bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023–11–26
nineteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mitochondrial phosphoproteomes are functionally specialized across tissues.
  2. Mitochondria, a Key Target in Amyotrophic Lateral Sclerosis Pathogenesis.
  3. Mitochondrial nucleoid condensates drive peripheral fission through high membrane curvature.
  4. Penetrance and expressivity of mitochondrial variants in a large clinically unselected population.
  5. Mechanisms of stress management in mitochondrial protein import.
  6. Progress in diagnosis and treatment of Leber's hereditary optic neuropathy.
  7. Pregnancy-responsive pools of adult neural stem cells for transient neurogenesis in mothers.
  8. Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome.
  9. Mutation at the entrance of the quinone cavity severely disrupts quinone binding in respiratory complex I.
  10. Mitochondria-sequestered Aβ renders synaptic mitochondria vulnerable in the elderly with a risk of Alzheimer disease.
  11. PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling.
  12. Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice.
  13. Inferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution.
  14. Lower muscle mitochondrial energetics is associated with greater phenotypic frailty in older women and men: the Study of Muscle, Mobility and Aging.
  15. Celastrol Alleviates Mitochondrial Oxidative Stress and Brain Injury after Intracerebral Hemorrhage by Promoting OPA1-Dependent Mitochondrial Fusion.
  16. Improvement Effect of Mitotherapy on the Cognitive Ability of Alzheimer's Disease through NAD+/SIRT1-Mediated Autophagy.
  17. Targeting Mitochondrial Dysfunction and Oxidative Stress to Prevent the Neurodegeneration of Retinal Ganglion Cells.
  18. The ribosome-associated chaperone Zuo1 controls translation upon TORC1 inhibition.
  19. Autophagy drives the conversion of developmental neural stem cells to the adult quiescent state.
  1. Life Sci Alliance. 2024 Feb;pii: e202302147. [Epub ahead of print]7(2):
    Mitochondrial phosphoproteomes are functionally specialized across tissues.
    Fynn M Hansen, Laura S Kremer, Ozge Karayel, Isabell Bludau, Nils-Göran Larsson, Inge Kühl, Matthias Mann.
      Mitochondria are essential organelles whose dysfunction causes human pathologies that often manifest in a tissue-specific manner. Accordingly, mitochondrial fitness depends on versatile proteomes specialized to meet diverse tissue-specific requirements. Increasing evidence suggests that phosphorylation may play an important role in regulating tissue-specific mitochondrial functions and pathophysiology. Building on recent advances in mass spectrometry (MS)-based proteomics, we here quantitatively profile mitochondrial tissue proteomes along with their matching phosphoproteomes. We isolated mitochondria from mouse heart, skeletal muscle, brown adipose tissue, kidney, liver, brain, and spleen by differential centrifugation followed by separation on Percoll gradients and performed high-resolution MS analysis of the proteomes and phosphoproteomes. This in-depth map substantially quantifies known and predicted mitochondrial proteins and provides a resource of core and tissue-specific mitochondrial proteins (mitophos.de). Predicting kinase substrate associations for different mitochondrial compartments indicates tissue-specific regulation at the phosphoproteome level. Illustrating the functional value of our resource, we reproduce mitochondrial phosphorylation events on dynamin-related protein 1 responsible for its mitochondrial recruitment and fission initiation and describe phosphorylation clusters on MIGA2 linked to mitochondrial fusion.
    DOI:  https://doi.org/10.26508/lsa.202302147
  2. Genes (Basel). 2023 Oct 24. pii: 1981. [Epub ahead of print]14(11):
    Mitochondria, a Key Target in Amyotrophic Lateral Sclerosis Pathogenesis.
    Emmanuelle C Genin, Mélanie Abou-Ali, Véronique Paquis-Flucklinger.
