bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024‒03‒24
forty-six papers selected by
Catalina Vasilescu, Helmholz Munich
  1. The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.
  2. Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
  3. MCU-independent Ca2+ uptake mediates mitochondrial Ca2+ overload and necrotic cell death in a mouse model of Duchenne muscular dystrophy.
  4. Revolutionizing cellular energy: The convergence of mitochondrial dynamics and delivery technologies.
  5. A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.
  6. AMPK and insulin control the switch between mitochondrial hitchhiking of Pink1 mRNA and mitophagy in neurons.
  7. A kinetic dichotomy between mitochondrial and nuclear gene expression processes.
  8. Structural determinants of mitochondrial STAT3 targeting and function.
  9. Future perspectives on the roles of mitochondrial dynamics in the heart in obesity and aging.
  10. Integrating the response to stressed mitochondria.
  11. Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.
  12. Mitochondrial dynamics: Regulating cell metabolism, homoeostasis, health and disease.
  13. Nocturnal vestibular stimulation using a rocking bed improves a severe sleep disorder in a patient with mitochondrial disease.
  14. Local mitochondrial replication in the periphery of neurons requires the eEF1A1 protein and thetranslation of nuclear-encoded proteins.
  15. Interplay of mitochondria associated membrane proteins and autophagy: Implications in neurodegeneration.
  16. Mitochondrial transcription factor A (TFAM) has 5'-deoxyribose phosphate lyase activity in vitro.
  17. Activating soluble adenylyl cyclase protects mitochondria, rescues retinal ganglion cells, and ameliorates visual dysfunction caused by oxidative stress.
  18. A SIFI odyssey: Silencing the stress response amid mitochondrial import blockade to safeguard cell survival.
  19. Mitochondria-lysosome-extracellular vesicles axis and nanotheranostics in neurodegenerative diseases.
  20. Clinical, biochemical, and genotypical characteristics in urea cycle mitochondrial transporter disorders.
  21. Mitochondria-ER contact sites expand during mitosis.
  22. Nanopore sequencing of 1000 Genomes Project samples to build a comprehensive catalog of human genetic variation.
  23. The zinc finger motif in the mitochondrial large ribosomal subunit protein bL36m is essential for optimal yeast mitoribosome assembly and function.
  24. Quantifying nanoscopic alterations associated with mitochondrial dysfunction using three-dimensional single-molecule localization microscopy.
  25. Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons.
  26. Mitochondrial DNA deletions in the cerebrospinal fluid of patients with idiopathic REM sleep behaviour disorder.
  27. Cardiac phenotype in adolescents and young adults with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency.
  28. Tradeoffs in alignment and assembly-based methods for structural variant detection with long-read sequencing data.
  29. The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions.
  30. AMPK Suppression Due to Obesity Drives Oocyte mtDNA Heteroplasmy via ATF5-POLG Axis.
  31. Synchronized assembly of the oxidative phosphorylation system controls mitochondrial respiration in yeast.
  32. Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization.
  33. Strengthening health systems for access to gene therapy in rare genetic disorders.
  34. Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1.
  35. Investigating the Therapeutic Effects of Ferroptosis on Myocardial Ischemia-Reperfusion Injury Using Dual-Locking Mitochondrial Targeting Strategy.
  36. Mitochondrial Raf1 Regulates Glutamine Catabolism.
  37. Long read sequencing on its way to the routine diagnostics of genetic diseases.
  38. A single-nuclei paired multiomic analysis of the human midbrain reveals age- and Parkinson's disease-associated glial changes.
  39. Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation.
  40. 'Bandit' algorithms help chemists to discover generally applicable conditions for reactions.
  41. Fusion activators enhance mitochondrial function.
  42. An evolutionary mechanism to assimilate new nutrient sensors into the mTORC1 pathway.
  43. 'A landmark moment': scientists use AI to design antibodies from scratch.
  44. A universal molecular control for DNA, mRNA and protein expression.
  45. How the body's cholesterol factory avoids producing too much.
  46. Endogenous BAX and BAK form mosaic rings of variable size and composition on apoptotic mitochondria.
  1. J Cell Biol. 2024 May 06. pii: e202302069. [Epub ahead of print]223(5):
    The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.
    Tianyao Xiao, Alyssa M English, Zachary N Wilson, J Alan Maschek, James E Cox, Adam L Hughes.
      Cells utilize multiple mechanisms to maintain mitochondrial homeostasis. We recently characterized a pathway that remodels mitochondria in response to metabolic alterations and protein overload stress. This remodeling occurs via the formation of large membranous structures from the mitochondrial outer membrane called mitochondrial-derived compartments (MDCs), which are eventually released from mitochondria and degraded. Here, we conducted a microscopy-based screen in budding yeast to identify factors that regulate MDC formation. We found that two phospholipids, cardiolipin (CL) and phosphatidylethanolamine (PE), differentially regulate MDC biogenesis. CL depletion impairs MDC biogenesis, whereas blocking mitochondrial PE production leads to constitutive MDC formation. Additionally, in response to metabolic MDC activators, cellular and mitochondrial PE declines, and overexpressing mitochondrial PE synthesis enzymes suppress MDC biogenesis. Altogether, our data indicate a requirement for CL in MDC biogenesis and suggest that PE depletion may stimulate MDC formation downstream of MDC-inducing metabolic stress.
    DOI:  https://doi.org/10.1083/jcb.202302069
  2. bioRxiv. 2024 Mar 07. pii: 2024.03.06.583589. [Epub ahead of print]
    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 the 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. Nevertheless, the signaling consequences of primary mitochondrial malfunction and of primary lysosomal defects are not similar, despite in both cases there are impairments of mitochondria and of lysosomes. Here, we used RNA sequencing to obtain transcriptomes from cells with primary mitochondrial or lysosomal defects, to identify what are the global cellular consequences that are associated with malfunction of mitochondria or lysosomes. We used these data to determine what are the pathways that are affected by defects in both organelles, which revealed a prominent role for the cholesterol synthesis pathway. This pathway is transcriptionally up-regulated in cellular and mouse models of lysosomal defects and is transcriptionally down-regulated in cellular and mouse models of mitochondrial defects. We identified a role for post-transcriptional regulation of the transcription factor SREBF1, a master regulator of cholesterol and lipid biosynthesis, in models of mitochondrial respiratory chain deficiency. Furthermore, the retention of Ca 2+ in the 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 models of mitochondria-associated diseases in C. elegans , that normalization of lysosomal Ca 2+ levels results in partial rescue of the developmental arrest induced by the respiratory chain deficiency.
    DOI:  https://doi.org/10.1101/2024.03.06.583589
  3. Sci Rep. 2024 Mar 21. 14(1): 6751
    MCU-independent Ca2+ uptake mediates mitochondrial Ca2+ overload and necrotic cell death in a mouse model of Duchenne muscular dystrophy.
    Michael J Bround, Eaman Abay, Jiuzhou Huo, Julian R Havens, Allen J York, Donald M Bers, Jeffery D Molkentin.
      Mitochondrial Ca2+ overload can mediate mitochondria-dependent cell death, a major contributor to several human diseases. Indeed, Duchenne muscular dystrophy (MD) is driven by dysfunctional Ca2+ influx across the sarcolemma that causes mitochondrial Ca2+ overload, organelle rupture, and muscle necrosis. The mitochondrial Ca2+ uniporter (MCU) complex is the primary characterized mechanism for acute mitochondrial Ca2+ uptake. One strategy for preventing mitochondrial Ca2+ overload is deletion of the Mcu gene, the pore forming subunit of the MCU-complex. Conversely, enhanced MCU-complex Ca2+ uptake is achieved by deleting the inhibitory Mcub gene. Here we show that myofiber-specific Mcu deletion was not protective in a mouse model of Duchenne MD. Specifically, Mcu gene deletion did not reduce muscle histopathology, did not improve muscle function, and did not prevent mitochondrial Ca2+ overload. Moreover, myofiber specific Mcub gene deletion did not augment Duchenne MD muscle pathology. Interestingly, we observed MCU-independent Ca2+ uptake in dystrophic mitochondria that was sufficient to drive mitochondrial permeability transition pore (MPTP) activation and skeletal muscle necrosis, and this same type of activity was observed in heart, liver, and brain mitochondria. These results demonstrate that mitochondria possess an uncharacterized MCU-independent Ca2+ uptake mechanism that is sufficient to drive MPTP-dependent necrosis in MD in vivo.
