bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024–11–03
fourteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Structure of the turnover-ready state of an ancestral respiratory complex I.
  2. Comprehensive phenotypic assessment of nonsense mutations in mitochondrial ND5 in mice.
  3. Membrane potential stimulates ADP import and ATP export by the mitochondrial ADP/ATP carrier due to its positively charged binding site.
  4. Activation of the mitochondrial unfolded protein response regulates the dynamic formation of stress granules.
  5. Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models.
  6. COX15 deficiency causes oocyte ferroptosis.
  7. Accumulation of F-actin drives brain aging and limits healthspan in Drosophila.
  8. A hierarchical hepatic de novo lipogenesis substrate supply network utilizing pyruvate, acetate, and ketones.
  9. Exceptional longevity of mammalian ovarian and oocyte macromolecules throughout the reproductive lifespan.
  10. A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia.
  11. The multifaceted role of mitochondria in cardiac function: insights and approaches.
  12. Fighting ischemia-reperfusion injury: Focusing on mitochondria-derived ferroptosis.
  13. Establishment and characterization of three human pluripotent stem cell lines from Charcot-Marie-Tooth disease Type 4B3 patients bearing mutations in MTMR5/Sbf1 gene.
  14. Temporal dynamics of membrane contact sites.
  1. Nat Commun. 2024 Oct 29. 15(1): 9340
    Structure of the turnover-ready state of an ancestral respiratory complex I.
    Bozhidar S Ivanov, Hannah R Bridges, Owen D Jarman, Judy Hirst.
      Respiratory complex I is pivotal for cellular energy conversion, harnessing energy from NADH:ubiquinone oxidoreduction to drive protons across energy-transducing membranes for ATP synthesis. Despite detailed structural information on complex I, its mechanism of catalysis remains elusive due to lack of accompanying functional data for comprehensive structure-function analyses. Here, we present the 2.3-Å resolution structure of complex I from the α-proteobacterium Paracoccus denitrificans, a close relative of the mitochondrial progenitor, in phospholipid-bilayer nanodiscs. Three eukaryotic-type supernumerary subunits (NDUFS4, NDUFS6 and NDUFA12) plus a novel L-isoaspartyl-O-methyltransferase are bound to the core complex. Importantly, the enzyme is in a single, homogeneous resting state that matches the closed, turnover-ready (active) state of mammalian complex I. Our structure reveals the elements that stabilise the closed state and completes P. denitrificans complex I as a unified platform for combining structure, function and genetics in mechanistic studies.
    DOI:  https://doi.org/10.1038/s41467-024-53679-3
  2. Exp Mol Med. 2024 Nov 01.
    Comprehensive phenotypic assessment of nonsense mutations in mitochondrial ND5 in mice.
    Sanghun Kim, Seul Gi Park, Jieun Kim, Seongho Hong, Sang-Mi Cho, Soo-Yeon Lim, Eun-Kyoung Kim, Sungjin Ju, Su Bin Lee, Sol Pin Kim, Tae Young Jeong, Yeji Oh, Seunghun Han, Hae-Rim Kim, Taek Chang Lee, Hyoung-Chin Kim, Won Kee Yoon, Tae Hyeon An, Kyoung-Jin Oh, Ki-Hoan Nam, Seonghyun Lee, Kyoungmi Kim, Je Kyung Seong, Hyunji Lee.
      Mitochondrial dysfunction induced by mitochondrial DNA (mtDNA) mutations has been implicated in various human diseases. A comprehensive analysis of mitochondrial genetic disorders requires suitable animal models for human disease studies. While gene knockout via premature stop codons is a powerful method for investigating the unique functions of target genes, achieving knockout of mtDNA has been rare. Here, we report the genotypes and phenotypes of heteroplasmic MT-ND5 gene-knockout mice. These mutant mice presented damaged mitochondrial cristae in the cerebral cortex, hippocampal atrophy, and asymmetry, leading to learning and memory abnormalities. Moreover, mutant mice are susceptible to obesity and thermogenetic disorders. We propose that these mtDNA gene-knockdown mice could serve as valuable animal models for studying the MT-ND5 gene and developing therapies for human mitochondrial disorders in the future.
    DOI:  https://doi.org/10.1038/s12276-024-01333-9
  3. Sci Adv. 2024 Nov;10(44): eadp7725
    Membrane potential stimulates ADP import and ATP export by the mitochondrial ADP/ATP carrier due to its positively charged binding site.