      Mitochondrial dysfunction occurs in numerous neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS), where it contributes to motor neuron (MN) death. Of all the factors involved in ALS, mitochondria have been considered as a major player, as secondary mitochondrial dysfunction has been found in various models and patients. Abnormal mitochondrial morphology, defects in mitochondrial dynamics, altered activities of respiratory chain enzymes and increased production of reactive oxygen species have been described. Moreover, the identification of CHCHD10 variants in ALS patients was the first genetic evidence that a mitochondrial defect may be a primary cause of MN damage and directly links mitochondrial dysfunction to the pathogenesis of ALS. In this review, we focus on the role of mitochondria in ALS and highlight the pathogenic variants of ALS genes associated with impaired mitochondrial functions. The multiple pathways demonstrated in ALS pathogenesis suggest that all converge to a common endpoint leading to MN loss. This may explain the disappointing results obtained with treatments targeting a single pathological process. Fighting against mitochondrial dysfunction appears to be a promising avenue for developing combined therapies in the future.
    Keywords:  ALS genes; CHCHD10; amyotrophic lateral sclerosis; frontotemporal dementia; mitochondria; motor neuron disease
    DOI:  https://doi.org/10.3390/genes14111981
  3. Cell Rep. 2023 Nov 23. pii: S2211-1247(23)01484-5. [Epub ahead of print]42(12): 113472
    Mitochondrial nucleoid condensates drive peripheral fission through high membrane curvature.
    Qixin Chen, Liu-Yi Liu, Zhiqi Tian, Zhou Fang, Kang-Nan Wang, Xintian Shao, Chengying Zhang, Weiwei Zou, Fiona Rowan, Kangqiang Qiu, Baohua Ji, Jun-Lin Guan, Dechang Li, Zong-Wan Mao, Jiajie Diao.
      Mitochondria are dynamic organelles that undergo fusion and fission events, in which the mitochondrial membrane and DNA (mtDNA) play critical roles. The spatiotemporal organization of mtDNA reflects and impacts mitochondrial dynamics. Herein, to study the detailed dynamics of mitochondrial membrane and mtDNA, we rationally develop a dual-color fluorescent probe, mtGLP, that could be used for simultaneously monitoring mitochondrial membrane and mtDNA dynamics via separate color outputs. By combining mtGLP with structured illumination microscopy to monitor mitochondrial dynamics, we discover the formation of nucleoid condensates in damaged mitochondria. We further reveal that nucleoid condensates promoted the peripheral fission of damaged mitochondria via asymmetric segregation. Through simulations, we find that the peripheral fission events occurred when the nucleoid condensates interacted with the highly curved membrane regions at the two ends of the mitochondria. Overall, we show that mitochondrial nucleoid condensates utilize peripheral fission to maintain mitochondrial homeostasis.
    Keywords:  CP: Cell biology; chemical biology
    DOI:  https://doi.org/10.1016/j.celrep.2023.113472
  4. Hum Mol Genet. 2023 Nov 21. pii: ddad194. [Epub ahead of print]
    Penetrance and expressivity of mitochondrial variants in a large clinically unselected population.
    Stuart J Cannon, Timothy Hall, Gareth Hawkes, Kevin Colclough, Roisin M Boggan, Caroline F Wright, Sarah J Pickett, Andrew T Hattersley, Michael N Weedon, Kashyap A Patel.
       BACKGROUND: Whole genome sequencing (WGS) from large clinically unselected cohorts provides a unique opportunity to assess the penetrance and expressivity of rare and/or known pathogenic mitochondrial variants in population.
    METHOD: Using WGS from 179 862 clinically unselected individuals from the UK Biobank, we performed extensive single and rare variant aggregation association analyses of 15 881 mtDNA variants and 73 known pathogenic variants with 15 mitochondrial disease-relevant phenotypes.
    RESULTS: We identified 12 homoplasmic and one heteroplasmic variant (m.3243A>G) with genome-wide significant associations in our clinically unselected cohort. Heteroplasmic m.3243A>G (MAF = 0.0002, a known pathogenic variant) was associated with diabetes, deafness and heart failure and 12 homoplasmic variants increased aspartate aminotransferase levels including three low-frequency variants (MAF ~0.002 and beta~0.3 SD). Most pathogenic mitochondrial disease variants (n = 66/74) were rare in the population (<1:9000). Aggregated or single variant analysis of pathogenic variants showed low penetrance in unselected settings for the relevant phenotypes, except m.3243A>G. Multi-system disease risk and penetrance of diabetes, deafness and heart failure greatly increased with m.3243A>G level ≥ 10%. The odds ratio of these traits increased from 5.61, 12.3 and 10.1 to 25.1, 55.0 and 39.5 respectively. Diabetes risk with m.3243A>G was further influenced by type 2 diabetes genetic risk.
