bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024–05–26
28 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mitochondria at the crossroads of health and disease.
  2. Origins of tissue and cell-type specificity in mitochondrial DNA (mtDNA) disease.
  3. Coordinating mitochondrial translation with assembly of the OXPHOS complexes.
  4. Mitochondrial molecular genetics and human disease.
  5. Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation.
  6. Mitochondrial DNA release and sensing in innate immune responses.
  7. Illuminating mitochondrial translation through mouse models.
  8. Expedited Exome Reanalysis Following Deep Phenotyping and Muscle Biopsy in Suspected Mitochondrial Disorder.
  9. Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
  10. Decoding the Enigma: Translation Termination in Human Mitochondria.
  11. Molecular and cellular consequences of mitochondrial DNA double-stranded breaks.
  12. Weak neuronal glycolysis sustains cognition and organismal fitness.
  13. The molecular machinery for maturation of primary mtDNA transcripts.
  14. Central dogma rates in human mitochondria.
  15. Tools for editing the mammalian mitochondrial genome.
  16. RNA degradation in human mitochondria: the journey is not finished.
  17. Chelating mitochondrial iron and copper: Recipes, pitfalls and promise.
  18. NEKL-4 regulates microtubule stability and mitochondrial health in ciliated neurons.
  19. TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA.
  20. Compartmental Differences in the Retinal Ganglion Cell Mitochondrial Proteome.
  21. Supplementation with autologous adipose stem cell-derived mitochondria can be a safe and promising strategy for improving oocyte quality.
  22. Lab-grown sperm and eggs: 'epigenetic' reset in human cells paves the way.
  23. Dystonia and mitochondrial disease: the movement disorder connection revisited in 900 genetically diagnosed patients.
  24. Mitochondria transplantation alleviates cardiomyocytes apoptosis through inhibiting AMPKα-mTOR mediated excessive autophagy.
  25. Artificially transplanted mitochondria in endothelial cells promote mitophagy.
  26. An RNA-seq study in Friedreich ataxia patients identified hsa-miR-148a-3p as a putative prognostic biomarker of the disease.
  27. Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy.
  28. The tissue-specific nature of physiological zebrafish mitochondrial bioenergetics.
  1. Cell. 2024 May 23. pii: S0092-8674(24)00463-X. [Epub ahead of print]187(11): 2601-2627
    Mitochondria at the crossroads of health and disease.
    Anu Suomalainen, Jodi Nunnari.
      Mitochondria reside at the crossroads of catabolic and anabolic metabolism-the essence of life. How their structure and function are dynamically tuned in response to tissue-specific needs for energy, growth repair, and renewal is being increasingly understood. Mitochondria respond to intrinsic and extrinsic stresses and can alter cell and organismal function by inducing metabolic signaling within cells and to distal cells and tissues. Here, we review how the centrality of mitochondrial functions manifests in health and a broad spectrum of diseases and aging.
    DOI:  https://doi.org/10.1016/j.cell.2024.04.037
  2. Hum Mol Genet. 2024 May 22. 33(R1): R3-R11
    Origins of tissue and cell-type specificity in mitochondrial DNA (mtDNA) disease.
    Stephen P Burr, Patrick F Chinnery.
      Mutations of mitochondrial (mt)DNA are a major cause of morbidity and mortality in humans, accounting for approximately two thirds of diagnosed mitochondrial disease. However, despite significant advances in technology since the discovery of the first disease-causing mtDNA mutations in 1988, the comprehensive diagnosis and treatment of mtDNA disease remains challenging. This is partly due to the highly variable clinical presentation linked to tissue-specific vulnerability that determines which organs are affected. Organ involvement can vary between different mtDNA mutations, and also between patients carrying the same disease-causing variant. The clinical features frequently overlap with other non-mitochondrial diseases, both rare and common, adding to the diagnostic challenge. Building on previous findings, recent technological advances have cast further light on the mechanisms which underpin the organ vulnerability in mtDNA diseases, but our understanding is far from complete. In this review we explore the origins, current knowledge, and future directions of research in this area.
    Keywords:  heteroplasmy; mitochondria; mtDNA; single cell
    DOI:  https://doi.org/10.1093/hmg/ddae059
  3. Hum Mol Genet. 2024 May 22. 33(R1): R47-R52
    Coordinating mitochondrial translation with assembly of the OXPHOS complexes.
    Laura S Kremer, Peter Rehling.
      The mitochondrial oxidative phosphorylation (OXPHOS) system produces the majority of energy required by cells. Given the mitochondrion's endosymbiotic origin, the OXPHOS machinery is still under dual genetic control where most OXPHOS subunits are encoded by the nuclear DNA and imported into mitochondria, while a small subset is encoded on the mitochondrion's own genome, the mitochondrial DNA (mtDNA). The nuclear and mtDNA encoded subunits must be expressed and assembled in a highly orchestrated fashion to form a functional OXPHOS system and meanwhile prevent the generation of any harmful assembly intermediates. While several mechanisms have evolved in eukaryotes to achieve such a coordinated expression, this review will focus on how the translation of mtDNA encoded OXPHOS subunits is tailored to OXPHOS assembly.