    Vasiliki Mavridou, Martin S King, Andre Bazzone, Roger Springett, Edmund R S Kunji.
      The mitochondrial adenosine 5'-diphosphate (ADP)/adenosine 5'-triphosphate (ATP) carrier imports ADP into the mitochondrion and exports ATP to the cell. Here, we demonstrate that 3.3 positive charges are translocated with the negatively charged substrate in each transport step. They can be assigned to three positively charged residues of the central substrate-binding site and two asparagine/arginine pairs. In this way, the membrane potential stimulates not only the ATP4- export step, as a net -0.7 charge is transported, but also the ADP3- import step, as a net +0.3 charge is transported with the electric field. These positive charge movements also inhibit the import of ATP and export of ADP in the presence of a membrane potential, allowing these nucleotides to be maintained at high concentrations in the cytosol and mitochondrial matrix to drive the hydrolysis and synthesis of ATP, respectively. Thus, this is the mechanism by which the membrane potential drives adenine nucleotide exchange with high directional fluxes to fuel the cellular processes.
    DOI:  https://doi.org/10.1126/sciadv.adp7725
  4. J Cell Sci. 2024 Oct 28. pii: jcs.263548. [Epub ahead of print]
    Activation of the mitochondrial unfolded protein response regulates the dynamic formation of stress granules.
    Marta Lopez-Nieto, Zhaozhi Sun, Emily Relton, Rahme Safakli, Brian D Freibaum, J Paul Taylor, Alessia Ruggieri, Ioannis Smyrnias, Nicolas Locker.
      To rapidly adapt to harmful changes to their environment, cells activate the integrated stress response (ISR). This results in an adaptive transcriptional and translational rewiring, and the formation of biomolecular condensates named stress granules (SGs), to resolve stress. In addition to this first line of defence, the mitochondrial unfolded protein response (UPRmt) activates a specific transcriptional programme to maintain mitochondrial homeostasis. We present evidence that SGs and UPRmt pathways are intertwined and communicate. UPRmt induction results in eIF2a phosphorylation and the initial and transient formation of SGs, which subsequently disassemble. The induction of GADD34 during late UPRmt protects cells from prolonged stress by impairing further assembly of SGs. Furthermore, mitochondrial functions and cellular survival are enhanced during UPRmt activation when SGs are absent, suggesting that UPRmt-induced SGs have an adverse effect on mitochondrial homeostasis. These findings point to a novel crosstalk between SGs and the UPRmt that may contribute to restoring mitochondrial functions under stressful conditions.
    Keywords:  GADD34; Integrated stress response; Mitochondrial stress response; Stress granules; UPRmt
    DOI:  https://doi.org/10.1242/jcs.263548
  5. Brain. 2024 Oct 30. pii: awae348. [Epub ahead of print]
    Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models.
    Baptiste Ropert, Sylvie Bannwarth, Emmanuelle C Genin, Loan Vaillant-Beuchot, Sandra Lacas-Gervais, Blandine Madji Hounoum, Aurore Bernardin, Nhu Dinh, Alessandra Mauri-Crouzet, Marc-Alexandre D'Elia, Gaelle Augé, Françoise Lespinasse, Audrey Di Giorgio, Willian Meira, Nathalie Bonnefoy, Laurent Monassier, Manuel Schiff, Laila Sago, Devrim Kilinc, Frédéric Brau, Virginie Redeker, Delphine Bohl, Déborah Tribouillard-Tanvier, Vincent Procaccio, Stéphane Azoulay, Jean-Ehrland Ricci, Agnès Delahodde, Véronique Paquis-Flucklinger.
      The identification of a point mutation (p.Ser59Leu) in the CHCHD10 gene was the first genetic evidence that mitochondrial dysfunction can trigger motor neuron disease. Since then, we have shown that this mutation leads to the disorganization of the MItochondrial contact site and Cristae Organizing System (MICOS) complex that maintains the mitochondrial cristae structure. Here, we generated yeast mutant strains mimicking MICOS instability and used them to test the ability of more than 1600 compounds from 2 repurposed libraries to rescue the growth defect of those cells. Among the hits identified, we selected nifuroxazide, a broad-spectrum antibacterial molecule. We show that nifuroxazide rescues mitochondrial network fragmentation and cristae abnormalities in CHCHD10S59L/+ patient fibroblasts. This molecule also decreases caspase-dependent death of human CHCHD10S59L/+ iPSC-derived motor neurons. Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons. Our findings strengthen the MICOS-mitochondrial transport connection. Nifuroxazide and analogues emerge as potential therapeutics for MICOS-related disorders like motor neuron disease. Its impact on syntaphilin hints at broader neurological disorder applicability for nifuroxazide.
