bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–02–11
fifty-six papers selected by
Catalina Vasilescu, Helmholz Munich
  1. MT-TN mutations lead to progressive mitochondrial encephalopathy and promotes mitophagy.
  2. Mitochondrial transfer - a novel promising approach for the treatment of metabolic diseases.
  3. Navigating the landscape of mitochondrial-ER communication in health and disease.
  4. Deficient tRNA posttranscription modification dysregulated the mitochondrial quality controls and apoptosis.
  5. mtDNA extramitochondrial replication mediates mitochondrial defect effects.
  6. Activation of mitochondrial oxygen consumption rate by delivering coenzyme Q10 to mitochondria of rat skeletal muscle cell (L6).
  7. Preimplantation genetic testing as a preventive strategy for the transmission of mitochondrial DNA disorders.
  8. Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency.
  9. Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis.
  10. Characterizing Age-related Changes in Intact Mitochondrial Proteoforms in Murine Hearts using Quantitative Top-Down Proteomics.
  11. Super-resolution microscopies, technological breakthrough to decipher mitochondrial structure and dynamic.
  12. Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal.
  13. AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.
  14. Mitochondrial stress: a key role of neuroinflammation in stroke.
  15. Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status.
  16. Regulation of proteostasis and innate immunity via mitochondria-nuclear communication.
  17. Evaluation of Oxygen Consumption Rates In Situ.
  18. Mitochondrial DNA instability in Huntington disease.
  19. Remodelling of mitochondrial function by import of specific lipids at multiple membrane-contact sites.
  20. The role of mitochondrial dynamics in oocyte and early embryo development.
  21. Biallelic variants in GTPBP3: New patients, phenotypic spectrum, and outcome.
  22. The role of mitochondrial uncoupling in the regulation of mitostasis after traumatic brain injury.
  23. Function of NAD metabolism in white adipose tissue: lessons from mouse models.
  24. A mammalian-specific Alex3/Gαq protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival.
  25. Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding.
  26. PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.
  27. Transfer of inflammatory mitochondria via extracellular vesicles from M1 macrophages induces ferroptosis of pancreatic beta cells in acute pancreatitis.
  28. Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis.
  29. The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice.
  30. Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response.
  31. Q&A with Jiajie Diao.
  32. Hypoxia Sensing and Responses in Parkinson's Disease.
  33. Mitochondrial Sirtuins: Energy Dynamics and Cancer Metabolism.
  34. Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis.
  35. Long-Chain Fluorescent Probe for Straightforward and Nondestructive Staining Mitochondria in Fixed Cells and Tissues.
  36. Mitochondrial D-loop methylation levels inversely correlate with disease duration in amyotrophic lateral sclerosis.
  37. Mieap forms membrane-less organelles involved in cardiolipin metabolism.
  38. Top Stories: Mitochondrial origin of inherited cardiac arrhythmias.
  39. Interplay of Mitochondria and Diabetes: Unveiling Novel Therapeutic Strategies.
  40. Spreading depolarization causes reversible neuronal mitochondria fragmentation and swelling in healthy, normally perfused neocortex.
  41. Unlocking the mitochondria for nanomedicine-based Treatments: Overcoming biological Barriers, improving Designs, and selecting verification techniques.
  42. IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency.
  43. Hypermetabolism and energetic constraints in mitochondrial disorders.
  44. VDR regulates mitochondrial function as a protective mechanism against renal tubular cell injury in diabetic rats.
  45. Mitochondrial deoxyguanosine kinase is required for female fertility in mice.
  46. Mitochondrial Unfolded Protein Response Gene Clpp Is Required for Oocyte Function and Female Fertility.
  47. Mitochondrial function in peripheral blood cells across the human lifespan.
  48. A metabolite sensor subunit of the Atg1/ULK complex regulates selective autophagy.
  49. Overlay databank unlocks data-driven analyses of biomolecules for all.
  50. The Sjögren's Working Group: The 2023 OMERACT meeting and provisional domain generation.
  51. Children born after assisted reproduction more commonly carry a mitochondrial genotype associating with low birthweight.
  52. Physician-machine partnerships boost diagnostic accuracy, but bias persists.
  53. Application of AI in biological age prediction.
  54. Enhanced translocation of TRIM32 to mitochondria sensitizes dopaminergic neuronal cells to apoptosis during stress conditions in Parkinson's disease.
  55. The Bespoke Gene Therapy Consortium: facilitating development of AAV gene therapies for rare diseases.
  56. Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport.
  1. Biochim Biophys Acta Mol Basis Dis. 2024 Feb 05. pii: S0925-4439(24)00028-0. [Epub ahead of print]1870(4): 167043
    MT-TN mutations lead to progressive mitochondrial encephalopathy and promotes mitophagy.
    Haolin Duan, Cunhui Pan, Tenghui Wu, Jing Peng, Li Yang.
      Mitochondrial encephalopathy is a neurological disorder caused by impaired mitochondrial function and energy production. One of the genetic causes of this condition is the mutation of MT-TN, a gene that encodes the mitochondrial transfer RNA (tRNA) for asparagine. MT-TN mutations affect the stability and structure of the tRNA, resulting in reduced protein synthesis and complex enzymatic deficiency of the mitochondrial respiratory chain. Our patient cohort manifests with epileptic encephalopathy, ataxia, hypotonia, and bilateral basal ganglia calcification, which differs from previously reported cases. MT-TN mutation deficiency leads to decreased basal and maximal oxygen consumption rates, disrupted spare respiratory capacity, declined mitochondrial membrane potential, and impaired ATP production. Moreover, MT-TN mutations promote mitophagy, a process of selective degradation of damaged mitochondria by autophagy. Excessive mitophagy further leads to mitochondrial biogensis as a compensatory mechanism. In this study, we provided evidence of pathogenicity for two MT-TN mutations, m.5688 T > C and m.G5691A, explored the molecular mechanisms, and summarized the clinical manifestations of MT-TN mutations. Our study expanded the genotype and phenotypic spectrum and provided new insight into mt-tRNA (Asn)-associated mitochondrial encephalopathy.
    Keywords:  Epilepsy; MT-TN; Mitochondrial encephalopathy; Mitophagy
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167043
  2. Front Endocrinol (Lausanne). 2023 ;14 1346441
    Mitochondrial transfer - a novel promising approach for the treatment of metabolic diseases.
    Ruijing Chen, Jun Chen.
      Metabolic disorders remain a major global health concern in the 21st century, with increasing incidence and prevalence. Mitochondria play a critical role in cellular energy production, calcium homeostasis, signal transduction, and apoptosis. Under physiological conditions, mitochondrial transfer plays a crucial role in tissue homeostasis and development. Mitochondrial dysfunction has been implicated in the pathogenesis of metabolic disorders. Numerous studies have demonstrated that mitochondria can be transferred from stem cells to pathologically injured cells, leading to mitochondrial functional restoration. Compared to cell therapy, mitochondrial transplantation has lower immunogenicity, making exogenous transplantation of healthy mitochondria a promising therapeutic approach for treating diseases, particularly metabolic disorders. This review summarizes the association between metabolic disorders and mitochondria, the mechanisms of mitochondrial transfer, and the therapeutic potential of mitochondrial transfer for metabolic disorders. We hope this review provides novel insights into targeted mitochondrial therapy for metabolic disorders.
    Keywords:  metabolic diseases; mitochondria; mitochondrial transfer; therapy; transplantation
    DOI:  https://doi.org/10.3389/fendo.2023.1346441
  3. Front Mol Biosci. 2024 ;11 1356500
    Navigating the landscape of mitochondrial-ER communication in health and disease.
    Conor T Ronayne, Pedro Latorre-Muro.
      Intracellular organelle communication enables the maintenance of tissue homeostasis and health through synchronized adaptive processes triggered by environmental cues. Mitochondrial-Endoplasmic Reticulum (ER) communication sustains cellular fitness by adjusting protein synthesis and degradation, and metabolite and protein trafficking through organelle membranes. Mitochondrial-ER communication is bidirectional and requires that the ER-components of the Integrated Stress Response signal to mitochondria upon activation and, likewise, mitochondria signal to the ER under conditions of metabolite and protein overload to maintain proper functionality and ensure cellular survival. Declines in the mitochondrial-ER communication occur upon ageing and correlate with the onset of a myriad of heterogeneous age-related diseases such as obesity, type 2 diabetes, cancer, or neurodegenerative pathologies. Thus, the exploration of the molecular mechanisms of mitochondrial-ER signaling and regulation will provide insights into the most fundamental cellular adaptive processes with important therapeutical opportunities. In this review, we will discuss the pathways and mechanisms of mitochondrial-ER communication at the mitochondrial-ER interface and their implications in health and disease.
    Keywords:  calcium signaling; cellular fitness; endoplasmic reticulum; lipid trafficking; mitochondria; mitochondrial-ER communication; protein homeostasis; unfolded protein response
    DOI:  https://doi.org/10.3389/fmolb.2024.1356500
  4. iScience. 2024 Feb 16. 27(2): 108883
    Deficient tRNA posttranscription modification dysregulated the mitochondrial quality controls and apoptosis.
    Yunfan He, Gao Zhu, Xincheng Li, Mi Zhou, Min-Xin Guan.
      Mitochondria are dynamic organelles in cellular metabolism and physiology. Mitochondrial DNA (mtDNA) mutations are associated with a broad spectrum of clinical abnormalities. However, mechanisms underlying mtDNA mutations regulate intracellular signaling related to the mitochondrial and cellular integrity are less explored. Here, we demonstrated that mt-tRNAMet 4435A>G mutation-induced nucleotide modification deficiency dysregulated the expression of nuclear genes involved in cytosolic proteins involved in oxidative phosphorylation system (OXPHOS) and impaired the assemble and integrity of OXPHOS complexes. These dysfunctions caused mitochondrial dynamic imbalance, thereby increasing fission and decreasing fusion. Excessive fission impaired the process of autophagy including initiation phase, formation, and maturation of autophagosome. Strikingly, the m.4435A>G mutation upregulated the PARKIN dependent mitophagy pathways but downregulated the ubiquitination-independent mitophagy. These alterations promoted intrinsic apoptotic process for the removal of damaged cells. Our findings provide new insights into mechanism underlying deficient tRNA posttranscription modification regulated intracellular signaling related to the mitochondrial and cellular integrity.
    Keywords:  Cell biology; Molecular physiology; Properties of biomolecules
    DOI:  https://doi.org/10.1016/j.isci.2024.108883
  5. iScience. 2024 Feb 16. 27(2): 108970
    mtDNA extramitochondrial replication mediates mitochondrial defect effects.
    Zhaoliang Shan, Shengnan Li, Yuxue Gao, Chunhua Jian, Xiuxiu Ti, Hui Zuo, Ying Wang, Guochun Zhao, Yan Wang, Qing Zhang.