    DOI:  https://doi.org/10.1038/s41598-024-57340-3
  4. Mitochondrion. 2024 Mar 17. pii: S1567-7249(24)00031-X. [Epub ahead of print]76 101873
    Revolutionizing cellular energy: The convergence of mitochondrial dynamics and delivery technologies.
    Dilpreet Singh.
      The intersection of mitochondrial dynamics and delivery technologies heralds a paradigm shift in cellular biology and therapeutic intervention. Mitochondrial dynamics, encompassing fusion, fission, transport, and mitophagy, are critical for cellular energy production, signaling, and homeostasis. Dysregulation of these processes is implicated in a myriad of diseases, including neurodegenerative disorders, cardiovascular diseases, and cancer. Concurrently, advances in delivery technologies, such as nanocarriers, targeted delivery systems, and gene editing tools, offer unprecedented opportunities to manipulate mitochondrial function directly. This review synthesizes current knowledge on mitochondrial dynamics, examines recent breakthroughs in targeted delivery methods, and explores their potential convergence to modulate cellular energetics for therapeutic purposes. By integrating insights from biology, chemistry, and bioengineering, this review highlights the innovative approaches being developed to enhance mitochondrial function, underscoring the potential of this convergence to address complex diseases. This interdisciplinary perspective not only broadens our understanding of cellular processes but also paves the way for novel therapeutic strategies, marking a significant step forward in the quest for precision medicine and targeted interventions in mitochondrial-related diseases.
    Keywords:  Delivery; Mitochondria; Personalized medicine; Strategies; Technologies; Therapeutic effect
    DOI:  https://doi.org/10.1016/j.mito.2024.101873
  5. bioRxiv. 2024 Mar 07. pii: 2024.03.05.583623. [Epub ahead of print]
    A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.
    Eugene V Mosharov, Ayelet M Rosenberg, Anna S Monzel, Corey A Osto, Linsey Stiles, Gorazd B Rosoklija, Andrew J Dwork, Snehal Bindra, Ya Zhang, Masashi Fujita, Madeline B Mariani, Mihran Bakalian, David Sulzer, Philip L De Jager, Vilas Menon, Orian S Shirihai, J John Mann, Mark Underwood, Maura Boldrini, Michel Thiebaut de Schotten, Martin Picard.
      Mitochondrial oxidative phosphorylation (OxPhos) powers brain activity 1,2 , and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders 3,4 , underscoring the need to define the brain's molecular energetic landscape 5-10 . To bridge the cognitive neuroscience and cell biology scale gap, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3×3×3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes including OxPhos enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains a diversity of mitochondrial phenotypes driven by both topology and cell types. Compared to white matter, grey matter contains >50% more mitochondria. We show that the more abundant grey matter mitochondria also are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backward linear regression model integrating several neuroimaging modalities 11 , thereby generating a brain-wide map of mitochondrial distribution and specialization that predicts mitochondrial characteristics in an independent brain region of the same donor brain. This new approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain functions, relating it to neuroimaging data, and defining the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders.
    DOI:  https://doi.org/10.1101/2024.03.05.583623
  6. Nat Metab. 2024 Mar 19.
    AMPK and insulin control the switch between mitochondrial hitchhiking of Pink1 mRNA and mitophagy in neurons.
      
    DOI:  https://doi.org/10.1038/s42255-024-01006-x
  7. Mol Cell. 2024 Mar 14. pii: S1097-2765(24)00170-9. [Epub ahead of print]
    A kinetic dichotomy between mitochondrial and nuclear gene expression processes.
    Erik McShane, Mary Couvillion, Robert Ietswaart, Gyan Prakash, Brendan M Smalec, Iliana Soto, Autum R Baxter-Koenigs, Karine Choquet, L Stirling Churchman.
      Oxidative phosphorylation (OXPHOS) complexes, encoded by both mitochondrial and nuclear DNA, are essential producers of cellular ATP, but how nuclear and mitochondrial gene expression steps are coordinated to achieve balanced OXPHOS subunit biogenesis remains unresolved. Here, we present a parallel quantitative analysis of the human nuclear and mitochondrial messenger RNA (mt-mRNA) life cycles, including transcript production, processing, ribosome association, and degradation. The kinetic rates of nearly every stage of gene expression differed starkly across compartments. Compared with nuclear mRNAs, mt-mRNAs were produced 1,100-fold more, degraded 7-fold faster, and accumulated to 160-fold higher levels. Quantitative modeling and depletion of mitochondrial factors LRPPRC and FASTKD5 identified critical points of mitochondrial regulatory control, revealing that the mitonuclear expression disparities intrinsically arise from the highly polycistronic nature of human mitochondrial pre-mRNA. We propose that resolving these differences requires a 100-fold slower mitochondrial translation rate, illuminating the mitoribosome as a nexus of mitonuclear co-regulation.
    Keywords:  LRPPRC; Leighs disease; RNA life cycle; gene regulation; genetic conflict; metabolic regulation; mitochondrial gene expression; mitochondrial translation; mitonuclear balance; organellular biogenesis; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.028
  8. Mitochondrial Commun. 2024 ;2 1-13
    Structural determinants of mitochondrial STAT3 targeting and function.
    Isabelle J Marié, Tanaya Lahiri, Özlem Önder, Kojo S J Elenitoba-Johnson, David E Levy.
      Signal transducer and activator of transcription (STAT) 3 has been found within mitochondria in addition to its canonical role of shuttling between cytoplasm and nucleus during cytokine signaling. Mitochondrial STAT3 has been implicated in modulation of cellular metabolism, largely through effects on the respiratory electron transport chain. However, the structural requirements underlying mitochondrial targeting and function have remained unclear. Here, we show that mitochondrial STAT3 partitions between mitochondrial compartments defined by differential detergent solubility, suggesting that mitochondrial STAT3 is membrane associated. The majority of STAT3 was found in an SDS soluble fraction copurifying with respiratory chain proteins, including numerous components of the complex I NADH dehydrogenase, while a minor component was found with proteins of the mitochondrial translation machinery. Mitochondrial targeting of STAT3 required the amino-terminal domain, and an internal linker domain motif also directed mitochondrial translocation. However, neither the phosphorylation of serine 727 nor the presence of mitochondrial DNA was required for the mitochondrial localization of STAT3. Two cysteine residues in the STAT3 SH2 domain, which have been previously suggested to be targets for protein palmitoylation, were also not required for mitochondrial translocation, but were required for its function as an enhancer of complex I activity. These structural determinants of STAT3 mitochondrial targeting and function provide potential therapeutic targets for disrupting the activity of mitochondrial STAT3 in diseases such as cancer.
    Keywords:  Electron transport chain; Mitochondrial import; Stat3
    DOI:  https://doi.org/10.1016/j.mitoco.2024.01.001
  9. Life Sci. 2024 Mar 14. pii: S0024-3205(24)00164-4. [Epub ahead of print]344 122575
    Future perspectives on the roles of mitochondrial dynamics in the heart in obesity and aging.
    Chayodom Maneechote, Siriporn C Chattipakorn, Nipon Chattipakorn.
      Increasing global obesity rates and an aging population are independently linked to cardiac complications. Consequently, it is crucial to comprehensively understand the mechanisms behind these conditions to advance innovative therapies for age-related diseases. Mitochondrial dysfunction, specifically defects in mitochondrial fission/fusion processes, has emerged as a central regulator of cardiac complications in aging and age-related diseases (e.g., obesity). Since excessive fission and impaired fusion of cardiac mitochondria lead to disruptions in mitochondrial dynamics and cellular metabolism in aging and obesity, modulating mitochondrial dynamics with either fission inhibitors or fusion promoters has offered cardioprotection against these pathological conditions in preclinical models. This review explores the molecular mechanisms governing mitochondrial dynamics as well as the disturbances observed in aging and obesity. Additionally, pharmaceutical interventions that specifically target the processes of mitochondrial fission and fusion are presented and discussed. By establishing a connection between mitochondrial dynamism through fission and fusion and the advancement or mitigation of age-related diseases, particularly obesity, this review provides valuable insights into the progression and potential prevention strategies for such conditions.
    Keywords:  Aging; Cardiovascular disease; Mitochondria; Mitochondrial dynamics; Obesity
    DOI:  https://doi.org/10.1016/j.lfs.2024.122575
  10. Mol Cell. 2024 Mar 21. pii: S1097-2765(24)00168-0. [Epub ahead of print]84(6): 995-997
    Integrating the response to stressed mitochondria.