    Keywords:  ALS; MICOS; mitochondrial disease; nifuroxazide
    DOI:  https://doi.org/10.1093/brain/awae348
  6. Proc Natl Acad Sci U S A. 2024 Nov 05. 121(45): e2406174121
    COX15 deficiency causes oocyte ferroptosis.
    Zhihua Zhang, Ran Yu, Qiuwen Shi, Zhi-Jing Wu, Qingchun Li, Jian Mu, Biaobang Chen, Juanzi Shi, Renmin Ni, Ling Wu, Qiaoli Li, Jing Fu, Rong Li, Xiaoxi Sun, Jiucun Wang, Lin He, Yanping Kuang, Qing Sang, Lei Wang.
      Mitochondria play diverse roles in mammalian physiology. The architecture, activity, and physiological functions of mitochondria in oocytes are largely different from those in somatic cells, but the mitochondrial proteins related to oocyte quality and reproductive longevity remain largely unknown. Here, using whole-exome sequencing data from 1,024 women (characterized by oocyte maturation arrest and degenerated or morphologically abnormal oocytes) and 2,868 healthy controls, we performed a population and gene-based burden test for mitochondrial genes and identified a candidate gene, cytochrome c oxidase assembly protein 15 (COX15). We report that biallelic COX15 pathogenic variants cause human oocyte ferroptosis and female infertility in a recessive inheritance pattern. COX15 variants impaired mitochondrial respiration in Saccharomyces cerevisiae and led to reduced protein levels in HeLa cells. Oocyte-specific deletion of Cox15 led to impaired Fe2+ and reactive oxygen species homeostasis that caused mitochondrial dysfunction and ultimately sensitized oocytes to ferroptosis. In addition, ferrostatin-1 (an inhibitor of ferroptosis) could rescue the oocyte ferroptosis phenotype in vitro and ex vivo. Our findings not only provide a genetic diagnostic marker for oocyte development defects but also expand the spectrum of mitochondrial disorders to female infertility and contribute to unique insights into the role of ferroptosis in human oocyte defects.
    Keywords:  COX15 deficiency; female infertility; ferroptosis; mitochondrial disorders; oocyte defects
    DOI:  https://doi.org/10.1073/pnas.2406174121
  7. Nat Commun. 2024 Oct 25. 15(1): 9238
    Accumulation of F-actin drives brain aging and limits healthspan in Drosophila.
    Edward T Schmid, Joseph M Schinaman, Naomi Liu-Abramowicz, Kylie S Williams, David W Walker.
      The actin cytoskeleton is a key determinant of cell structure and homeostasis. However, possible tissue-specific changes to actin dynamics during aging, notably brain aging, are not understood. Here, we show that there is an age-related increase in filamentous actin (F-actin) in Drosophila brains, which is counteracted by prolongevity interventions. Critically, decreasing F-actin levels in aging neurons prevents age-onset cognitive decline and extends organismal healthspan. Mechanistically, we show that autophagy, a recycling process required for neuronal homeostasis, is disabled upon actin dysregulation in the aged brain. Remarkably, disrupting actin polymerization in aged animals with cytoskeletal drugs restores brain autophagy to youthful levels and reverses cellular hallmarks of brain aging. Finally, reducing F-actin levels in aging neurons slows brain aging and promotes healthspan in an autophagy-dependent manner. Our data identify excess actin polymerization as a hallmark of brain aging, which can be targeted to reverse brain aging phenotypes and prolong healthspan.
    DOI:  https://doi.org/10.1038/s41467-024-53389-w
  8. Cell Metab. 2024 Oct 25. pii: S1550-4131(24)00409-1. [Epub ahead of print]
    A hierarchical hepatic de novo lipogenesis substrate supply network utilizing pyruvate, acetate, and ketones.
    Adam J Rauckhorst, Ryan D Sheldon, Daniel J Pape, Adnan Ahmed, Kelly C Falls-Hubert, Ronald A Merrill, Reid F Brown, Kshitij Deshmukh, Thomas A Vallim, Stanislaw Deja, Shawn C Burgess, Eric B Taylor.