    Keywords:  Coordination of translation and assembly; Gene expression; Mitochondria; OXPHOS assembly; Oxidative phosphorylation (OXPHOS); Translation
    DOI:  https://doi.org/10.1093/hmg/ddae025
  4. Hum Mol Genet. 2024 May 22. 33(R1): R1-R2
    Mitochondrial molecular genetics and human disease.
    Eric A Shoubridge, Antoni Barrientos.
      
    DOI:  https://doi.org/10.1093/hmg/ddae049
  5. Biomolecules. 2024 May 18. pii: 598. [Epub ahead of print]14(5):
    Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation.
    Paula Cilleros-Holgado, David Gómez-Fernández, Rocío Piñero-Pérez, José Manuel Romero Domínguez, Marta Talaverón-Rey, Diana Reche-López, Juan Miguel Suárez-Rivero, Mónica Álvarez-Córdoba, Ana Romero-González, Alejandra López-Cabrera, Marta Castro De Oliveira, Andrés Rodríguez-Sacristan, José Antonio Sánchez-Alcázar.
      Primary mitochondrial diseases result from mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) genes, encoding proteins crucial for mitochondrial structure or function. Given that few disease-specific therapies are available for mitochondrial diseases, novel treatments to reverse mitochondrial dysfunction are necessary. In this work, we explored new therapeutic options in mitochondrial diseases using fibroblasts and induced neurons derived from patients with mutations in the GFM1 gene. This gene encodes the essential mitochondrial translation elongation factor G1 involved in mitochondrial protein synthesis. Due to the severe mitochondrial defect, mutant GFM1 fibroblasts cannot survive in galactose medium, making them an ideal screening model to test the effectiveness of pharmacological compounds. We found that the combination of polydatin and nicotinamide enabled the survival of mutant GFM1 fibroblasts in stress medium. We also demonstrated that polydatin and nicotinamide upregulated the mitochondrial Unfolded Protein Response (mtUPR), especially the SIRT3 pathway. Activation of mtUPR partially restored mitochondrial protein synthesis and expression, as well as improved cellular bioenergetics. Furthermore, we confirmed the positive effect of the treatment in GFM1 mutant induced neurons obtained by direct reprogramming from patient fibroblasts. Overall, we provide compelling evidence that mtUPR activation is a promising therapeutic strategy for GFM1 mutations.
    Keywords:  EF-G1; GFM1; direct reprogramming; fibroblasts; induced neurons; mitochondria; mitochondrial diseases; mtUPR; treatment
    DOI:  https://doi.org/10.3390/biom14050598
  6. Hum Mol Genet. 2024 May 22. 33(R1): R80-R91
    Mitochondrial DNA release and sensing in innate immune responses.
    Jordyn J VanPortfliet, Cole Chute, Yuanjiu Lei, Timothy E Shutt, A Phillip West.
      Mitochondria are pleiotropic organelles central to an array of cellular pathways including metabolism, signal transduction, and programmed cell death. Mitochondria are also key drivers of mammalian immune responses, functioning as scaffolds for innate immune signaling, governing metabolic switches required for immune cell activation, and releasing agonists that promote inflammation. Mitochondrial DNA (mtDNA) is a potent immunostimulatory agonist, triggering pro-inflammatory and type I interferon responses in a host of mammalian cell types. Here we review recent advances in how mtDNA is detected by nucleic acid sensors of the innate immune system upon release into the cytoplasm and extracellular space. We also discuss how the interplay between mtDNA release and sensing impacts cellular innate immune endpoints relevant to health and disease.
    Keywords:  NLRP3; TLR9; cGAS-STING; inflammation; innate immunity; mitochondria; mitochondrial DNA
    DOI:  https://doi.org/10.1093/hmg/ddae031
  7. Hum Mol Genet. 2024 May 22. 33(R1): R61-R79
    Illuminating mitochondrial translation through mouse models.
    Laetitia A Hughes, Oliver Rackham, Aleksandra Filipovska.
      Mitochondria are hubs of metabolic activity with a major role in ATP conversion by oxidative phosphorylation (OXPHOS). The mammalian mitochondrial genome encodes 11 mRNAs encoding 13 OXPHOS proteins along with 2 rRNAs and 22 tRNAs, that facilitate their translation on mitoribosomes. Maintaining the internal production of core OXPHOS subunits requires modulation of the mitochondrial capacity to match the cellular requirements and correct insertion of particularly hydrophobic proteins into the inner mitochondrial membrane. The mitochondrial translation system is essential for energy production and defects result in severe, phenotypically diverse diseases, including mitochondrial diseases that typically affect postmitotic tissues with high metabolic demands. Understanding the complex mechanisms that underlie the pathologies of diseases involving impaired mitochondrial translation is key to tailoring specific treatments and effectively targeting the affected organs. Disease mutations have provided a fundamental, yet limited, understanding of mitochondrial protein synthesis, since effective modification of the mitochondrial genome has proven challenging. However, advances in next generation sequencing, cryoelectron microscopy, and multi-omic technologies have revealed unexpected and unusual features of the mitochondrial protein synthesis machinery in the last decade. Genome editing tools have generated unique models that have accelerated our mechanistic understanding of mitochondrial translation and its physiological importance. Here we review the most recent mouse models of disease pathogenesis caused by defects in mitochondrial protein synthesis and discuss their value for preclinical research and therapeutic development.