    Elliot Dine, Richard J Youle.
      Chakrabarty et al.1 demonstrate that phospho-EIF2α (pEIF2α), the translation initiation factor that mediates the integrated stress response (ISR), is necessary and sufficient for the autophagic degradation of mitochondria following the addition of mitochondrial stressors.
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.026
  11. Nat Metab. 2024 Mar 19.
    Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.
    Mathieu Membrez, Eugenia Migliavacca, Stefan Christen, Keisuke Yaku, Jennifer Trieu, Alaina K Lee, Francesco Morandini, Maria Pilar Giner, Jade Stiner, Mikhail V Makarov, Emma S Garratt, Maria F Vasiloglou, Lucie Chanvillard, Emilie Dalbram, Amy M Ehrlich, José Luis Sanchez-Garcia, Carles Canto, Leonidas G Karagounis, Jonas T Treebak, Marie E Migaud, Ramin Heshmat, Farideh Razi, Neerja Karnani, Afshin Ostovar, Farshad Farzadfar, Stacey K H Tay, Matthew J Sanders, Karen A Lillycrop, Keith M Godfrey, Takashi Nakagawa, Sofia Moco, René Koopman, Gordon S Lynch, Vincenzo Sorrentino, Jerome N Feige.
      Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1-3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss-Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.
    DOI:  https://doi.org/10.1038/s42255-024-00997-x
  12. Semin Cell Dev Biol. 2024 Mar 19. pii: S1084-9521(24)00023-5. [Epub ahead of print]161-162 20-21
    Mitochondrial dynamics: Regulating cell metabolism, homoeostasis, health and disease.
    Karoline D Raven, Ronan Kapetanovic.
      
    DOI:  https://doi.org/10.1016/j.semcdb.2024.02.002
  13. J Sleep Res. 2024 Mar 18. e14153
    Nocturnal vestibular stimulation using a rocking bed improves a severe sleep disorder in a patient with mitochondrial disease.
    Alexander Breuss, Marco Strasser, Jean-Marc Nuoffer, Andrea Klein, Eveline Perret-Hoigné, Christine Felder, Ruth Stauffer, Peter Wolf, Robert Riener, Matthias Gautschi.
      Mitochondrial diseases are rare genetic disorders often accompanied by severe sleep disorders. We present the case of a 12-year-old boy diagnosed with a severe primary mitochondrial disease, exhibiting ataxia, spasticity, progressive external ophthalmoplegia, cardiomyopathy and severely disrupted sleep, but no cognitive impairment. Interestingly, his parents reported improved sleep during night train rides. Based on this observation, we installed a rocking bed in the patient's bedroom and performed different interventions, including immersive multimodal vestibular, kinesthetic and auditory stimuli, reminiscent of the sensory experiences encountered during train rides. Over a 5-month period, we conducted four 2-week nocturnal interventions, separated by 1-week washout phases, to determine the subjectively best-perceived stimulation parameters, followed by a final 4-week intervention using the optimal parameters. We assessed sleep duration and quality using the Mini Sleep Questionnaire, monitored pulse rate changes and used videography to document nocturnal interactions between the patient and caregivers. Patient-reported outcome measures, clinical examinations and personal outcomes of specific interests were used to document daytime sleepiness, restlessness, anxiety, fatigue, cognitive performance and physical posture. In the final 4-week intervention, sleep duration increased by 25%, required caregiver interactions reduced by 75%, and caregiving time decreased by 40%. Subjective fatigue, assessed by the Checklist Individual Strength, decreased by 40%, falling below the threshold of severe fatigue. Our study suggests that rocking beds could provide a promising treatment regime for selected patients with persistent severe sleep disorders. Further research is required to validate these findings in larger patient populations with sleep disorders and other conditions.
    Keywords:  Somnomat Casa; alternative treatment; auditory stimulations; kinesthetic stimulation; mitochondrial disease; mitochondrial disease management; mitochondrial disease with an associated severe sleep disorder; robotic bed; rocking bed; sensory experiences; sleep disorder; stimulation; vestibular stimulation
    DOI:  https://doi.org/10.1111/jsr.14153
  14. iScience. 2024 Apr 19. 27(4): 109136
    Local mitochondrial replication in the periphery of neurons requires the eEF1A1 protein and thetranslation of nuclear-encoded proteins.
    Carlos Cardanho-Ramos, Rúben Alves Simões, Yi-Zhi Wang, Andreia Faria-Pereira, Ewa Bomba-Warczak, Katleen Craessaerts, Marco Spinazzi, Jeffrey N Savas, Vanessa A Morais.
      In neurons, it is commonly assumed that mitochondrial replication only occurs in the cell body, after which the mitochondria must travel to the neuron's periphery. However, while mitochondrial DNA replication has been observed to occur away from the cell body, the specific mechanisms involved remain elusive. Using EdU-labelling in mouse primary neurons, we developed a tool to determine the mitochondrial replication rate. Taking of advantage of microfluidic devices, we confirmed that mitochondrial replication also occurs locally in the periphery of neurons. To achieve this, mitochondria require de novo nuclear-encoded, but not mitochondrial-encoded protein translation. Following a proteomic screen comparing synaptic with non-synaptic mitochondria, we identified two elongation factors - eEF1A1 and TUFM - that were upregulated in synaptic mitochondria. We found that mitochondrial replication is impaired upon the downregulation of eEF1A1, and this is particularly relevant in the periphery of neurons.
    Keywords:  Biochemistry; Biological sciences; Cellular neuroscience; Molecular neuroscience; Natural sciences; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2024.109136
  15. Mitochondrion. 2024 Mar 19. pii: S1567-7249(24)00032-1. [Epub ahead of print] 101874
    Interplay of mitochondria associated membrane proteins and autophagy: Implications in neurodegeneration.
    Prakash G Kulkarni, Vaibhavi M Mohire, Pranjal P Waghmare, Tanushree Banerjee.
      Since the discovery of membrane contact sites between ER and mitochondria called mitochondria-associated membranes (MAMs), several pieces of evidence identified their role in the regulation of different cellular processes such as Ca2+ signalling, mitochondrial transport, and dynamics, ER stress, inflammation, glucose homeostasis, and autophagy. The integrity of these membranes was found to be essential for the maintenance of these cellular functions. Accumulating pieces of evidence suggest that MAMs serve as a platform for autophagosome formation. However, the alteration within MAMs' structure is associated with the progression of neurodegenerative diseases. Dysregulated autophagy is a hallmark of neurodegeneration. Here, in this review, we highlight the present knowledge on MAMs, their structural composition, and their roles in different cellular functions. We also discuss the association of MAMs proteins with impaired autophagy and their involvement in the progression of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.
    Keywords:  Alzheimer’s disease (AD); Autophagy; Mitochondrial associated membranes (MAMs); Mitophagy; Parkinson’s disease (PD)
    DOI:  https://doi.org/10.1016/j.mito.2024.101874
  16. DNA Repair (Amst). 2024 Mar 08. pii: S1568-7864(24)00042-9. [Epub ahead of print]137 103666
    Mitochondrial transcription factor A (TFAM) has 5'-deoxyribose phosphate lyase activity in vitro.
    Wenxin Zhao, Adil S Hussen, Bret D Freudenthal, Zucai Suo, Linlin Zhao.
      Mitochondrial DNA (mtDNA) plays a key role in mitochondrial and cellular functions. mtDNA is maintained by active DNA turnover and base excision repair (BER). In BER, one of the toxic repair intermediates is 5'-deoxyribose phosphate (5'dRp). Human mitochondrial DNA polymerase γ has weak dRp lyase activities, and another known dRp lyase in the nucleus, human DNA polymerase β, can also localize to mitochondria in certain cell and tissue types. Nonetheless, whether additional proteins have the ability to remove 5'dRp in mitochondria remains unknown. Our prior work on the AP lyase activity of mitochondrial transcription factor A (TFAM) has prompted us to examine its ability to remove 5'dRp residues in vitro. TFAM is the primary DNA-packaging factor in human mitochondria and interacts with mitochondrial DNA extensively. Our data demonstrate that TFAM has the dRp lyase activity with different DNA substrates. Under single-turnover conditions, TFAM removes 5'dRp residues at a rate comparable to that of DNA polymerase (pol) β, albeit slower than that of pol λ. Among the three proteins examined, pol λ shows the highest single-turnover rates in dRp lyase reactions. The catalytic effect of TFAM is facilitated by lysine residues of TFAM via Schiff base chemistry, as evidenced by the observation of dRp-lysine adducts in mass spectrometry experiments. The catalytic effect of TFAM observed here is analogous to the AP lyase activity of TFAM reported previously. Together, these results suggest a potential role of TFAM in preventing the accumulation of toxic DNA repair intermediates.
