bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023‒11‒12
28 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico 
  1. Mitohormesis.
  2. Glycolysis-derived alanine from glia fuels neuronal mitochondria for memory in Drosophila.
  3. The power and potential of mitochondria transfer.
  4. ER-mitochondria contact sites in mitochondrial DNA dynamics, maintenance, and distribution.
  5. Mitophagy Activation by Urolithin A to Target Muscle Aging.
  6. Mitochondrial Inherited Disorders and their Correlation with Neurodegenerative Diseases.
  7. Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells.
  8. A novel pathogenic variant in the SCA25-related gene expanding the etiology of early-onset and progressive cerebellar ataxia in childhood.
  9. The inhibition of inner mitochondrial fusion in hepatocytes reduces NAFL and improves metabolic profile during obesity by modulating bile acid conjugation.
  10. Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver.
  11. Development of mitochondrial gene-editing strategies and their potential applications in mitochondrial hereditary diseases: a review.
  12. De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke.
  13. A century of mitochondrial research, 1922-2022.
  14. Temporal dynamics of muscle mitochondrial uncoupling-induced integrated stress response and ferroptosis defense.
  15. This hybrid baby monkey is made of cells from two embryos.
  16. Live birth of chimeric monkey with high contribution from embryonic stem cells.
  17. Correction of a homoplasmic mitochondrial tRNA mutation in patient-derived iPSCs via a mitochondrial base editor.
  18. The mitochondrial respiration signature of the bovine blastocyst reflects both environmental conditions of development as well as embryo quality.
  19. STING signaling in the brain: Molecular threats, signaling activities, and therapeutic challenges.
  20. Mitopherogenesis, a form of mitochondria-specific ectocytosis, regulates sperm mitochondrial quantity and fertility.
  21. A TTC19 mutation associated with progressive movement disorders and peripheral neuropathy: Case report and systematic review.
  22. Cristae formation is a mechanical buckling event controlled by the inner mitochondrial membrane lipidome.
  23. Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome.
  24. Transfer of massive mitochondria from astrocytes reduce propofol neurotoxicity.
  25. Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging.
  26. Mitochondrial dysfunction and neurological disorders: A narrative review and treatment overview.
  27. Mitochondrial DNA-triggered innate immune response: mechanisms and diseases.
  28. Linking of oxidative stress and mitochondrial DNA damage to the pathophysiology of idiopathic intrauterine growth restriction.
  1. Cell Metab. 2023 Nov 07. pii: S1550-4131(23)00380-7. [Epub ahead of print]35(11): 1872-1886
    Mitohormesis.
    Yu-Wei Cheng, Jie Liu, Toren Finkel.
      Perturbation of mitochondrial function can trigger a host of cellular responses that seek to restore cellular metabolism, cytosolic proteostasis, and redox homeostasis. In some cases, these responses persist even after the stress is relieved, leaving the cell or tissue in a less vulnerable state. This process-termed mitohormesis-is increasingly viewed as an important aspect of normal physiology and a critical modulator of various disease processes. Here, we review aspects of mitochondrial stress signaling that, among other things, can rewire the cell's metabolism, activate the integrated stress response, and alter cytosolic quality-control pathways. We also discuss how these pathways are implicated in various disease states from pathogen challenge to chemotherapeutic resistance and how their therapeutic manipulation can lead to new strategies for a host of chronic conditions including aging itself.
    DOI:  https://doi.org/10.1016/j.cmet.2023.10.011
  2. Nat Metab. 2023 Nov 06.
    Glycolysis-derived alanine from glia fuels neuronal mitochondria for memory in Drosophila.
    Yasmine Rabah, Raquel Francés, Julia Minatchy, Laura Guédon, Coraline Desnous, Pierre-Yves Plaçais, Thomas Preat.
      Glucose is the primary source of energy for the brain; however, it remains controversial whether, upon neuronal activation, glucose is primarily used by neurons for ATP production or if it is partially oxidized in astrocytes, as proposed by the astrocyte-neuron lactate shuttle model for glutamatergic neurons. Thus, an in vivo picture of glucose metabolism during cognitive processes is missing. Here, we uncover in Drosophila melanogaster a glia-to-neuron alanine transfer involving alanine aminotransferase that sustains memory formation. Following associative conditioning, glycolysis in glial cells produces alanine, which is back-converted into pyruvate in cholinergic neurons of the olfactory memory center to uphold their increased mitochondrial needs. Alanine, as a mediator of glia-neuron coupling, could be an alternative to lactate in cholinergic systems. In parallel, a dedicated glial glucose transporter imports glucose specifically for long-term memory, by directly transferring it to neurons for use by the pentose phosphate pathway. Our results demonstrate in vivo the compartmentalization of glucose metabolism between neurons and glial cells during memory formation.
    DOI:  https://doi.org/10.1038/s42255-023-00910-y
  3. Nature. 2023 Nov;623(7986): 283-291
    The power and potential of mitochondria transfer.
    Nicholas Borcherding, Jonathan R Brestoff.
      Mitochondria are believed to have originated through an ancient endosymbiotic process in which proteobacteria were captured and co-opted for energy production and cellular metabolism. Mitochondria segregate during cell division and differentiation, with vertical inheritance of mitochondria and the mitochondrial DNA genome from parent to daughter cells. However, an emerging body of literature indicates that some cell types export their mitochondria for delivery to developmentally unrelated cell types, a process called intercellular mitochondria transfer. In this Review, we describe the mechanisms by which mitochondria are transferred between cells and discuss how intercellular mitochondria transfer regulates the physiology and function of various organ systems in health and disease. In particular, we discuss the role of mitochondria transfer in regulating cellular metabolism, cancer, the immune system, maintenance of tissue homeostasis, mitochondrial quality control, wound healing and adipose tissue function. We also highlight the potential of targeting intercellular mitochondria transfer as a therapeutic strategy to treat human diseases and augment cellular therapies.