      A high ratio of severe mitochondrial defects causes multiple human mitochondrial diseases. However, until now, the in vivo rescue signal of such mitochondrial defect effects has not been clear. Here, we built fly mitochondrial defect models by knocking down the essential mitochondrial genes dMterf4 and dMrps23. Following genome-wide RNAi screens, we found that knockdown of Med8/Tfb4/mtSSB/PolG2/mtDNA-helicase rescued dMterf4/dMrps23 RNAi-mediated mitochondrial defect effects. Extremely surprisingly, they drove mtDNA replication outside mitochondria through the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis to amplify cytosolic mtDNA, leading to activation of the cGAS-Sting-like IMD pathway to partially mediate dMterf4/dMrps23 RNAi-triggered effects. Moreover, we found that the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis also mediated other fly mitochondrial gene defect-triggered dysfunctions and Drosophila aging. Overall, our study demarcates the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis as a candidate mechanism to mediate mitochondrial defect effects through driving mtDNA extramitochondrial replication; dysfunction of this axis might be used for potential treatments for many mitochondrial and age-related diseases.
    Keywords:  Biological sciences; Molecular biology; Molecular genetics; Molecular interaction
    DOI:  https://doi.org/10.1016/j.isci.2024.108970
  6. J Pharm Sci. 2024 Feb 05. pii: S0022-3549(24)00041-8. [Epub ahead of print]
    Activation of mitochondrial oxygen consumption rate by delivering coenzyme Q10 to mitochondria of rat skeletal muscle cell (L6).
    Itsumi Sato, Mitsue Hibino, Atsuhito Takeda, Hideyoshi Harashima, Yuma Yamada.
      Numerous mitochondria are present in skeletal muscle cells. Muscle disease and aging impair mitochondrial functioning in the skeletal muscle. However, there have been few reports of therapeutic intervention via drug delivery to mitochondria owing to methodological difficulties. We surmised that mitochondrial activation is associated with improved skeletal muscle function. In this study, we attempted to activate the mitochondrial respiratory capacity in rat skeletal muscle cells (L6 cells) by delivering Coenzyme Q10 (CoQ10), a mitochondrial functional activator, to mitochondria using MITO-Porter, a nanoparticle that facilitates mitochondria-targeted drug delivery. Cellular uptake was confirmed by measuring the amount of fluorescence-modified MITO-Porter taken up by cells using flow cytometry. Intracellular dynamics of MITO-Porter was observed using confocal laser scanning microscopy. Mitochondrial function was assessed by measuring the mitochondrial oxygen consumption rate using an extracellular flux analyzer. The results indicated MITO-Porter-assisted delivery of CoQ10 to the mitochondria activated mitochondrial respiratory capacity in L6 cells. We believe that our results indicate the possibility of skeletal muscle therapy using mitochondrial drug delivery.
    Keywords:  Drug delivery system; Lipid Nanoparticle (LNP); Liposome; Microfluidics; Muscle; Nanoparticle; Nanotechnology
    DOI:  https://doi.org/10.1016/j.xphs.2024.01.020
  7. Syst Biol Reprod Med. 2024 Dec;70(1): 38-51
    Preimplantation genetic testing as a preventive strategy for the transmission of mitochondrial DNA disorders.
    Xinpeng Lan, Wu Liji Ao, Ji Li.
      Mitochondrial diseases are distinct types of metabolic and/or neurologic abnormalities that occur as a consequence of dysfunction in oxidative phosphorylation, affecting several systems in the body. There is no effective treatment modality for mitochondrial disorders so far, emphasizing the clinical significance of preventing the inheritance of these disorders. Various reproductive options are available to reduce the probability of inheriting mitochondrial disorders, including in vitro fertilization (IVF) using donated oocytes, preimplantation genetic testing (PGT), and prenatal diagnosis (PND), among which PGT not only makes it possible for families to have genetically-owned children but also PGT has the advantage that couples do not have to decide to terminate the pregnancy if a mutation is detected in the fetus. PGT for mitochondrial diseases originating from nuclear DNA includes analyzing the nuclear genome for the presence or absence of corresponding mutations. However, PGT for mitochondrial disorders arising from mutations in mitochondrial DNA (mtDNA) is more intricate, due to the specific characteristics of mtDNA such as multicopy nature, heteroplasmy phenomenon, and exclusive maternal inheritance. Therefore, the present review aims to discuss the utility and challenges of PGT as a preventive approach to inherited mitochondrial diseases caused by mtDNA mutations.
    Keywords:  Heteroplasmic mutations; Maternal inheritance; Mitochondria; Preimplantation diagnosis; mtDNA diseases
    DOI:  https://doi.org/10.1080/19396368.2024.2306389
  8. Hum Mol Genet. 2024 Feb 07. pii: ddae018. [Epub ahead of print]
    Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency.
    Vanitha Nithianandam, Souvarish Sarkar, Mel B Feany.
      Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number of mitochondrial genes, including electron transport chain components, in a large forward genetic screen for mutations causing age-related neurodegeneration in the context of proteostasis dysfunction. We created a model of complex I deficiency in the Drosophila retina to probe the role of protein degradation abnormalities in mitochondrial encephalomyopathies. Using our genetic model, we found that complex I deficiency regulates both the ubiquitin/proteasome and autophagy/lysosome arms of the proteostasis machinery. We further performed an in vivo kinome screen to uncover new and potentially druggable mechanisms contributing to complex I related neurodegeneration and proteostasis failure. Reduction of RIOK kinases and the innate immune signaling kinase pelle prevented neurodegeneration in complex I deficiency animals. Genetically targeting oxidative stress, but not RIOK1 or pelle knockdown, normalized proteostasis markers. Our findings outline distinct pathways controlling neurodegeneration and protein degradation in complex I deficiency and introduce an experimentally facile model in which to study these debilitating and currently treatment-refractory disorders.
    Keywords:  Drosophila; complex I deficiency; mitochondria; neurotoxicity; proteostasis
    DOI:  https://doi.org/10.1093/hmg/ddae018
  9. medRxiv. 2023 Aug 13. pii: 2023.08.08.23293829. [Epub ahead of print]
    Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis.
    Monica H Wojcik, Gabrielle Lemire, Maha S Zaki, Mariel Wissman, Wathone Win, Sue White, Ben Weisburd, Leigh B Waddell, Jeffrey M Verboon, Grace E VanNoy, Ana Töpf, Tiong Yang Tan, Volker Straub, Sarah L Stenton, Hana Snow, Moriel Singer-Berk, Josh Silver, Shirlee Shril, Eleanor G Seaby, Ronen Schneider, Vijay G Sankaran, Alba Sanchis-Juan, Kathryn A Russell, Karit Reinson, Gianina Ravenscroft, Eric A Pierce, Emily M Place, Sander Pajusalu, Lynn Pais, Katrin Õunap, Ikeoluwa Osei-Owusu, Volkan Okur, Kaisa Teele Oja, Melanie O'Leary, Emily O'Heir, Chantal Morel, Rhett G Marchant, Brian E Mangilog, Jill A Madden, Daniel MacArthur, Alysia Lovgren, Jordan P Lerner-Ellis, Jasmine Lin, Nigel Laing, Friedhelm Hildebrandt, Emily Groopman, Julia Goodrich, Joseph G Gleeson, Roula Ghaoui, Casie A Genetti, Hanna T Gazda, Vijay S Ganesh, Mythily Ganapathy, Lyndon Gallacher, Jack Fu, Emily Evangelista, Eleina England, Sandra Donkervoort, Stephanie DiTroia, Sandra T Cooper, Wendy K Chung, John Christodoulou, Katherine R Chao, Liam D Cato, Kinga M Bujakowska, Samantha J Bryen, Harrison Brand, Carsten Bonnemann, Alan H Beggs, Samantha M Baxter, Pankaj B Agrawal, Michael Talkowski, Chrissy Austin-Tse, Heidi L Rehm, Anne O'Donnell-Luria.
       Background: Causal variants underlying rare disorders may remain elusive even after expansive gene panels or exome sequencing (ES). Clinicians and researchers may then turn to genome sequencing (GS), though the added value of this technique and its optimal use remain poorly defined. We therefore investigated the advantages of GS within a phenotypically diverse cohort.
    Methods: GS was performed for 744 individuals with rare disease who were genetically undiagnosed. Analysis included review of single nucleotide, indel, structural, and mitochondrial variants.
    Results: We successfully solved 218/744 (29.3%) cases using GS, with most solves involving established disease genes (157/218, 72.0%). Of all solved cases, 148 (67.9%) had previously had non-diagnostic ES. We systematically evaluated the 218 causal variants for features requiring GS to identify and 61/218 (28.0%) met these criteria, representing 8.2% of the entire cohort. These included small structural variants (13), copy neutral inversions and complex rearrangements (8), tandem repeat expansions (6), deep intronic variants (15), and coding variants that may be more easily found using GS related to uniformity of coverage (19).
    Conclusion: We describe the diagnostic yield of GS in a large and diverse cohort, illustrating several types of pathogenic variation eluding ES or other techniques. Our results reveal a higher diagnostic yield of GS, supporting the utility of a genome-first approach, with consideration of GS as a secondary or tertiary test when higher-resolution structural variant analysis is needed or there is a strong clinical suspicion for a condition and prior targeted genetic testing has been negative.
    DOI:  https://doi.org/10.1101/2023.08.08.23293829
  10. Res Sq. 2024 Jan 18. pii: rs.3.rs-3868218. [Epub ahead of print]
    Characterizing Age-related Changes in Intact Mitochondrial Proteoforms in Murine Hearts using Quantitative Top-Down Proteomics.
    Andrea Ramirez-Sagredo, Anju Sunny, Kellye Cupp-Sutton, Trishika Chowdhury, Zhitao Zhao, Si Wu, Ying Ann Chiao.
      Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and the prevalence of CVDs increases markedly with age. Due to the high energetic demand, the heart is highly sensitive to mitochondrial dysfunction. The complexity of the cardiac mitochondrial proteome hinders the development of effective strategies that target mitochondrial dysfunction in CVDs. Mammalian mitochondria are composed of over 1000 proteins, most of which can undergo post-translational protein modifications (PTMs). Top-down proteomics is a powerful technique for characterizing and quantifying all protein sequence variations and PTMs. However, there are still knowledge gaps in the study of age-related mitochondrial proteoform changes using this technique. In this study, we used top-down proteomics to identify intact mitochondrial proteoforms in young and old hearts and determined changes in protein abundance and PTMs in cardiac aging. METHODS: Intact mitochondria were isolated from the hearts of young (4-month-old) and old (24-25-month-old) mice. The mitochondria were lysed, and mitochondrial lysates were subjected to denaturation, reduction, and alkylation. For quantitative top-down analysis, there were 12 runs in total arising from 3 biological replicates in two conditions, with technical duplicates for each sample. The collected top-down datasets were deconvoluted and quantified, and then the proteoforms were identified. RESULTS: From a total of 12 LC-MS/MS runs, we identified 134 unique mitochondrial proteins in the different sub-mitochondrial compartments (OMM, IMS, IMM, matrix). 823 unique proteoforms in different mass ranges were identified. Compared to cardiac mitochondria of young mice, 7 proteoforms exhibited increased abundance and 13 proteoforms exhibited decreased abundance in cardiac mitochondria of old mice. Our analysis also detected PTMs of mitochondrial proteoforms, including N -terminal acetylation, lysine succinylation, lysine acetylation, oxidation, and phosphorylation. CONCLUSION: By combining mitochondrial protein enrichment using mitochondrial fractionation with quantitative top-down analysis using ultrahigh-pressure liquid chromatography (UPLC)-MS and label-free quantitation, we successfully identified and quantified intact proteoforms in the complex mitochondrial proteome. Using this approach, we detected age-related changes in abundance and PTMs of mitochondrial proteoforms in the heart.