    Keywords:  animal models; gene expression; mitochondria; protein synthesis
    DOI:  https://doi.org/10.1093/hmg/ddae020
  8. Pediatr Neurol. 2024 Apr 12. pii: S0887-8994(24)00134-6. [Epub ahead of print]156 178-181
    Expedited Exome Reanalysis Following Deep Phenotyping and Muscle Biopsy in Suspected Mitochondrial Disorder.
    Elizabeth Pickup, Steven A Moore, Pim Suwannarat, Christina Grant, Nicholas Ah Mew, Andrea Gropman, Kuntal Sen.
       BACKGROUND: Exome sequencing (ES) is a useful tool in diagnosing suspected mitochondrial disease but can miss pathogenic variants for several reasons. Additional testing, such as muscle biopsy or biochemical testing, can be helpful in exome-negative cases.
    METHODS: We report a patient who presented with repeated episodes of lactic acidosis and failure to thrive.
    RESULTS: ES and mitochondrial sequencing were initially negative but clinical suspicion for mitochondrial disease remained high. After muscle biopsy showed evidence of mitochondrial dysfunction, the ES was reanalyzed and revealed novel variants in AARS2.
    CONCLUSION: This case demonstrates the importance of muscle biopsy and biochemical testing in evaluating patients with a high suspicion of mitochondrial disease, even in the genomics era. Closed-loop communication between molecular genetics laboratories and clinical geneticists is an important step to help establish diagnosis in unsolved cases.
    Keywords:  AARS2; Aminoacyl-tRNA synthetase deficiency; Exome-negative; Mitochondrial disease; Muscle biopsy
    DOI:  https://doi.org/10.1016/j.pediatrneurol.2024.04.007
  9. J Biol Chem. 2024 May 21. pii: S0021-9258(24)01904-5. [Epub ahead of print] 107403
    Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
    Francesco Agostini, Leonardo Pereyra, Justin Dale, King Faisal Yambire, Silvia Maglioni, Alfonso Schiavi, Natascia Ventura, Ira Milosevic, Nuno Raimundo.
      Mitochondria and lysosomes are two organelles that carry out both signaling and metabolic roles in cells. Recent evidence has shown that mitochondria and lysosomes are dependent on one another, as primary defects in one cause secondary defects in the other. Although there are functional impairments in both cases, the signaling consequences of primary mitochondrial dysfunction and lysosomal defects are dissimilar. Here, we used RNA sequencing to obtain transcriptomes from cells with primary mitochondrial or lysosomal defects to identify the global cellular consequences associated with mitochondrial or lysosomal dysfunction. We used these data to determine the pathways affected by defects in both organelles, which revealed a prominent role for the cholesterol synthesis pathway. We observed a transcriptional up-regulated of this pathway in cellular and murine models of lysosomal defects, while it is transcriptionally down-regulated in cellular and murine models of mitochondrial defects. We identified a role for the post-transcriptional regulation of transcription factor SREBF1, a master regulator of cholesterol and lipid biosynthesis, in models of mitochondrial respiratory chain deficiency. Furthermore, we found that retention of Ca2+ in lysosomes of cells with mitochondrial respiratory chain defects contributes to the differential regulation of the cholesterol synthesis pathway in the mitochondrial and lysosomal defects tested. Finally, we verified in vivo, using a model of mitochondria-associated disease in C. elegans, that normalization of lysosomal Ca2+ levels results in partial rescue of the developmental delay induced by the respiratory chain deficiency.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107403
  10. Hum Mol Genet. 2024 May 22. 33(R1): R42-R46
    Decoding the Enigma: Translation Termination in Human Mitochondria.
    Annika Krüger, Daria Kovalchuk, Dmitrii Shiriaev, Joanna Rorbach.
      Mitochondrial translation is a complex process responsible for the synthesis of essential proteins involved in oxidative phosphorylation, a fundamental pathway for cellular energy production. Central to this process is the termination phase, where dedicated factors play a pivotal role in ensuring accurate and timely protein production. This review provides a comprehensive overview of the current understanding of translation termination in human mitochondria, emphasizing structural features and molecular functions of two mitochondrial termination factors mtRF1 and mtRF1a.
    Keywords:  Mitochondrial translation; mitochondrial translation termination factors; mitoribosomes
    DOI:  https://doi.org/10.1093/hmg/ddae032
  11. Hum Mol Genet. 2024 May 22. 33(R1): R12-R18
    Molecular and cellular consequences of mitochondrial DNA double-stranded breaks.
    Chenxiao Yu, Samieh Asadian, Marco Tigano.
      Mitochondria are subcellular organelles essential for life. Beyond their role in producing energy, mitochondria govern various physiological mechanisms, encompassing energy generation, metabolic processes, apoptotic events, and immune responses. Mitochondria also contain genetic material that is susceptible to various forms of damage. Mitochondrial double-stranded breaks (DSB) are toxic lesions that the nucleus repairs promptly. Nevertheless, the significance of DSB repair in mammalian mitochondria is controversial. This review presents an updated view of the available research on the consequences of mitochondrial DNA DSB from the molecular to the cellular level. We discuss the crucial function of mitochondrial DNA damage in regulating processes such as senescence, integrated stress response, and innate immunity. Lastly, we discuss the potential role of mitochondrial DNA DSB in mediating the cellular consequences of ionizing radiations, the standard of care in treating solid tumors.