    CONCLUSION: Our study of mitochondrial variation in a large-unselected population identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected settings. m.3243A>G was an exception at higher heteroplasmy showing a significant impact on health making it a good candidate for incidental reporting.
    Keywords:  UK biobank; maternally inherited diabetes and deafness; mitochondria; mitochondrial disease
    DOI:  https://doi.org/10.1093/hmg/ddad194
  5. Biochem Soc Trans. 2023 Nov 21. pii: BST20230377. [Epub ahead of print]
    Mechanisms of stress management in mitochondrial protein import.
    Maryam Mukhtar, Krutika Thakkur, Agnieszka Chacinska, Piotr Bragoszewski.
      Mitochondria are vital to the functions of eukaryotic cells. Most mitochondrial proteins are transported into the organelle following their synthesis by cytoplasmic ribosomes. However, precise protein targeting is complex because the two diverse lipid membranes encase mitochondria. Efficient protein translocation across membranes and accurate sorting to specific sub-compartments require the cooperation of multiple factors. Any failure in mitochondrial protein import can disrupt organelle fitness. Proteins intended for mitochondria make up a significant portion of all proteins produced in the cytosol. Therefore, import defects causing their mislocalization can significantly stress cellular protein homeostasis. Recognition of this phenomenon has increased interest in molecular mechanisms that respond to import-related stress and restore proteostasis, which is the focus of this review. Significantly, disruptions in protein homeostasis link strongly to the pathology of several degenerative disorders highly relevant in ageing societies. A comprehensive understanding of protein import quality control will allow harnessing this machinery in therapeutic approaches.
    Keywords:  mitochondria; protein degradation; protein transport; proteostasis; proteotoxicity; stress
    DOI:  https://doi.org/10.1042/BST20230377
  6. J Mol Med (Berl). 2023 Nov 20.
    Progress in diagnosis and treatment of Leber's hereditary optic neuropathy.
    Qingyue Ma, Ying Sun, Ke Lei, Wenjuan Luo.
      Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease with central vision loss as the main symptom. It is one of the diseases that cause vision loss and optic atrophy in young and middle-aged people. The mutations of these three primary mitochondrial mutations, m.11778G>A, m.14484T>C, and m.3460G>A, are the main molecular basis, but their pathogenesis is also affected by nuclear genes, mitochondrial genetic background, and environmental factors. This article summarizes the research progress on molecular pathogenesis, clinical symptoms, and treatment of LHON in recent years, aiming to summarize the genetic pathogenesis and clinical treatment points of LHON.
    Keywords:  Diagnosis; Leber’s hereditary optic neuropathy; Progress; Treatment; mtDNA
    DOI:  https://doi.org/10.1007/s00109-023-02389-2
  7. Science. 2023 Nov 24. 382(6673): 958-963
    Pregnancy-responsive pools of adult neural stem cells for transient neurogenesis in mothers.
    Zayna Chaker, Corina Segalada, Jonas A Kretz, Ilhan E Acar, Ana C Delgado, Valerie Crotet, Andreas E Moor, Fiona Doetsch.
      Adult neural stem cells (NSCs) contribute to lifelong brain plasticity. In the adult mouse ventricular-subventricular zone, NSCs are heterogeneous and, depending on their location in the niche, give rise to different subtypes of olfactory bulb (OB) interneurons. Here, we show that multiple regionally distinct NSCs, including domains that are usually quiescent, are recruited on different gestation days during pregnancy. Synchronized activation of these adult NSC pools generates transient waves of short-lived OB interneurons, especially in layers with less neurogenesis under homeostasis. Using spatial transcriptomics, we identified molecular markers of pregnancy-associated interneurons and showed that some subsets are temporarily needed for own pup recognition. Thus, pregnancy triggers transient yet behaviorally relevant neurogenesis, highlighting the physiological relevance of adult stem cell heterogeneity.
    DOI:  https://doi.org/10.1126/science.abo5199
  8. Nat Metab. 2023 Nov 23.
    Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome.
