  6. Nat Commun. 2023 Apr 06. 14(1): 1930
    Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.
    Pascale Baden, Maria Jose Perez, Hariam Raji, Federico Bertoli, Stefanie Kalb, María Illescas, Fokion Spanos, Claudio Giuliano, Alessandra Maria Calogero, Marvin Oldrati, Hannah Hebestreit, Graziella Cappelletti, Kathrin Brockmann, Thomas Gasser, Anthony H V Schapira, Cristina Ugalde, Michela Deleidi.
      Mutations in GBA1, the gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher's disease, are the most frequent genetic risk factor for Parkinson's disease (PD). Here, we employ global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from the cytosol into the mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, GCase promotes the maintenance of mitochondrial complex I (CI) integrity and function. Furthermore, GCase interacts with the mitochondrial quality control proteins HSP60 and LONP1. Disease-associated mutations impair CI stability and function and enhance the interaction with the mitochondrial quality control machinery. These findings reveal a mitochondrial role of GCase and suggest that defective CI activity and energy metabolism may drive the pathogenesis of GCase-linked neurodegeneration.
    DOI:  https://doi.org/10.1038/s41467-023-37454-4
  7. AJNR Am J Neuroradiol. 2023 Apr 06.
    MELAS: Phenotype Classification into Classic-versus-Atypical Presentations.
    C A P F Alves, A Zandifar, J T Peterson, S Z Tara, R Ganetzky, A N Viaene, S Andronikou, M J Falk, A Vossough, A C Goldstein.
       BACKGROUND AND PURPOSE: An increased number of pathogenic variants have been described in mitochondrial encephalomyopathy lactic acidosis and strokelike episodes (MELAS). Different imaging presentations have emerged in parallel with a growing recognition of clinical and outcome variability, which pose a diagnostic challenge to neurologists and radiologists and may impact an individual patient's response to therapeutic interventions. By evaluating clinical, neuroimaging, laboratory, and genetic findings, we sought to improve our understanding of the sources of potential phenotype variability in patients with MELAS.
    MATERIALS AND METHODS: This retrospective single-center study included individuals who had confirmed mitochondrial DNA pathogenic variants and a diagnosis of MELAS and whose data were reviewed from January 2000 through November 2021. The approach included a review of clinical, neuroimaging, laboratory, and genetic data, followed by an unsupervised hierarchical cluster analysis looking for sources of phenotype variability in MELAS. Subsequently, experts identified "victory-variables" that best differentiated MELAS cohort clusters.
    RESULTS: Thirty-five patients with a diagnosis of mitochondrial DNA-based MELAS (median age, 12 years; interquartile range, 7-24 years; 24 female) were eligible for this study. Fifty-three discrete variables were evaluated by an unsupervised cluster analysis, which revealed that two distinct phenotypes exist among patients with MELAS. After experts reviewed the variables, they selected 8 victory-variables with the greatest impact in determining the MELAS subgroups: developmental delay, sensorineural hearing loss, vision loss in the first strokelike episode, Leigh syndrome overlap, age at the first strokelike episode, cortical lesion size, regional brain distribution of lesions, and genetic groups. Ultimately, 2-step differentiating criteria were defined to classify atypical MELAS.
    CONCLUSIONS: We identified 2 distinct patterns of MELAS: classic MELAS and atypical MELAS. Recognizing different patterns in MELAS presentations will enable clinical and research care teams to better understand the natural history and prognosis of MELAS and identify the best candidates for specific therapeutic interventions.
    DOI:  https://doi.org/10.3174/ajnr.A7837
  8. Nat Rev Rheumatol. 2023 Apr 06.
    Mitochondrial fumarate implicated in inflammation.
    Sarah Onuora.
      
    DOI:  https://doi.org/10.1038/s41584-023-00963-z
  9. Biochem Soc Trans. 2023 Apr 04. pii: BST20221010. [Epub ahead of print]
    Mitochondrial DNA as inflammatory DAMP: a warning of an aging immune system?
    Giada Zanini, Valentina Selleri, Sandra Lopez Domenech, Mara Malerba, Milena Nasi, Anna Vittoria Mattioli, Marcello Pinti.