    Keywords:  5'-deoxyribose phosphate; DNA repair intermediates; DNA-protein cross-links; abasic sites; base excision repair; mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.dnarep.2024.103666
  17. bioRxiv. 2024 Mar 04. pii: 2024.03.04.583371. [Epub ahead of print]
    Activating soluble adenylyl cyclase protects mitochondria, rescues retinal ganglion cells, and ameliorates visual dysfunction caused by oxidative stress.
    Tonking Bastola, Guy A Perkins, Viet Anh Nguyen Huu, Saeyeon Ju, Keun-Young Kim, Ziyao Shen, Dorota Skowronska-Krawczyk, Robert N Weinreb, Won-Kyu Ju.
      Oxidative stress is a key factor causing mitochondrial dysfunction and retinal ganglion cell (RGC) death in glaucomatous neurodegeneration. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway is involved in mitochondrial protection, promoting RGC survival. Soluble adenylyl cyclase (sAC) is one of the key regulators of the cAMP/PKA signaling pathway. However, the precise molecular mechanisms underlying the sAC-mediated signaling pathway and mitochondrial protection in RGCs that counter oxidative stress are not well characterized. Here, we demonstrate that sAC plays a critical role in protecting RGC mitochondria from oxidative stress. Using mouse models of oxidative stress, we found that activating sAC protected RGCs, blocked AMP-activated protein kinase activation, inhibited glial activation, and improved visual function. Moreover, we found that this is the result of preserving mitochondrial dynamics (fusion and fission), promoting mitochondrial bioenergetics and biogenesis, and preventing metabolic stress and apoptotic cell death in a paraquat oxidative stress model. Notably, sAC activation ameliorated mitochondrial dysfunction in RGCs by enhancing mitochondrial biogenesis, preserving mitochondrial structure, and increasing ATP production in oxidatively stressed RGCs. These findings suggest that activating sAC enhances the mitochondrial structure and function in RGCs to counter oxidative stress, consequently promoting RGC protection. We propose that modulation of the sAC-mediated signaling pathway has therapeutic potential acting on RGC mitochondria for treating glaucoma and other retinal diseases.
    DOI:  https://doi.org/10.1101/2024.03.04.583371
  18. Mol Cell. 2024 Mar 21. pii: S1097-2765(24)00174-6. [Epub ahead of print]84(6): 1000-1002
    A SIFI odyssey: Silencing the stress response amid mitochondrial import blockade to safeguard cell survival.
    Yuleika G Martinez Castillo, Chantell S Evans.
      In a recent study in Nature, Haakonsen et al.1 identify the SIFI complex as a stress response silencer via its E3 ligase activity to target unimported mitochondrial proteins and stress response components for degradation via the proteasome.
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.034
  19. Exp Neurol. 2024 Mar 18. pii: S0014-4886(24)00083-9. [Epub ahead of print]376 114757
    Mitochondria-lysosome-extracellular vesicles axis and nanotheranostics in neurodegenerative diseases.
    Liang Kou, Yiming Wang, Jingwen Li, Wenkai Zou, Zongjie Jin, Sijia Yin, Xiaosa Chi, Yadi Sun, Jiawei Wu, Tao Wang, Yun Xia.
      The intricate functional interactions between mitochondria and lysosomes play a pivotal role in maintaining cellular homeostasis and proper cellular functions. This dynamic interplay involves the exchange of molecules and signaling, impacting cellular metabolism, mitophagy, organellar dynamics, and cellular responses to stress. Dysregulation of these processes has been implicated in various neurodegenerative diseases. Additionally, mitochondrial-lysosomal crosstalk regulates the exosome release in neurons and glial cells. Under stress conditions, neurons and glial cells exhibit mitochondrial dysfunction and a fragmented network, which further leads to lysosomal dysfunction, thereby inhibiting autophagic flux and enhancing exosome release. This comprehensive review synthesizes current knowledge on mitochondrial regulation of cell death, organelle dynamics, and vesicle trafficking, emphasizing their significant contributions to neurodegenerative diseases. Furthermore, we explore the emerging field of nanomedicine in the management of neurodegenerative diseases. The review provides readers with an insightful overview of nano strategies that are currently advancing the mitochondrial-lysosome-extracellular vesicle axis as a therapeutic approach for mitigating neurodegenerative diseases.
    Keywords:  Extracellular vesicles axis; Lysosome; Mitochondria; Nanotheranostics; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.expneurol.2024.114757
  20. Eur Rev Med Pharmacol Sci. 2024 Mar;pii: 35601. [Epub ahead of print]28(5): 1873-1880
    Clinical, biochemical, and genotypical characteristics in urea cycle mitochondrial transporter disorders.
    H Bilgin, S Bilge, M Binici, S Tekes.
      BACKGROUND: This study aimed to evaluate clinical, biochemical, and genotypic findings of patients diagnosed with urea cycle mitochondrial transporter disorders.CASE SERIES: In this study, patients followed up with the diagnosis of urea cycle mitochondrial transporter disorders in the pediatric metabolism outpatient clinic of Diyarbakir Children's Hospital were retrospectively examined. Height, weight, head circumference, gender, age at diagnosis, follow-up period, consanguinity history between parents, and treatments of the patients included in the study were evaluated. Eight patients suffering from urea cycle mitochondrial transporter disorders were enrolled in the study. Five patients were found to have biallelic variants of the SLC25A15 gene. Two patients were found to have biallelic variants of the SLC25A13 gene. Two of our patients presented with gait disturbances and were diagnosed with HHH syndrome. One patient presented with liver failure and was diagnosed with HHH syndrome. The other three patients were identified by family screening. Citrin deficiency was detected in two patients with cholestasis and hepatomegaly in the infantile period. Ornithine levels increased in three of our patients with HHH syndrome during the first month of treatment despite a protein-restricted diet and adequate caloric intake.
    CONCLUSIONS: Increasing patients' caloric intake with HHH syndrome improves their ornithine levels. Our patients with citrin deficiency recovered clinically and biochemically before seven months.
    DOI:  https://doi.org/10.26355/eurrev_202403_35601
  21. iScience. 2024 Apr 19. 27(4): 109379
    Mitochondria-ER contact sites expand during mitosis.
    Fang Yu, Raphael Courjaret, Lama Assaf, Asha Elmi, Ayat Hammad, Melanie Fisher, Mark Terasaki, Khaled Machaca.
      Mitochondria-ER contact sites (MERCS) are involved in energy homeostasis, redox and Ca2+ signaling, and inflammation. MERCS are heavily studied; however, little is known about their regulation during mitosis. Here, we show that MERCS expand during mitosis in three cell types using various approaches, including transmission electron microscopy, serial EM coupled to 3D reconstruction, and a split GFP MERCS marker. We further show enhanced Ca2+ transfer between the ER and mitochondria using either direct Ca2+ measurements or by quantifying the activity of Ca2+-dependent mitochondrial dehydrogenases. Collectively, our results support a lengthening of MERCS in mitosis that is associated with improved Ca2+ coupling between the two organelles. This augmented Ca2+ coupling could be important to support the increased energy needs of the cell during mitosis.
    Keywords:  Biological sciences; Cell biology; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2024.109379
  22. medRxiv. 2024 Mar 07. pii: 2024.03.05.24303792. [Epub ahead of print]
    Nanopore sequencing of 1000 Genomes Project samples to build a comprehensive catalog of human genetic variation.
    1000 Genomes ONT Sequencing Consortium
      Less than half of individuals with a suspected Mendelian condition receive a precise molecular diagnosis after comprehensive clinical genetic testing. Improvements in data quality and costs have heightened interest in using long-read sequencing (LRS) to streamline clinical genomic testing, but the absence of control datasets for variant filtering and prioritization has made tertiary analysis of LRS data challenging. To address this, the 1000 Genomes Project ONT Sequencing Consortium aims to generate LRS data from at least 800 of the 1000 Genomes Project samples. Our goal is to use LRS to identify a broader spectrum of variation so we may improve our understanding of normal patterns of human variation. Here, we present data from analysis of the first 100 samples, representing all 5 superpopulations and 19 subpopulations. These samples, sequenced to an average depth of coverage of 37x and sequence read N50 of 54 kbp, have high concordance with previous studies for identifying single nucleotide and indel variants outside of homopolymer regions. Using multiple structural variant (SV) callers, we identify an average of 24,543 high-confidence SVs per genome, including shared and private SVs likely to disrupt gene function as well as pathogenic expansions within disease-associated repeats that were not detected using short reads. Evaluation of methylation signatures revealed expected patterns at known imprinted loci, samples with skewed X-inactivation patterns, and novel differentially methylated regions. All raw sequencing data, processed data, and summary statistics are publicly available, providing a valuable resource for the clinical genetics community to discover pathogenic SVs.