    Valerian E Kagan, Yulia Y Tyurina, Karolina Mikulska-Ruminska, Deena Damschroder, Eduardo Vieira Neto, Alessia Lasorsa, Alexander A Kapralov, Vladimir A Tyurin, Andrew A Amoscato, Svetlana N Samovich, Austin B Souryavong, Haider H Dar, Abu Ramim, Zhuqing Liang, Pablo Lazcano, Jiajia Ji, Michael W Schmidtke, Kirill Kiselyov, Aybike Korkmaz, Georgy K Vladimirov, Margarita A Artyukhova, Pushpa Rampratap, Laura K Cole, Ammanamanchi Niyatie, Emma-Kate Baker, Jim Peterson, Grant M Hatch, Jeffrey Atkinson, Jerry Vockley, Bernhard Kühn, Robert Wessells, Patrick C A van der Wel, Ivet Bahar, Hülya Bayir, Miriam L Greenberg.
      Barth syndrome (BTHS) is a life-threatening genetic disorder with unknown pathogenicity caused by mutations in TAFAZZIN (TAZ) that affect remodeling of mitochondrial cardiolipin (CL). TAZ deficiency leads to accumulation of mono-lyso-CL (MLCL), which forms a peroxidase complex with cytochrome c (cyt c) capable of oxidizing polyunsaturated fatty acid-containing lipids. We hypothesized that accumulation of MLCL facilitates formation of anomalous MLCL-cyt c peroxidase complexes and peroxidation of polyunsaturated fatty acid phospholipids as the primary BTHS pathogenic mechanism. Using genetic, biochemical/biophysical, redox lipidomic and computational approaches, we reveal mechanisms of peroxidase-competent MLCL-cyt c complexation and increased phospholipid peroxidation in different TAZ-deficient cells and animal models and in pre-transplant biopsies from hearts of patients with BTHS. A specific mitochondria-targeted anti-peroxidase agent inhibited MLCL-cyt c peroxidase activity, prevented phospholipid peroxidation, improved mitochondrial respiration of TAZ-deficient C2C12 myoblasts and restored exercise endurance in a BTHS Drosophila model. Targeting MLCL-cyt c peroxidase offers therapeutic approaches to BTHS treatment.
    DOI:  https://doi.org/10.1038/s42255-023-00926-4
  9. Sci Rep. 2023 Nov 21. 13(1): 20413
    Mutation at the entrance of the quinone cavity severely disrupts quinone binding in respiratory complex I.
    Jason Tae Yi, Panyue Wang, Alexei A Stuchebrukhov.
      In all resolved structures of complex I, there exists a tunnel-like Q-chamber for ubiquinone binding and reduction. The entrance to the Q-chamber in ND1 subunit forms a narrow bottleneck, which is rather tight and requires thermal conformational changes for ubiquinone to get in and out of the binding chamber. The substitution of alanine with threonine at the bottleneck (AlaThr MUT), associated with 3460/ND1 mtDNA mutation in human complex I, is implicated in Leber's Hereditary Optic Neuropathy (LHON). Here, we show the AlaThr MUT further narrows the Q-chamber entrance cross-section area by almost 30%, increasing the activation free energy barrier of quinone passage by approximately 5 kJ mol-1. This severely disrupts quinone binding and reduction as quinone passage through the bottleneck is slowed down almost tenfold. Our estimate of the increase in free energy barrier is entirely due to the bottleneck narrowing, leading to a reduction of the transition state entropy between WT and MUT, and thus more difficult quinone passage. Additionally, we investigate details of possible water exchange between the Q-chamber and membrane. We find water exchange is dynamic in WT but may be severely slowed in MUT. We propose that LHON symptoms caused by 3460/ND1 mtDNA mutation are due to slowed quinone binding. This leads to an increased production of reactive oxidative species due to upstream electron backup at the FMN site of complex I, thus resulting in a mt bioenergetic defect.
    DOI:  https://doi.org/10.1038/s41598-023-47314-2
  10. JCI Insight. 2023 Nov 22. pii: e174290. [Epub ahead of print]8(22):
    Mitochondria-sequestered Aβ renders synaptic mitochondria vulnerable in the elderly with a risk of Alzheimer disease.