    DOI:  https://doi.org/10.1038/s41586-023-06537-z
  4. Int J Biochem Cell Biol. 2023 Nov 04. pii: S1357-2725(23)00131-0. [Epub ahead of print] 106492
    ER-mitochondria contact sites in mitochondrial DNA dynamics, maintenance, and distribution.
    Hema Saranya Ilamathi, Marc Germain.
      Mitochondria are central cellular metabolic hubs. Their function requires proteins encoded by nuclear DNA, but also mitochondrial DNA (mtDNA) whose maintenance is essential for the proper function of the organelle. Defective mtDNA maintenance and distribution are associated with mitochondrial diseases. mtDNA is organized into nucleo-protein complexes called nucleoids that dynamically move along the mitochondrial network and interact with each other. mtDNA replication and nucleoid distribution is an active process regulated by the complex interplay of mitochondrial dynamics, endoplasmic reticulum (ER)-mitochondria contact sites, and cytoskeletal networks. For example, defects in mitochondrial fusion and fission or ER-mitochondria contact sites affect nucleoid maintenance and distribution. In this review, we discuss the process of nucleoid dynamics and the factors regulating nucleoid maintenance and distribution.
    Keywords:  ER sheets; ERMCS; mitochondria; mtDNA-nucleoid
    DOI:  https://doi.org/10.1016/j.biocel.2023.106492
  5. Calcif Tissue Int. 2023 Nov 05.
    Mitophagy Activation by Urolithin A to Target Muscle Aging.
    Julie Faitg, Davide D'Amico, Chris Rinsch, Anurag Singh.
      The age-related loss of skeletal muscle function starts from midlife and if left unaddressed can lead to an impaired quality of life. A growing body of evidence indicates that mitochondrial dysfunction is causally involved with muscle aging. Muscles are tissues with high metabolic requirements, and contain rich mitochondria supply to support their continual energy needs. Cellular mitochondrial health is maintained by expansing of the mitochondrial pool though mitochondrial biogenesis, by preserving the natural mitochondrial dynamic process, via fusion and fission, and by ensuring the removal of damaged mitochondria through mitophagy. During aging, mitophagy levels decline and negatively impact skeletal muscle performance. Nutritional and pharmacological approaches have been proposed to manage the decline in muscle function due to impaired mitochondria bioenergetics. The natural postbiotic Urolithin A has been shown to promote mitophagy, mitochondrial function and improved muscle function across species in different experimental models and across multiple clinical studies. In this review, we explore the biology of Urolithin A and the clinical evidence of its impact on promoting healthy skeletal muscles during age-associated muscle decline.
    Keywords:  Aging; Mitochondria; Mitophagy; Muscle health; Urolithin A
    DOI:  https://doi.org/10.1007/s00223-023-01145-5
  6. Endocr Metab Immune Disord Drug Targets. 2023 Nov 01.
    Mitochondrial Inherited Disorders and their Correlation with Neurodegenerative Diseases.
    Sofjana Gushi, Dr Vasileios Balis PhD Mrsb.
      Mitochondria are essential organelles for the survival of a cell because they produce energy. The cells that need more mitochondria are neurons because they perform a variety of tasks that are necessary to support brain homeostasis. The build-up of abnormal proteins in neurons, as well as their interactions with mitochondrial proteins, or MAM proteins, cause serious health issues. As a result, mitochondrial functions, such as mitophagy, are impaired, resulting in the disorders described in this review. They are also due to mtDNA mutations, which alter the heritability of diseases. The topic of disease prevention, as well as the diagnosis, requires further explanation and exploration. Finally, there are treatments that are quite promising, but more detailed research is needed.
    Keywords:  Mitochondria; diagnosis; heritability.; mitochondrial DNA; mitophagy; neurodegeneration; prevention; treatment
    DOI:  https://doi.org/10.2174/0118715303250271231018103202
  7. Cell Chem Biol. 2023 Oct 26. pii: S2451-9456(23)00367-7. [Epub ahead of print]
    Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells.
    Valerie Perea, Kelsey R Baron, Vivian Dolina, Giovanni Aviles, Grace Kim, Jessica D Rosarda, Xiaoyan Guo, Martin Kampmann, R Luke Wiseman.
      The integrated stress response (ISR) comprises the eIF2α kinases PERK, GCN2, HRI, and PKR, which induce translational and transcriptional signaling in response to diverse insults. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activation of compensatory eIF2α kinases to rescue ISR signaling and promote mitochondrial adaptation in PERK-deficient cells. We show that the HRI activator BtdCPU and GCN2 activator halofuginone promote ISR signaling and rescue ER stress sensitivity in PERK-deficient cells. However, BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and activation of the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and adaptive mitochondrial respiration, mimicking regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK signaling and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly selective ISR activators.
    Keywords:  ISR; UPR; integrated stress response; pharmacologic activator; stress-responsive signaling pathway; unfolded protein response
    DOI:  https://doi.org/10.1016/j.chembiol.2023.10.006
  8. Neuropediatrics. 2023 Nov 07.
    A novel pathogenic variant in the SCA25-related gene expanding the etiology of early-onset and progressive cerebellar ataxia in childhood.
    Giulia Ferrera, Rossella Izzo, Daniele Ghezzi, Lorenzo Nanetti, Eleonora Lamantea, Anna Ardissone.