    Keywords:  1000 Genomes Project; Nanopore sequencing; long-read sequencing; methylation; repeat expansions; structural variation
    DOI:  https://doi.org/10.1101/2024.03.05.24303792
  23. Biochim Biophys Acta Mol Cell Res. 2024 Mar 16. pii: S0167-4889(24)00050-8. [Epub ahead of print]1871(4): 119707
    The zinc finger motif in the mitochondrial large ribosomal subunit protein bL36m is essential for optimal yeast mitoribosome assembly and function.
    Hui Zhong, Antoni Barrientos.
      Ribosomes across species contain subsets of zinc finger proteins that play structural roles by binding to rRNA. While the majority of these zinc fingers belong to the C2-C2 type, the large subunit protein L36 in bacteria and mitochondria exhibits an atypical C2-CH motif. To comprehend the contribution of each coordinating residue in S. cerevisiae bL36m to mitoribosome assembly and function, we engineered and characterized strains carrying single and double mutations in the zinc coordinating residues. Our findings reveal that although all four residues markedly influence protein stability, C to A mutations in C66 and/or C69 have a more pronounced effect compared to those at C82 and H88. Importantly, protein stability directly correlates with the assembly and function of the mitoribosome and the growth rate of yeast in respiratory conditions. Mass spectrometry analysis of large subunit particles indicates that strains deleted for bL36m or expressing mutant variants have defective assembly of the L7/L12 stalk base, limiting their functional competence. Furthermore, we employed a synthetic bL36m protein collection, including both wild-type and mutant proteins, to elucidate their ability to bind zinc. Our data indicate that mutations in C82 and, particularly, H88 allow for some zinc binding albeit inefficient or unstable, explaining the residual accumulation and activity in mitochondria of bL36m variants carrying mutations in these residues. In conclusion, stable zinc binding by bL36m is essential for optimal mitoribosome assembly and function. MS data are available via ProteomeXchange with identifierPXD046465.
    Keywords:  Mitochondrial ribosome; Mitoribosome; Zinc finger; bL36m; mtLSU
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119707
  24. Biomed Opt Express. 2024 Mar 01. 15(3): 1571-1584
    Quantifying nanoscopic alterations associated with mitochondrial dysfunction using three-dimensional single-molecule localization microscopy.
    Benjamin Brenner, Fengyuanshan Xu, Yang Zhang, Junghun Kweon, Raymond Fang, Nader Sheibani, Sarah X Zhang, Cheng Sun, Hao F Zhang.
      Mitochondrial morphology provides unique insights into their integrity and function. Among fluorescence microscopy techniques, 3D super-resolution microscopy uniquely enables the analysis of mitochondrial morphological features individually. However, there is a lack of tools to extract morphological parameters from super-resolution images of mitochondria. We report a quantitative method to extract mitochondrial morphological metrics, including volume, aspect ratio, and local protein density, from 3D single-molecule localization microscopy images, with single-mitochondrion sensitivity. We validated our approach using simulated ground-truth SMLM images of mitochondria. We further tested our morphological analysis on mitochondria that have been altered functionally and morphologically in controlled manners. This work sets the stage to quantitatively analyze mitochondrial morphological alterations associated with disease progression on an individual basis.
    DOI:  https://doi.org/10.1364/BOE.510351
  25. Nat Metab. 2024 Mar 19.
    Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons.
    J Tabitha Hees, Simone Wanderoy, Jana Lindner, Marlena Helms, Hariharan Murali Mahadevan, Angelika B Harbauer.
      Mitochondrial quality control failure is frequently observed in neurodegenerative diseases. The detection of damaged mitochondria by stabilization of PTEN-induced kinase 1 (PINK1) requires transport of Pink1 messenger RNA (mRNA) by tethering it to the mitochondrial surface. Here, we report that inhibition of AMP-activated protein kinase (AMPK) by activation of the insulin signalling cascade prevents Pink1 mRNA binding to mitochondria. Mechanistically, AMPK phosphorylates the RNA anchor complex subunit SYNJ2BP within its PDZ domain, a phosphorylation site that is necessary for its interaction with the RNA-binding protein SYNJ2. Notably, loss of mitochondrial Pink1 mRNA association upon insulin addition is required for PINK1 protein activation and its function as a ubiquitin kinase in the mitophagy pathway, thus placing PINK1 function under metabolic control. Induction of insulin resistance in vitro by the key genetic Alzheimer risk factor apolipoprotein E4 retains Pink1 mRNA at the mitochondria and prevents proper PINK1 activity, especially in neurites. Our results thus identify a metabolic switch controlling Pink1 mRNA localization and PINK1 activity via insulin and AMPK signalling in neurons and propose a mechanistic connection between insulin resistance and mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s42255-024-01007-w
  26. EBioMedicine. 2024 Mar 18. pii: S2352-3964(24)00100-2. [Epub ahead of print]102 105065
    Mitochondrial DNA deletions in the cerebrospinal fluid of patients with idiopathic REM sleep behaviour disorder.
    Margalida Puigròs, Anna Calderon, Daniel Martín-Ruiz, Mònica Serradell, Manel Fernández, Amaia Muñoz-Lopetegi, Gerard Mayà, Joan Santamaria, Carles Gaig, Anna Colell, Eduard Tolosa, Alex Iranzo, Ramon Trullas.
      BACKGROUND: Idiopathic rapid eye movement (REM) sleep behaviour disorder (IRBD) represents the prodromal stage of Lewy body disorders (Parkinson's disease (PD) and dementia with Lewy bodies (DLB)) which are linked to variations in circulating cell-free mitochondrial DNA (cf-mtDNA). Here, we assessed whether altered cf-mtDNA release and integrity are already present in IRBD.METHODS: We used multiplex digital PCR (dPCR) to quantify cf-mtDNA copies and deletion ratio in cerebrospinal fluid (CSF) and serum in a cohort of 71 participants, including 1) 17 patients with IRBD who remained disease-free (non-converters), 2) 34 patients initially diagnosed with IRBD who later developed either PD or DLB (converters), and 3) 20 age-matched controls without IRBD or Parkinsonism. In addition, we investigated whether CD9-positive extracellular vesicles (CD9-EVs) from CSF and serum samples contained cf-mtDNA.
    FINDINGS: Patients with IRBD, both converters and non-converters, exhibited more cf-mtDNA with deletions in the CSF than controls. This finding was confirmed in CD9-EVs. The high levels of deleted cf-mtDNA in CSF corresponded to a significant decrease in cf-mtDNA copies in CD9-EVs in both IRBD non-converters and converters. Conversely, a significant increase in cf-mtDNA copies was found in serum and CD9-EVs from the serum of patients with IRBD who later converted to a Lewy body disorder.
    INTERPRETATION: Alterations in cf-mtDNA copy number and deletion ratio known to occur in Lewy body disorders are already present in IRBD and are not a consequence of Lewy body disease conversion. This suggests that mtDNA dysfunction is a primary molecular mechanism of the pathophysiological cascade that precedes the full clinical motor and cognitive manifestation of Lewy body disorders.
    FUNDING: Funded by Michael J. Fox Foundation research grant MJFF-001111. Funded by MICIU/AEI/10.13039/501100011033 "ERDF A way of making Europe", grants PID2020-115091RB-I00 (RT) and PID2022-143279OB-I00 (ACo). Funded by Instituto de Salud Carlos III and European Union NextGenerationEU/PRTR, grant PMP22/00100 (RT and ACo). Funded by AGAUR/Generalitat de Catalunya, grant SGR00490 (RT and ACo). MP has an FPI fellowship, PRE2018-083297, funded by MICIU/AEI/10.13039/501100011033 "ESF Investing in your future".
    Keywords:  Dementia with Lewy bodies; Digital PCR; Idiopathic REM sleep behaviour disorder; Mitochondrial DNA; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.ebiom.2024.105065
  27. Genet Med. 2024 Mar 16. pii: S1098-3600(24)00056-X. [Epub ahead of print] 101123
    Cardiac phenotype in adolescents and young adults with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency.