      Senescence of the immune system is characterized by a state of chronic, subclinical, low-grade inflammation termed 'inflammaging', with increased levels of proinflammatory cytokines, both at the tissue and systemic levels. Age-related inflammation can be mainly driven by self-molecules with immunostimulant properties, named Damage/death Associated Molecular Patterns (DAMPs), released by dead, dying, injured cells or aged cells. Mitochondria are an important source of DAMPs, including mitochondrial DNA - the small, circular, double-stranded DNA molecule found in multiple copies in the organelle. mtDNA can be sensed by at least three molecules: the Toll-like receptor 9, the NLRP3 inflammasomes, and the cyclic GMP-AMP synthase (cGAS). All these sensors can lead to the release of proinflammatory cytokines when engaged. The release of mtDNA by damaged or necrotic cells has been observed in several pathological conditions, often aggravating the course of the disease. Several lines of evidence indicate that the impairment of mtDNA quality control and of the organelle homeostasis associated with aging determines an increase in the leakage of mtDNA from the organelle to the cytosol, from the cell to the extracellular space, and into plasma. This phenomenon, mirrored by an increase in mtDNA circulating levels in elderly people, can lead to the activation of different innate immune cell types, sustaining the chronic inflammatory status that is characteristic of aging.
    Keywords:  TLR9; inflammaging; mitochondria; mtDNA
    DOI:  https://doi.org/10.1042/BST20221010
  10. EMBO Rep. 2023 Apr 03. e55764
    The mitochondrial ribosomal protein mRpL4 regulates Notch signaling.
    Dongqing Mo, Chenglin Liu, Yao Chen, Xinkai Cheng, Jie Shen, Long Zhao, Junzheng Zhang.
      Mitochondrial ribosomal proteins (MRPs) assemble as specialized ribosome to synthesize mtDNA-encoded proteins, which are essential for mitochondrial bioenergetic and metabolic processes. MRPs are required for fundamental cellular activities during animal development, but their roles beyond mitochondrial protein translation are poorly understood. Here, we report a conserved role of the mitochondrial ribosomal protein L4 (mRpL4) in Notch signaling. Genetic analyses demonstrate that mRpL4 is required in the Notch signal-receiving cells to permit target gene transcription during Drosophila wing development. We find that mRpL4 physically and genetically interacts with the WD40 repeat protein wap and activates the transcription of Notch signaling targets. We show that human mRpL4 is capable of replacing fly mRpL4 during wing development. Furthermore, knockout of mRpL4 in zebrafish leads to downregulated expression of Notch signaling components. Thus, we have discovered a previously unknown function of mRpL4 during animal development.
    Keywords:   Drosophila ; Notch; mitochondrial ribosomal protein L4; wap; zebrafish
    DOI:  https://doi.org/10.15252/embr.202255764
  11. Front Pharmacol. 2023 ;14 1142001
    Natural products for kidney disease treatment: Focus on targeting mitochondrial dysfunction.
    Jiewu Huang, Ye Liang, Lili Zhou.
      The patients with kidney diseases are increasing rapidly all over the world. With the rich abundance of mitochondria, kidney is an organ with a high consumption of energy. Hence, renal failure is highly correlated with the breakup of mitochondrial homeostasis. However, the potential drugs targeting mitochondrial dysfunction are still in mystery. The natural products have the superiorities to explore the potential drugs regulating energy metabolism. However, their roles in targeting mitochondrial dysfunction in kidney diseases have not been extensively reviewed. Herein, we reviewed a series of natural products targeting mitochondrial oxidative stress, mitochondrial biogenesis, mitophagy, and mitochondrial dynamics. We found lots of them with great medicinal values in kidney disease. Our review provides a wide prospect for seeking the effective drugs targeting kidney diseases.
    Keywords:  energy metabolism; kidney diseases; mitochondrial dysfunction; mitochondrial homeostasis; natural products
    DOI:  https://doi.org/10.3389/fphar.2023.1142001
  12. FEBS Lett. 2023 Apr 05.
    Protein translocation in mitochondria: Sorting out the Toms, Tims, Pams, Sams and Mia.