      Spinocerebellar ataxias (SCAs) are heterogeneous autosomal dominant progressive ataxic disorders. SCA25 has been linked to PNPT1 pathogenic variants. Although pediatric onset is not unusual, to date only one patient with onset in the first years of life has been reported. This study presents an additional case, wherein symptoms emerged during the toddler phase, accompanied by the identification of a novel PNPT1 variant. The childwas seen at 3 years because of frequent falls. Neurological examination revealed cerebellar signsand psychomotor delay. Brain MRI showed cerebellar atrophy (CA), cerebellar cortex and dentate nuclei hyperintensities. Metabolic and genetic testing was inconclusive. At follow up (age 6), the child had clinically and radiologically worsened; ENG revealed axonal sensory neuropathy. Screening of genes associated with ataxias and mitochondrial disease identified a novel, heterozygous variant in PNPT1, which was probably pathogenic. This variant was also detected in the proband's mother and maternal grandmother both asymptomatic, which aligns with the previously documented incomplete penetrance of heterozygous PNPT1 variants. Our study confirms that SCA25 can have onset in early-childhood and characterizes natural history in pediatric cases: progressive cerebellar ataxia, sensory neuropathy which manifests during the course of the disease. We report for the first time cerebellar gray matter hyperintensities, suggesting that SCA25 should be included in the differential diagnosis of cerebellar ataxias associated with such brain imaging features. In summary, SCA25 should be considered in the diagnostic workup of early onset pediatric progressive ataxias Additionally, we confirm an incomplete penetrance and highly variable expressivity of PNPT1-associated SCA25.
    DOI:  https://doi.org/10.1055/a-2205-2402
  9. Cardiovasc Res. 2023 Oct 31. pii: cvad169. [Epub ahead of print]
    The inhibition of inner mitochondrial fusion in hepatocytes reduces NAFL and improves metabolic profile during obesity by modulating bile acid conjugation.
    Lorenzo Da Dalt, Annalisa Moregola, Monika Svecla, Silvia Pedretti, Francesca Fantini, Mirko Ronzio, Patrizia Uboldi, Diletta Dolfini, Elena Donetti, Andrea Baragetti, Nico Mitro, Luca Scorrano, Giuseppe Danilo Norata.
      BACKGROUND AND AIM: Mitochondria are plastic organelles that continuously undergo biogenesis, fusion, fission, and mitophagy to control cellular energy metabolism, calcium homeostasis, hormones, sterols and bile acids (BAs) synthesis. Here we evaluated how the impairment of mitochondrial fusion in hepatocytes affect diet induced liver steatosis and obesity.METHODS AND RESULTS: Male mice selectively lacking the key protein involved in inner mitochondrial fusion, OPA1, (OPA1ΔHep) on a High Fat Diet (HFD) for 20 weeks. OPA1ΔHep mice were protected from the development of hepatic steatosis and obesity because of reduced lipid absorption; a profile which was accompanied by increased respiratory exchange ratio in vivo, suggesting a preference for carbohydrate in OPA1ΔHep in agreement with the defect in mitochondrial fusion. At the molecular level, this phenotype emerged as a consequence of poor mitochondrial-peroxisome-ER tethering in OPA1 deficient hepatocytes thus impairing bile acid conjugation and therefore its release in the bile, thus impacting lipid absorption from the diet. Concordantly the liver of NAFLD subjects presented an increased expression of OPA1 and of the network of proteins involved in mitochondrial when compared to controls.
    CONCLUSION: Patients with NAFLD present increased expression of proteins involved in mitochondrial fusion in the liver. The selective inhibition of liver mitochondrial fusion observed in hepatocyte OPA1 deficient mice protects mice from HFD-induced metabolic dysfunction by reducing lipid dietary absorption and bile acid secretion as a consequence of reduced liver mitochondria-peroxisome-ER tethering.
    Keywords:  Bile Acids; Dietary Lipid Absorption; Liver; Mitochondria
    DOI:  https://doi.org/10.1093/cvr/cvad169
  10. Nat Aging. 2023 Nov 09.
    Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver.
    Chrysa Nikopoulou, Niklas Kleinenkuhnen, Swati Parekh, Tonantzi Sandoval, Christoph Ziegenhain, Farina Schneider, Patrick Giavalisco, Kat-Folz Donahue, Anna Juliane Vesting, Marcel Kirchner, Mihaela Bozukova, Christian Vossen, Janine Altmüller, Thomas Wunderlich, Rickard Sandberg, Vangelis Kondylis, Achim Tresch, Peter Tessarz.
      Tissues within an organism and even cell types within a tissue can age with different velocities. However, it is unclear whether cells of one type experience different aging trajectories within a tissue depending on their spatial location. Here, we used spatial transcriptomics in combination with single-cell ATAC-seq and RNA-seq, lipidomics and functional assays to address how cells in the male murine liver are affected by age-related changes in the microenvironment. Integration of the datasets revealed zonation-specific and age-related changes in metabolic states, the epigenome and transcriptome. The epigenome changed in a zonation-dependent manner and functionally, periportal hepatocytes were characterized by decreased mitochondrial fitness, whereas pericentral hepatocytes accumulated large lipid droplets. Together, we provide evidence that changing microenvironments within a tissue exert strong influences on their resident cells that can shape epigenetic, metabolic and phenotypic outputs.
    DOI:  https://doi.org/10.1038/s43587-023-00513-y
  11. Cytotherapy. 2023 Nov 06. pii: S1465-3249(23)01076-9. [Epub ahead of print]
    Development of mitochondrial gene-editing strategies and their potential applications in mitochondrial hereditary diseases: a review.
    Yanyan Gao, Linlin Guo, Fei Wang, Yin Wang, Peifeng Li, Dejiu Zhang.
