bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023‒10‒22
sixteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Molecular mechanism of glutaminase activation through filamentation and the role of filaments in mitophagy protection.
  2. A PINK1 input threshold arises from positive feedback in the PINK1/Parkin mitophagy decision circuit.
  3. Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation.
  4. The SARS-CoV-2 protein ORF3c is a mitochondrial modulator of innate immunity.
  5. Long-term super-resolution inner mitochondrial membrane imaging with a lipid probe.
  6. Mitochondrial metabolism in Drosophila macrophage-like cells regulates body growth via modulation of cytokine and insulin signaling.
  7. Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis.
  8. SIRT4 is a regulator of human skeletal muscle fatty acid metabolism influencing inner and outer mitochondrial-mediated fusion.
  9. Control of mitochondrial dynamics by a fusogenic lipid.
  10. Targeting mitochondrial degradation by chimeric autophagy-tethering compounds.
  11. Mechanism of sperm mtDNA elimination.
  12. mtFociCounter for automated single-cell mitochondrial nucleoid quantification and reproducible foci analysis.
  13. MAO-SiR is a tool for visualizing the inner workings of mitochondria.
  14. Contact sites between host organelles and pathogens: boon or bane?
  15. Super-resolution imaging of mitochondrial cristae using a more hydrophobic far-red Si-rhodamine probe.
  16. Mitochondrial OPA1 deficiency is associated to reversible defects in spatial memory related to adult neurogenesis in mice.
  1. Nat Struct Mol Biol. 2023 Oct 19.
    Molecular mechanism of glutaminase activation through filamentation and the role of filaments in mitophagy protection.
    Douglas Adamoski, Marilia Meira Dias, Jose Edwin Neciosup Quesñay, Zhengyi Yang, Ievgeniia Zagoriy, Anna M Steyer, Camila Tanimoto Rodrigues, Alliny Cristiny da Silva Bastos, Bianca Novaes da Silva, Renna Karoline Eloi Costa, Flávia Mayumi Odahara de Abreu, Zeyaul Islam, Alexandre Cassago, Marin Gerard van Heel, Sílvio Roberto Consonni, Simone Mattei, Julia Mahamid, Rodrigo Villares Portugal, Andre Luis Berteli Ambrosio, Sandra Martha Gomes Dias.
      Glutaminase (GLS), which deaminates glutamine to form glutamate, is a mitochondrial tetrameric protein complex. Although inorganic phosphate (Pi) is known to promote GLS filamentation and activation, the molecular basis of this mechanism is unknown. Here we aimed to determine the molecular mechanism of Pi-induced mouse GLS filamentation and its impact on mitochondrial physiology. Single-particle cryogenic electron microscopy revealed an allosteric mechanism in which Pi binding at the tetramer interface and the activation loop is coupled to direct nucleophile activation at the active site. The active conformation is prone to enzyme filamentation. Notably, human GLS filaments form inside tubulated mitochondria following glutamine withdrawal, as shown by in situ cryo-electron tomography of cells thinned by cryo-focused ion beam milling. Mitochondria with GLS filaments exhibit increased protection from mitophagy. We reveal roles of filamentous GLS in mitochondrial morphology and recycling.
    DOI:  https://doi.org/10.1038/s41594-023-01118-0
  2. Cell Rep. 2023 Oct 17. pii: S2211-1247(23)01272-X. [Epub ahead of print]42(10): 113260
    A PINK1 input threshold arises from positive feedback in the PINK1/Parkin mitophagy decision circuit.
    Christopher S Waters, Sigurd B Angenent, Steven J Altschuler, Lani F Wu.
      Mechanisms that prevent accidental activation of the PINK1/Parkin mitophagy circuit on healthy mitochondria are poorly understood. On the surface of damaged mitochondria, PINK1 accumulates and acts as the input signal to a positive feedback loop of Parkin recruitment, which in turn promotes mitochondrial degradation via mitophagy. However, PINK1 is also present on healthy mitochondria, where it could errantly recruit Parkin and thereby activate this positive feedback loop. Here, we explore emergent properties of the PINK1/Parkin circuit by quantifying the relationship between mitochondrial PINK1 concentrations and Parkin recruitment dynamics. We find that Parkin is recruited to mitochondria only if PINK1 levels exceed a threshold and then only after a delay that is inversely proportional to PINK1 levels. Furthermore, these two regulatory properties arise from the input-coupled positive feedback topology of the PINK1/Parkin circuit. These results outline an intrinsic mechanism by which the PINK1/Parkin circuit can avoid errant activation on healthy mitochondria.