      Hepatic de novo lipogenesis (DNL) is a fundamental physiologic process that is often pathogenically elevated in metabolic disease. Treatment is limited by incomplete understanding of the metabolic pathways supplying cytosolic acetyl-CoA, the obligate precursor to DNL, including their interactions and proportional contributions. Here, we combined extensive 13C tracing with liver-specific knockout of key mitochondrial and cytosolic proteins mediating cytosolic acetyl-CoA production. We show that the mitochondrial pyruvate carrier (MPC) and ATP-citrate lyase (ACLY) gate the major hepatic lipogenic acetyl-CoA production pathway, operating in parallel with acetyl-CoA synthetase 2 (ACSS2). Given persistent DNL after mitochondrial citrate carrier (CiC) and ACSS2 double knockout, we tested the contribution of exogenous and leucine-derived acetoacetate to acetoacetyl-CoA synthetase (AACS)-dependent DNL. CiC knockout increased acetoacetate-supplied hepatic acetyl-CoA production and DNL, indicating that ketones function as mitochondrial-citrate reciprocal DNL precursors. By delineating a mitochondrial-cytosolic DNL substrate supply network, these findings may inform strategies to therapeutically modulate DNL.
    Keywords:  AACS; ACLY; ACSS2; ATP-citrate lyase; CiC; DNL; MPC; acetoacetyl-CoA synthetase; acetyl-CoA synthetase 2; de novo lipogenesis; liver; metabolomics; mitochondrial citrate carrier; mitochondrial pyruvate carrier; stable isotope tracers
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.013
  9. Elife. 2024 Oct 31. pii: RP93172. [Epub ahead of print]13
    Exceptional longevity of mammalian ovarian and oocyte macromolecules throughout the reproductive lifespan.
    Ewa K Bomba-Warczak, Karen M Velez, Luhan T Zhou, Christelle Guillermier, Seby Edassery, Matthew L Steinhauser, Jeffrey N Savas, Francesca E Duncan.
      The mechanisms contributing to age-related deterioration of the female reproductive system are complex, however aberrant protein homeostasis is a major contributor. We elucidated exceptionally stable proteins, structures, and macromolecules that persist in mammalian ovaries and gametes across the reproductive lifespan. Ovaries exhibit localized structural and cell-type-specific enrichment of stable macromolecules in both the follicular and extrafollicular environments. Moreover, ovaries and oocytes both harbor a panel of exceptionally long-lived proteins, including cytoskeletal, mitochondrial, and oocyte-derived proteins. The exceptional persistence of these long-lived molecules suggest a critical role in lifelong maintenance and age-dependent deterioration of reproductive tissues.
    Keywords:  cell biology; long-lived proteins; mass spectrometry imaging; mouse; oocyte; ovaries; proteomics; reproductive aging
    DOI:  https://doi.org/10.7554/eLife.93172
  10. Mov Disord. 2024 Oct 28.
    A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia.
    Yan Shi, Junhao Xie, Junyi Jiang, Xinyu Yan, Xuejiao Chen, Shunyan Hong, Jiyuan Liu, Guorong Xu, Huizhen Su, Wanjin Chen, Ning Wang, Xiang Lin.
       BACKGROUND: Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb weakness and spasticity, with unknown genetic cause in many cases.
    OBJECTIVES: To identify novel genetic causes of HSP.
    METHODS: Phenotypic characterization, genetic screening, transcriptome sequencing, and peroneal nerve biopsy were conducted in a Chinese HSP family.
    RESULTS: We found a homoplasmic MT-TV (mitochondrial tRNAVal) mutation, m.1661A > G, present in all affected individuals across four generations of a family with complex HSP. Fourth-generation affected individuals displayed earlier onset, likely due to presumptive anticipation, and greater symptom severity, potentially caused by decreased mitochondrial DNA (mtDNA) copy number. Upregulation of mitochondrial autophagy genes in these patients suggested that MT-TV mutations could lead to reduced mtDNA copy number. Neural biopsies revealed ultrastructural abnormalities in myelin and mitochondria.
    CONCLUSIONS: The rare MT-TV m.1661A > G mutation is associated with HSP. Variations in mtDNA copy number may play a causal role in differences among clinical phenotypes. © 2024 International Parkinson and Movement Disorder Society.
    Keywords:  MT‐TV gene; hereditary spastic paraplegia; m.1661A > G mutation; mtDNA copy number
    DOI:  https://doi.org/10.1002/mds.30048
  11. Cell Commun Signal. 2024 Oct 29. 22(1): 525
    The multifaceted role of mitochondria in cardiac function: insights and approaches.