      Mitochondrial DNA (mtDNA) is a critical genome contained within the mitochondria of eukaryotic cells, with many copies present in each mitochondrion. Mutations in mtDNA often are inherited and can lead to severe health problems, including various inherited diseases and premature aging. The lack of efficient repair mechanisms and the susceptibility of mtDNA to damage exacerbate the threat to human health. Heteroplasmy, the presence of different mtDNA genotypes within a single cell, increases the complexity of these diseases and requires an effective editing method for correction. Recently, gene-editing techniques, including programmable nucleases such as restriction endonuclease, zinc finger nuclease, transcription activator-like effector nuclease, clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated 9 and base editors, have provided new tools for editing mtDNA in mammalian cells. Base editors are particularly promising because of their high efficiency and precision in correcting mtDNA mutations. In this review, we discuss the application of these techniques in mitochondrial gene editing and their limitations. We also explore the potential of base editors for mtDNA modification and discuss the opportunities and challenges associated with their application in mitochondrial gene editing. In conclusion, this review highlights the advancements, limitations and opportunities in current mitochondrial gene-editing technologies and approaches. Our insights aim to stimulate the development of new editing strategies that can ultimately alleviate the adverse effects of mitochondrial hereditary diseases.
    Keywords:  DddA-derived cytosine base editors (DdCBEs); adenoviruses; mitochondrial DNA (mtDNA); mitochondrially targeted nucleases; mtDNA editing technology; mtDNA heteroplasmy
    DOI:  https://doi.org/10.1016/j.jcyt.2023.10.004
  12. Genet Med. 2023 Oct 31. pii: S1098-3600(23)01029-8. [Epub ahead of print] 101013
    De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke.
    Theresa Brunet, Benedikt Zott, Victoria Lieftüchter, Dominic Lenz, Axel Schmidt, Philipp Peters, Robert Kopajtich, Malin Zaddach, Hanna Zimmermann, Irina Hüning, Diana Ballhausen, Christian Staufner, Alyssa Bianzano, Joanne Hughes, Robert W Taylor, Robert McFarland, Anita Devlin, Mihaela Mihaljević, Nina Barišić, Meino Rohlfs, Sibylle Wilfling, Neal Sondheimer, Stacy Hewson, Nikolaos M Marinakis, Konstantina Kosma, Joanne Traeger-Synodinos, Miriam Elbracht, Matthias Begemann, Sonja Trepels-Kottek, Dimah Hasan, Marcello Scala, Valeria Capra, Federico Zara, Amelie T van der Ven, Joenna Driemeyer, Christian Apitz, Johannes Krämer, Alanna Strong, Hakon Hakonarson, Deborah Watson, Johannes A Mayr, Holger Prokisch, Thomas Meitinger, Ingo Borggraefe, Juliane Spiegler, Ivo Baric, Marco Paolini, Lucia Gerstl, Matias Wagner.
      PURPOSE: RNF213, encoding a giant E3 ubiquitin ligase, has been recognized for its role as a key susceptibility gene for moyamoya disease (MMD). Case reports have also implicated specific variants in RNF213 with an early-onset form of MMD with full penetrance. We aimed to expand the phenotypic spectrum of monogenic RNF213-related disease and to evaluate genotype-phenotype correlations.METHODS: Patients were identified through reanalysis of exome sequencing (ES) data of an unselected cohort of unsolved pediatric cases and through GeneMatcher or ClinVar. Functional characterization was done by proteomics analysis and oxidative phosphorylation enzyme activities using patient derived fibroblasts.
    RESULTS: We identified 14 individuals from 13 unrelated families with (de novo) missense variants in RNF213 clustering within or around the RING domain. Individuals presented either with early-onset stroke (n=11) or with Leigh syndrome (n=3). No genotype-phenotype correlation could be established. Proteomics using patient derived fibroblasts revealed no significant differences between clinical subgroups. 3D-modeling revealed a clustering of missense variants in the tertiary structure of RNF213 potentially affecting Zinc-binding suggesting a gain-of-function or dominant negative effect.
    CONCLUSIONS: De novo missense variants in RNF213 clustering in the E3 RING or other regions affecting Zinc-binding lead to an early-onset syndrome characterized by stroke or Leigh syndrome.
    Keywords:  RNF213; exome sequencing; leigh syndrome; moyamoya; stroke
    DOI:  https://doi.org/10.1016/j.gim.2023.101013
  13. Enzymes. 2023 ;pii: S1874-6047(23)00008-2. [Epub ahead of print]54 37-70
    A century of mitochondrial research, 1922-2022.
    Howard T Jacobs.
      Although recognized earlier as subcellular entities by microscopists, mitochondria have been the subject of functional studies since 1922, when their biochemical similarities with bacteria were first noted. In this overview I trace the history of research on mitochondria from that time up to the present day, focussing on the major milestones of the overlapping eras of mitochondrial biochemistry, genetics, pathology and cell biology, and its explosion into new areas in the past 25 years. Nowadays, mitochondria are considered to be fully integrated into cell physiology, rather than serving specific functions in isolation.
    Keywords:  Apoptosis; Calcium homeostasis; Cell signalling; Chemiosmotic hypothesis; DNA replication; Endosymbiosis; Eukaryote origins; Heteroplasmy; Immunity; Krebs cycle; Mitochondrial DNA; Mitochondrial disease; Mitochondrial dynamics; Mitophagy; Oxidative phosphorylation; Reactive oxygen species; Supercomplexes
    DOI:  https://doi.org/10.1016/bs.enz.2023.07.002
  14. Front Endocrinol (Lausanne). 2023 ;14 1277866
    Temporal dynamics of muscle mitochondrial uncoupling-induced integrated stress response and ferroptosis defense.
    Carla Igual Gil, Alina Löser, Kristina Lossow, Maria Schwarz, Daniela Weber, Tilman Grune, Anna P Kipp, Susanne Klaus, Mario Ost.