    Johannes M Herrmann, Yury Bykov.
      Mitochondria contain 902 (yeast) to 1.136 (mouse, humans) verified proteins. Except for a very small number of mitochondrially encoded core components of the respiratory chain, mitochondrial proteins are encoded by nuclear genes and synthesized in the cytosol. Different import pathways direct proteins to their respective mitochondrial subcompartment (outer membrane, intermembrane space (IMS), inner membrane and matrix). Specific targeting signals in their sequence direct proteins to their target destination and allow the proteins to embark on their respective import pathway. The main import pathways are shown here on the poster and are introduced in the following, using the mitochondrial import system of the baker's yeast Saccharomyces cerevisiae as example. However, the mitochondrial import system of mammalian cells is highly similar and deviates only in minor aspects. Even the mitochondrial import machineries of less closely related eukaryotes, such as plants and trypanosomes, are very similar and adhere to the same general principles.
    Keywords:  Mitochondria; Protein Import; Protein translocation; Translocase of the inner membrane; Translocase of the outer membrane
    DOI:  https://doi.org/10.1002/1873-3468.14614
  13. Front Mol Neurosci. 2023 ;16 1117146
    Exogenous L-lactate administration in rat hippocampus increases expression of key regulators of mitochondrial biogenesis and antioxidant defense.
    Mastura Akter, Haiying Ma, Mahadi Hasan, Anwarul Karim, Xiaowei Zhu, Liang Zhang, Ying Li.
      L-lactate plays a critical role in learning and memory. Studies in rats showed that administration of exogenous L-lactate into the anterior cingulate cortex and hippocampus (HPC) improved decision-making and enhanced long-term memory formation, respectively. Although the molecular mechanisms by which L-lactate confers its beneficial effect are an active area of investigations, one recent study found that L-lactate supplementation results in a mild reactive oxygen species burst and induction of pro-survival pathways. To further investigate the molecular changes induced by L-lactate, we injected rats with either L-lactate or artificial CSF bilaterally into the dorsal HPC and collected the HPC after 60 minutes for mass spectrometry. We identified increased levels of several proteins that include SIRT3, KIF5B, OXR1, PYGM, and ATG7 in the HPC of the L-lactate treated rats. SIRT3 (Sirtuin 3) is a key regulator of mitochondrial functions and homeostasis and protects cells against oxidative stress. Further experiments identified increased expression of the key regulator of mitochondrial biogenesis (PGC-1α) and mitochondrial proteins (ATPB, Cyt-c) as well as increased mitochondrial DNA (mtDNA) copy number in the HPC of L-lactate treated rats. OXR1 (Oxidation resistance protein 1) is known to maintain mitochondrial stability. It mitigates the deleterious effects of oxidative damage in neurons by inducing a resistance response against oxidative stress. Together, our study suggests that L-lactate can induce expression of key regulators of mitochondrial biogenesis and antioxidant defense. These findings create new research avenues to explore their contribution to the L-lactate's beneficial effect in cognitive functions as these cellular responses might enable neurons to generate more ATP to meet energy demand of neuronal activity and synaptic plasticity as well as attenuate the associated oxidative stress.
    Keywords:  PGC-1 alpha; SIRT3; hippocampus; lactate; mitochondrial biogenesis; oxidative stress; proteomics
    DOI:  https://doi.org/10.3389/fnmol.2023.1117146
  14. Mol Med. 2023 Apr 03. 29(1): 45
    Cryopreserved placental biopsies maintain mitochondrial activity for high-resolution respirometry.
    Matteo Giovarelli, Anais Serati, Silvia Zecchini, Fabiola Guelfi, Emilio Clementi, Chiara Mandò.
       BACKGROUND: High-resolution respirometry (HRR) of human biopsies can provide useful metabolic, diagnostic, and mechanistic insights for clinical research and comparative medical studies. Fresh tissues analysis offers the potential best condition, the drawback being the need to use them shortly after dissection for mitochondrial respiratory experiments. The development of effective long-term storage protocols for biopsies that allow the assessment of key Electron Transport System (ETS) parameters at later stages is thus a major need.