    Kun Jia, Jing Tian, Tienju Wang, Lan Guo, Zhenyu Xuan, Russell H Swerdlow, Heng Du.
      Mitochondria are critical for neurophysiology, and mitochondrial dysfunction constitutes a characteristic pathology in both brain aging and Alzheimer disease (AD). Whether mitochondrial deficiency in brain aging and AD is mechanistically linked, however, remains controversial. We report a correlation between intrasynaptosomal amyloid β 42 (Aβ42) and synaptic mitochondrial bioenergetics inefficiency in both aging and amnestic mild cognitive impairment, a transitional stage between normal aging and AD. Experiments using a mouse model expressing nonmutant humanized Aβ (humanized Aβ-knockin [hAβ-KI] mice) confirmed the association of increased intramitochondrial sequestration of Aβ42 with exacerbated synaptic mitochondrial dysfunction in an aging factor- and AD risk-bearing context. Also, in comparison with global cerebral Aβ, intramitochondrial Aβ was relatively preserved from activated microglial phagocytosis in aged hAβ-KI mice. The most parsimonious interpretation of our results is that aging-related mitochondrial Aβ sequestration renders synaptic mitochondrial dysfunction in the transitional stage between normal aging and AD. Mitochondrial dysfunction in both brain aging and the prodromal stage of AD may follow a continuous transition in response to escalated intraneuronal, especially intramitochondrial Aβ, accumulation. Moreover, our findings further implicate a pivotal role of mitochondria in harboring early amyloidosis during the conversion from normal to pathological aging.
    Keywords:  Aging; Alzheimer disease; Mitochondria; Mouse models; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.174290
  11. Nat Commun. 2023 Nov 21. 14(1): 7567
    PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling.
    Yongfang Lin, Jing Yang, Qili Yang, Sha Zeng, Jiayu Zhang, Yuanxiang Zhu, Yuxin Tong, Lin Li, Weiqi Tan, Dahua Chen, Qinmiao Sun.
      TANK-binding kinase 1 (TBK1) is a key kinase in regulating antiviral innate immune responses. While the oligomerization of TBK1 is critical for its full activation, the molecular mechanism of how TBK1 forms oligomers remains unclear. Here, we show that protein tyrosine kinase 2 beta (PTK2B) acts as a TBK1-interacting protein and regulates TBK1 oligomerization. Functional assays reveal that PTK2B depletion reduces antiviral signaling in mouse embryonic fibroblasts, macrophages and dendritic cells, and genetic experiments show that Ptk2b-deficient mice are more susceptible to viral infection than control mice. Mechanistically, we demonstrate that PTK2B directly phosphorylates residue Tyr591 of TBK1, which increases TBK1 oligomerization and activation. In addition, we find that PTK2B also interacts with the stimulator of interferon genes (STING) and can promote its oligomerization in a kinase-independent manner. Collectively, PTK2B enhances the oligomerization of TBK1 and STING via different mechanisms, subsequently regulating STING-TBK1 activation to ensure efficient antiviral innate immune responses.
    DOI:  https://doi.org/10.1038/s41467-023-43419-4
  12. Nat Metab. 2023 Nov 20.
    Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice.
    Wan-Ting Dong, Li-Hong Long, Qiao Deng, Duo Liu, Jia-Lin Wang, Fang Wang, Jian-Guo Chen.
      Neurons are particularly susceptible to energy fluctuations in response to stress. Mitochondrial fission is highly regulated to generate ATP via oxidative phosphorylation; however, the role of a regulator of mitochondrial fission in neuronal energy metabolism and synaptic efficacy under chronic stress remains elusive. Here, we show that chronic stress promotes mitochondrial fission in the medial prefrontal cortex via activating dynamin-related protein 1 (Drp1), resulting in mitochondrial dysfunction in male mice. Both pharmacological inhibition and genetic reduction of Drp1 ameliorates the deficit of excitatory synaptic transmission and stress-related depressive-like behavior. In addition, enhancing Drp1 fission promotes stress susceptibility, which is alleviated by coenzyme Q10, which potentiates mitochondrial ATP production. Together, our findings unmask the role of Drp1-dependent mitochondrial fission in the deficits of neuronal metabolic burden and depressive-like behavior and provides medication basis for metabolism-related emotional disorders.