    Keywords:  innate immunity; integrated stress response; mitochondria; mitochondrial DNA; senescence
    DOI:  https://doi.org/10.1093/hmg/ddae048
  12. Nat Metab. 2024 May 24.
    Weak neuronal glycolysis sustains cognition and organismal fitness.
    Daniel Jimenez-Blasco, Jesús Agulla, Rebeca Lapresa, Marina Garcia-Macia, Veronica Bobo-Jimenez, Dario Garcia-Rodriguez, Israel Manjarres-Raza, Emilio Fernandez, Yannick Jeanson, Spiro Khoury, Jean-Charles Portais, Daniel Padro, Pedro Ramos-Cabrer, Peter Carmeliet, Angeles Almeida, Juan P Bolaños.
      The energy cost of neuronal activity is mainly sustained by glucose1,2. However, in an apparent paradox, neurons modestly metabolize glucose through glycolysis3-6, a circumstance that can be accounted for by the constant degradation of 6-phosphofructo-2-kinase-fructose-2,6-bisphosphatase-3 (PFKFB3)3,7,8, a key glycolysis-promoting enzyme. To evaluate the in vivo physiological importance of this hypoglycolytic metabolism, here we genetically engineered mice with their neurons transformed into active glycolytic cells through Pfkfb3 expression. In vivo molecular, biochemical and metabolic flux analyses of these neurons revealed an accumulation of anomalous mitochondria, complex I disassembly, bioenergetic deficiency and mitochondrial redox stress. Notably, glycolysis-mediated nicotinamide adenine dinucleotide (NAD+) reduction impaired sirtuin-dependent autophagy. Furthermore, these mice displayed cognitive decline and a metabolic syndrome that was mimicked by confining Pfkfb3 expression to hypothalamic neurons. Neuron-specific genetic ablation of mitochondrial redox stress or brain NAD+ restoration corrected these behavioural alterations. Thus, the weak glycolytic nature of neurons is required to sustain higher-order organismal functions.
    DOI:  https://doi.org/10.1038/s42255-024-01049-0
  13. Hum Mol Genet. 2024 May 22. 33(R1): R19-R25
    The molecular machinery for maturation of primary mtDNA transcripts.
    Ana Vučković, Christoph Freyer, Anna Wredenberg, Hauke S Hillen.
      Human mitochondria harbour a circular, polyploid genome (mtDNA) encoding 11 messenger RNAs (mRNAs), two ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs). Mitochondrial transcription produces long, polycistronic transcripts that span almost the entire length of the genome, and hence contain all three types of RNAs. The primary transcripts then undergo a number of processing and maturation steps, which constitute key regulatory points of mitochondrial gene expression. The first step of mitochondrial RNA processing consists of the separation of primary transcripts into individual, functional RNA molecules and can occur by two distinct pathways. Both are carried out by dedicated molecular machineries that substantially differ from RNA processing enzymes found elsewhere. As a result, the underlying molecular mechanisms remain poorly understood. Over the last years, genetic, biochemical and structural studies have identified key players involved in both RNA processing pathways and provided the first insights into the underlying mechanisms. Here, we review our current understanding of RNA processing in mammalian mitochondria and provide an outlook on open questions in the field.
    Keywords:  Mitochondria; Mitochondriopathy; RNA; RNA Processing
    DOI:  https://doi.org/10.1093/hmg/ddae023
  14. Hum Mol Genet. 2024 May 22. 33(R1): R34-R41
    Central dogma rates in human mitochondria.
    Erik McShane, L Stirling Churchman.
      In human cells, the nuclear and mitochondrial genomes engage in a complex interplay to produce dual-encoded oxidative phosphorylation (OXPHOS) complexes. The coordination of these dynamic gene expression processes is essential for producing matched amounts of OXPHOS protein subunits. This review focuses on our current understanding of the mitochondrial central dogma rates, highlighting the striking differences in gene expression rates between mitochondrial and nuclear genes. We synthesize a coherent model of mitochondrial gene expression kinetics, highlighting the emerging principles and emphasizing where more precise measurements would be beneficial. Such an understanding is pivotal for grasping the unique aspects of mitochondrial function and its role in cellular energetics, and it has profound implications for aging, metabolic disorders, and neurodegenerative diseases.
    Keywords:  gene regulation; mitochondrial DNA; mitonuclear balance; oxidative phosphorylation
    DOI:  https://doi.org/10.1093/hmg/ddae036
  15. Hum Mol Genet. 2024 May 22. 33(R1): R92-R99
    Tools for editing the mammalian mitochondrial genome.
    Carlos T Moraes.