    Keywords:  CP: Molecular biology; PINK1; Parkin; circuit; delay; mathematical model; mitophagy decision; quantitative microscopy; synthetic biology; systems biology; threshold
    DOI:  https://doi.org/10.1016/j.celrep.2023.113260
  3. Cell Rep. 2023 Oct 19. pii: S2211-1247(23)01303-7. [Epub ahead of print]42(10): 113291
    Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation.
    Xiaowen Ma, Sharon Manley, Hui Qian, Yuan Li, Chen Zhang, Kevin Li, Benjamin Ding, Fengli Guo, Allen Chen, Xing Zhang, Meilian Liu, Meihua Hao, Benjamin Kugler, E Matthew Morris, John Thyfault, Ling Yang, Hiromi Sesaki, Hong-Min Ni, Heidi McBride, Wen-Xing Ding.
      Dysfunctional mitochondria are removed via multiple pathways, such as mitophagy, a selective autophagy process. Here, we identify an intracellular hybrid mitochondria-lysosome organelle (termed the mitochondria-lysosome-related organelle [MLRO]), which regulates mitochondrial homeostasis independent of canonical mitophagy during hepatocyte dedifferentiation. The MLRO is an electron-dense organelle that has either a single or double membrane with both mitochondria and lysosome markers. Mechanistically, the MLRO is likely formed from the fusion of mitochondria-derived vesicles (MDVs) with lysosomes through a PARKIN-, ATG5-, and DRP1-independent process, which is negatively regulated by transcription factor EB (TFEB) and associated with mitochondrial protein degradation and hepatocyte dedifferentiation. The MLRO, which is galectin-3 positive, is reminiscent of damaged lysosome and could be cleared by overexpression of TFEB, resulting in attenuation of hepatocyte dedifferentiation. Together, results from this study suggest that the MLRO may act as an alternative mechanism for mitochondrial quality control independent of canonical autophagy/mitophagy involved in cell dedifferentiation.
    Keywords:  ATG5; CP: Cell biology; DRP1; autophagy; hepatocytes; lysosome; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2023.113291
  4. iScience. 2023 Nov 17. 26(11): 108080
    The SARS-CoV-2 protein ORF3c is a mitochondrial modulator of innate immunity.
    Hazel Stewart, Yongxu Lu, Sarah O'Keefe, Anusha Valpadashi, Luis Daniel Cruz-Zaragoza, Hendrik A Michel, Samantha K Nguyen, George W Carnell, Nina Lukhovitskaya, Rachel Milligan, Yasmin Adewusi, Irwin Jungreis, Valeria Lulla, David A Matthews, Stephen High, Peter Rehling, Edward Emmott, Jonathan L Heeney, Andrew D Davidson, James R Edgar, Geoffrey L Smith, Andrew E Firth.
      The SARS-CoV-2 genome encodes a multitude of accessory proteins. Using comparative genomic approaches, an additional accessory protein, ORF3c, has been predicted to be encoded within the ORF3a sgmRNA. Expression of ORF3c during infection has been confirmed independently by ribosome profiling. Despite ORF3c also being present in the 2002-2003 SARS-CoV, its function has remained unexplored. Here we show that ORF3c localizes to mitochondria, where it inhibits innate immunity by restricting IFN-β production, but not NF-κB activation or JAK-STAT signaling downstream of type I IFN stimulation. We find that ORF3c is inhibitory after stimulation with cytoplasmic RNA helicases RIG-I or MDA5 or adaptor protein MAVS, but not after TRIF, TBK1 or phospho-IRF3 stimulation. ORF3c co-immunoprecipitates with the antiviral proteins MAVS and PGAM5 and induces MAVS cleavage by caspase-3. Together, these data provide insight into an uncharacterized mechanism of innate immune evasion by this important human pathogen.
    Keywords:  Immunology; Microbiology; Molecular biology; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2023.108080
  5. Nat Chem Biol. 2023 Oct 19.
    Long-term super-resolution inner mitochondrial membrane imaging with a lipid probe.