    DOI:  https://doi.org/10.21203/rs.3.rs-3868218/v1
  11. Semin Cell Dev Biol. 2024 Feb 03. pii: S1084-9521(24)00018-1. [Epub ahead of print]159-160 38-51
    Super-resolution microscopies, technological breakthrough to decipher mitochondrial structure and dynamic.
    Pauline Teixeira, Rémi Galland, Arnaud Chevrollier.
      Mitochondria are complex organelles with an outer membrane enveloping a second inner membrane that creates a vast matrix space partitioned by pockets or cristae that join the peripheral inner membrane with several thin junctions. Several micrometres long, mitochondria are generally close to 300 nm in diameter, with membrane layers separated by a few tens of nanometres. Ultrastructural data from electron microscopy revealed the structure of these mitochondria, while conventional optical microscopy revealed their extraordinary dynamics through fusion, fission, and migration processes but its limited resolution power restricted the possibility to go further. By overcoming the limits of light diffraction, Super-Resolution Microscopy (SRM) now offers the potential to establish the links between the ultrastructure and remodelling of mitochondrial membranes, leading to major advances in our understanding of mitochondria's structure-function. Here we review the contributions of SRM imaging to our understanding of the relationship between mitochondrial structure and function. What are the hopes for these new imaging approaches which are particularly important for mitochondrial pathologies?
    Keywords:  MICOS; Microscopy; Mitochondria; Nucleoids; Super-resolution
    DOI:  https://doi.org/10.1016/j.semcdb.2024.01.006
  12. Nat Cell Biol. 2024 Feb 08.
    Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal.
    Laura E Newman, Sammy Weiser Novak, Gladys R Rojas, Nimesha Tadepalle, Cara R Schiavon, Danielle A Grotjahn, Christina G Towers, Marie-Ève Tremblay, Matthew P Donnelly, Sagnika Ghosh, Michaela Medina, Sienna Rocha, Ricardo Rodriguez-Enriquez, Joshua A Chevez, Ian Lemersal, Uri Manor, Gerald S Shadel.
      Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into circulation. As a DAMP, mtDNA not only contributes to anti-viral resistance, but also causes pathogenic inflammation in many disease contexts. Cells experiencing mtDNA stress caused by depletion of the mtDNA-packaging protein, transcription factor A, mitochondrial (TFAM) or during herpes simplex virus-1 infection exhibit elongated mitochondria, enlargement of nucleoids (mtDNA-protein complexes) and activation of cGAS-STING innate immune signalling via mtDNA released into the cytoplasm. However, the relationship among aberrant mitochondria and nucleoid dynamics, mtDNA release and cGAS-STING activation remains unclear. Here we show that, under a variety of mtDNA replication stress conditions and during herpes simplex virus-1 infection, enlarged nucleoids that remain bound to TFAM exit mitochondria. Enlarged nucleoids arise from mtDNA experiencing replication stress, which causes nucleoid clustering via a block in mitochondrial fission at a stage when endoplasmic reticulum actin polymerization would normally commence, defining a fission checkpoint that ensures mtDNA has completed replication and is competent for segregation into daughter mitochondria. Chronic engagement of this checkpoint results in enlarged nucleoids trafficking into early and then late endosomes for disposal. Endosomal rupture during transit through this endosomal pathway ultimately causes mtDNA-mediated cGAS-STING activation. Thus, we propose that replication-incompetent nucleoids are selectively eliminated by an adaptive mitochondria-endosomal quality control pathway that is prone to innate immune system activation, which might represent a therapeutic target to prevent mtDNA-mediated inflammation during viral infection and other pathogenic states.
    DOI:  https://doi.org/10.1038/s41556-023-01343-1
  13. Sci Adv. 2024 Feb 09. 10(6): eadj2752
    AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.
    Liwei Xiao, Yujing Yin, Zongchao Sun, Jing Liu, Yuhuan Jia, Likun Yang, Yan Mao, Shujun Peng, Zhifu Xie, Lei Fang, Jingya Li, Xiaoduo Xie, Zhenji Gan.
      Exercise-induced activation of adenosine monophosphate-activated protein kinase (AMPK) and substrate phosphorylation modulate the metabolic capacity of mitochondria in skeletal muscle. However, the key effector(s) of AMPK and the regulatory mechanisms remain unclear. Here, we showed that AMPK phosphorylation of the folliculin interacting protein 1 (FNIP1) serine-220 (S220) controls mitochondrial function and muscle fuel utilization during exercise. Loss of FNIP1 in skeletal muscle resulted in increased mitochondrial content and augmented metabolic capacity, leading to enhanced exercise endurance in mice. Using skeletal muscle-specific nonphosphorylatable FNIP1 (S220A) and phosphomimic (S220D) transgenic mouse models as well as biochemical analysis in primary skeletal muscle cells, we demonstrated that exercise-induced FNIP1 (S220) phosphorylation by AMPK in muscle regulates mitochondrial electron transfer chain complex assembly, fuel utilization, and exercise performance without affecting mechanistic target of rapamycin complex 1-transcription factor EB signaling. Therefore, FNIP1 is a multifunctional AMPK effector for mitochondrial adaptation to exercise, implicating a mechanism for exercise tolerance in health and disease.
    DOI:  https://doi.org/10.1126/sciadv.adj2752
  14. J Neuroinflammation. 2024 Feb 06. 21(1): 44
    Mitochondrial stress: a key role of neuroinflammation in stroke.
    Ling Gao, Li Peng, Jian Wang, John H Zhang, Ying Xia.
      Stroke is a clinical syndrome characterized by an acute, focal neurological deficit, primarily caused by the occlusion or rupture of cerebral blood vessels. In stroke, neuroinflammation emerges as a pivotal event contributing to neuronal cell death. The occurrence and progression of neuroinflammation entail intricate processes, prominently featuring mitochondrial dysfunction and adaptive responses. Mitochondria, a double membrane-bound organelle are recognized as the "energy workshop" of the body. Brain is particularly vulnerable to mitochondrial disturbances due to its high energy demands from mitochondria-related energy production. The interplay between mitochondria and neuroinflammation plays a significant role in the pathogenesis of stroke. The biological and pathological consequences resulting from mitochondrial stress have substantial implications for cerebral function. Mitochondrial stress serves as an adaptive mechanism aimed at mitigating the stress induced by the import of misfolded proteins, which occurs in response to stroke. This adaptive response involves a reduction in misfolded protein accumulation and overall protein synthesis. The influence of mitochondrial stress on the pathological state of stroke is underscored by its capacity to interact with neuroinflammation. The impact of mitochondrial stress on neuroinflammation varies according to its severity. Moderate mitochondrial stress can bolster cellular adaptive defenses, enabling cells to better withstand detrimental stressors. In contrast, sustained and excessive mitochondrial stress detrimentally affects cellular and tissue integrity. The relationship between neuroinflammation and mitochondrial stress depends on the degree of mitochondrial stress present. Understanding its role in stroke pathogenesis is instrumental in excavating the novel treatment of stroke. This review aims to provide the evaluation of the cross-talk between mitochondrial stress and neuroinflammation within the context of stroke. We aim to reveal how mitochondrial stress affects neuroinflammation environment in stroke.
    Keywords:  Mitochondrial stress; Mitophagy; Neuroinflammation; Stroke
    DOI:  https://doi.org/10.1186/s12974-024-03033-7
  15. Nat Commun. 2024 Feb 06. 15(1): 1124
    Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status.
    Aidan Anderson, Nada Alfahad, Dulani Wimalachandra, Kaouthar Bouzinab, Paula Rudzinska, Heather Wood, Isabel Fazey, Heping Xu, Timothy J Lyons, Nicholas M Barnes, Parth Narendran, Janet M Lord, Saaeha Rauz, Ian G Ganley, Tim M Curtis, Graham R Wallace, Jose R Hombrebueno.
      The recovery of mitochondrial quality control (MQC) may bring innovative solutions for neuroprotection, while imposing a significant challenge given the need of holistic approaches to restore mitochondrial dynamics (fusion/fission) and turnover (mitophagy and biogenesis). In diabetic retinopathy, this is compounded by our lack of understanding of human retinal neurodegeneration, but also how MQC processes interact during disease progression. Here, we show that mitochondria hyperfusion is characteristic of retinal neurodegeneration in human and murine diabetes, blunting the homeostatic turnover of mitochondria and causing metabolic and neuro-inflammatory stress. By mimicking this mitochondrial remodelling in vitro, we ascertain that N6-furfuryladenosine enhances mitochondrial turnover and bioenergetics by relaxing hyperfusion in a controlled fashion. Oral administration of N6-furfuryladenosine enhances mitochondrial turnover in the diabetic mouse retina (Ins2Akita males), improving clinical correlates and conferring neuroprotection regardless of glycaemic status. Our findings provide translational insights for neuroprotection in the diabetic retina through the holistic recovery of MQC.
    DOI:  https://doi.org/10.1038/s41467-024-45387-9
  16. J Cell Biol. 2024 Mar 04. pii: e202310005. [Epub ahead of print]223(3):
    Regulation of proteostasis and innate immunity via mitochondria-nuclear communication.
    Sookyung Kim, Theresa R Ramalho, Cole M Haynes.
      Mitochondria are perhaps best known as the "powerhouse of the cell" for their role in ATP production required for numerous cellular activities. Mitochondria have emerged as an important signaling organelle. Here, we first focus on signaling pathways mediated by mitochondria-nuclear communication that promote protein homeostasis (proteostasis). We examine the mitochondrial unfolded protein response (UPRmt) in C. elegans, which is regulated by a transcription factor harboring both a mitochondrial- and nuclear-targeting sequence, the integrated stress response in mammals, as well as the regulation of chromatin by mitochondrial metabolites. In the second section, we explore the role of mitochondria-to-nuclear communication in the regulation of innate immunity and inflammation. Perhaps related to their prokaryotic origin, mitochondria harbor molecules also found in viruses and bacteria. If these molecules accumulate in the cytosol, they elicit the same innate immune responses as viral or bacterial infection.
    DOI:  https://doi.org/10.1083/jcb.202310005
  17. Methods Mol Biol. 2024 ;2755 215-226
    Evaluation of Oxygen Consumption Rates In Situ.
    Anqi Li, Yuan Qin, Ying Zhang, Xiaoqun Zhen, Guohua Gong.