      Mitochondria play multifaceted roles in cellular function, and impairments across domains of mitochondrial biology are known to promote cellular integrated stress response (ISR) pathways as well as systemic metabolic adaptations. However, the temporal dynamics of specific mitochondrial ISR related to physiological variations in tissue-specific energy demands remains unknown. Here, we conducted a comprehensive 24-hour muscle and plasma profiling of male and female mice with ectopic mitochondrial respiratory uncoupling in skeletal muscle (mUcp1-transgenic, TG). TG mice are characterized by increased muscle ISR, elevated oxidative stress defense, and increased secretion of FGF21 and GDF15 as ISR-induced myokines. We observed a temporal signature of both cell-autonomous and systemic ISR in the context of endocrine myokine signaling and cellular redox balance, but not of ferroptotic signature which was also increased in TG muscle. We show a progressive increase of muscle ISR on transcriptional level during the active phase (night time), with a subsequent peak in circulating FGF21 and GDF15 in the early resting phase. Moreover, we found highest levels of muscle oxidative defense (GPX and NQO1 activity) between the late active to early resting phase, which could aim to counteract excessive iron-dependent lipid peroxidation and ferroptosis in muscle of TG mice. These findings highlight the temporal dynamics of cell-autonomous and endocrine ISR signaling under skeletal muscle mitochondrial uncoupling, emphasizing the importance of considering such dissociation in translational strategies and sample collection for diagnostic biomarker analysis.
    Keywords:  FGF21; GDF15; circadian rhythm; ferroptosis; integrated stress response; mitochondrial uncoupling; oxidative stress; skeletal muscle
    DOI:  https://doi.org/10.3389/fendo.2023.1277866
  15. Nature. 2023 Nov 09.
    This hybrid baby monkey is made of cells from two embryos.
    Carissa Wong.
      
    Keywords:  Cell biology; Developmental biology; Stem cells
    DOI:  https://doi.org/10.1038/d41586-023-03473-w
  16. Cell. 2023 Nov 09. pii: S0092-8674(23)01087-5. [Epub ahead of print]186(23): 4996-5014.e24
    Live birth of chimeric monkey with high contribution from embryonic stem cells.
    Jing Cao, Wenjuan Li, Jie Li, Md Abdul Mazid, Chunyang Li, Yu Jiang, Wenqi Jia, Liang Wu, Zhaodi Liao, Shiyu Sun, Weixiang Song, Jiqiang Fu, Yan Wang, Yong Lu, Yuting Xu, Yanhong Nie, Xinyan Bian, Changshan Gao, Xiaotong Zhang, Liansheng Zhang, Shenshen Shang, Yunpan Li, Lixin Fu, Hao Liu, Junjian Lai, Yang Wang, Yue Yuan, Xin Jin, Yan Li, Chuanyu Liu, Yiwei Lai, Xuyang Shi, Patrick H Maxwell, Xun Xu, Longqi Liu, Muming Poo, Xiaolong Wang, Qiang Sun, Miguel A Esteban, Zhen Liu.
      A formal demonstration that mammalian pluripotent stem cells possess preimplantation embryonic cell-like (naive) pluripotency is the generation of chimeric animals through early embryo complementation with homologous cells. Whereas such naive pluripotency has been well demonstrated in rodents, poor chimerism has been achieved in other species including non-human primates due to the inability of the donor cells to match the developmental state of the host embryos. Here, we have systematically tested various culture conditions for establishing monkey naive embryonic stem cells and optimized the procedures for chimeric embryo culture. This approach generated an aborted fetus and a live chimeric monkey with high donor cell contribution. A stringent characterization pipeline demonstrated that donor cells efficiently (up to 90%) incorporated into various tissues (including the gonads and placenta) of the chimeric monkeys. Our results have major implications for the study of primate naive pluripotency and genetic engineering of non-human primates.
    DOI:  https://doi.org/10.1016/j.cell.2023.10.005
  17. Commun Biol. 2023 Nov 03. 6(1): 1116
    Correction of a homoplasmic mitochondrial tRNA mutation in patient-derived iPSCs via a mitochondrial base editor.
    Xiaoxu Chen, Mingyue Chen, Yuqing Zhu, Haifeng Sun, Yue Wang, Yuan Xie, Lianfu Ji, Cheng Wang, Zhibin Hu, Xuejiang Guo, Zhengfeng Xu, Jun Zhang, Shiwei Yang, Dong Liang, Bin Shen.
      Pathogenic mutations in mitochondrial DNA cause severe and often lethal multi-system symptoms in primary mitochondrial defects. However, effective therapies for these defects are still lacking. Strategies such as employing mitochondrially targeted restriction enzymes or programmable nucleases to shift the ratio of heteroplasmic mutations and allotopic expression of mitochondrial protein-coding genes have limitations in treating mitochondrial homoplasmic mutations, especially in non-coding genes. Here, we conduct a proof of concept study applying a screened DdCBE pair to correct the homoplasmic m.A4300G mutation in induced pluripotent stem cells derived from a patient with hypertrophic cardiomyopathy. We achieve efficient G4300A correction with limited off-target editing, and successfully restore mitochondrial function in corrected induced pluripotent stem cell clones. Our study demonstrates the feasibility of using DdCBE to treat primary mitochondrial defects caused by homoplasmic pathogenic mitochondrial DNA mutations.
    DOI:  https://doi.org/10.1038/s42003-023-05500-y
  18. Sci Rep. 2023 11 08. 13(1): 19408
    The mitochondrial respiration signature of the bovine blastocyst reflects both environmental conditions of development as well as embryo quality.
    Jessica Kurzella, Dennis Miskel, Franca Rings, Ernst Tholen, Dawit Tesfaye, Karl Schellander, Dessie Salilew-Wondim, Eva Held-Hoelker, Christine Große-Brinkhaus, Michael Hoelker.