    Shuai Zheng, Neville Dadina, Deepto Mozumdar, Lauren Lesiak, Kayli N Martinez, Evan W Miller, Alanna Schepartz.
      The inner mitochondrial membrane (IMM) generates power to drive cell function, and its dynamics control mitochondrial health and cellular homeostasis. Here, we describe the cell-permeant, lipid-like small molecule MAO-N3 and use it to assemble high-density environmentally sensitive (HIDE) probes that selectively label and image the IMM in live cells and multiple cell states. MAO-N3 pairs with strain-promoted azide-alkyne click chemistry-reactive fluorophores to support HIDE imaging using confocal, structured illumination, single-molecule localization and stimulated emission depletion microscopy, all with significantly improved resistance to photobleaching. These probes generate images with excellent spatial and temporal resolution, require no genetic manipulations, are non-toxic in model cell lines and primary cardiomyocytes (even under conditions that amplify the effects of mitochondrial toxins) and can visualize mitochondrial dynamics for 12.5 h. This probe will enable comprehensive studies of IMM dynamics with high temporal and spatial resolution.
    DOI:  https://doi.org/10.1038/s41589-023-01450-y
  6. Biol Open. 2023 Oct 13. pii: bio.059968. [Epub ahead of print]
    Mitochondrial metabolism in Drosophila macrophage-like cells regulates body growth via modulation of cytokine and insulin signaling.
    Shrivani Sriskanthadevan-Pirahas, Abdul Qadeer Tinwala, Michael J Turingan, Shahoon Khan, Savraj S Grewal.
      Macrophages play critical roles in regulating and maintaining tissue and whole-body metabolism in normal and disease states. While the cell-cell signaling pathways that underlie these functions are becoming clear, less is known about how alterations in macrophage metabolism influence their roles as regulators of systemic physiology. Here, we investigate this by examining Drosophila macrophage-like cells called hemocytes. We used knockdown of TFAM, a mitochondrial genome transcription factor, to reduce mitochondrial OxPhos activity specifically in larval hemocytes. We find that this reduction in hemocyte OxPhos leads to a decrease in larval growth and body size. These effects are associated with a suppression of systemic insulin, the main endocrine stimulator of body growth. We also find that TFAM knockdown leads to decreased hemocyte JNK signaling and decreased expression of the TNF alpha homolog, Eiger in hemocytes. Furthermore, we show that genetic knockdown of hemocyte JNK signaling or Eiger expression mimics the effects of TFAM knockdown and leads to a non-autonomous suppression of body size without altering hemocyte numbers. Our data suggest that modulation of hemocyte mitochondrial metabolism can determine their non-autonomous effects on organismal growth by altering cytokine and systemic insulin signaling. Given that nutrient availability can control mitochondrial metabolism, our findings may explain how macrophages function as nutrient-responsive regulators of tissue and whole-body physiology and homeostasis.
    Keywords:   Drosophila ; Cytokine TNF-α/Eiger; Hemocytes; Insulin signaling; JNK signaling; Metabolism; Mitochondria; OxPhos; Systemic growth; TFAM
    DOI:  https://doi.org/10.1242/bio.059968
  7. Nat Commun. 2023 Oct 16. 14(1): 6513
    Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis.
    Rebecca V Walker, Qin Yao, Hangxue Xu, Anthony Maranto, Kristen F Swaney, Sreekumar Ramachandran, Rong Li, Laura Cassina, Brian M Polster, Patricia Outeda, Alessandra Boletta, Terry Watnick, Feng Qian.
      Fibrocystin/Polyductin (FPC), encoded by PKHD1, is associated with autosomal recessive polycystic kidney disease (ARPKD), yet its precise role in cystogenesis remains unclear. Here we show that FPC undergoes complex proteolytic processing in developing kidneys, generating three soluble C-terminal fragments (ICDs). Notably, ICD15, contains a novel mitochondrial targeting sequence at its N-terminus, facilitating its translocation into mitochondria. This enhances mitochondrial respiration in renal epithelial cells, partially restoring impaired mitochondrial function caused by FPC loss. FPC inactivation leads to abnormal ultrastructural morphology of mitochondria in kidney tubules without cyst formation. Moreover, FPC inactivation significantly exacerbates renal cystogenesis and triggers severe pancreatic cystogenesis in a Pkd1 mouse mutant Pkd1V/V in which cleavage of Pkd1-encoded Polycystin-1 at the GPCR Proteolysis Site is blocked. Deleting ICD15 enhances renal cystogenesis without inducing pancreatic cysts in Pkd1V/V mice. These findings reveal a direct link between FPC and a mitochondrial pathway through ICD15 cleavage, crucial for cystogenesis mechanisms.