    DOI:  https://doi.org/10.1038/s42255-023-00924-6
  13. Nat Commun. 2023 11 18. 14(1): 7525
    Inferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution.
    Alon Stern, Mariam Fokra, Boris Sarvin, Ahmad Abed Alrahem, Won Dong Lee, Elina Aizenshtein, Nikita Sarvin, Tomer Shlomi.
      The inability to inspect metabolic activities within distinct subcellular compartments has been a major barrier to our understanding of eukaryotic cell metabolism. Previous work addressed this challenge by analyzing metabolism in isolated organelles, which grossly bias metabolic activity. Here, we describe a method for inferring physiological metabolic fluxes and metabolite concentrations in mitochondria and cytosol based on isotope tracing experiments performed with intact cells. This is made possible by computational deconvolution of metabolite isotopic labeling patterns and concentrations into cytosolic and mitochondrial counterparts, coupled with metabolic and thermodynamic modelling. Our approach lowers the uncertainty regarding compartmentalized fluxes and concentrations by one and three orders of magnitude compared to existing modelling approaches, respectively. We derive a quantitative view of mitochondrial and cytosolic metabolic activities in central carbon metabolism across cultured cell lines without performing cell fractionation, finding major variability in compartmentalized malate-aspartate shuttle fluxes. We expect our approach for inferring metabolism at a subcellular resolution to be instrumental for a variety of studies of metabolic dysfunction in human disease and for bioengineering.
    DOI:  https://doi.org/10.1038/s41467-023-42824-z
  14. Geroscience. 2023 Nov 21.
    Lower muscle mitochondrial energetics is associated with greater phenotypic frailty in older women and men: the Study of Muscle, Mobility and Aging.
    Theresa Mau, Haley N Barnes, Terri L Blackwell, Philip A Kramer, Scott R Bauer, David J Marcinek, Sofhia V Ramos, Daniel E Forman, Frederico G S Toledo, Russell T Hepple, Stephen B Kritchevsky, Steven R Cummings, Anne B Newman, Paul M Coen, Peggy M Cawthon.
       BACKGROUND: Phenotypic frailty syndrome identifies older adults at greater risk for adverse health outcomes. Despite the critical role of mitochondria in maintaining cellular function, including energy production, the associations between muscle mitochondrial energetics and frailty have not been widely explored in a large, well-phenotyped, older population.
    METHODS: The Study of Muscle, Mobility and Aging (SOMMA) assessed muscle energetics in older adults (N = 879, mean age = 76.3 years, 59.2% women). 31Phosporous magnetic resonance spectroscopy measured maximal production of adenosine triphosphate (ATPmax) in vivo, while ex vivo high-resolution respirometry of permeabilized muscle fibers from the vastus lateralis measured maximal oxygen consumption supported by fatty acids and complex I- and II-linked carbohydrates (e.g., Max OXPHOSCI+CII). Five frailty criteria, shrinking, weakness, exhaustion, slowness, and low activity, were used to classify participants as robust (0, N = 397), intermediate (1-2, N = 410), or frail (≥ 3, N = 66). We estimated the proportional odds ratio (POR) for greater frailty, adjusted for multiple potential confounders.
    RESULTS: One-SD decrements of most respirometry measures (e.g., Max OXPHOSCI+CII, adjusted POR = 1.5, 95%CI [1.2,1.8], p = 0.0001) were significantly associated with greater frailty classification. The associations of ATPmax with frailty were weaker than those between Max OXPHOSCI+CII and frailty. Muscle energetics was most strongly associated with slowness and low physical activity components.
    CONCLUSIONS: Our data suggest that deficits in muscle mitochondrial energetics may be a biological driver of frailty in older adults. On the other hand, we did observe differential relationships between measures of muscle mitochondrial energetics and the individual components of frailty.
    Keywords:  Aging; Mitochondria; Muscle energetics; Phenotypic frailty
    DOI:  https://doi.org/10.1007/s11357-023-01002-1
  15. Neuroscience. 2023 Nov 21. pii: S0306-4522(23)00516-X. [Epub ahead of print]
    Celastrol Alleviates Mitochondrial Oxidative Stress and Brain Injury after Intracerebral Hemorrhage by Promoting OPA1-Dependent Mitochondrial Fusion.