      The manipulation of animal mitochondrial genomes has long been a challenge due to the lack of an effective transformation method. With the discovery of specific gene editing enzymes, designed to target pathogenic mitochondrial DNA mutations (often heteroplasmic), the selective removal or modification of mutant variants has become a reality. Because mitochondria cannot efficiently import RNAs, CRISPR has not been the first choice for editing mitochondrial genes. However, the last few years witnessed an explosion in novel and optimized non-CRISPR approaches to promote double-strand breaks or base-edit of mtDNA in vivo. Engineered forms of specific nucleases and cytidine/adenine deaminases form the basis for these techniques. I will review the newest developments that constitute the current toolbox for animal mtDNA gene editing in vivo, bringing these approaches not only to the exploration of mitochondrial function, but also closer to clinical use.
    Keywords:  TALEN technology; base editing; gene modification; genetic enhancements; mitochondrial manipulation
    DOI:  https://doi.org/10.1093/hmg/ddae037
  16. Hum Mol Genet. 2024 May 22. 33(R1): R26-R33
    RNA degradation in human mitochondria: the journey is not finished.
    Giulia Santonoceto, Aneta Jurkiewicz, Roman J Szczesny.
      Mitochondria are vital organelles present in almost all eukaryotic cells. Although most of the mitochondrial proteins are nuclear-encoded, mitochondria contain their own genome, whose proper expression is necessary for mitochondrial function. Transcription of the human mitochondrial genome results in the synthesis of long polycistronic transcripts that are subsequently processed by endonucleases to release individual RNA molecules, including precursors of sense protein-encoding mRNA (mt-mRNA) and a vast amount of antisense noncoding RNAs. Because of mitochondrial DNA (mtDNA) organization, the regulation of individual gene expression at the transcriptional level is limited. Although transcription of most protein-coding mitochondrial genes occurs with the same frequency, steady-state levels of mature transcripts are different. Therefore, post-transcriptional processes are important for regulating mt-mRNA levels. The mitochondrial degradosome is a complex composed of the RNA helicase SUV3 (also known as SUPV3L1) and polynucleotide phosphorylase (PNPase, PNPT1). It is the best-characterized RNA-degrading machinery in human mitochondria, which is primarily responsible for the decay of mitochondrial antisense RNA. The mechanism of mitochondrial sense RNA decay is less understood. This review aims to provide a general picture of mitochondrial genome expression, with a particular focus on mitochondrial RNA (mtRNA) degradation.
    Keywords:  mitochondrial RNA decay; mitochondrial RNA surveillance; mitochondrial gene expression; polyadenylation
    DOI:  https://doi.org/10.1093/hmg/ddae043
  17. Mitochondrion. 2024 May 20. pii: S1567-7249(24)00061-8. [Epub ahead of print] 101903
    Chelating mitochondrial iron and copper: Recipes, pitfalls and promise.
    Lucie J Lamačová, Jan Trnka.
      Iron and copper chelation therapy plays a crucial role in treating conditions associated with metal overload, such as hemochromatosis or Wilson's disease. However, conventional chelators face challenges in reaching the core of iron and copper metabolism - the mitochondria. Mitochondria-targeted chelators can specifically target and remove metal ions from mitochondria, showing promise in treating diseases linked to mitochondrial dysfunction, including neurodegenerative diseases and cancer. Additionally, they serve as specific mitochondrial metal sensors. However, designing these new molecules presents its own set of challenges. Depending on the chelator's intended use to prevent or to promote redox cycling of the metals, the chelating moiety must possess different donor atoms and an optimal value of the electrode potential of the chelator-metal complex. Various targeting moieties can be employed for selective delivery into the mitochondria. This review also provides an overview of the current progress in the design of mitochondria-targeted chelators and their biological activity investigation.
    Keywords:  Chelator; Copper; Iron; Mitochondria; Redox cycling; Targeting
    DOI:  https://doi.org/10.1016/j.mito.2024.101903
  18. J Cell Biol. 2024 Sep 02. pii: e202402006. [Epub ahead of print]223(9):
    NEKL-4 regulates microtubule stability and mitochondrial health in ciliated neurons.
    Kaiden M Power, Ken C Nguyen, Andriele Silva, Shaneen Singh, David H Hall, Christopher Rongo, Maureen M Barr.
      Ciliopathies are often caused by defects in the ciliary microtubule core. Glutamylation is abundant in cilia, and its dysregulation may contribute to ciliopathies and neurodegeneration. Mutation of the deglutamylase CCP1 causes infantile-onset neurodegeneration. In C. elegans, ccpp-1 loss causes age-related ciliary degradation that is suppressed by a mutation in the conserved NEK10 homolog nekl-4. NEKL-4 is absent from cilia, yet it negatively regulates ciliary stability via an unknown, glutamylation-independent mechanism. We show that NEKL-4 was mitochondria-associated. Additionally, nekl-4 mutants had longer mitochondria, a higher baseline mitochondrial oxidation state, and suppressed ccpp-1∆ mutant lifespan extension in response to oxidative stress. A kinase-dead nekl-4(KD) mutant ectopically localized to ccpp-1∆ cilia and rescued degenerating microtubule doublet B-tubules. A nondegradable nekl-4(PEST∆) mutant resembled the ccpp-1∆ mutant with dye-filling defects and B-tubule breaks. The nekl-4(PEST∆) Dyf phenotype was suppressed by mutation in the depolymerizing kinesin-8 KLP-13/KIF19A. We conclude that NEKL-4 influences ciliary stability by activating ciliary kinesins and promoting mitochondrial homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202402006
  19. Nat Cell Biol. 2024 May 23.
    TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA.