    Gabriela Elizondo, Ajesh Saini, Cesar Gonzalez de Alba, Ashley Gregor, Cary O Harding, Melanie B Gillingham, Jeffrey M Vinocur.
      BACKGROUND: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare fatty acid oxidation disorder characterized by recurrent episodes of metabolic decompensation and rhabdomyolysis as well as retinopathy, peripheral neuropathy, and cardiac involvement such as infantile dilated cardiomyopathy. As LCHADD patients are surviving longer, we sought to characterize LCHADD-associated major cardiac involvement in adolescence and young adulthood.METHODS: A retrospective cohort of 16 adolescent and young adult participants with LCHADD was reviewed for cardiac phenotype.
    RESULTS: Major cardiac involvement occurred in 9 of 16 participants, including sudden death, out-of-hospital cardiac arrest, acute cardiac decompensations with heart failure and/or in-hospital cardiac arrest, end-stage dilated cardiomyopathy, and moderate restrictive cardiomyopathy. Sudden cardiac arrest was more common in males and those with a history of infant cardiomyopathy.
    CONCLUSION: The cardiac manifestations of LCHADD in adolescence and early adulthood are complex and distinct from the phenotype seen in infancy. Life-threatening arrhythmia occurs at substantial rates in LCHADD, often in the absence of metabolic decompensation or rhabdomyolysis. The potential risk factors identified here - male gender and history of infant cardiomyopathy -may hint at strategies for risk stratification and possibly prevention of these events.
    Keywords:  Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; cardiomyopathy; fatty acid oxidation disorder; sudden cardiac arrest; sudden cardiac death
    DOI:  https://doi.org/10.1016/j.gim.2024.101123
  28. Nat Commun. 2024 Mar 19. 15(1): 2447
    Tradeoffs in alignment and assembly-based methods for structural variant detection with long-read sequencing data.
    Yichen Henry Liu, Can Luo, Staunton G Golding, Jacob B Ioffe, Xin Maizie Zhou.
      Long-read sequencing offers long contiguous DNA fragments, facilitating diploid genome assembly and structural variant (SV) detection. Efficient and robust algorithms for SV identification are crucial with increasing data availability. Alignment-based methods, favored for their computational efficiency and lower coverage requirements, are prominent. Alternative approaches, relying solely on available reads for de novo genome assembly and employing assembly-based tools for SV detection via comparison to a reference genome, demand significantly more computational resources. However, the lack of comprehensive benchmarking constrains our comprehension and hampers further algorithm development. Here we systematically compare 14 read alignment-based SV calling methods (including 4 deep learning-based methods and 1 hybrid method), and 4 assembly-based SV calling methods, alongside 4 upstream aligners and 7 assemblers. Assembly-based tools excel in detecting large SVs, especially insertions, and exhibit robustness to evaluation parameter changes and coverage fluctuations. Conversely, alignment-based tools demonstrate superior genotyping accuracy at low sequencing coverage (5-10×) and excel in detecting complex SVs, like translocations, inversions, and duplications. Our evaluation provides performance insights, highlighting the absence of a universally superior tool. We furnish guidelines across 31 criteria combinations, aiding users in selecting the most suitable tools for diverse scenarios and offering directions for further method development.
    DOI:  https://doi.org/10.1038/s41467-024-46614-z
  29. Nat Commun. 2024 Mar 21. 15(1): 2487
    The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions.
    Marine Lanfranchi, Sozerko Yandiev, Géraldine Meyer-Dilhet, Salma Ellouze, Martijn Kerkhofs, Raphael Dos Reis, Audrey Garcia, Camille Blondet, Alizée Amar, Anita Kneppers, Hélène Polvèche, Damien Plassard, Marc Foretz, Benoit Viollet, Kei Sakamoto, Rémi Mounier, Cyril F Bourgeois, Olivier Raineteau, Evelyne Goillot, Julien Courchet.
      The cellular mechanisms underlying axonal morphogenesis are essential to the formation of functional neuronal networks. We previously identified the autism-linked kinase NUAK1 as a central regulator of axon branching through the control of mitochondria trafficking. However, (1) the relationship between mitochondrial position, function and axon branching and (2) the downstream effectors whereby NUAK1 regulates axon branching remain unknown. Here, we report that mitochondria recruitment to synaptic boutons supports collateral branches stabilization rather than formation in mouse cortical neurons. NUAK1 deficiency significantly impairs mitochondrial metabolism and axonal ATP concentration, and upregulation of mitochondrial function is sufficient to rescue axonal branching in NUAK1 null neurons in vitro and in vivo. Finally, we found that NUAK1 regulates axon branching through the mitochondria-targeted microprotein BRAWNIN. Our results demonstrate that NUAK1 exerts a dual function during axon branching through its ability to control mitochondrial distribution and metabolic activity.
    DOI:  https://doi.org/10.1038/s41467-024-46146-6
  30. Adv Sci (Weinh). 2024 Mar 18. e2307480
    AMPK Suppression Due to Obesity Drives Oocyte mtDNA Heteroplasmy via ATF5-POLG Axis.
    Yanting Chen, Guiling Ma, Yang Gai, Qiyuan Yang, Xiangdong Liu, Jeanene M de Avila, Shengyong Mao, Mei-Jun Zhu, Min Du.
      Due to the exclusive maternal transmission, oocyte mitochondrial dysfunction reduces fertility rates, affects embryonic development, and programs offspring to metabolic diseases. However, mitochondrial DNA (mtDNA) are vulnerable to mutations during oocyte maturation, leading to mitochondrial nucleotide variations (mtSNVs) within a single oocyte, referring to mtDNA heteroplasmy. Obesity (OB) accounts for more than 40% of women at the reproductive age in the USA, but little is known about impacts of OB on mtSNVs in mature oocytes. It is found that OB reduces mtDNA content and increases mtSNVs in mature oocytes, which impairs mitochondrial energetic functions and oocyte quality. In mature oocytes, OB suppresses AMPK activity, aligned with an increased binding affinity of the ATF5-POLG protein complex to mutated mtDNA D-loop and protein-coding regions. Similarly, AMPK knockout increases the binding affinity of ATF5-POLG proteins to mutated mtDNA, leading to the replication of heteroplasmic mtDNA and impairing oocyte quality. Consistently, AMPK activation blocks the detrimental impacts of OB by preventing ATF5-POLG protein recruitment, improving oocyte maturation and mitochondrial energetics. Overall, the data uncover key features of AMPK activation in suppressing mtSNVs, and improving mitochondrial biogenesis and oocyte maturation in obese females.
    Keywords:  AMPK; female obesity; mature oocyte; mtDNA heteroplasmy
    DOI:  https://doi.org/10.1002/advs.202307480
  31. Dev Cell. 2024 Mar 18. pii: S1534-5807(24)00110-2. [Epub ahead of print]
    Synchronized assembly of the oxidative phosphorylation system controls mitochondrial respiration in yeast.
    Daiana N Moretti-Horten, Carlotta Peselj, Asli Aras Taskin, Lisa Myketin, Uwe Schulte, Oliver Einsle, Friedel Drepper, Marcin Luzarowski, F-Nora Vögtle.
      Control of protein stoichiometry is essential for cell function. Mitochondrial oxidative phosphorylation (OXPHOS) presents a complex stoichiometric challenge as the ratio of the electron transport chain (ETC) and ATP synthase must be tightly controlled, and assembly requires coordinated integration of proteins encoded in the nuclear and mitochondrial genome. How correct OXPHOS stoichiometry is achieved is unknown. We identify the MitochondrialRegulatory hub for respiratoryAssembly (MiRA) platform, which synchronizes ETC and ATP synthase biogenesis in yeast. Molecularly, this is achieved by a stop-and-go mechanism: the uncharacterized protein Mra1 stalls complex IV assembly. Two "Go" signals are required for assembly progression: binding of the complex IV assembly factor Rcf2 and Mra1 interaction with an Atp9-translating mitoribosome induce Mra1 degradation, allowing synchronized maturation of complex IV and the ATP synthase. Failure of the stop-and-go mechanism results in cell death. MiRA controls OXPHOS assembly, ensuring correct stoichiometry of protein machineries encoded by two different genomes.
    Keywords:  complex stoichiometry; mitochondria; mitoribosome; protein complex assembly; protein import; protein quality control; respiratory chain
    DOI:  https://doi.org/10.1016/j.devcel.2024.02.011
  32. FASEB J. 2024 Mar 31. 38(6): e23505
    Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization.