    DOI:  https://doi.org/10.1038/s41467-023-42196-4
  8. Cell Signal. 2023 Oct 17. pii: S0898-6568(23)00346-7. [Epub ahead of print] 110931
    SIRT4 is a regulator of human skeletal muscle fatty acid metabolism influencing inner and outer mitochondrial-mediated fusion.
    John Noone, Keith D Rochfort, Finbarr O'Sullivan, Donal J O'Gorman.
      OBJECTIVE: The mitochondrial phenotype, governed by the balance of fusion-fission, is a key determinant of energy metabolism. The inner and outer mitochondrial membrane (IMM) fusion proteins optic atrophy 1 (OPA1) and Mitofusin 1 and 2 (Mfn1/2) play an important role in this process. Recent evidence also shows that Sirtuin 4 (SIRT4), located within the mitochondria, is involved in the regulation of fatty acid oxidation. The purpose of this study was to determine if SIRT4 expression regulates inner and outer mitochondrial-mediated fusion and substrate utilization within differentiated human skeletal muscle cells (HSkMC).MATERIAL AND METHODS: SIRT4 expression was knocked down using small interfering RNA (siRNA) transfection in differentiated HSkMC. Following knockdown, mitochondrial respiration was determined by high-resolution respirometry (HRR) using the Oroboros Oxygraph O2k. Live cell confocal microscopy, quantified using the Mitochondrial Network Analysis (MiNA) toolset, was used to examine mitochondrial morphological change. This was further examined through the measurement of key metabolic and mitochondrial morphological regulators (mRNA and protein) induced by knockdown.
    RESULTS: SIRT4 knockdown resulted in a significant decrease in LEAK respiration, potentially explained by a decrease in ANT1 protein expression. Knockdown further increased oxidative phosphorylation and protein expression of key regulators of fatty acid metabolism. Quantitative analysis of live confocal imaging of fluorescently labelled mitochondria following SIRT4 knockdown supported the role SIRT4 plays in the regulation of mitochondrial morphology, as emphasized by an increase in mitochondrial network branches and junctions. Measurement of key regulators of mitochondrial dynamics illustrated a significant increase in mitochondrial fusion proteins Mfn1, OPA1 respectively, indicative of an increase in mitochondrial size.
    CONCLUSIONS: This study provides evidence of a direct relationship between the mitochondrial phenotype and substrate oxidation in HSkMC. We identify SIRT4 as a key protagonist of energy metabolism via its regulation of IMM and OMM fusion proteins, OPA1 and Mfn1. SIRT4 knockdown increases mitochondrial capacity to oxidize fatty acids, decreasing LEAK respiration and further increasing mitochondrial elongation via its regulation of mitochondrial fusion.
    Keywords:  Metabolism; Mitochondrial dynamics; Mitochondrial function; OPA1; Sirtuin; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.cellsig.2023.110931
  9. Trends Cell Biol. 2023 Oct 17. pii: S0962-8924(23)00210-6. [Epub ahead of print]
    Control of mitochondrial dynamics by a fusogenic lipid.
    Zheng Yang, David C Chan.
      Mitochondrial fusion enables cooperation between the mitochondrial population and is critical for mitochondrial function. Phosphatidic acid (PA) on the mitochondrial surface has a key role in mitochondrial fusion. A recent study by Su et al. shows that the nucleoside diphosphate (NDP) kinase NME3 recognizes PA and mediates its effects on mitochondrial dynamics.
    Keywords:  membrane fusion; mitochondria; organelle; phospholipid
    DOI:  https://doi.org/10.1016/j.tcb.2023.10.006
  10. Chem Sci. 2023 Oct 18. 14(40): 11192-11202
    Targeting mitochondrial degradation by chimeric autophagy-tethering compounds.
    Zhenqi Liu, Geng Qin, Jie Yang, Wenjie Wang, Wenting Zhang, Boxun Lu, Jinsong Ren, Xiaogang Qu.