    Sriram Ravindran, Christoph D Rau.
      Cardiovascular disease (CVD) remains a global economic burden even in the 21st century with 85% of deaths resulting from heart attacks. Despite efforts in reducing the risk factors, and enhancing pharmacotherapeutic strategies, challenges persist in early identification of disease progression and functional recovery of damaged hearts. Targeting mitochondrial dysfunction, a key player in the pathogenesis of CVD has been less successful due to its role in other coexisting diseases. Additionally, it is the only organelle with an agathokakological function that is a remedy and a poison for the cell. In this review, we describe the origins of cardiac mitochondria and the role of heteroplasmy and mitochondrial subpopulations namely the interfibrillar, subsarcolemmal, perinuclear, and intranuclear mitochondria in maintaining cardiac function and in disease-associated remodeling. The cumulative evidence of mitochondrial retrograde communication with the nucleus is addressed, highlighting the need to study the genotype-phenotype relationships of specific organelle functions with CVD by using approaches like genome-wide association study (GWAS). Finally, we discuss the practicality of computational methods combined with single-cell sequencing technologies to address the challenges of genetic screening in the identification of heteroplasmy and contributory genes towards CVD.
    Keywords:  Cardiovascular disease; Cell-organelle communication; Computational biology; Mitochondrial genetics; Mitochondrial subpopulations; Organellogenesis
    DOI:  https://doi.org/10.1186/s12964-024-01899-x
  12. Mitochondrion. 2024 Oct 24. pii: S1567-7249(24)00132-6. [Epub ahead of print]79 101974
    Fighting ischemia-reperfusion injury: Focusing on mitochondria-derived ferroptosis.
    Lei Tian, Qian Liu, Hong Guo, Honggang Zang, Yulan Li.
      Ischemia-reperfusion injury (IRI) is a major cause of mortality and morbidity. Current treatments for IRI have limited efficacy and novel therapeutic strategies are needed. Mitochondrial dysfunction not only initiates IRI but also plays a significant role in ferroptosis pathogenesis. Recent studies have highlighted that targeting mitochondrial pathways is a promising therapeutic approach for ferroptosis-induced IRI. The association between ferroptosis and IRI has been reviewed many times, but our review provides the first comprehensive overview with a focus on recent mitochondrial research. First, we present the role of mitochondria in ferroptosis. Then, we summarize the evidence on mitochondrial manipulation of ferroptosis in IRI and review recent therapeutic strategies aimed at targeting mitochondria-related ferroptosis to mitigate IRI. We hope our review will provide new ideas for the treatment of IRI and accelerate the transition from bench to bedside.
    Keywords:  Ferroptosis; Ischemia-Reperfusion injury; Mitochondria
    DOI:  https://doi.org/10.1016/j.mito.2024.101974
  13. Stem Cell Res. 2024 Oct 22. pii: S1873-5061(24)00297-6. [Epub ahead of print]81 103599
    Establishment and characterization of three human pluripotent stem cell lines from Charcot-Marie-Tooth disease Type 4B3 patients bearing mutations in MTMR5/Sbf1 gene.
    Elizabeth H Jacobs, Jacquelyn Schatzman Raposo, Annarita Scardamaglia, Fowzan S Alkuraya, Shahriar Nafissi, Henry Houlden, Stephan Zuchner, Mario A Saporta.
      Myotubularin-Related Protein 5 (MTMR5) is an inactive, poorly characterized D3-phosphatidylinositol phosphatase. Mutations in MTMR5 have been linked to Charcot-Marie-Tooth Disease Type 4B3 (CMT4B3), a rare, early-onset, recessive peripheral neuropathy. Here, we describe the establishment and validation of three human induced pluripotent stem cell (iPSC) lines derived from unrelated CMT4B3 patients, each harboring homozygous MTMR5/Sbf1 mutations. Current MTMR5 -/- animal models do not clearly link Sbf1 mutations to severe neuropathy, so such a resource is highly desired to further elucidate the relationship between MTMR5 dysfunction and peripheral nerve degeneration.
    DOI:  https://doi.org/10.1016/j.scr.2024.103599
  14. Nat Cell Biol. 2024 Oct 31.
    Temporal dynamics of membrane contact sites.
    Tomas Knedlik, Marta Giacomello.
      
    DOI:  https://doi.org/10.1038/s41556-024-01539-z
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