    Chunyan Diao, Zhengxuan Yang, Qing Hu, Pengfei Yao, Xiaodong Qu, Changdong Li, Shenghao Zhang, Jie Zhou.
      Mitochondrial oxidative stress is one of the characteristics of secondary brain injury (SBI) after intracerebral hemorrhage (ICH), contributing largely to the apoptosis of neurons. Celastrol, a quinone methide triterpene that possesses antioxidant and mitochondrial protective properties, has emerged as a neuroprotective agent. However, the activity of celastrol has not been tested in ICH-induced SBI. In this study, we found that celastrol could effectively alleviate neurological function deficits and reduce brain oedema and neuronal apoptosis caused by ICH. Through electron microscopy, we found that celastrol could significantly attenuate mitochondrial morphology impairment. Therefore, we tested the regulatory proteins of mitochondrial dynamics and found that celastrol could reverse the downwards trend of OPA1 expression after ICH. In view of this, by culturing OPA1-deficient primary neurons and constructing neuron-specific OPA1 conditional knockout mice, we found that the protective effects of celastrol on mitochondrial morphology and function after ICH were counteracted in the absence of OPA1. Further experiments also showed that OPA1 is indispensable for the protective effects of celastrol on ICH-induced secondary brain injury. In summary, we have demonstrated that celastrol is a potential drug for the treatment of ICH and have revealed a novel mechanism by which celastrol exerts its antioxidant effects by promoting OPA1-mediated mitochondrial fusion.
    Keywords:  Celastrol; ICH; Mitochondria; OPA1; Oxidative stress
    DOI:  https://doi.org/10.1016/j.neuroscience.2023.11.022
  16. Antioxidants (Basel). 2023 Nov 16. pii: 2006. [Epub ahead of print]12(11):
    Improvement Effect of Mitotherapy on the Cognitive Ability of Alzheimer's Disease through NAD+/SIRT1-Mediated Autophagy.
    Xiaoxi Yang, Peiyu Zhou, Zizhen Zhao, Jingli Li, Zhigang Fan, Xiaorong Li, Zhihong Cui, Ailing Fu.
      To date, Alzheimer's disease (AD) has grown to be a predominant health challenge that disturbs the elderly population. Studies have shown that mitochondrial dysfunction is one of the most significant features of AD. Transplantation therapy of healthy mitochondria (mitotherapy), as a novel therapeutic strategy to restore mitochondrial function, is proposed to treat the mitochondria-associated disease. Also, the molecular mechanism of mitotherapy remains unclear. Here, we applied the mitotherapy in AD model mice induced by amyloid-β (Aβ) plaque deposition and suggested that autophagy would be an important mechanism of the mitotherapy. After the healthy mitochondria entered the defective neuronal cells damaged by the misfolded Aβ protein, autophagy was activated through the NAD+-dependent deacetylase sirtuin 1 (SIRT1) signal. The damaged mitochondria and Aβ protein were eliminated by autophagy, which could also decrease the content of radical oxygen species (ROS). Moreover, the levels of brain-derived neurotrophic factor (BDNF) and extracellular-regulated protein kinases (ERK) phosphorylation increased after mitotherapy, which would be beneficial to repair neuronal function. As a result, the cognitive ability of AD animals was ameliorated in a water maze test after the healthy mitochondria were administrated to the mice. The study indicated that mitotherapy would be an effective approach to AD treatment through the mechanism of autophagy activation.
    Keywords:  AD; NAD+/SIRT1; autophagy; mitotherapy
    DOI:  https://doi.org/10.3390/antiox12112006
  17. Antioxidants (Basel). 2023 Nov 17. pii: 2011. [Epub ahead of print]12(11):
    Targeting Mitochondrial Dysfunction and Oxidative Stress to Prevent the Neurodegeneration of Retinal Ganglion Cells.
    Elisabetta Catalani, Kashi Brunetti, Simona Del Quondam, Davide Cervia.