    METHODS: We optimised a cryopreservation protocol that preserves mitochondrial membranes intactness, otherwise affected by direct tissue freezing. The protocol is based on a gradual freezing step from on-ice to liquid nitrogen and - 80 °C storage using a specific DMSO-based buffer.
    RESULTS: Placenta is a suitable tissue to design and test the effectiveness of long-term storage protocols being metabolically active foetal tissue with mitochondrial dysfunctions contributing to placental disease and gestational disorders. Here we designed and tested the effectiveness of the cryopreservation protocol using human placenta biopsies; we measured the ETS activity by HRR of placenta specimens comparing fresh, cryopreserved, and snap frozen conditions.
    CONCLUSIONS: By this protocol, Oxygen Consumption Rate (OCR) measurements of fresh and cryopreserved placental specimens are comparable whereas snap frozen procedure impairs mitochondrial activity.
    Keywords:  Cryopreservation; High-resolution respirometry; Mitochondria; Placental biopsies
    DOI:  https://doi.org/10.1186/s10020-023-00645-2
  15. FASEB J. 2023 05;37(5): e22863
    Acute, next-generation AMPK activation initiates a disease-resistant gene expression program in dystrophic skeletal muscle.
    Sean Y Ng, Andrew I Mikhail, Stephanie R Mattina, Alexander Manta, Ian J Diffey, Vladimir Ljubicic.
      Duchenne muscular dystrophy (DMD) is a life-limiting neuromuscular disorder characterized by muscle weakness and wasting. Previous proof-of-concept studies demonstrate that the dystrophic phenotype can be mitigated with the pharmacological stimulation of AMP-activated protein kinase (AMPK). However, first-generation AMPK activators have failed to translate from bench to bedside due to either their lack of potency or toxic, off-target effects. The identification of safe and efficacious molecules that stimulate AMPK in dystrophic muscle is of particular importance as it may broaden the therapeutic landscape for DMD patients regardless of their specific dystrophin mutation. Here, we demonstrate that a single dose of the next generation, orally-bioactive AMPK agonist MK-8722 (MK) to mdx mice evoked skeletal muscle AMPK and extensive downstream stimulation within 12 h post-treatment. Specifically, MK elicited a gene expression profile indicative of a more disease-resistant slow, oxidative phenotype including increased peroxisome proliferator-activated receptor ɣ coactivator-1⍺ activity and utrophin levels. In addition, we observed augmented autophagy signaling downstream of AMPK, as well as elevations in critical autophagic genes such as Map1lc3 and Sqstm1 subsequent to the myonuclear accumulation of the master regulator of the autophagy gene program, transcription factor EB. Lastly, we show that pharmacological AMPK stimulation normalizes the expression of myogenic regulatory factors and amends activated muscle stem cell content in mdx muscle. Our results indicate that AMPK activation via MK enhances disease-mitigating mechanisms in dystrophic muscle and prefaces further investigation on the chronic effects of novel small molecule AMPK agonists.
    Keywords:  PGC-1α; autophagy; muscular dystrophy; myogenic regulatory factors; utrophin
    DOI:  https://doi.org/10.1096/fj.202201846RR
  16. Free Radic Biol Med. 2023 Apr 04. pii: S0891-5849(23)00370-2. [Epub ahead of print]
    Transient inhibition of mitochondrial function by chrysin and apigenin prolong longevity via mitohormesis in C. elegans.
    Yu Cheng, Bing-Hao Hou, Gui-Lin Xie, Ya-Ting Shao, Jie Yang, Chen Xu.