      The ability to regulate mitophagy in a living system with small molecules remains a great challenge. We hypothesize that adding fragments specific to the key autophagosome protein LC3 to mitochondria will mimic receptor-mediated mitophagy, thus engaging the autophagy-lysosome pathway to induce mitochondrial degradation. Herein, we develop a general biochemical approach to modulate mitophagy, dubbed mito-ATTECs, which employ chimera molecules composed of LC3-binding moieties linked to mitochondria-targeting ligands. Mito-ATTECs trigger mitophagy via targeting mitochondria to autophagosomes through direct interaction between mito-ATTECs and LC3 on mitochondrial membranes. Subsequently, autophagosomes containing mitochondria rapidly fuse with lysosomes to facilitate the degradation of mitochondria. Therefore, mito-ATTECs circumvent the detrimental effects related to disruption of mitochondrial membrane integrity by inducers routinely used to manipulate mitophagy, and provide a versatile biochemical approach to investigate the physiological roles of mitophagy. Furthermore, we found that sustained mitophagy lead to mitochondrial depletion and autophagic cell death in several malignant cell lines (lethal mitophagy). Among them, apoptosis-resistant malignant melanoma cell lines are particularly sensitive to lethal mitophagy. The therapeutic efficacy of mito-ATTECs has been further evaluated by using subcutaneous and pulmonary metastatic melanoma models. Together, the mitochondrial depletion achieved by mito-ATTECs may demonstrate the general concept of inducing cancer cell lethality through excessive mitochondrial clearance, establishing a promising therapeutic paradigm for apoptosis-resistant tumors.
    DOI:  https://doi.org/10.1039/d3sc03600f
  11. Nat Rev Mol Cell Biol. 2023 Oct 19.
    Mechanism of sperm mtDNA elimination.
    Eytan Zlotorynski.
      
    DOI:  https://doi.org/10.1038/s41580-023-00679-8
  12. Nucleic Acids Res. 2023 Oct 18. pii: gkad864. [Epub ahead of print]
    mtFociCounter for automated single-cell mitochondrial nucleoid quantification and reproducible foci analysis.
    Timo Rey, Luis Carlos Tábara, Julien Prudent, Michal Minczuk.
      Mitochondrial DNA (mtDNA) encodes the core subunits for OXPHOS, essential in near-all eukaryotes. Packed into distinct foci (nucleoids) inside mitochondria, the number of mtDNA copies differs between cell-types and is affected in several human diseases. Currently, common protocols estimate per-cell mtDNA-molecule numbers by sequencing or qPCR from bulk samples. However, this does not allow insight into cell-to-cell heterogeneity and can mask phenotypical sub-populations. Here, we present mtFociCounter, a single-cell image analysis tool for reproducible quantification of nucleoids and other foci. mtFociCounter is a light-weight, open-source freeware and overcomes current limitations to reproducible single-cell analysis of mitochondrial foci. We demonstrate its use by analysing 2165 single fibroblasts, and observe a large cell-to-cell heterogeneity in nucleoid numbers. In addition, mtFociCounter quantifies mitochondrial content and our results show good correlation (R = 0.90) between nucleoid number and mitochondrial area, and we find nucleoid density is less variable than nucleoid numbers in wild-type cells. Finally, we demonstrate mtFociCounter readily detects differences in foci-numbers upon sample treatment, and applies to Mitochondrial RNA Granules and superresolution microscopy. mtFociCounter provides a versatile solution to reproducibly quantify cellular foci in single cells and our results highlight the importance of accounting for cell-to-cell variance and mitochondrial context in mitochondrial foci analysis.
    DOI:  https://doi.org/10.1093/nar/gkad864
  13. Nat Chem Biol. 2023 Oct 20.
    MAO-SiR is a tool for visualizing the inner workings of mitochondria.
      
    DOI:  https://doi.org/10.1038/s41589-023-01451-x
  14. mSphere. 2023 Oct 18. e0044823
    Contact sites between host organelles and pathogens: boon or bane?
    Chahat Mehra, Lena Pernas.
      A microbe and its host are in constant communication. An emerging platform for direct communication is the membrane contact sites that form between several pathogens and host organelles. Here, we review our progress on the molecular mechanisms underlying contact sites between host mitochondria and the human parasite Toxoplasma gondii. We discuss open questions regarding their function during infection as well as those formed between the host endoplasmic reticulum and Toxoplasma.