    Hao Liu, Cien Zhen, Jianming Xie, Zhenhuan Luo, Lin Zeng, Guojun Zhao, Shaohua Lu, Haixia Zhuang, Hualin Fan, Xia Li, Zhaojie Liu, Shiyin Lin, Huilin Jiang, Yuqian Chen, Jiahao Cheng, Zhiyu Cao, Keyu Dai, Jinhua Shi, Zhaohua Wang, Yongquan Hu, Tian Meng, Chuchu Zhou, Zhiyuan Han, Huansen Huang, Qinghua Zhou, Pengcheng He, Du Feng.
      When cells are stressed, DNA from energy-producing mitochondria can leak out and drive inflammatory immune responses if not cleared. Cells employ a quality control system called autophagy to specifically degrade damaged components. We discovered that mitochondrial transcription factor A (TFAM)-a protein that binds mitochondrial DNA (mtDNA)-helps to eliminate leaked mtDNA by interacting with the autophagy protein LC3 through an autolysosomal pathway (we term this nucleoid-phagy). TFAM contains a molecular zip code called the LC3 interacting region (LIR) motif that enables this binding. Although mutating TFAM's LIR motif did not affect its normal mitochondrial functions, more mtDNA accumulated in the cell cytoplasm, activating inflammatory signalling pathways. Thus, TFAM mediates autophagic removal of leaked mtDNA to restrict inflammation. Identifying this mechanism advances understanding of how cells exploit autophagy machinery to selectively target and degrade inflammatory mtDNA. These findings could inform research on diseases involving mitochondrial damage and inflammation.
    DOI:  https://doi.org/10.1038/s41556-024-01419-6
  20. bioRxiv. 2024 May 10. pii: 2024.05.07.593032. [Epub ahead of print]
    Compartmental Differences in the Retinal Ganglion Cell Mitochondrial Proteome.
    Liam S C Lewis, Nikolai P Skiba, Ying Hao, Howard M Bomze, Vadim Y Arshavsky, Romain Cartoni, Sidney M Gospe.
      Among neurons, retinal ganglion cells (RGCs) are uniquely sensitive to mitochondrial dysfunction. The RGC is highly polarized, with a somatodendritic compartment in the inner retina and an axonal compartment projecting to targets in the brain. The drastically dissimilar functions of these compartments implies that mitochondria face different bioenergetic and other physiological demands. We hypothesized that compartmental differences in mitochondrial biology would be reflected by disparities in mitochondrial protein composition. Here, we describe a protocol to isolate intact mitochondria separately from mouse RGC somatodendritic and axonal compartments by immunoprecipitating labeled mitochondria from RGC MitoTag mice. Using mass spectrometry, 471 and 357 proteins were identified in RGC somatodendritic and axonal mitochondrial immunoprecipitates, respectively. We identified 10 mitochondrial proteins exclusively in the somatodendritic compartment and 19 enriched ≥2-fold there, while 3 proteins were exclusively identified and 18 enriched in the axonal compartment. Our observation of compartment-specific enrichment of mitochondrial proteins was validated through immunofluorescence analysis of the localization and relative abundance of superoxide dismutase ( SOD2 ), sideroflexin-3 ( SFXN3 ) and trifunctional enzyme subunit alpha ( HADHA ) in retina and optic nerve specimens. The identified compartmental differences in RGC mitochondrial composition may provide promising leads for uncovering physiologically relevant pathways amenable to therapeutic intervention for optic neuropathies.
    DOI:  https://doi.org/10.1101/2024.05.07.593032
  21. J Assist Reprod Genet. 2024 May 22.
    Supplementation with autologous adipose stem cell-derived mitochondria can be a safe and promising strategy for improving oocyte quality.
    Sanath Udayanga Kankanam Gamage, Shu Hashimoto, Yuki Miyamoto, Tatsuya Nakano, Masaya Yamanaka, Hideki Kitaji, Yuki Takada, Hiroshi Matsumoto, Akiko Koike, Manabu Satoh, Masako Ichishi, Masatoshi Watanabe, Yoshiharu Morimoto.
       PURPOSE: In our previous study, we confirmed that the supplementation of vitrified-warmed murine oocytes with autologous adipose stem cell (ASC)-derived mitochondria during intracytoplasmic sperm injection enhances post-fertilization developmental competence in mice. To ensure the safety of this technology, we conducted a thorough study in mice to investigate the potential presence of specific malformations in offspring developed from this approach.
    METHODS: A transgenerational comparative analysis was conducted on founder mice from embryos that developed after mitochondrial supplementation, and two subsequent generations. Reproductive performance, body growth rate, histopathological parameters, hematological parameters, daily activity patterns, and daily body temperature changes in male and female mice across these three generations were assessed in comparison to wild-type mice of the same age.