      Mild inhibition of mitochondrial function leads to longevity. Genetic disruption of mitochondrial respiratory components either by mutation or RNAi greatly extends the lifespan in yeast, worms, and drosophila. This has given rise to the idea that pharmacologically inhibiting mitochondrial function would be a workable strategy for postponing aging. Toward this end, we used a transgenic worm strain that expresses the firefly luciferase enzyme widely to evaluate compounds by tracking real-time ATP levels. We identified chrysin and apigenin, which reduced ATP production and increased the lifespan of worms. Mechanistically, we discovered that chrysin and apigenin transiently inhibit mitochondrial respiration and induce an early ROS, and the lifespan-extending effect is dependent on transient ROS formation. We also show that AAK-2/AMPK, DAF-16/FOXO, and SKN-1/NRF-2 are required for chrysin or apigenin-mediated lifespan extension. Temporary increases in ROS levels trigger an adaptive response in a mitohormetic way, thereby increasing oxidative stress capacity and cellular metabolic adaptation, finally leading to longevity. Thus, chrysin and apigenin represent a class of compounds isolated from natural products that delay senescence and improve age-related diseases by inhibiting mitochondrial function and shed new light on the function of additional plant-derived polyphenols in enhancing health and delaying aging. Collectively, this work provides an avenue for pharmacological inhibition of mitochondrial function and the mechanism underlining their lifespan-extending properties.
    Keywords:  Aging; Apigenin; C. elegans; Chrysin; Mitohormesis; ROS
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.03.264
  17. Nucleic Acids Res. 2023 Apr 04. pii: gkad209. [Epub ahead of print]
    Quantitative haplotype-resolved analysis of mitochondrial DNA heteroplasmy in Human single oocytes, blastoids, and pluripotent stem cells.
    Chongwei Bi, Lin Wang, Yong Fan, Baolei Yuan, Samhan Alsolami, Yingzi Zhang, Pu-Yao Zhang, Yanyi Huang, Yang Yu, Juan Carlos Izpisua Belmonte, Mo Li.
      Maternal mitochondria are the sole source of mtDNA for every cell of the offspring. Heteroplasmic mtDNA mutations inherited from the oocyte are a common cause of metabolic diseases and associated with late-onset diseases. However, the origin and dynamics of mtDNA heteroplasmy remain unclear. We used our individual Mitochondrial Genome sequencing (iMiGseq) technology to study mtDNA heterogeneity, quantitate single nucleotide variants (SNVs) and large structural variants (SVs), track heteroplasmy dynamics, and analyze genetic linkage between variants at the individual mtDNA molecule level in single oocytes and human blastoids. Our study presented the first single-mtDNA analysis of the comprehensive heteroplasmy landscape in single human oocytes. Unappreciated levels of rare heteroplasmic variants well below the detection limit of conventional methods were identified in healthy human oocytes, of which many are reported to be deleterious and associated with mitochondrial disease and cancer. Quantitative genetic linkage analysis revealed dramatic shifts of variant frequency and clonal expansions of large SVs during oogenesis in single-donor oocytes. iMiGseq of a single human blastoid suggested stable heteroplasmy levels during early lineage differentiation of naïve pluripotent stem cells. Therefore, our data provided new insights of mtDNA genetics and laid a foundation for understanding mtDNA heteroplasmy at early stages of life.
    DOI:  https://doi.org/10.1093/nar/gkad209
  18. Cell Metab. 2023 Apr 04. pii: S1550-4131(23)00090-6. [Epub ahead of print]35(4): 553-554
    Metabolic set points of mammalian neurodevelopment.
    Fumi Suomi, Anna Rappe, Thomas G McWilliams.
      The human nervous system matures over a protracted developmental time frame relative to other species. What sets the pace of maturation has remained a mystery. In a recent publication in Science, Iwata et al. unearth critical contributions of mitochondrial metabolism in setting the pace of species-specific corticogenesis.
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.012
  19. Hum Mol Genet. 2023 Apr 07. pii: ddad051. [Epub ahead of print]
    Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich's Ataxia.
    Elisabetta Indelicato, Alexander Kirchmair, Matthias Amprosi, Stephan Steixner, Wolfgang Nachbauer, Andreas Eigentler, Nico Wahl, Galina Apostolova, Anne Krogsdam, Rainer Schneider, Julia Wanschitz, Zlatko Trajanoski, Sylvia Boesch.