    Keywords:  Toxoplasma gondii; endoplasmic reticulum; membrane; membrane contact sites; mitochondria; pathogens
    DOI:  https://doi.org/10.1128/msphere.00448-23
  15. Chem Commun (Camb). 2023 Oct 16.
    Super-resolution imaging of mitochondrial cristae using a more hydrophobic far-red Si-rhodamine probe.
    Jing Sun, Xichuan Ge, Boya Jin, Shiyi Li, Yiwei Hou, Suyi Zhong, Zikang Yang, Peng Xi, Meiqi Li, Baoxiang Gao.
      Mitochondrial probe SiRPFA was synthesized by attaching a long perfluoroalkyl chain on Si-rhodamine cationic dye. High lipophilicity endowed SiRPFA with mitochondrial membrane potential independent properties. Under stimulated emission depletion microscopy, SiRPFA clearly revealed changes in mitochondrial cristae morphology during autophagy induced by starvation or apoptosis.
    DOI:  https://doi.org/10.1039/d3cc04696f
  16. eNeuro. 2023 Oct 20. pii: ENEURO.0073-23.2023. [Epub ahead of print]
    Mitochondrial OPA1 deficiency is associated to reversible defects in spatial memory related to adult neurogenesis in mice.
    Trinovita Andraini, Lionel Moulédous, Petnoi Petsophonsakul, Cédrick Florian, Sébastien Gauzin, Marlène Botella-Daloyau, Macarena Arrázola, Kamela Nikolla, Adam Philip, Alice Leydier, Manon Marque, Laetitia Arnauné-Pelloquin, Pascale Belenguer, Claire Rampon, Marie-Christine Miquel.
      Mitochondria are integrative hubs central to cellular adaptive pathways. Such pathways are critical in highly differentiated post-mitotic neurons, the plasticity of which sustains brain function. Consequently, defects in mitochondria and in their dynamics appear instrumental in neurodegenerative diseases and may also participate in cognitive impairments. To directly test this hypothesis, we analyzed cognitive performances in a mouse mitochondria-based disease model, due to haploinsufficiency in the mitochondrial optic-atrophy-type-1 (OPA1) protein involved in mitochondrial dynamics. In males, we evaluated adult hippocampal neurogenesis parameters using immunohistochemistry. We performed a battery of tests to assess basal behavioral characteristics and cognitive performances, and tested putative treatments.While in Dominant Optic Atrophy (DOA) mouse models, the known main symptoms are late onset visual deficits, we discovered early impairments in hippocampus-dependent spatial memory attributable to defects in adult neurogenesis. Moreover, less connected adult-born hippocampal neurons showed a decrease in mitochondrial content. Remarkably, voluntary exercise or pharmacological treatment targeting mitochondrial dynamics restored spatial memory in DOA mice. Altogether, our study identifies a crucial role for OPA1-dependent mitochondrial functions in adult neurogenesis, and thus in hippocampal-dependent cognitive functions. More generally, our findings show that adult neurogenesis is highly sensitive to mild mitochondrial defects, generating impairments in spatial memory that can be detected at an early stage and counterbalanced by physical exercise and pharmacological targeting of mitochondrial dynamics. Thus, amplification of mitochondrial function at an early stage appears beneficial for late-onset neurodegenerative diseases.Significance StatementThe adult hippocampus continues to produce new neurons in mammals. These new neurons are highly sensitive to mitochondrial perturbation. Dominant optic atrophy (DOA) is a rare disease mainly caused by mutations in the gene coding the mitochondrial protein OPA1. Using a mouse model of OPA1 deficiency, we found that hippocampal new neurons have dendritic spine density defects and altered mitochondrial content. We further detected impairments in spatial memory capacities relying on adult-neurogenesis. We report that these memory impairments can be corrected by physical exercise and pharmacological treatment targeting mitochondria in mice. Our results indicate that early detection of spatial memory deficits related to adult neurogenesis may allow a precocious action in pathologies involving mitochondria, such as DOA or neurodegenerative diseases.
    Keywords:  Adult Neurogenesis; Dominant Optic Atrophy; Hippocampus; Mitochondria; Pattern separation; Physical exercise
    DOI:  https://doi.org/10.1523/ENEURO.0073-23.2023
This page is being maintained by Thomas Krichel. It was last updated on 2023‒10‒24 at 11:44.