      An analysis of the mitochondrial respiration function represented by the oxygen consumption rate is necessary to assess mitochondrial bioenergetics and redox function. This protocol describes two alternative techniques to evaluate mitochondrial respiration function in situ: (1) measure oxygen consumption rates via an electrode; (2) measure oxygen consumption rates via a seahorse instrument. These in situ approaches provide more physiological access to mitochondria to evaluate mitochondrial respiration function in a relatively integrated cellular system.
    Keywords:  ATP; Mitochondria; Mitochondrial stress test; Oxidative phosphorylation; Oxygen consumption
    DOI:  https://doi.org/10.1007/978-1-0716-3633-6_16
  18. Nat Rev Neurol. 2024 Feb 07.
    Mitochondrial DNA instability in Huntington disease.
    Lisa Kiani.
      
    DOI:  https://doi.org/10.1038/s41582-024-00937-z
  19. FEBS Lett. 2024 Feb 04.
    Remodelling of mitochondrial function by import of specific lipids at multiple membrane-contact sites.
    Aksel J Saukko-Paavola, Robin W Klemm.
      Organelles form physical and functional contact between each other to exchange information, metabolic intermediates, and signaling molecules. Tethering factors and contact site complexes bring partnering organelles into close spatial proximity to establish membrane contact sites (MCSs), which specialize in unique functions like lipid transport or Ca2+ signaling. Here, we discuss how MCSs form dynamic platforms that are important for lipid metabolism. We provide a perspective on how import of specific lipids from the ER and other organelles may contribute to remodeling of mitochondria during nutrient starvation. We speculate that mitochondrial adaptation is achieved by connecting several compartments into a highly dynamic organelle network. The lipid droplet appears to be a central hub in coordinating the function of these organelle neighborhoods.
    Keywords:  autophagy; endoplasmic reticulum (ER); lipid droplets (LDs); membrane contact sites; metabolic adaptation; mitochondria; mitochondrial shape; organelle-network; starvation
    DOI:  https://doi.org/10.1002/1873-3468.14813
  20. Semin Cell Dev Biol. 2024 Feb 06. pii: S1084-9521(24)00019-3. [Epub ahead of print]159-160 52-61
    The role of mitochondrial dynamics in oocyte and early embryo development.
    Raziye Melike Yildirim, Emre Seli.
      Mitochondrial dysfunction is widely implicated in various human diseases, through mechanisms that go beyond mitochondria's well-established role in energy generation. These dynamic organelles exert vital control over numerous cellular processes, including calcium regulation, phospholipid synthesis, innate immunity, and apoptosis. While mitochondria's importance is acknowledged in all cell types, research has revealed the exceptionally dynamic nature of the mitochondrial network in oocytes and embryos, finely tuned to meet unique needs during gamete and pre-implantation embryo development. Within oocytes, both the quantity and morphology of mitochondria can significantly change during maturation and post-fertilization. These changes are orchestrated by fusion and fission processes (collectively known as mitochondrial dynamics), crucial for energy production, content exchange, and quality control as mitochondria adjust to the shifting energy demands of oocytes and embryos. The roles of proteins that regulate mitochondrial dynamics in reproductive processes have been primarily elucidated through targeted deletion studies in animal models. Notably, impaired mitochondrial dynamics have been linked to female reproductive health, affecting oocyte quality, fertilization, and embryo development. Dysfunctional mitochondria can lead to fertility problems and can have an impact on the success of pregnancy, particularly in older reproductive age women.
    Keywords:  Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; MtDNA
    DOI:  https://doi.org/10.1016/j.semcdb.2024.01.007
  21. Ann Clin Transl Neurol. 2024 Feb 07.
    Biallelic variants in GTPBP3: New patients, phenotypic spectrum, and outcome.
    Francesca Nardecchia, Rosalba Carrozzo, Alice Innocenti, Alessandra Torraco, Valerio Zaccaria, Teresa Rizza, Francesco Pisani, Enrico Bertini, Vincenzo Leuzzi.
       INTRODUCTION: COXPD23 is a rare mitochondrial disease caused by biallelic pathogenic variants in GTPBP3. We report on two siblings with a mild phenotype.
    CASE REPORTS: The young boy presented with global developmental delay, ataxic gait and upper limbs tremor, and the older sister with absence seizures and hypertrophic cardiomyopathy. Respiratory chain impairment was confirmed in muscle.
    DISCUSSION: Reviewed cases point toward clustering around two prevalent phenotypes: an early-onset presentation with severe fatal encephalopathy and a late milder presentation with global developmental delay/ID and cardiopathy, with the latter as, is the main feature. Our patients showed an intermediate phenotype with intrafamilial variability.
    DOI:  https://doi.org/10.1002/acn3.51980
  22. Neurochem Int. 2024 Feb 02. pii: S0197-0186(24)00007-X. [Epub ahead of print] 105680
    The role of mitochondrial uncoupling in the regulation of mitostasis after traumatic brain injury.
    W Brad Hubbard, Gopal V Velmurugan, Patrick G Sullivan.
      Mitostasis, the maintenance of healthy mitochondria, plays a critical role in brain health. The brain's high energy demands and reliance on mitochondria for energy production make mitostasis vital for neuronal function. Traumatic brain injury (TBI) disrupts mitochondrial homeostasis, leading to secondary cellular damage, neuronal degeneration, and cognitive deficits. Mild mitochondrial uncoupling, which dissociates ATP production from oxygen consumption, offers a promising avenue for TBI treatment. Accumulating evidence, from endogenous and exogenous mitochondrial uncoupling, suggests that mitostasis is closely regulating by mitochondrial uncoupling and cellular injury environments may be more sensitive to uncoupling. Mitochondrial uncoupling can mitigate calcium overload, reduce oxidative stress, and induce mitochondrial proteostasis and mitophagy, a process that eliminates damaged mitochondria. The interplay between mitochondrial uncoupling and mitostasis is ripe for further investigation in the context of TBI. These multi-faceted mechanisms of action for mitochondrial uncoupling hold promise for TBI therapy, with the potential to restore mitochondrial health, improve neurological outcomes, and prevent long-term TBI-related pathology.
    Keywords:  Calcium; Dinitrophenol; Mitochondria; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.neuint.2024.105680
  23. Adipocyte. 2024 Feb 05. 2313297
    Function of NAD metabolism in white adipose tissue: lessons from mouse models.
    So Young Kwon, Yoon Jung Park.
      Nicotinamide adenine dinucleotide (NAD) is an endogenous substance in redox reactions and regulates various functions in metabolism. NAD and its precursors are known for their anti-ageing and anti-obesity properties and are mainly active in the liver and muscle. Boosting NAD+ through supplementation with the precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), enhances insulin sensitivity and circadian rhythm in the liver, and improves mitochondrial function in the muscle. Recent evidence has revealed that the adipose tissue could be another direct target of NAD supplementation by attenuating inflammation and fat accumulation. Moreover, murine studies with genetically modified models demonstrated that nicotinamide phosphoribosyltransferase (NAMPT), a NAD regulatory enzyme that synthesizes NMN, played a critical role in lipogenesis and lipolysis in an adipocyte-specific manner. The tissue-specific effects of NAD+ metabolic pathways indicate a potential of the NAD precursors to control metabolic stress particularly via focusing on adipose tissue. Therefore, this narrative review raises an importance of NAD metabolism in white adipose tissue (WAT) through a variety of studies using different mouse models.
    Keywords:  NAD metabolism; NAD supplementation; nicotinamide adenine dinucleotide; nicotinamide phosphoribosyltransferase; white adipose tissue
    DOI:  https://doi.org/10.1080/21623945.2024.2313297
  24. Sci Signal. 2024 Feb 06. 17(822): eabq1007
    A mammalian-specific Alex3/Gαq protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival.
    Ismael Izquierdo-Villalba, Serena Mirra, Yasmina Manso, Antoni Parcerisas, Javier Rubio, Jaume Del Valle, Francisco J Gil-Bea, Fausto Ulloa, Marina Herrero-Lorenzo, Ester Verdaguer, Cristiane Benincá, Rubén D Castro-Torres, Elena Rebollo, Gemma Marfany, Carme Auladell, Xavier Navarro, José A Enríquez, Adolfo López de Munain, Eduardo Soriano, Anna M Aragay.
      Mitochondrial dynamics and trafficking are essential to provide the energy required for neurotransmission and neural activity. We investigated how G protein-coupled receptors (GPCRs) and G proteins control mitochondrial dynamics and trafficking. The activation of Gαq inhibited mitochondrial trafficking in neurons through a mechanism that was independent of the canonical downstream PLCβ pathway. Mitoproteome analysis revealed that Gαq interacted with the Eutherian-specific mitochondrial protein armadillo repeat-containing X-linked protein 3 (Alex3) and the Miro1/Trak2 complex, which acts as an adaptor for motor proteins involved in mitochondrial trafficking along dendrites and axons. By generating a CNS-specific Alex3 knockout mouse line, we demonstrated that Alex3 was required for the effects of Gαq on mitochondrial trafficking and dendritic growth in neurons. Alex3-deficient mice had altered amounts of ER stress response proteins, increased neuronal death, motor neuron loss, and severe motor deficits. These data revealed a mammalian-specific Alex3/Gαq mitochondrial complex, which enables control of mitochondrial trafficking and neuronal death by GPCRs.
    DOI:  https://doi.org/10.1126/scisignal.abq1007
  25. Cell Metab. 2024 Feb 06. pii: S1550-4131(24)00007-X. [Epub ahead of print]36(2): 422-437.e8
    Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding.
    Ashley S Williams, Scott B Crown, Scott P Lyons, Timothy R Koves, Rebecca J Wilson, Jordan M Johnson, Dorothy H Slentz, Daniel P Kelly, Paul A Grimsrud, Guo-Fang Zhang, Deborah M Muoio.
      Time-restricted feeding (TRF) has gained attention as a dietary regimen that promotes metabolic health. This study questioned if the health benefits of an intermittent TRF (iTRF) schedule require ketone flux specifically in skeletal and cardiac muscles. Notably, we found that the ketolytic enzyme beta-hydroxybutyrate dehydrogenase 1 (BDH1) is uniquely enriched in isolated mitochondria derived from heart and red/oxidative skeletal muscles, which also have high capacity for fatty acid oxidation (FAO). Using mice with BDH1 deficiency in striated muscles, we discover that this enzyme optimizes FAO efficiency and exercise tolerance during acute fasting. Additionally, iTRF leads to robust molecular remodeling of muscle tissues, and muscle BDH1 flux does indeed play an essential role in conferring the full adaptive benefits of this regimen, including increased lean mass, mitochondrial hormesis, and metabolic rerouting of pyruvate. In sum, ketone flux enhances mitochondrial bioenergetics and supports iTRF-induced remodeling of skeletal muscle and heart.