       OBJECTIVE: In Friedreich ́s Ataxia (FRDA), the most affected tissues are not accessible to sampling and available transcriptomic findings originate from blood-derived cells and animal models. Herein, we aimed at dissecting for the first time the pathophysiology of FRDA by means of RNA-sequencing in an affected tissue sampled in vivo.
    METHODS: Skeletal muscle biopsies were collected from seven FRDA patients before and after treatment with recombinant human Erythropoietin (rhuEPO) within a clinical trial. Total RNA extraction, 3'-mRNA library preparation and sequencing were performed according to standard procedures. We tested for differential gene expression with DESeq2 and performed gene set enrichment analysis with respect to control subjects.
    RESULTS: FRDA transcriptomes showed 1873 genes differentially expressed from controls. Two main signatures emerged: 1) a global downregulation of the mitochondrial transcriptome as well as of ribosome/translational machinery and 2) an upregulation of genes related to transcription and chromatin regulation, especially of repressor terms. Downregulation of the mitochondrial transcriptome was more profound than previously shown in other cellular systems. Furthermore, we observed in FRDA patients a marked upregulation of leptin, the master regulator of energy homeostasis. RhuEPO treatment further enhanced leptin expression.
    INTERPRETATION: Our findings reflect a double hit in the pathophysiology of FRDA: a transcriptional/translational issue, and a profound mitochondrial failure downstream. Leptin upregulation in the skeletal muscle in FRDA may represent a compensatory mechanism of mitochondrial dysfunction, which is amenable to pharmacological boosting. Skeletal muscle transcriptomics is a valuable biomarker to monitor therapeutic interventions in FRDA.
    DOI:  https://doi.org/10.1093/hmg/ddad051
  20. Brain Commun. 2023 ;5(2): fcad020
    Sequencing through hyperexpanded Friedreich's ataxia-GAA repeats by nanopore technology: implications in genotype-phenotype correlation.
    Bharathram Uppili, Pooja Sharma, Istaq Ahmad, Shweta Sahni, Vivekanand Asokachandran, Anil B Nagaraja, Achal K Srivastava, Mohammed Faruq.
      Friedreich's ataxia, an autosomal recessive disorder, is caused by tandem GAA nucleotide repeat expansions in intron 1 of the frataxin gene. The GAA repeats over 66 in number are considered as pathogenic, and commonly occurring pathogenic repeats are within a range of 600-1200. Clinically, the spectrum of features is confined mainly to neurological tissues; however, cardiomyopathy and diabetes mellitus have been reported in 60 and 30% of the subjects, respectively. The accurate detection of GAA repeat count is of utmost importance for clinical genetic correlation, and no study so far has attempted an approach that is of high-throughput nature and defines the exact sequence of GAA repeats. Largely, the method for detection of GAA repeats so far is either through the conventional polymerase chain reaction-based screening or Southern blot, which remains the gold standard method. We utilized an approach of long-range targeted amplification of FXN-GAA repeats using Oxford Nanopore Technologies MinION platform for accurate estimation of repeat length. We were able to achieve successful amplification of GAA repeats ranging from ∼120 to 1100 at ∼2600× mean coverage. The total throughput achievable through our protocol can allow for screening of up to 96 samples per flow cell in less than 24 h. The proposed method is clinically scalable and deployable for day-to-day diagnostics. In this paper, we demonstrate to resolve the genotype-phenotype correlation of Friedreich's ataxia patients with better accuracy.
    Keywords:  FRDA; GAA repeats; long-read sequencing; trinucleotide repeats
    DOI:  https://doi.org/10.1093/braincomms/fcad020
  21. Mov Disord. 2023 Apr 07.
    Autosomal Recessive Cerebellar Ataxias in Europe: Frequency, Onset, and Severity in 677 Patients.
    Andreas Traschütz, Astrid D Adarmes-Gomez, Mathieu Anheim, Jonathan Baets, Björn H Falkenburger, Janina Gburek-Augustat, Sarah Doss, Christoph Kamm, Peter Klivenyi, Marcus Grobe-Einsler, Thomas Klopstock, Martina Minnerop, Alexander Münchau, Chiara Pane, Mathilde Renaud, Filippo M Santorelli, Ludger Schöls, Dagmar Timmann, Stefan Vielhaber, Tobias B Haack, Bart P van de Warrenburg, Ginevra Zanni, Matthis Synofzik.