    RESULTS: Both male and female animals in all three generations showed comparable reproductive performance to the control group. Additionally, body growth rate by the age of 8 weeks were found to be comparable to controls across all three generations. Notably, no significant histopathological abnormalities were detected in vital organs, including the brain, heart, liver, kidneys, lungs, ovaries, and testes, in any individuals from the studied cohorts. The blood parameters were consistent with the control data. The continuous monitoring of activity and body temperature changes (both day and night) over a 1-week period revealed a pattern closely resembling that observed in the control animals.
    CONCLUSION: Injection of ASC-mitochondria into oocytes may be a promising technique to support developmental potential without causing adverse epigenetic events in the offspring in mice. However, before considering clinical application, additional safety screening using larger animals or non-human primates is essential.
    Keywords:  Adipose stem cell; Mitochondrial supplementation; Oocyte quality enhancement; Transgenerational safety
    DOI:  https://doi.org/10.1007/s10815-024-03137-2
  22. Nature. 2024 May 21.
    Lab-grown sperm and eggs: 'epigenetic' reset in human cells paves the way.
    Heidi Ledford.
      
    Keywords:  Developmental biology; Epigenetics; Medical research; Stem cells
    DOI:  https://doi.org/10.1038/d41586-024-01404-x
  23. J Neurol. 2024 May 22.
    Dystonia and mitochondrial disease: the movement disorder connection revisited in 900 genetically diagnosed patients.
    Elisabetta Indelicato, Lea D Schlieben, Sarah L Stenton, Sylvia Boesch, Matej Skorvanek, Jan Necpal, Robert Jech, Juliane Winkelmann, Holger Prokisch, Michael Zech.
      
    DOI:  https://doi.org/10.1007/s00415-024-12447-5
  24. FASEB J. 2024 May 31. 38(10): e23655
    Mitochondria transplantation alleviates cardiomyocytes apoptosis through inhibiting AMPKα-mTOR mediated excessive autophagy.
    Ning Jin, Mengyao Zhang, Li Zhou, Shanshan Jin, Haiqin Cheng, Xuewei Li, Yaqian Shi, Tong Xiang, Zongxiao Zhang, Zhizhen Liu, Hong Zhao, Jun Xie.
      The disruption of mitochondria homeostasis can impair the contractile function of cardiomyocytes, leading to cardiac dysfunction and an increased risk of heart failure. This study introduces a pioneering therapeutic strategy employing mitochondria derived from human umbilical cord mesenchymal stem cells (hu-MSC) (MSC-Mito) for heart failure treatment. Initially, we isolated MSC-Mito, confirming their functionality. Subsequently, we monitored the process of single mitochondria transplantation into recipient cells and observed a time-dependent uptake of mitochondria in vivo. Evidence of human-specific mitochondrial DNA (mtDNA) in murine cardiomyocytes was observed after MSC-Mito transplantation. Employing a doxorubicin (DOX)-induced heart failure model, we demonstrated that MSC-Mito transplantation could safeguard cardiac function and avert cardiomyocyte apoptosis, indicating metabolic compatibility between hu-MSC-derived mitochondria and recipient mitochondria. Finally, through RNA sequencing and validation experiments, we discovered that MSC-Mito transplantation potentially exerted cardioprotection by reinstating ATP production and curtailing AMPKα-mTOR-mediated excessive autophagy.
    Keywords:  AMPKα‐mTOR; ATP; autophagy; cardiomyocyte apoptosis; mitochondria transplantation
    DOI:  https://doi.org/10.1096/fj.202400375R
  25. Nat Rev Cardiol. 2024 May 21.
    Artificially transplanted mitochondria in endothelial cells promote mitophagy.
    Karina Huynh.
      
    DOI:  https://doi.org/10.1038/s41569-024-01041-x
  26. Hum Genomics. 2024 May 22. 18(1): 50
    An RNA-seq study in Friedreich ataxia patients identified hsa-miR-148a-3p as a putative prognostic biomarker of the disease.
    Chiara Vancheri, Andrea Quatrana, Elena Morini, Caterina Mariotti, Alessia Mongelli, Mario Fichera, Alessandra Rufini, Ivano Condò, Roberto Testi, Giuseppe Novelli, Florence Malisan, Francesca Amati.
      Friedreich ataxia (FRDA) is a life-threatening hereditary ataxia; its incidence is 1:50,000 individuals in the Caucasian population. A unique therapeutic drug for FRDA, the antioxidant Omaveloxolone, has been recently approved by the US Food and Drug Administration (FDA). FRDA is a multi-systemic neurodegenerative disease; in addition to a progressive neurodegeneration, FRDA is characterized by hypertrophic cardiomyopathy, diabetes mellitus and musculoskeletal deformities. Cardiomyopathy is the predominant cause of premature death. The onset of FRDA typically occurs between the ages of 5 and 15. Given the complexity and heterogeneity of clinical features and the variability of their onset, the identification of biomarkers capable of assessing disease progression and monitoring the efficacy of treatments is essential to facilitate decision making in clinical practice. We conducted an RNA-seq analysis in peripheral blood mononuclear cells from FRDA patients and healthy donors, identifying a signature of small non-coding RNAs (sncRNAs) capable of distinguishing healthy individuals from the majority of FRDA patients. Among the differentially expressed sncRNAs, microRNAs are a class of small non-coding endogenous RNAs that regulate posttranscriptional silencing of target genes. In FRDA plasma samples, hsa-miR-148a-3p resulted significantly upregulated. The analysis of the Receiver Operating Characteristic (ROC) curve, combining the circulating expression levels of hsa-miR-148a-3p and hsa-miR-223-3p (previously identified by our group), revealed an Area Under the Curve (AUC) of 0.86 (95%, Confidence Interval 0.77-0.95; p-value < 0.0001). An in silico prediction analysis indicated that the IL6ST gene, an interesting marker of neuroinflammation in FRDA, is a common target gene of both miRNAs. Our findings support the evaluation of combined expression levels of different circulating miRNAs as potent epi-biomarkers in FRDA. Moreover, we found hsa-miR-148a-3p significantly over-expressed in Intermediate and Late-Onset Friedreich Ataxia patients' group (IOG and LOG, respectively) compared to healthy individuals, indicating it as a putative prognostic biomarker in this pathology.