      The imbalance of redox homeostasis contributes to neurodegeneration, including that related to the visual system. Mitochondria, essential in providing energy and responsible for several cell functions, are a significant source of reactive oxygen and/or nitrogen species, and they are, in turn, sensitive to free radical imbalance. Dysfunctional mitochondria are implicated in the development and progression of retinal pathologies and are directly involved in retinal neuronal degeneration. Retinal ganglion cells (RGCs) are higher energy consumers susceptible to mitochondrial dysfunctions that ultimately cause RGC loss. Proper redox balance and mitochondrial homeostasis are essential for maintaining healthy retinal conditions and inducing neuroprotection. In this respect, the antioxidant treatment approach is effective against neuronal oxidative damage and represents a challenge for retinal diseases. Here, we highlighted the latest findings about mitochondrial dysfunction in retinal pathologies linked to RGC degeneration and discussed redox-related strategies with potential neuroprotective properties.
    Keywords:  ganglion cells; mitochondria; neurodegeneration; redox homeostasis; retina
    DOI:  https://doi.org/10.3390/antiox12112011
  18. EMBO J. 2023 Nov 20. e113240
    The ribosome-associated chaperone Zuo1 controls translation upon TORC1 inhibition.
    Ailsa Black, Thomas D Williams, Flavie Soubigou, Ifeoluwapo M Joshua, Houjiang Zhou, Frederic Lamoliatte, Adrien Rousseau.
      Protein requirements of eukaryotic cells are ensured by proteostasis, which is mediated by tight control of TORC1 activity. Upon TORC1 inhibition, protein degradation is increased and protein synthesis is reduced through inhibition of translation initiation to maintain cell viability. Here, we show that the ribosome-associated complex (RAC)/Ssb chaperone system, composed of the HSP70 chaperone Ssb and its HSP40 co-chaperone Zuo1, is required to maintain proteostasis and cell viability under TORC1 inhibition in Saccharomyces cerevisiae. In the absence of Zuo1, translation does not decrease in response to the loss of TORC1 activity. A functional interaction between Zuo1 and Ssb is required for proper translational control and proteostasis maintenance upon TORC1 inhibition. Furthermore, we have shown that the rapid degradation of eIF4G following TORC1 inhibition is mediated by autophagy and is prevented in zuo1Δ cells, contributing to decreased survival in these conditions. We found that autophagy is defective in zuo1Δ cells, which impedes eIF4G degradation upon TORC1 inhibition. Our findings identify an essential role for RAC/Ssb in regulating translation in response to changes in TORC1 signalling.
    Keywords:  TORC1; proteostasis; ribosome-associated chaperones; stress; translation
    DOI:  https://doi.org/10.15252/embj.2022113240
  19. Nat Commun. 2023 Nov 24. 14(1): 7541
    Autophagy drives the conversion of developmental neural stem cells to the adult quiescent state.
    Isabel Calatayud-Baselga, Lucía Casares-Crespo, Carmina Franch-Ibáñez, José Guijarro-Nuez, Pascual Sanz, Helena Mira.
      Neurogenesis in the adult mammalian brain relies on the lifelong persistence of quiescent neural stem cell (NSC) reservoirs. Little is known about the mechanisms that lead to the initial establishment of quiescence, the main hallmark of adult stem cells, during development. Here we show that protein aggregates and autophagy machinery components accumulate in developmental radial glia-like NSCs as they enter quiescence and that pharmacological or genetic blockade of autophagy disrupts quiescence acquisition and maintenance. Conversely, increasing autophagy through AMPK/ULK1 activation instructs the acquisition of the quiescent state without affecting BMP signaling, a gatekeeper of NSC quiescence during adulthood. Selective ablation of Atg7, a critical gene for autophagosome formation, in radial glia-like NSCs at early and late postnatal stages compromises the initial acquisition and maintenance of quiescence during the formation of the hippocampal dentate gyrus NSC niche. Therefore, we demonstrate that autophagy is cell-intrinsically required to establish NSC quiescence during hippocampal development. Our results uncover an important role of autophagy in the transition of developmental NSCs into their dormant adult form, paving the way for studies directed at further understanding the mechanisms of stem cell niche formation and maintenance in the mammalian brain.
    DOI:  https://doi.org/10.1038/s41467-023-43222-1
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