      
    DOI:  https://doi.org/10.1002/mds.29397
  22. Front Genet. 2023 ;14 1141167
    CLPP inhibition triggers apoptosis in human ovarian granulosa cells via COX5A abnormality-Mediated mitochondrial dysfunction.
    Xiong Yuan, Wenjie Ma, Shuping Chen, Huiyuan Wang, Chenyi Zhong, Li Gao, Yugui Cui, Danhua Pu, Rongrong Tan, Jie Wu.
      Premature ovarian insufficiency (POI) is characterized by early loss of ovarian function before the age of 40 years. It is confirmed to have a strong and indispensable genetic component. Caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP) is a key inducer of mitochondrial protein quality control for the clearance of misfolded or damaged proteins, which is necessary to maintain mitochondrial function. Previous findings have shown that the variation in CLPP is closely related to the occurrence of POI, which is consistent with our findings. This study identified a novel CLPP missense variant (c.628G > A) in a woman with POI who presented with secondary amenorrhea, ovarian dysfunction, and primary infertility. The variant was located in exon 5 and resulted in a change from alanine to threonine (p.Ala210Thr). Importantly, Clpp was mainly localized in the cytoplasm of mouse ovarian granulosa cells and oocytes, and was relatively highly expressed in granulosa cells. Moreover, the overexpression of c.628G > A variant in human ovarian granulosa cells decreased the proliferative capacity. Functional experiments revealed that the inhibition of CLPP decreased the content and activity of oxidative respiratory chain complex IV by affecting the degradation of aggregated or misfolded COX5A, leading to the accumulation of reactive oxygen species and reduction of mitochondrial membrane potential, ultimately activating the intrinsic apoptotic pathways. The present study demonstrated that CLPP affected the apoptosis of granulosa cells, which might be one of the mechanisms by which CLPP aberrations led to the development of POI.
    Keywords:  CLPP; COX5A; POI; apoptosis; granulosa cell (GC)
    DOI:  https://doi.org/10.3389/fgene.2023.1141167
  23. Nature. 2023 Apr 06.
    Stem-cell derived 'embryos' implanted in monkeys.
    Gemma Conroy.
      
    Keywords:  Cell biology; Ethics; Stem cells
    DOI:  https://doi.org/10.1038/d41586-023-00996-0
  24. J Biomech. 2023 Mar 27. pii: S0021-9290(23)00128-8. [Epub ahead of print]152 111559
    Skeletal muscle aging and sarcopenia: Perspectives from mechanical studies of single permeabilized muscle fibers.
    Jae-Young Lim, Walter R Frontera.
      The decline in muscle mass and strength with age is well documented and associated with weakness, decreased flexibility, vulnerability to diseases and/or injuries, and impaired functional restoration. The term sarcopenia has been used to refer to the loss of muscle mass, strength and impaired physical performance with advanced adult age and recently has become a major clinical entity in a super-aged society. To understand the pathophysiology and clinical manifestations of sarcopenia, it is essential to explore the age-related changes in the intrinsic properties of muscle fibers. Mechanical experiments with single muscle fibers have been conducted during the last 80 years and applied to human muscle research in the last 45 years as an in-vitro muscle function test. Fundamental active and passive mechanical properties of skeletal muscle can be evaluated using the isolated permeabilized (chemically skinned) single muscle fiber preparation. Changes in the intrinsic properties of older human single muscle fibers can be useful biomarkers of aging and sarcopenia. In this review, we summarize the historical development of single muscle fiber mechanical studies, the definition and diagnosis of muscle aging and sarcopenia, and age-related change of active and passive mechanical properties in single muscle fibers and discuss how these changes can be used to assess muscle aging and sarcopenia.
    Keywords:  Muscle mechanics; Older adults; Skinned muscle fibers
    DOI:  https://doi.org/10.1016/j.jbiomech.2023.111559
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