      The major limitation of the widespread use of IVP derived embryos is their consistent deficiencies in vitality when compared with their ex vivo derived counterparts. Although embryo metabolism is considered a useful metric of embryo quality, research connecting mitochondrial function with the developmental capacity of embryos is still lacking. Therefore, the aim of the present study was to analyse bovine embryo respiration signatures in relation to developmental capacity. This was achieved by taking advantage of two generally accepted metrics for developmental capacity: (I) environmental conditions during development (vivo vs. vitro) and (II) developmental kinetics (day 7 vs. day 8 blastocysts). Our study showed that the developmental environment affected total embryo oxygen consumption while different morphokinetics illustrating the embryo qualities correlate with maximal mitochondrial respiration, mitochondrial spare capacity, ATP-linked respiration as well as efficiency of ATP generation. This respiration fingerprint for high embryo quality is reflected by relatively lower lipid contents and relatively higher ROS contents. In summary, the results of the present study extend the existing knowledge on the relationship between bovine embryo quality and the signature of mitochondrial respiration by considering contrasting developmental environments as well as different embryo morphokinetics.
    DOI:  https://doi.org/10.1038/s41598-023-45691-2
  19. Neuron. 2023 Nov 03. pii: S0896-6273(23)00795-X. [Epub ahead of print]
    STING signaling in the brain: Molecular threats, signaling activities, and therapeutic challenges.
    Kun Yang, Zhen Tang, Cong Xing, Nan Yan.
      Stimulator of interferon genes (STING) is an innate immune signaling protein critical to infections, autoimmunity, and cancer. STING signaling is also emerging as an exciting and integral part of many neurological diseases. Here, we discuss recent advances in STING signaling in the brain. We summarize how molecular threats activate STING signaling in the diseased brain and how STING signaling activities in glial and neuronal cells cause neuropathology. We also review human studies of STING neurobiology and consider therapeutic challenges in targeting STING to treat neurological diseases.
    Keywords:  A-T; AD; AGS; ALS; Aicardi-Goutières syndrome; Alzheimer's disease; Hungtington's disease, HD; PD; Parkinson's disease; STING; amyotrophic lateral sclerosis; ataxia-telangiectasia; neurodegenerative disease; neuroinflammation; type I interferon
    DOI:  https://doi.org/10.1016/j.neuron.2023.10.014
  20. Nat Cell Biol. 2023 Nov;25(11): 1625-1636
    Mitopherogenesis, a form of mitochondria-specific ectocytosis, regulates sperm mitochondrial quantity and fertility.
    Peng Liu, Jing Shi, Danli Sheng, Wenqing Lu, Jie Guo, Lei Gao, Xiaoqing Wang, Shaofeng Wu, Yanwen Feng, Dashan Dong, Xiaoshuai Huang, Hongyun Tang.
      Mitochondrial export into the extracellular space is emerging as a fundamental cellular process implicated in diverse physiological activities. Although a few studies have shed light on the process of discarding damaged mitochondria, how mitochondria are exported and the functions of mitochondrial release remain largely unclear. Here we describe mitopherogenesis, a formerly unknown process that specifically secretes mitochondria through a unique extracellular vesicle termed a 'mitopher'. We observed that during sperm development in male Caenorhabditis elegans, healthy mitochondria are exported out of the spermatids through mitopherogenesis and each of the generated mitophers harbours only one mitochondrion. In mitopherogenesis, the plasma membrane first forms mitochondrion-embedding outward buds, which then promptly bud off and thereby result in the generation of mitophers. Mechanistically, extracellular protease signalling in the testis triggers mitopher formation from spermatids, which is partially mediated by the tyrosine kinase SPE-8. Moreover, mitopherogenesis requires normal microfilament dynamics, whereas myosin VI antagonizes mitopher generation. Strikingly, our three-dimensional electron microscopy analyses indicate that mitochondrial quantity requires precise modulation during sperm development, which is critically mediated by mitopherogenesis. Inhibition of mitopherogenesis causes accumulation of mitochondria in sperm, which may lead to sperm motility and fertility defects. Our findings identify mitopherogenesis as a previously undescribed process for mitochondria-specific ectocytosis, which may represent a fundamental branch of mechanisms underlying mitochondrial quantity control to regulate cell functions during development.
    DOI:  https://doi.org/10.1038/s41556-023-01264-z
  21. CNS Neurosci Ther. 2023 Nov 06.
    A TTC19 mutation associated with progressive movement disorders and peripheral neuropathy: Case report and systematic review.
    Xianjun Xuan, Jie Ruan, Chunhong Wu, Yiyi Gao, Lingfei Li, Xiaoguang Lei.
      BACKGROUND: Mitochondrial complex III (CIII) deficiency is an autosomal recessive disease characterized by symptoms such as ataxia, cognitive dysfunction, and spastic paraplegia. Multiple genes are associated with complex III defects. Among them, the mutation of TTC19 is a rare subtype.METHODS: We screened a Chinese boy with weakness of limbs and his non-consanguineous parents by whole exome sequencing and targeted sequencing.
    RESULTS: We report a Chinese boy diagnosed with mitochondrial complex III defect type 2 carrying a homozygous variant (c.719-732del, p.Leu240Serfs*17) of the TTC19 gene. According to the genotype analysis of his family members, this is an autosomal recessive inheritance. We provide his clinical manifestation.
    CONCLUSIONS: A new type of TTC19 mutation (c.719-732del, p.Leu240Serfs*17) was found, which enriched the TTC19 gene mutation spectrum and provided new data for elucidating the pathogenesis of CIII-deficient diseases.
    DOI:  https://doi.org/10.1111/cns.14425
  22. EMBO J. 2023 Nov 07. e114054
    Cristae formation is a mechanical buckling event controlled by the inner mitochondrial membrane lipidome.
    Kailash Venkatraman, Christopher T Lee, Guadalupe C Garcia, Arijit Mahapatra, Daniel Milshteyn, Guy Perkins, Keun-Young Kim, H Amalia Pasolli, Sebastien Phan, Jennifer Lippincott-Schwartz, Mark H Ellisman, Padmini Rangamani, Itay Budin.