    Keywords:  acylcarnitines; beta-oxidation; fiber type; intermittent fasting; ketones; metabolic flux; mitochondria; proteomics; striated muscles; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.007
  26. bioRxiv. 2024 Jan 25. pii: 2024.01.24.576953. [Epub ahead of print]
    PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.
    Lianjie Wei, Mehmet Oguz Gok, Jordyn D Svoboda, Merima Forny, Jonathan R Friedman, Natalie M Niemi.
      PPTC7 is a mitochondrial-localized PP2C phosphatase that maintains mitochondrial protein content and metabolic homeostasis. We previously demonstrated that knockout of Pptc7 elevates mitophagy in a BNIP3- and NIX-dependent manner, but the mechanisms by which PPTC7 influences receptor-mediated mitophagy remain ill-defined. Here, we demonstrate that loss of PPTC7 upregulates BNIP3 and NIX post-transcriptionally and independent of HIF-1α stabilization. On a molecular level, loss of PPTC7 prolongs the half-life of BNIP3 and NIX while blunting their accumulation in response to proteasomal inhibition, suggesting that PPTC7 promotes the ubiquitin-mediated turnover of BNIP3 and NIX. Consistently, overexpression of PPTC7 limits the accumulation of BNIP3 and NIX protein levels in response to pseudohypoxia, a well-known inducer of mitophagy. This PPTC7-mediated suppression of BNIP3 and NIX protein expression requires an intact PP2C catalytic motif but is surprisingly independent of its mitochondrial targeting, indicating that PPTC7 influences mitophagy outside of the mitochondrial matrix. We find that PPTC7 exists in at least two distinct states in cells: a longer isoform, which likely represents full length protein, and a shorter isoform, which likely represents an imported, matrix-localized phosphatase pool. Importantly, anchoring PPTC7 to the outer mitochondrial membrane is sufficient to blunt BNIP3 and NIX accumulation, and proximity labeling and fluorescence co-localization experiments suggest that PPTC7 associates with BNIP3 and NIX within the native cellular environment. Importantly, these associations are enhanced in cellular conditions that promote BNIP3 and NIX turnover, demonstrating that PPTC7 is dynamically recruited to BNIP3 and NIX to facilitate their degradation. Collectively, these data reveal that a fraction of PPTC7 dynamically localizes to the outer mitochondrial membrane to promote the proteasomal turnover of BNIP3 and NIX.
    DOI:  https://doi.org/10.1101/2024.01.24.576953
  27. J Extracell Vesicles. 2024 Feb;13(2): e12410
    Transfer of inflammatory mitochondria via extracellular vesicles from M1 macrophages induces ferroptosis of pancreatic beta cells in acute pancreatitis.
    Yuhua Gao, Ningning Mi, Wenxiang Wu, Yuxuan Zhao, Fangzhou Fan, Wangwei Liao, Yongliang Ming, Weijun Guan, Chunyu Bai.
      Extracellular vesicles (EVs) exert a significant influence not only on the pathogenesis of diseases but also on their therapeutic interventions, contingent upon the variances observed in their originating cells. Mitochondria can be transported between cells via EVs to promote pathological changes. In this study, we found that EVs derived from M1 macrophages (M1-EVs), which encapsulate inflammatory mitochondria, can penetrate pancreatic beta cells. Inflammatory mitochondria fuse with the mitochondria of pancreatic beta cells, resulting in lipid peroxidation and mitochondrial disruption. Furthermore, fragments of mitochondrial DNA (mtDNA) are released into the cytosol, activating the STING pathway and ultimately inducing apoptosis. The potential of adipose-derived stem cell (ADSC)-released EVs in suppressing M1 macrophage reactions shows promise. Subsequently, ADSC-EVs were utilized and modified with an F4/80 antibody to specifically target macrophages, aiming to treat ferroptosis of pancreatic beta cells in vivo. In summary, our data further demonstrate that EVs secreted from M1 phenotype macrophages play major roles in beta cell ferroptosis, and the modified ADSC-EVs exhibit considerable potential for development as a vehicle for targeted delivery to macrophages.
    Keywords:  M1 macrophages; extracellular vesicles; ferroptosis; mitochondria; pancreatic beta cells
    DOI:  https://doi.org/10.1002/jev2.12410
  28. Cells. 2024 Jan 29. pii: 248. [Epub ahead of print]13(3):
    Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis.
    Teresa Cunha-Oliveira, Liliana Montezinho, Rui F Simões, Marcelo Carvalho, Elisabete Ferreiro, Filomena S G Silva.
      Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, for which current treatment options are limited. Recent studies have shed light on the role of mitochondria in ALS pathogenesis, making them an attractive therapeutic intervention target. This review contains a very comprehensive critical description of the involvement of mitochondria and mitochondria-mediated mechanisms in ALS. The review covers several key areas related to mitochondria in ALS, including impaired mitochondrial function, mitochondrial bioenergetics, reactive oxygen species, metabolic processes and energy metabolism, mitochondrial dynamics, turnover, autophagy and mitophagy, impaired mitochondrial transport, and apoptosis. This review also highlights preclinical and clinical studies that have investigated various mitochondria-targeted therapies for ALS treatment. These include strategies to improve mitochondrial function, such as the use of dichloroacetate, ketogenic and high-fat diets, acetyl-carnitine, and mitochondria-targeted antioxidants. Additionally, antiapoptotic agents, like the mPTP-targeting agents minocycline and rasagiline, are discussed. The paper aims to contribute to the identification of effective mitochondria-targeted therapies for ALS treatment by synthesizing the current understanding of the role of mitochondria in ALS pathogenesis and reviewing potential convergent therapeutic interventions. The complex interplay between mitochondria and the pathogenic mechanisms of ALS holds promise for the development of novel treatment strategies to combat this devastating disease.
    Keywords:  amyotrophic lateral sclerosis; mitochondria-targeted therapies; mitochondrial dysfunction; motor neuron degeneration; neurodegeneration; pathological mechanisms; therapeutic interventions
    DOI:  https://doi.org/10.3390/cells13030248
  29. Cell Mol Life Sci. 2024 Feb 09. 81(1): 80
    The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice.
    Corentin Affortit, Carolanne Coyat, Anissa Rym Saidia, Jean-Charles Ceccato, Majida Charif, Emmanuelle Sarzi, Frédéric Flamant, Romain Guyot, Chantal Cazevieille, Jean-Luc Puel, Guy Lenaers, Jing Wang.
      Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.
    Keywords:  Deafness; Hereditary optic neuropathy; Hidden hearing loss; Inner ear; Inner hair cell; Mitochondrial homeostasis; Outer hair cell; Retina
    DOI:  https://doi.org/10.1007/s00018-024-05115-4
  30. EMBO J. 2024 Feb 09.
    Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response.
    Esmee Vringer, Rosalie Heilig, Joel S Riley, Annabel Black, Catherine Cloix, George Skalka, Alfredo E Montes-Gómez, Aurore Aguado, Sergio Lilla, Henning Walczak, Mads Gyrd-Hansen, Daniel J Murphy, Danny T Huang, Sara Zanivan, Stephen Wg Tait.
      Mitochondrial outer membrane permeabilisation (MOMP) is often essential for apoptosis, by enabling cytochrome c release that leads to caspase activation and rapid cell death. Recently, MOMP has been shown to be inherently pro-inflammatory with emerging cellular roles, including its ability to elicit anti-tumour immunity. Nonetheless, how MOMP triggers inflammation and how the cell regulates this remains poorly defined. We find that upon MOMP, many proteins localised either to inner or outer mitochondrial membranes are ubiquitylated in a promiscuous manner. This extensive ubiquitylation serves to recruit the essential adaptor molecule NEMO, leading to the activation of pro-inflammatory NF-κB signalling. We show that disruption of mitochondrial outer membrane integrity through different means leads to the engagement of a similar pro-inflammatory signalling platform. Therefore, mitochondrial integrity directly controls inflammation, such that permeabilised mitochondria initiate NF-κB signalling.
    Keywords:  Cell Death; Inflammation; Mitochondria; NF-κB; Ubiquitin
    DOI:  https://doi.org/10.1038/s44318-024-00044-1
  31. Cell Rep. 2024 Feb 08. pii: S2211-1247(24)00069-X. [Epub ahead of print]43(2): 113741
    Q&A with Jiajie Diao.
    Jiajie Diao.
      Jiajie (JJ) Diao spoke with us at Cell Reports about his outlook on science, the value of collaboration, and his exciting work asking cell biology questions using biophysical approaches. Specifically, he discusses the recent study from his team where they discover that mitochondrial nucleoid condensates can remodel the mitochondrial membrane through high membrane curvature.
    DOI:  https://doi.org/10.1016/j.celrep.2024.113741
  32. Int J Mol Sci. 2024 Feb 01. pii: 1759. [Epub ahead of print]25(3):
    Hypoxia Sensing and Responses in Parkinson's Disease.
    Johannes Burtscher, Yves Duderstadt, Hannes Gatterer, Martin Burtscher, Roman Vozdek, Grégoire P Millet, Andrew A Hicks, Hannelore Ehrenreich, Martin Kopp.
      Parkinson's disease (PD) is associated with various deficits in sensing and responding to reductions in oxygen availability (hypoxia). Here we summarize the evidence pointing to a central role of hypoxia in PD, discuss the relation of hypoxia and oxygen dependence with pathological hallmarks of PD, including mitochondrial dysfunction, dopaminergic vulnerability, and alpha-synuclein-related pathology, and highlight the link with cellular and systemic oxygen sensing. We describe cases suggesting that hypoxia may trigger Parkinsonian symptoms but also emphasize that the endogenous systems that protect from hypoxia can be harnessed to protect from PD. Finally, we provide examples of preclinical and clinical research substantiating this potential.
    Keywords:  Parkinson’s disease; hypoxia; mitochondria; neurodegeneration; respiratory diseases; synuclein
    DOI:  https://doi.org/10.3390/ijms25031759
  33. Mol Cells. 2024 Feb 06. pii: S1016-8478(24)00034-7. [Epub ahead of print] 100029
    Mitochondrial Sirtuins: Energy Dynamics and Cancer Metabolism.
    Hojun Lee, Haejin Yoon.
      Mitochondria are pivotal for energy regulation and are linked to cancer. Mitochondrial sirtuins, SIRT3, SIRT4, and SIRT5, play crucial roles in cancer metabolism. This review explores their impact on cellular processes, with a focus on the NAD+ interplay and the modulation of their enzymatic activities. The varied roles of SIRT3, SIRT4, and SIRT5 in metabolic adaptation and cancer are outlined, emphasizing their tumor suppressor or oncogenic nature. We propose new insights into sirtuin biology, and cancer therapeutics, suggesting an integrated proteomics and metabolomics approach for a comprehensive understanding of mitochondrial sirtuins in cancer.
    Keywords:  Cancer metabolism; Mitochondrial Sirtuins; NAD+; SIRT3; SIRT4; SIRT5
    DOI:  https://doi.org/10.1016/j.mocell.2024.100029
  34. Heliyon. 2024 Feb 15. 10(3): e24975
    Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis.