    Keywords:  Biomarkers; Frataxin; Friedreich ataxia; RNA-seq; microRNA
    DOI:  https://doi.org/10.1186/s40246-024-00602-y
  27. Brain. 2024 May 20. pii: awae038. [Epub ahead of print]
    Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy.
    Nathalie Launay, Jone Lopez-Erauskin, Patrizia Bianchi, Sanjib Guha, Janani Parameswaran, Andrea Coppa, Lorenzo Torreni, Agatha Schlüter, Stéphane Fourcade, Abraham J Paredes-Fuentes, Rafael Artuch, Carlos Casasnovas, Montserrat Ruiz, Aurora Pujol.
      The peroxisomal disease adrenoleukodystrophy (X-ALD) is caused by loss of the transporter of very-long-chain fatty acids (VLCFAs), ABCD1. An excess of VLCFAs disrupts essential homeostatic functions crucial for axonal maintenance, including redox metabolism, glycolysis and mitochondrial respiration. As mitochondrial function and morphology are intertwined, we set out to investigate the role of mitochondrial dynamics in X-ALD models. Using quantitative 3D transmission electron microscopy, we revealed mitochondrial fragmentation in corticospinal axons in Abcd1- mice. In patient fibroblasts, an excess of VLCFAs triggers mitochondrial fragmentation through the redox-dependent phosphorylation of DRP1 (DRP1S616). The blockade of DRP1-driven fission by the peptide P110 effectively preserved mitochondrial morphology. Furthermore, mRNA inhibition of DRP1 not only prevented mitochondrial fragmentation but also protected axonal health in a Caenorhabditis elegans model of X-ALD, underscoring DRP1 as a potential therapeutic target. Elevated levels of circulating cell-free mtDNA in patients' CSF align this leukodystrophy with primary mitochondrial disorders. Our findings underscore the intricate interplay between peroxisomal dysfunction, mitochondrial dynamics and axonal integrity in X-ALD, shedding light on potential avenues for therapeutic intervention.
    Keywords:  DRP1; P110; VLCFA; X-ALD; ccfmtDNA; mitochondrial dynamics
    DOI:  https://doi.org/10.1093/brain/awae038
  28. Mitochondrion. 2024 May 21. pii: S1567-7249(24)00059-X. [Epub ahead of print]77 101901
    The tissue-specific nature of physiological zebrafish mitochondrial bioenergetics.
    Rafael David Souto de Azevedo, Kivia Vanessa Gomes Falcão, Sinara Monica Vitalino de Almeida, Marlyete Chagas Araújo, Reginaldo Correia Silva-Filho, Maria Bernadete de Souza Maia, Ian Porto Gurgel do Amaral, Ana Catarina Rezende Leite, Ranilson de Souza Bezerra.
      Zebrafish are a powerful tool to study a myriad of experimental conditions, including mitochondrial bioenergetics. Considering that mitochondria are different in many aspects depending on the tissue evaluated, in the zebrafish model there is still a lack of this investigation. Especially for juvenile zebrafish. In the present study, we examined whether different tissues from zebrafish juveniles show mitochondrial density- and tissue-specificity comparing brain, liver, heart, and skeletal muscle (SM). The liver and brain complex IV showed the highest O2 consumption of all ETC in all tissues (10x when compared to other respiratory complexes). The liver showed a higher potential for ROS generation. In this way, the brain and liver showed more susceptibility to O2- generation when compared to other tissues. Regarding Ca2+ transport, the brain showed greater capacity for Ca2+ uptake and the liver presented low Ca2+ uptake capacity. The liver and brain were more susceptible to producing NO. The enzymes SOD and Catalase showed high activity in the brain, whereas GPx showed higher activity in the liver and CS in the SM. TEM reveals, as expected, a physiological diverse mitochondrial morphology. The essential differences between zebrafish tissues investigated probably reflect how the mitochondria play a diverse role in systemic homeostasis. This feature may not be limited to normal metabolic functions but also to stress conditions. In summary, mitochondrial bioenergetics in zebrafish juvenile permeabilized tissues showed a tissue-specificity and a useful tool to investigate conditions of redox system imbalance, mainly in the liver and brain.
    Keywords:  Calcium; Danio rerio; Mitochondrial function; Nitric oxide; Redox state
    DOI:  https://doi.org/10.1016/j.mito.2024.101901
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