    Nikhil Pal, Animesh Acharjee, Zsuzsanna Ament, Tim Dent, Arash Yavari, Masliza Mahmod, Rina Ariga, James West, Violetta Steeples, Mark Cassar, Neil J Howell, Helen Lockstone, Kate Elliott, Parisa Yavari, William Briggs, Michael Frenneaux, Bernard Prendergast, Jeremy S Dwight, Rajesh Kharbanda, Hugh Watkins, Houman Ashrafian, Julian L Griffin.
      Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non-LVH controls to investigate cardiac fuel selection and metabolic remodeling. These patients were assessed under different physiological states (at rest, during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts. We identified a highly discriminant metabolomic signature in severe AS in all samples, regardless of sampling site, characterized by striking accumulation of long-chain acylcarnitines, intermediates of fatty acid transport across the inner mitochondrial membrane, and validated this in a separate cohort. Mechanistically, we identify a downregulation in the PPAR-α transcriptional network, including expression of genes regulating fatty acid oxidation (FAO). In silico modeling of β-oxidation demonstrated that flux could be inhibited by both the accumulation of fatty acids as a substrate for mitochondria and the accumulation of medium-chain carnitines which induce competitive inhibition of the acyl-CoA dehydrogenases. We present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate a progressive impairment of β-oxidation from HCM to AS, particularly for FAO of long-chain fatty acids, and that the PPAR-α signaling network may be a specific metabolic therapeutic target in AS.
    Keywords:  cardiac gradient; cardiac metabolism; ischemic heart disease; metabolomics; precision medicine
    DOI:  https://doi.org/10.1096/fj.202301710RR
  33. Mol Ther Methods Clin Dev. 2024 Jun 13. 32(2): 101220
    Strengthening health systems for access to gene therapy in rare genetic disorders.
    Sonal Bhatia, Yann Le Cam, Juan Carrion, Lauren Diamond, Paul Fennessy, Safiyya Gassman, Felix Gutzwiller, Stephen Kagan, Diana Pankevich, Jennifer Young Maloney, Nitin Mahadev, Martin Schulz, Durhane Wong-Rieger, Paolo Morgese.
      
    DOI:  https://doi.org/10.1016/j.omtm.2024.101220
  34. Mol Cell. 2024 Mar 11. pii: S1097-2765(24)00176-X. [Epub ahead of print]
    Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1.
    Tristen Wright, Meghan E Turnis, Christy R Grace, Xiao Li, Lauren A Brakefield, Yong-Dong Wang, Haiyan Xu, Ewa Kaminska, Leslie K Climer, Tresor O Mukiza, Chi-Lun Chang, Tudor Moldoveanu, Joseph T Opferman.
      MCL-1 is essential for promoting the survival of many normal cell lineages and confers survival and chemoresistance in cancer. Beyond apoptosis regulation, MCL-1 has been linked to modulating mitochondrial metabolism, but the mechanism(s) by which it does so are unclear. Here, we show in tissues and cells that MCL-1 supports essential steps in long-chain (but not short-chain) fatty acid β-oxidation (FAO) through its binding to specific long-chain acyl-coenzyme A (CoA) synthetases of the ACSL family. ACSL1 binds to the BH3-binding hydrophobic groove of MCL-1 through a non-conventional BH3-domain. Perturbation of this interaction, via genetic loss of Mcl1, mutagenesis, or use of selective BH3-mimetic MCL-1 inhibitors, represses long-chain FAO in cells and in mouse livers and hearts. Our findings reveal how anti-apoptotic MCL-1 facilitates mitochondrial metabolism and indicate that disruption of this function may be associated with unanticipated cardiac toxicities of MCL-1 inhibitors in clinical trials.
    Keywords:  MCL-1; acyl-coenzyme A synthetase; apoptosis; fatty acid; metabolism; mitochondria; β-oxidation
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.035
  35. Angew Chem Int Ed Engl. 2024 Mar 21. e202402537
    Investigating the Therapeutic Effects of Ferroptosis on Myocardial Ischemia-Reperfusion Injury Using Dual-Locking Mitochondrial Targeting Strategy.
    Junling Yin, Xueying Zheng, Yuxi Zhao, Xiaotong Shen, Tian Cheng, Xinyu Shao, Xinying Jing, Shuhong Huang, Weiying Lin.
      Research of ferroptosis in myocardial ischemia/reperfusion injury (MIRI) using mitochondrial viscosity as a nexus holds great promise for MIRI therapeutics. However, high precision visualizing mitochondrial viscosity remains a formidable task owing to the debilitating electrostatic interaction caused by damaged mitochondrial membrane potential. Herein, we proposed a dual-locking mitochondrial targeting strategy that incorporates the idea of electrostatic forces and probe-protein molecular docking. Even in the damaged mitochondria, stable and precise visualization of mitochondrial viscosity in triggered and medicated MIRI was achieved owing to the sustained driving forces (pi-cation, pi-alkyl interactions etc.) between the developed probe CBS and mitochondrial membrane protein. Moreover, complemented by the western blot technology, we confirmed that ferrostatin-1 exerts its therapeutic effect on MIRI by improving the system xc-/GSH/GPX4 antioxidant system, confirming the therapeutic value of ferroptosis in MIRI. This work presents a new strategy for developing robust mitochondrial probes, thereby advancing the treatments for MIRI.
    Keywords:  Mitochondrial targerting; ferroptosis; fluorescent probe; mitochondrial viscosity; myocardial ischemia-reperfusion injury
    DOI:  https://doi.org/10.1002/anie.202402537
  36. bioRxiv. 2024 Mar 09. pii: 2024.03.08.581297. [Epub ahead of print]
    Mitochondrial Raf1 Regulates Glutamine Catabolism.
    Ronald L Shanderson, Ian D Ferguson, Zurab Siprashvili, Luca Ducoli, Albert M Li, Weili Miao, Suhas Srinivasan, Mary Grace Velasco, Yang Li, Jiangbin Ye, Paul A Khavari.
      Raf kinases play vital roles in normal mitogenic signaling and cancer, however, the identities of functionally important Raf-proximal proteins throughout the cell are not fully known. Raf1 proximity proteomics/BioID in Raf1-dependent cancer cells unexpectedly identified Raf1-adjacent proteins known to reside in the mitochondrial matrix. Inner-mitochondrial localization of Raf1 was confirmed by mitochondrial purification and super-resolution microscopy. Inside mitochondria, Raf1 associated with glutaminase (GLS) in diverse human cancers and enabled glutaminolysis, an important source of biosynthetic precursors in cancer. These impacts required Raf1 kinase activity and were independent of canonical MAP kinase pathway signaling. Kinase-dead mitochondrial matrix-localized Raf1 impaired glutaminolysis and tumorigenesis in vivo. These data indicate that Raf1 localizes inside mitochondria where it interacts with GLS to engage glutamine catabolism and support tumorigenesis.
    DOI:  https://doi.org/10.1101/2024.03.08.581297
  37. Front Genet. 2024 ;15 1374860
    Long read sequencing on its way to the routine diagnostics of genetic diseases.
    Giulia Olivucci, Emanuela Iovino, Giovanni Innella, Daniela Turchetti, Tommaso Pippucci, Pamela Magini.
      The clinical application of technological progress in the identification of DNA alterations has always led to improvements of diagnostic yields in genetic medicine. At chromosome side, from cytogenetic techniques evaluating number and gross structural defects to genomic microarrays detecting cryptic copy number variants, and at molecular level, from Sanger method studying the nucleotide sequence of single genes to the high-throughput next-generation sequencing (NGS) technologies, resolution and sensitivity progressively increased expanding considerably the range of detectable DNA anomalies and alongside of Mendelian disorders with known genetic causes. However, particular genomic regions (i.e., repetitive and GC-rich sequences) are inefficiently analyzed by standard genetic tests, still relying on laborious, time-consuming and low-sensitive approaches (i.e., southern-blot for repeat expansion or long-PCR for genes with highly homologous pseudogenes), accounting for at least part of the patients with undiagnosed genetic disorders. Third generation sequencing, generating long reads with improved mappability, is more suitable for the detection of structural alterations and defects in hardly accessible genomic regions. Although recently implemented and not yet clinically available, long read sequencing (LRS) technologies have already shown their potential in genetic medicine research that might greatly impact on diagnostic yield and reporting times, through their translation to clinical settings. The main investigated LRS application concerns the identification of structural variants and repeat expansions, probably because techniques for their detection have not evolved as rapidly as those dedicated to single nucleotide variants (SNV) identification: gold standard analyses are karyotyping and microarrays for balanced and unbalanced chromosome rearrangements, respectively, and southern blot and repeat-primed PCR for the amplification and sizing of expanded alleles, impaired by limited resolution and sensitivity that have not been significantly improved by the advent of NGS. Nevertheless, more recently, with the increased accuracy provided by the latest product releases, LRS has been tested also for SNV detection, especially in genes with highly homologous pseudogenes and for haplotype reconstruction to assess the parental origin of alleles with de novo pathogenic variants. We provide a review of relevant recent scientific papers exploring LRS potential in the diagnosis of genetic diseases and its potential future applications in routine genetic testing.