    Project MinE ALS Sequencing Consortium
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving selective vulnerability of energy-intensive motor neurons (MNs). It has been unclear whether mitochondrial function is an upstream driver or a downstream modifier of neurotoxicity. We separated upstream genetic determinants of mitochondrial function, including genetic variation within the mitochondrial genome or autosomes; from downstream changeable factors including mitochondrial DNA copy number (mtCN). Across three cohorts including 6,437 ALS patients, we discovered that a set of mitochondrial haplotypes, chosen because they are linked to measurements of mitochondrial function, are a determinant of ALS survival following disease onset, but do not modify ALS risk. One particular haplotype appeared to be neuroprotective and was significantly over-represented in two cohorts of long-surviving ALS patients. Causal inference for mitochondrial function was achievable using mitochondrial haplotypes, but not autosomal SNPs in traditional Mendelian randomization (MR). Furthermore, rare loss-of-function genetic variants within, and reduced MN expression of, ACADM and DNA2 lead to ∼50 % shorter ALS survival; both proteins are implicated in mitochondrial function. Both mtCN and cellular vulnerability are linked to DNA2 function in ALS patient-derived neurons. Finally, MtCN responds dynamically to the onset of ALS independently of mitochondrial haplotype, and is correlated with disease severity. We conclude that, based on the genetic measures we have employed, mitochondrial function is a therapeutic target for amelioration of disease severity but not prevention of ALS.
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e24975
  35. Anal Chem. 2024 Feb 08.
    Long-Chain Fluorescent Probe for Straightforward and Nondestructive Staining Mitochondria in Fixed Cells and Tissues.
    Qiuhua Hao, Xiuquan He, Kang-Nan Wang, Jie Niu, Fangfang Meng, Jinyu Fu, Chong Zong, Zhiqiang Liu, Xiaoqiang Yu.
      Normally, small-molecule fluorescent probes dependent on the mitochondrial membrane potential (MMP) are invalid for fixed cells and tissues, which limits their clinical applications when the fixation of pathological specimens is imperative. Given that mitochondrial morphology is closely associated with disease, we developed a long-chain mitochondrial probe for fixed cells and tissues, DMPQ-12, by installing a C12-alkyl chain into the quinoline moiety. In fixed cells stained with DMPQ-12, filament mitochondria and folded cristae were observed with confocal and structural illumination microscopy, respectively. In titration test with three major phospholipids, DMPQ-12 exhibited a stronger binding force to mitochondria-exclusive cardiolipin, revealing its targeting mechanism. Moreover, mitochondrial morphological changes in the three lesion models were clearly visualized in fixed cells. Finally, by DMPQ-12, three kinds of mitochondria with different morphologies were observed in situ in fixed muscle tissues. This work breaks the conventional concept that organic fluorescent probes only stain mitochondria with normal membrane potentials and opens new avenues for comprehensive mitochondrial investigations in research and clinical settings.
    DOI:  https://doi.org/10.1021/acs.analchem.3c05660
  36. Epigenomics. 2024 Feb 05.
    Mitochondrial D-loop methylation levels inversely correlate with disease duration in amyotrophic lateral sclerosis.
    Andrea Stoccoro, Adam R Smith, Lorena Mosca, Alessandro Marocchi, Francesca Gerardi, Christian Lunetta, Katie Lunnon, Lucia Migliore, Fabio Coppedè.
      Aim: To correlate mitochondrial D-loop region methylation levels and mtDNA copy number with disease duration in familial amyotrophic lateral sclerosis (ALS) patients. Patients & methods: The study population included 12 ALS patients with a mutation in SOD1 and 13 ALS patients with the C9orf72 hexanucleotide repeat expansion. Methylation levels of the D-loop region and mtDNA copy number were quantified using pyrosequencing and quantitative PCR, respectively. Results: We observed that D-loop methylation levels inversely correlated while mtDNA copy number positively correlated with disease duration. Conclusion: Considering the central role played by mitochondria in ALS, this preliminary study provides new knowledge for future studies aimed at identifying biomarkers of disease progression and new targets for therapeutic interventions.
    Keywords:  C9orf72; D-loop region; SOD1; amyotrophic lateral sclerosis; disease duration; mitochondrial DNA methylation; mtDNA copy number
    DOI:  https://doi.org/10.2217/epi-2023-0265
  37. iScience. 2024 Feb 16. 27(2): 108916
    Mieap forms membrane-less organelles involved in cardiolipin metabolism.
    Naoki Ikari, Katsuko Honjo, Yoko Sagami, Yasuyuki Nakamura, Hirofumi Arakawa.
      Biomolecular condensates (BCs) are formed by proteins with intrinsically disordered regions (IDRs) via liquid-liquid phase separation. Mieap/Spata18, a p53-inducible protein, participates in suppression of colorectal tumors by promoting mitochondrial quality control. However, the regulatory mechanism involved remains unclear. Here, we report that Mieap is an IDR-containing protein that drives formation of BCs involved in cardiolipin metabolism. Mieap BCs specifically phase separate the mitochondrial phospholipid, cardiolipin. Mieap directly binds to cardiolipin in vitro. Lipidomic analysis of cardiolipin suggests that Mieap promotes enzymatic reactions in cardiolipin biosynthesis and remodeling. Accordingly, four cardiolipin biosynthetic enzymes, TAMM41, PGS1, PTPMT1, and CRLS1 and two remodeling enzymes, PLA2G6 and TAZ, are phase-separated by Mieap BCs. Mieap-deficient cells exhibit altered crista structure, leading to decreased respiration activity and ATP production in mitochondria. These results suggest that Mieap may form membrane-less organelles to compartmentalize and facilitate cardiolipin metabolism, thus potentially contributing to mitochondrial quality control.
    Keywords:  Metabolomics; Molecular Structure; Molecular biology; Molecular interaction
    DOI:  https://doi.org/10.1016/j.isci.2024.108916
  38. Heart Rhythm. 2024 Feb;pii: S1547-5271(23)02880-1. [Epub ahead of print]21(2): 235-236
    Top Stories: Mitochondrial origin of inherited cardiac arrhythmias.
    Fadi G Akar, Christoph Maack.
      
    DOI:  https://doi.org/10.1016/j.hrthm.2023.10.020
  39. Mitochondrion. 2024 Feb 06. pii: S1567-7249(24)00008-4. [Epub ahead of print] 101850
    Interplay of Mitochondria and Diabetes: Unveiling Novel Therapeutic Strategies.
    Kristina Xiao Liang.
      The interplay between mitochondrial function and diabetes has gained significant attention due to its crucial role in the pathogenesis and progression of the disease. Mitochondria, known as the cellular powerhouses, are essential for glucose metabolism. Dysfunction of these organelles has been implicated in the development of insulin resistance and beta-cell failure, both prominent features of diabetes. This comprehensive review explores the intricate mechanisms involved, including the generation of reactive oxygen species and the impact of mitochondrial DNA mutations. Moreover, the review delves into emerging therapeutic strategies that specifically target mitochondria, such as mitochondria-targeted antioxidants, agents promoting mitochondrial biogenesis, and compounds modulating mitochondrial dynamics. The potential of these novel approaches is critically evaluated, taking into account their benefits and limitations, to provide a well-rounded perspective. Ultimately, this review emphasizes the importance of advancing our understanding of mitochondrial biology to revolutionize the treatment of diabetes.
    DOI:  https://doi.org/10.1016/j.mito.2024.101850
  40. bioRxiv. 2024 Jan 22. pii: 2024.01.22.576364. [Epub ahead of print]
    Spreading depolarization causes reversible neuronal mitochondria fragmentation and swelling in healthy, normally perfused neocortex.
    Jeremy Sword, Ioulia V Fomitcheva, Sergei A Kirov.
      Mitochondrial function is tightly linked to their morphology, and fragmentation of dendritic mitochondria during noxious conditions suggests loss of function. In the normoxic cortex, spreading depolarization (SD) is a phenomenon underlying migraine aura. It is unknown whether mitochondria structure is affected by normoxic SD. In vivo two-photon imaging followed by quantitative serial section electron microscopy (ssEM) was used to monitor dendritic mitochondria in the normoxic cortex of urethane-anesthetized mature male and female mice during and after SD initiated by focal KCl microinjection. Structural dynamics of dendrites and their mitochondria were visualized by transfecting excitatory, glutamatergic neurons of the somatosensory cortex with bicistronic AAV, which induced tdTomoto labeling in neuronal cytoplasm and mitochondria labeling with roGFP. Normoxic SD triggered a rapid fragmentation of dendritic mitochondria alongside dendritic beading, both reversible; however, mitochondria took significantly longer to recover. Several rounds of SD resulted in transient mitochondrial fragmentation and dendritic beading without accumulating injury, as both recovered. SsEM corroborated normoxic SD-elicited dendritic and mitochondrial swelling and transformation of the filamentous mitochondrial network into shorter, swollen tubular and globular structures. Our results revealed normoxic SD-induced disruption of the dendritic mitochondrial structure that might impact mitochondrial bioenergetics during migraine with aura.
    DOI:  https://doi.org/10.1101/2024.01.22.576364
  41. Adv Drug Deliv Rev. 2024 Feb 05. pii: S0169-409X(24)00017-6. [Epub ahead of print] 115195
    Unlocking the mitochondria for nanomedicine-based Treatments: Overcoming biological Barriers, improving Designs, and selecting verification techniques.
    Camilla Pegoraro, Inés Domingo, Inmaculada Conejos-Sánchez, María J Vicent.
      Enhanced targeting approaches will support the treatment of diseases associated with dysfunctional mitochondria, which play critical roles in energy generation and cell survival. Obstacles to mitochondria-specific targeting include the presence of distinct biological barriers and the need to pass through (or avoid) various cell internalization mechanisms. A range of studies have reported the design of mitochondrially-targeted nanomedicines that navigate the complex routes required to influence mitochondrial function; nonetheless, a significant journey lies ahead before mitochondrially-targeted nanomedicines become suitable for clinical use. Moving swiftly forward will require safety studies, in vivo assays confirming effectiveness, and methodologies to validate mitochondria-targeted nanomedicines' subcellular location/activity. From a nanomedicine standpoint, we describe the biological routes involved (from administration to arrival within the mitochondria), the features influencing rational design, and the techniques used to identify/validate successful targeting. Overall, rationally-designed mitochondria-targeted-based nanomedicines hold great promise for precise subcellular therapeutic delivery.
    Keywords:  Intracellular delivery; Mitochondrial activity and metabolism; Mitochondrially targeted precision nanomedicines; Physico-chemical characterization; Stimuli-responsive nanomedicine; Subcellular targeting
    DOI:  https://doi.org/10.1016/j.addr.2024.115195
  42. bioRxiv. 2024 Jan 22. pii: 2024.01.20.576443. [Epub ahead of print]
    IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency.
    Marco Flores-Mendez, Laura Ohl, Thomas Roule, Yijing Zhou, Jesus A Tintos-Hernández, Kelsey Walsh, Xilma R Ortiz-González, Naiara Akizu.