      Cristae are high-curvature structures in the inner mitochondrial membrane (IMM) that are crucial for ATP production. While cristae-shaping proteins have been defined, analogous lipid-based mechanisms have yet to be elucidated. Here, we combine experimental lipidome dissection with multi-scale modeling to investigate how lipid interactions dictate IMM morphology and ATP generation. When modulating phospholipid (PL) saturation in engineered yeast strains, we observed a surprisingly abrupt breakpoint in IMM topology driven by a continuous loss of ATP synthase organization at cristae ridges. We found that cardiolipin (CL) specifically buffers the inner mitochondrial membrane against curvature loss, an effect that is independent of ATP synthase dimerization. To explain this interaction, we developed a continuum model for cristae tubule formation that integrates both lipid and protein-mediated curvatures. This model highlighted a snapthrough instability, which drives IMM collapse upon small changes in membrane properties. We also showed that cardiolipin is essential in low-oxygen conditions that promote PL saturation. These results demonstrate that the mechanical function of cardiolipin is dependent on the surrounding lipid and protein components of the IMM.
    Keywords:  cardiolipin; cristae; lipids; mechanics; mitochondria
    DOI:  https://doi.org/10.15252/embj.2023114054
  23. Basic Res Cardiol. 2023 Nov 06. 118(1): 47
    Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome.
    Ilona Kutschka, Edoardo Bertero, Christina Wasmus, Ke Xiao, Lifeng Yang, Xinyu Chen, Yasuhiro Oshima, Marcus Fischer, Manuela Erk, Berkan Arslan, Lin Alhasan, Daria Grosser, Katharina J Ermer, Alexander Nickel, Michael Kohlhaas, Hanna Eberl, Sabine Rebs, Katrin Streckfuss-Bömeke, Werner Schmitz, Peter Rehling, Thomas Thum, Takahiro Higuchi, Joshua Rabinowitz, Christoph Maack, Jan Dudek.
      Barth Syndrome (BTHS) is an inherited cardiomyopathy caused by defects in the mitochondrial transacylase TAFAZZIN (Taz), required for the synthesis of the phospholipid cardiolipin. BTHS is characterized by heart failure, increased propensity for arrhythmias and a blunted inotropic reserve. Defects in Ca2+-induced Krebs cycle activation contribute to these functional defects, but despite oxidation of pyridine nucleotides, no oxidative stress developed in the heart. Here, we investigated how retrograde signaling pathways orchestrate metabolic rewiring to compensate for mitochondrial defects. In mice with an inducible knockdown (KD) of TAFAZZIN, and in induced pluripotent stem cell-derived cardiac myocytes, mitochondrial uptake and oxidation of fatty acids was strongly decreased, while glucose uptake was increased. Unbiased transcriptomic analyses revealed that the activation of the eIF2α/ATF4 axis of the integrated stress response upregulates one-carbon metabolism, which diverts glycolytic intermediates towards the biosynthesis of serine and fuels the biosynthesis of glutathione. In addition, strong upregulation of the glutamate/cystine antiporter xCT increases cardiac cystine import required for glutathione synthesis. Increased glutamate uptake facilitates anaplerotic replenishment of the Krebs cycle, sustaining energy production and antioxidative pathways. These data indicate that ATF4-driven rewiring of metabolism compensates for defects in mitochondrial uptake of fatty acids to sustain energy production and antioxidation.
    Keywords:  Amino acid; Barth syndrome; Fatty acid oxidation; Metabolism; Mitochondria; Oxidative stress
    DOI:  https://doi.org/10.1007/s00395-023-01017-x
  24. Neurosci Lett. 2023 Nov 04. pii: S0304-3940(23)00501-3. [Epub ahead of print]818 137542
    Transfer of massive mitochondria from astrocytes reduce propofol neurotoxicity.
    Zhan Zhou, Weixin Dai, Tianxiao Liu, Min Shi, Yi Wei, Lifei Chen, Yubo Xie.
      Studies have shown that propofol-induced neurotoxicity is mediated by disruption of mitochondrial fission and fusion, leading to an imbalance in energy supply for developing neurons. Healthy mitochondria released from astrocytes migrate to compromised neurons to mitigate propofol-induced neurotoxicity, yet the precise mechanisms involved require further clarification. In our investigation, primary neurons were incubated with propofol, which decreased ATP synthesis and mitochondrial membrane potential, increased ROS generation and neuronal apoptosis. Notably, astrocytes did not respond to the deleterious effects of propofol. The culture medium of neurons or astrocytes incubated with propofol was collected. It was found that mitochondrial ratio was decreased and mitochondrial function was impaired. Non-contact co-culture of neuro-astrocytes facilitated transcellular mitochondrial transfer in both physiological and propofol interventions, but failed to reverse propofol-induced neurotoxicity. The more pronounced damage to neuronal mitochondria induced by propofol compared to that in astrocytes alludes to secondary injury. Damaged neurons incubated with large, functional extracellular mitochondria derived from astrocytes demonstrates transfer of mitochondria to neurons, effectively reversing propofol-induced neurotoxicity. This discovery presents a novel mitochondrial transfer of neuro-astrocytes crosstalk that contributes to neuroprotection and neurological recovery in neurotoxicity.
    Keywords:  Astrocytes; Mitochondria; Neuron; Neurotoxicity; Propofol
    DOI:  https://doi.org/10.1016/j.neulet.2023.137542
  25. Nat Commun. 2023 Nov 03. 14(1): 7034
    Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging.
    Vanitha Nithianandam, Hassan Bukhari, Matthew J Leventhal, Rachel A Battaglia, Xianjun Dong, Ernest Fraenkel, Mel B Feany.