    Keywords:  RNA sequencing; genetic diseases; long read sequencing; methylation; molecular diagnosis; single nucleotide variants; structural variants; tandem repeats
    DOI:  https://doi.org/10.3389/fgene.2024.1374860
  38. Nat Aging. 2024 Mar;4(3): 364-378
    A single-nuclei paired multiomic analysis of the human midbrain reveals age- and Parkinson's disease-associated glial changes.
    Levi Adams, Min Kyung Song, Samantha Yuen, Yoshiaki Tanaka, Yoon-Seong Kim.
      Age is the primary risk factor for Parkinson's disease (PD), but how aging changes the expression and regulatory landscape of the brain remains unclear. Here we present a single-nuclei multiomic study profiling shared gene expression and chromatin accessibility of young, aged and PD postmortem midbrain samples. Combined multiomic analysis along a pseudopathogenesis trajectory reveals that all glial cell types are affected by age, but microglia and oligodendrocytes are further altered in PD. We present evidence for a disease-associated oligodendrocyte subtype and identify genes lost over the aging and disease process, including CARNS1, that may predispose healthy cells to develop a disease-associated phenotype. Surprisingly, we found that chromatin accessibility changed little over aging or PD within the same cell types. Peak-gene association patterns, however, are substantially altered during aging and PD, identifying cell-type-specific chromosomal loci that contain PD-associated single-nucleotide polymorphisms. Our study suggests a previously undescribed role for oligodendrocytes in aging and PD.
    DOI:  https://doi.org/10.1038/s43587-024-00583-6
  39. Elife. 2024 Mar 22. pii: RP90579. [Epub ahead of print]12
    Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation.
    Wayne Mitchell, Ludger J E Goeminne, Alexander Tyshkovskiy, Sirui Zhang, Julie Y Chen, Joao A Paulo, Kerry A Pierce, Angelina H Choy, Clary B Clish, Steven P Gygi, Vadim N Gladyshev.
      Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear. Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites. Using both transcriptomic and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems and warrant further investigation into adapting these approaches for in vivo age reversal.
    Keywords:  aging; biological age; cell biology; mitochondria; mouse; oxidative phosphorylation; reprogramming
    DOI:  https://doi.org/10.7554/eLife.90579
  40. Nature. 2024 Mar 18.
    'Bandit' algorithms help chemists to discover generally applicable conditions for reactions.
      
    Keywords:  Chemistry; Machine learning; Organic chemistry; Synthesis
    DOI:  https://doi.org/10.1038/d41586-024-00446-5
  41. Mitochondrial Commun. 2023 ;1 33-34
    Fusion activators enhance mitochondrial function.
    William M Rosencrans, David C Chan.
      
    DOI:  https://doi.org/10.1016/j.mitoco.2023.03.001
  42. Nat Commun. 2024 Mar 21. 15(1): 2517
    An evolutionary mechanism to assimilate new nutrient sensors into the mTORC1 pathway.
    Grace Y Liu, Patrick Jouandin, Raymond E Bahng, Norbert Perrimon, David M Sabatini.
      Animals sense and respond to nutrient availability in their environments, a task coordinated in part by the mTOR complex 1 (mTORC1) pathway. mTORC1 regulates growth in response to nutrients and, in mammals, senses specific amino acids through specialized sensors that bind the GATOR1/2 signaling hub. Given that animals can occupy diverse niches, we hypothesized that the pathway might evolve distinct sensors in different metazoan phyla. Whether such customization occurs, and how the mTORC1 pathway might capture new inputs, is unknown. Here, we identify the Drosophila melanogaster protein Unmet expectations (CG11596) as a species-restricted methionine sensor that directly binds the fly GATOR2 complex in a fashion antagonized by S-adenosylmethionine (SAM). We find that in Dipterans GATOR2 rapidly evolved the capacity to bind Unmet and to thereby repurpose a previously independent methyltransferase as a SAM sensor. Thus, the modular architecture of the mTORC1 pathway allows it to co-opt preexisting enzymes to expand its nutrient sensing capabilities, revealing a mechanism for conferring evolvability on an otherwise conserved system.
    DOI:  https://doi.org/10.1038/s41467-024-46680-3
  43. Nature. 2024 Mar 19.
    'A landmark moment': scientists use AI to design antibodies from scratch.
    Ewen Callaway.
      
    Keywords:  Drug discovery; Machine learning; Structural biology
    DOI:  https://doi.org/10.1038/d41586-024-00846-7
  44. Nat Commun. 2024 Mar 20. 15(1): 2480
    A universal molecular control for DNA, mRNA and protein expression.
    Helen M Gunter, Scott E Youlten, Andre L M Reis, Tim McCubbin, Bindu Swapna Madala, Ted Wong, Igor Stevanovski, Arcadi Cipponi, Ira W Deveson, Nadia S Santini, Sarah Kummerfeld, Peter I Croucher, Esteban Marcellin, Tim R Mercer.
      The expression of genes encompasses their transcription into mRNA followed by translation into protein. In recent years, next-generation sequencing and mass spectrometry methods have profiled DNA, RNA and protein abundance in cells. However, there are currently no reference standards that are compatible across these genomic, transcriptomic and proteomic methods, and provide an integrated measure of gene expression. Here, we use synthetic biology principles to engineer a multi-omics control, termed pREF, that can act as a universal molecular standard for next-generation sequencing and mass spectrometry methods. The pREF sequence encodes 21 synthetic genes that can be in vitro transcribed into spike-in mRNA controls, and in vitro translated to generate matched protein controls. The synthetic genes provide qualitative controls that can measure sensitivity and quantitative accuracy of DNA, RNA and peptide detection. We demonstrate the use of pREF in metagenome DNA sequencing and RNA sequencing experiments and evaluate the quantification of proteins using mass spectrometry. Unlike previous spike-in controls, pREF can be independently propagated and the synthetic mRNA and protein controls can be sustainably prepared by recipient laboratories using common molecular biology techniques. Together, this provides a universal synthetic standard able to integrate genomic, transcriptomic and proteomic methods.
    DOI:  https://doi.org/10.1038/s41467-024-46456-9
  45. Nature. 2024 Mar 18.
    How the body's cholesterol factory avoids producing too much.
      
    Keywords:  Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-00765-7
  46. Cell Death Differ. 2024 Mar 19.
    Endogenous BAX and BAK form mosaic rings of variable size and composition on apoptotic mitochondria.
    Sarah V Schweighofer, Daniel C Jans, Jan Keller-Findeisen, Anne Folmeg, Peter Ilgen, Mark Bates, Stefan Jakobs.
      One hallmark of apoptosis is the oligomerization of BAX and BAK to form a pore in the mitochondrial outer membrane, which mediates the release of pro-apoptotic intermembrane space proteins into the cytosol. Cells overexpressing BAX or BAK fusion proteins are a powerful model system to study the dynamics and localization of these proteins in cells. However, it is unclear whether overexpressed BAX and BAK form the same ultrastructural assemblies following the same spatiotemporal hierarchy as endogenously expressed proteins. Combining live- and fixed-cell STED super-resolution microscopy, we show that overexpression of BAK results in novel BAK structures, which are virtually absent in non-overexpressing apoptotic cells. We further demonstrate that in wild type cells, BAK is recruited to apoptotic pores before BAX. Both proteins together form unordered, mosaic rings on apoptotic mitochondria in immortalized cell culture models as well as in human primary cells. In BAX- or BAK- single-knockout cells, the remaining protein is able to form rings independently. The heterogeneous nature of these rings in both wild type as well as single-knockout cells corroborates the toroidal apoptotic pore model.
    DOI:  https://doi.org/10.1038/s41418-024-01273-x
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