      Metabolic dysregulation is one of the most common causes of pediatric neurodegenerative disorders. However, how the disruption of ubiquitous and essential metabolic pathways predominantly affect neural tissue remains unclear. Here we use mouse models of AMPD2 deficiency to study cellular and molecular mechanisms that lead to selective neuronal vulnerability to purine metabolism imbalance. We show that AMPD deficiency in mice primarily leads to hippocampal dentate gyrus degeneration despite causing a generalized reduction of brain GTP levels. Remarkably, we found that neurodegeneration resistant regions accumulate micron sized filaments of IMPDH2, the rate limiting enzyme in GTP synthesis. In contrast, IMPDH2 filaments are barely detectable in the hippocampal dentate gyrus, which shows a progressive neuroinflammation and neurodegeneration. Furthermore, using a human AMPD2 deficient neural cell culture model, we show that blocking IMPDH2 polymerization with a dominant negative IMPDH2 variant, impairs AMPD2 deficient neural progenitor growth. Together, our findings suggest that IMPDH2 polymerization prevents detrimental GTP deprivation in neurons with available GTP precursor molecules, providing resistance to neurodegeneration. Our findings open the possibility of exploring the involvement of IMPDH2 assembly as a therapeutic intervention for neurodegeneration.
    DOI:  https://doi.org/10.1101/2024.01.20.576443
  43. Nat Metab. 2024 Feb 09.
    Hypermetabolism and energetic constraints in mitochondrial disorders.
    Alexander J Sercel, Gabriel Sturm, Dympna Gallagher, Marie-Pierre St-Onge, Christopher P Kempes, Herman Pontzer, Michio Hirano, Martin Picard.
      
    DOI:  https://doi.org/10.1038/s42255-023-00968-8
  44. Redox Biol. 2024 Jan 26. pii: S2213-2317(24)00038-7. [Epub ahead of print]70 103062
    VDR regulates mitochondrial function as a protective mechanism against renal tubular cell injury in diabetic rats.
    Hong Chen, Hao Zhang, Ai-Mei Li, Yu-Ting Liu, Yan Liu, Wei Zhang, Cheng Yang, Na Song, Ming Zhan, Shikun Yang.
       PURPOSE: To investigate the regulatory effect and mechanism of Vitamin D receptor (VDR) on mitochondrial function in renal tubular epithelial cell under diabetic status.
    METHODS: The diabetic rats induced by streptozotocin (STZ) and HK-2 cells under high glocose(HG)/transforming growth factor beta (TGF-β) stimulation were used in this study. Calcitriol was administered for 24 weeks. Renal tubulointerstitial injury and some parameters of mitochondrial function including mitophagy, mitochondrial fission, mitochondrial ROS, mitochondrial membrane potential (MMP), mitochondrial ATP, Complex V activity and mitochondria-associated ER membranes (MAMs) integrity were examined. Additionally, paricalcitol, 3-MA (an autophagy inhibitor), VDR over-expression plasmid, VDR siRNA and Mfn2 siRNA were applied in vitro.
    RESULTS: The expression of VDR, Pink1, Parkin, Fundc1, LC3II, Atg5, Mfn2, Mfn1 in renal tubular cell of diabetic rats were decreased significantly. Calcitriol treatment reduced the levels of urinary albumin, serum creatinine and attenuated renal tubulointerstitial fibrosis in STZ induced diabetic rats. In addition, VDR agonist relieved mitophagy dysfunction, MAMs integrity, and inhibited mitochondrial fission, mitochondrial ROS. Co-immunoprecipitation analysis demonstrated that VDR interacted directly with Mfn2. Mitochondrial function including mitophagy, mitochondrial membrane potential (MMP), mitochondrial Ca2+, mitochondrial ATP and Complex V activity were decreased dramatically in HK-2 cells under HG/TGF-β ambience. In vitro pretreatment of HK-2 cells with autophagy inhibitor 3-MA, VDR siRNA or Mfn2 siRNA negated the activating effects of paricalcitol on mitochondrial function. Pricalcitol and VDR over-expression plasmid activated Mfn2 and then partially restored the MAMs integrity. Additionally, VDR restored mitophagy was partially associated with MAMs integrity through Fundc1.
    CONCLUSION: Activated VDR could contribute to restore mitophagy through Mfn2-MAMs-Fundc1 pathway in renal tubular cell. VDR could recover mitochondrial ATP, complex V activity and MAMs integrity, inhibit mitochondrial fission and mitochondrial ROS. It indicating that VDR agonists ameliorate renal tubulointerstitial fibrosis in diabetic rats partially via regulation of mitochondrial function.
    Keywords:  DN; MAMs; Mitochondrial; Renal tubular cell; VDR
    DOI:  https://doi.org/10.1016/j.redox.2024.103062
  45. Acta Biochim Biophys Sin (Shanghai). 2024 Feb 07.
    Mitochondrial deoxyguanosine kinase is required for female fertility in mice.
    Yake Gao, Rui Dong, Jiacong Yan, Huicheng Chen, Lei Sang, Xinyi Yao, Die Fan, Xin Wang, Xiaoyuan Zuo, Xu Zhang, Shengyu Yang, Ze Wu, Jianwei Sun.
      Mitochondrial homeostasis plays a pivotal role in oocyte maturation and embryonic development. Deoxyguanosine kinase (DGUOK) is a nucleoside kinase that salvages purine nucleosides in mitochondria and is critical for mitochondrial DNA replication and homeostasis in non-proliferating cells. Dguok loss-of-function mutations and deletions lead to hepatocerebral mitochondrial DNA deletion syndrome. However, its potential role in reproduction remains largely unknown. In this study, we find that Dguok knockout results in female infertility. Mechanistically, DGUOK deficiency hinders ovarian development and oocyte maturation. Moreover, DGUOK deficiency in oocytes causes a significant reduction in mitochondrial DNA copy number and abnormal mitochondrial dynamics and impairs germinal vesicle breakdown. Only few DGUOK-deficient oocytes can extrude their first polar body during in vitro maturation, and these oocytes exhibit irregular chromosome arrangements and different spindle lengths. In addition, DGUOK deficiency elevates reactive oxygen species levels and accelerates oocyte apoptosis. Our findings reveal novel physiological roles for the mitochondrial nucleoside salvage pathway in oocyte maturation and implicate DGUOK as a potential marker for the diagnosis of female infertility.
    Keywords:  DGUOK; infertility; mitochondria; nucleoside salvage pathway; oocyte maturation
    DOI:  https://doi.org/10.3724/abbs.2024003
  46. Int J Mol Sci. 2024 Feb 03. pii: 1866. [Epub ahead of print]25(3):
    Mitochondrial Unfolded Protein Response Gene Clpp Is Required for Oocyte Function and Female Fertility.
    Yagmur Ergun, Aysegul Gizem Imamoglu, Mauro Cozzolino, Cem Demirkiran, Murat Basar, Akanksha Garg, Raziye Melike Yildirim, Emre Seli.
      Mitochondrial unfolded protein stress response (mtUPR) plays a critical role in regulating cellular and metabolic stress response and helps maintain protein homeostasis. Caseinolytic peptidase P (CLPP) is one of the key regulators of mtUPR and promotes unfolded protein degradation. Previous studies demonstrated that global deletion of Clpp resulted in female infertility, whereas no impairment was found in the mouse model with targeted deletion of Clpp in cumulus/granulosa cells. These results suggest the need to delineate the function of Clpp in oocytes. In this study, we aimed to further explore the role of mtUPR in female reproductive competence and senescence using a mouse model. Oocyte-specific targeted deletion of Clpp in mice resulted in female subfertility associated with metabolic and functional abnormalities in oocytes, thus highlighting the importance of CLPP-mediated protein homeostasis in oocyte competence and reproductive function.
    Keywords:  CLPP; female fertility; mitochondrial dysfunction; mitochondrial stress response; oocyte function
    DOI:  https://doi.org/10.3390/ijms25031866
  47. NPJ Aging. 2024 Feb 07. 10(1): 10
    Mitochondrial function in peripheral blood cells across the human lifespan.
    Johannes K Ehinger, Emil Westerlund, Eleonor Åsander Frostner, Michael Karlsson, Gesine Paul, Fredrik Sjövall, Eskil Elmér.
      Mitochondrial dysfunction is considered a hallmark of aging. Up to now, a gradual decline of mitochondrial respiration with advancing age has mainly been demonstrated in human muscle tissue. A handful of studies have examined age-related mitochondrial dysfunction in human blood cells, and only with small sample sizes and mainly in platelets. In this study, we analyzed mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) and platelets from 308 individuals across the human lifespan (0-86 years). In regression analyses, with adjustment for false discovery rate (FDR), we found age-related changes in respiratory measurements to be either small or absent. The main significant changes were an age-related relative decline in complex I-linked respiration and a corresponding rise of complex II-linked respiration in PBMCs. These results add to the understanding of mitochondrial dysfunction in aging and to its possible role in immune cell and platelet senescence.
    DOI:  https://doi.org/10.1038/s41514-023-00130-4
  48. Nat Cell Biol. 2024 Feb 05.
    A metabolite sensor subunit of the Atg1/ULK complex regulates selective autophagy.
    A S Gross, R Ghillebert, M Schuetter, E Reinartz, A Rowland, B C Bishop, M Stumpe, J Dengjel, M Graef.
      Cells convert complex metabolic information into stress-adapted autophagy responses. Canonically, multilayered protein kinase networks converge on the conserved Atg1/ULK kinase complex (AKC) to induce non-selective and selective forms of autophagy in response to metabolic changes. Here we show that, upon phosphate starvation, the metabolite sensor Pho81 interacts with the adaptor subunit Atg11 at the AKC via an Atg11/FIP200 interaction motif to modulate pexophagy by virtue of its conserved phospho-metabolite sensing SPX domain. Notably, core AKC components Atg13 and Atg17 are dispensable for phosphate starvation-induced autophagy revealing significant compositional and functional plasticity of the AKC. Our data indicate that, instead of functioning as a selective autophagy receptor, Pho81 compensates for partially inactive Atg13 by promoting Atg11 phosphorylation by Atg1 critical for pexophagy during phosphate starvation. Our work shows Atg11/FIP200 adaptor subunits bind not only selective autophagy receptors but also modulator subunits that convey metabolic information directly to the AKC for autophagy regulation.
    DOI:  https://doi.org/10.1038/s41556-024-01348-4
  49. Nat Commun. 2024 Feb 07. 15(1): 1136
    Overlay databank unlocks data-driven analyses of biomolecules for all.
    Anne M Kiirikki, Hanne S Antila, Lara S Bort, Pavel Buslaev, Fernando Favela-Rosales, Tiago Mendes Ferreira, Patrick F J Fuchs, Rebeca Garcia-Fandino, Ivan Gushchin, Batuhan Kav, Norbert Kučerka, Patrik Kula, Milla Kurki, Alexander Kuzmin, Anusha Lalitha, Fabio Lolicato, Jesper J Madsen, Markus S Miettinen, Cedric Mingham, Luca Monticelli, Ricky Nencini, Alexey M Nesterenko, Thomas J Piggot, Ángel Piñeiro, Nathalie Reuter, Suman Samantray, Fabián Suárez-Lestón, Reza Talandashti, O H Samuli Ollila.