      Aβ peptides derived from the amyloid precursor protein (APP) have been strongly implicated in the pathogenesis of Alzheimer's disease. However, the normal function of APP and the importance of that role in neurodegenerative disease is less clear. We recover the Drosophila ortholog of APP, Appl, in an unbiased forward genetic screen for neurodegeneration mutants. We perform comprehensive single cell transcriptional and proteomic studies of Appl mutant flies to investigate Appl function in the aging brain. We find an unexpected role for Appl in control of multiple cellular pathways, including translation, mitochondrial function, nucleic acid and lipid metabolism, cellular signaling and proteostasis. We mechanistically define a role for Appl in regulating autophagy through TGFβ signaling and document the broader relevance of our findings using mouse genetic, human iPSC and in vivo tauopathy models. Our results demonstrate a conserved role for APP in controlling age-dependent proteostasis with plausible relevance to Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41467-023-42822-1
  26. Life Sci. 2023 Nov 08. pii: S0024-3205(23)00892-5. [Epub ahead of print] 122257
    Mitochondrial dysfunction and neurological disorders: A narrative review and treatment overview.
    Eman E Alshial, Muhammad Idris Abdulghaney, Al-Hassan Soliman Wadan, Mohamed Abdelfatah Abdellatif, Nada E Ramadan, Aya Muhammed Suleiman, Nahla Waheed, Maha Abdellatif, Haitham S Mohammed.
      Mitochondria play a vital role in the nervous system, as they are responsible for generating energy in the form of ATP and regulating cellular processes such as calcium (Ca2+) signaling and apoptosis. However, mitochondrial dysfunction can lead to oxidative stress (OS), inflammation, and cell death, which have been implicated in the pathogenesis of various neurological disorders. In this article, we review the main functions of mitochondria in the nervous system and explore the mechanisms related to mitochondrial dysfunction. We discuss the role of mitochondrial dysfunction in the development and progression of some neurological disorders including Parkinson's disease (PD), multiple sclerosis (MS), Alzheimer's disease (AD), depression, and epilepsy. Finally, we provide an overview of various current treatment strategies that target mitochondrial dysfunction, including pharmacological treatments, phototherapy, gene therapy, and mitotherapy. This review emphasizes the importance of understanding the role of mitochondria in the nervous system and highlights the potential for mitochondrial-targeted therapies in the treatment of neurological disorders. Furthermore, it highlights some limitations and challenges encountered by the current therapeutic strategies and puts them in future perspective.
    Keywords:  Alzheimer's disease; Depression; Epilepsy; Mitochondrial dysfunction; Multiple sclerosis; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.lfs.2023.122257
  27. Cell Mol Immunol. 2023 Nov 07.
    Mitochondrial DNA-triggered innate immune response: mechanisms and diseases.
    Ming-Ming Hu, Hong-Bing Shu.
      Various cellular stress conditions trigger mitochondrial DNA (mtDNA) release from mitochondria into the cytosol. The released mtDNA is sensed by the cGAS-MITA/STING pathway, resulting in the induced expression of type I interferon and other effector genes. These processes contribute to the innate immune response to viral infection and other stress factors. The deregulation of these processes causes autoimmune diseases, inflammatory metabolic disorders and cancer. Therefore, the cGAS-MITA/STING pathway is a potential target for intervention in infectious, inflammatory and autoimmune diseases as well as cancer. In this review, we focus on the mechanisms underlying the mtDNA-triggered activation of the cGAS-MITA/STING pathway, the effects of the pathway under various physiological and pathological conditions, and advances in the development of drugs that target cGAS and MITA/STING.
    Keywords:  Disease; Innate immunity; MITA/STING; Mitostress; Virus
    DOI:  https://doi.org/10.1038/s41423-023-01086-x
  28. Int J Health Sci (Qassim). 2023 Nov-Dec;17(6):17(6): 15-22
    Linking of oxidative stress and mitochondrial DNA damage to the pathophysiology of idiopathic intrauterine growth restriction.
    Apurva Singh, Shyam Pyari Jaiswar, Apala Priyadarshini, Sujata Deo.
      Objective: A common and serious pregnancy issue known as intrauterine growth restriction (IUGR) occurs when the fetus is unable to reach its full growth potential. Mitochondria are crucial to the development of the fetus and the placenta. We aimed to elucidate the role of oxidative stress parameters and markers of DNA damage. The integrity of the mitochondrial DNA (mtDNA) was studied.Materials and Methods: Blood samples were collected from 48 females (cases and controls, respectively). Oxidative stress parameters were analyzed. DNA was extracted followed by high-performance liquid chromatography to study 8-OH-dG and mt DNA by real-time polymerase chain reaction. Western blot analysis was performed for nuclear-encoded mitochondrial proteins and DNA damage markers.
    Results: When pregnant women were compared to non-pregnant women in their first, second, and third trimesters, a highly significant progressive drop in circulating mtDNA was found. In addition, mtDNA was considerably higher in mothers carrying IUGR fetuses than in healthy pregnancies. Sirtuin-3 protein expression was considerably suppressed in the IUGR placenta (P = 0.027), whereas Nrf1 expression was not statistically different from the control group in the IUGR. Increased oxidative stress led to greater DNA damage in IUGR. The highest concentrations of 8-OH-dG were found in IUGR with levels significantly higher than those in the non-pregnant group.
    Conclusion: Our research sets the path for further investigation into mitochondrial anomalies in IUGR pregnancies and offers evidence for disturbed mitochondrial homeostasis. The mtDNA might offer a fresh perspective on the processes involved in physiological gestation. In addition, the presence of mtDNA may aid in the diagnosis of IUGR during pregnancy.
    Keywords:  8-OH-dG; homeostasis; intrauterine growth restriction; mtDNA; oxidative stress
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