      Tools based on artificial intelligence (AI) are currently revolutionising many fields, yet their applications are often limited by the lack of suitable training data in programmatically accessible format. Here we propose an effective solution to make data scattered in various locations and formats accessible for data-driven and machine learning applications using the overlay databank format. To demonstrate the practical relevance of such approach, we present the NMRlipids Databank-a community-driven, open-for-all database featuring programmatic access to quality-evaluated atom-resolution molecular dynamics simulations of cellular membranes. Cellular membrane lipid composition is implicated in diseases and controls major biological functions, but membranes are difficult to study experimentally due to their intrinsic disorder and complex phase behaviour. While MD simulations have been useful in understanding membrane systems, they require significant computational resources and often suffer from inaccuracies in model parameters. Here, we demonstrate how programmable interface for flexible implementation of data-driven and machine learning applications, and rapid access to simulation data through a graphical user interface, unlock possibilities beyond current MD simulation and experimental studies to understand cellular membranes. The proposed overlay databank concept can be further applied to other biomolecules, as well as in other fields where similar barriers hinder the AI revolution.
    DOI:  https://doi.org/10.1038/s41467-024-45189-z
  50. Semin Arthritis Rheum. 2024 Jan 23. pii: S0049-0172(24)00019-2. [Epub ahead of print]65 152378
    The Sjögren's Working Group: The 2023 OMERACT meeting and provisional domain generation.
    Rachael A Gordon, Yann Nguyen, Nathan Foulquier, Maxime Beydon, Tamer A Gheita, Raouf Hajji, Ilfita Sahbudin, Alberta Hoi, Wan-Fai Ng, Jose Alexandre Mendonça, Daniel J Wallace, Beverley Shea, George Aw Bruyn, Susan M Goodman, Benjamin A Fisher, Chiara Baldini, Karina D Torralba, Hendrika Bootsma, Esen K Akpek, Sezen Karakus, Alan N Baer, Soumya D Chakravarty, Lene Terslev, Maria-Antonietta D'Agostino, Xavier Mariette, Dana DiRenzo, Astrid Rasmussen, Athena Papas, Cristina Montoya, Suzanne Arends, Md Yuzaiful Md Yusof, Ionut Pintilie, Blake M Warner, Katherine M Hammitt, Vibeke Strand, Coralie Bouillot, Peter Tugwell, Nevsun Inanc, José Luis Andreu, Marie Wahren-Herlenius, Valerie Devauchelle-Pensec, Caroline H Shiboski, Anas Benyoussef, Sharmila Masli, Adrian Y S Lee, Divi Cornec, Simon Bowman, Maureen Rischmueller, Sara S McCoy, Raphaele Seror.
      Sjögren's disease (SjD) is a systemic autoimmune exocrinopathy with key features of dryness, pain, and fatigue. SjD can affect any organ system with a variety of presentations across individuals. This heterogeneity is one of the major barriers for developing effective disease modifying treatments. Defining core disease domains comprising both specific clinical features and incorporating the patient experience is a critical first step to define this complex disease. The OMERACT SjD Working Group held its first international collaborative hybrid meeting in 2023, applying the OMERACT 2.2 filter toward identification of core domains. We accomplished our first goal, a scoping literature review that was presented at the Special Interest Group held in May 2023. Building on the domains identified in the scoping review, we uniquely deployed multidisciplinary experts as part of our collaborative team to generate a provisional domain list that captures SjD heterogeneity.
    Keywords:  Artificial intelligence; BIBOT; OMERACT; Review; Scoping literature review; Sjogren's disease
    DOI:  https://doi.org/10.1016/j.semarthrit.2024.152378
  51. Nat Commun. 2024 Feb 09. 15(1): 1232
    Children born after assisted reproduction more commonly carry a mitochondrial genotype associating with low birthweight.
    Joke Mertens, Florence Belva, Aafke P A van Montfoort, Marius Regin, Filippo Zambelli, Sara Seneca, Edouard Couvreu de Deckersberg, Maryse Bonduelle, Herman Tournaye, Katrien Stouffs, Kurt Barbé, Hubert J M Smeets, Hilde Van de Velde, Karen Sermon, Christophe Blockeel, Claudia Spits.
      Children conceived through assisted reproductive technologies (ART) have an elevated risk of lower birthweight, yet the underlying cause remains unclear. Our study explores mitochondrial DNA (mtDNA) variants as contributors to birthweight differences by impacting mitochondrial function during prenatal development. We deep-sequenced the mtDNA of 451 ART and spontaneously conceived (SC) individuals, 157 mother-child pairs and 113 individual oocytes from either natural menstrual cycles or after ovarian stimulation (OS) and find that ART individuals carried a different mtDNA genotype than SC individuals, with more de novo non-synonymous variants. These variants, along with rRNA variants, correlate with lower birthweight percentiles, independent of conception mode. Their higher occurrence in ART individuals stems from de novo mutagenesis associated with maternal aging and OS-induced oocyte cohort size. Future research will establish the long-term health consequences of these changes and how these findings will impact the clinical practice and patient counselling in the future.
    DOI:  https://doi.org/10.1038/s41467-024-45446-1
  52. Nat Med. 2024 Feb 05.
    Physician-machine partnerships boost diagnostic accuracy, but bias persists.
      
    DOI:  https://doi.org/10.1038/s41591-023-02733-6
  53. Curr Opin Struct Biol. 2024 Feb 03. pii: S0959-440X(24)00004-6. [Epub ahead of print]85 102777
    Application of AI in biological age prediction.
    Dawei Meng, Shiqiang Zhang, Yuanfang Huang, Kehang Mao, Jing-Dong J Han.
      The development of anti-aging interventions requires quantitative measurement of biological age. Machine learning models, known as "aging clocks," are built by leveraging diverse aging biomarkers that vary across lifespan to predict biological age. In addition to traditional aging clocks harnessing epigenetic signatures derived from bulk samples, emerging technologies allow the biological age estimating at single-cell level to dissect cellular diversity in aging tissues. Moreover, imaging-based aging clocks are increasingly employed with the advantage of non-invasive measurement, making it suitable for large-scale human cohort studies. To fully capture the features in the ever-growing multi-modal and high-dimensional aging-related data and uncover disease associations, deep-learning based approaches, which are effective to learn complex and non-linear relationships without relying on pre-defined features, are increasingly applied. The use of big data and AI-based aging clocks has achieved high accuracy, interpretability and generalizability, guiding clinical applications to delay age-related diseases and extend healthy lifespans.
    DOI:  https://doi.org/10.1016/j.sbi.2024.102777
  54. FEBS J. 2024 Feb 05.
    Enhanced translocation of TRIM32 to mitochondria sensitizes dopaminergic neuronal cells to apoptosis during stress conditions in Parkinson's disease.
    Shanikumar Goyani, Anjali Shinde, Shatakshi Shukla, M V Saranga, Fatema Currim, Minal Mane, Jyoti Singh, Milton Roy, Dhruv Gohel, Nisha Chandak, Hitesh Vasiyani, Rajesh Singh.
      Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by progressive loss of dopamine-producing neurons from the substantia nigra region of the brain. Mitochondrial dysfunction is one of the major causes of oxidative stress and neuronal cell death in PD. E3 ubiquitin ligases such as Parkin (PRKN) modulate mitochondrial quality control in PD; however, the role of other E3 ligases associated with mitochondria in the regulation of neuronal cell death in PD has not been explored. The current study investigated the role of TRIM32, RING E3 ligase, in sensitization to oxidative stress-induced neuronal apoptosis. The expression of TRIM32 sensitizes SH-SY5Y dopaminergic cells to rotenone and 6-OHDA-induced neuronal death, whereas the knockdown increased cell viability under PD stress conditions. The turnover of TRIM32 is enhanced under PD stress conditions and is mediated by autophagy. TRIM32 translocation to mitochondria is enhanced under PD stress conditions and localizes on the outer mitochondrial membrane. TRIM32 decreases complex-I assembly and activity as well as mitochondrial reactive oxygen species (ROS) and ATP levels under PD stress. Deletion of the RING domain of TRIM32 enhanced complex I activity and rescued ROS levels and neuronal viability under PD stress conditions. TRIM32 decreases the level of XIAP, and co-expression of XIAP with TRIM32 rescued the PD stress-induced cell death and mitochondrial ROS level. In conclusion, turnover of TRIM32 increases during stress conditions and translocation to mitochondria is enhanced, regulating mitochondrial functions and neuronal apoptosis by modulating the level of XIAP in PD.
    Keywords:  Parkinson's disease; TRIM32; XIAP; cell death; mitochondria
    DOI:  https://doi.org/10.1111/febs.17065
  55. Nat Rev Drug Discov. 2024 Feb 06.
    The Bespoke Gene Therapy Consortium: facilitating development of AAV gene therapies for rare diseases.
    P J Brooks, Timothy M Miller, Frédéric Revah, Junghae Suh, Bradley R Garrison, Lawrence C Starke, Timothy K MacLachlan, Edward G Neilan, Gopa Raychaudhuri, Sadik H Kassim, Jean Dehdashti, Joni L Rutter.
      
    DOI:  https://doi.org/10.1038/d41573-024-00020-8
  56. Proc Natl Acad Sci U S A. 2024 Feb 13. 121(7): e2305035121
    Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport.
    Johan Gustafsson, Jonathan L Robinson, Henrik Zetterberg, Jens Nielsen.
      The energy metabolism of the brain is poorly understood partly due to the complex morphology of neurons and fluctuations in ATP demand over time. To investigate this, we used metabolic models that estimate enzyme usage per pathway, enzyme utilization over time, and enzyme transportation to evaluate how these parameters and processes affect ATP costs for enzyme synthesis and transportation. Our models show that the total enzyme maintenance energy expenditure of the human body depends on how glycolysis and mitochondrial respiration are distributed both across and within cell types in the brain. We suggest that brain metabolism is optimized to minimize the ATP maintenance cost by distributing the different ATP generation pathways in an advantageous way across cell types and potentially also across synapses within the same cell. Our models support this hypothesis by predicting export of lactate from both neurons and astrocytes during peak ATP demand, reproducing results from experimental measurements reported in the literature. Furthermore, our models provide potential explanation for parts of the astrocyte-neuron lactate shuttle theory, which is recapitulated under some conditions in the brain, while contradicting other aspects of the theory. We conclude that enzyme usage per pathway, enzyme utilization over time, and enzyme transportation are important factors for defining the optimal distribution of ATP production pathways, opening a broad avenue to explore in brain metabolism.
    Keywords:  ANLS; brain metabolism; genome-scale models; mathematical modeling; metabolism
    DOI:  https://doi.org/10.1073/pnas.2305035121
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