bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023‒10‒15
forty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico 
  1. Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes.
  2. Drosophila Mpv17 forms an ion channel and regulates energy metabolism.
  3. Current management of primary mitochondrial disorders in EU countries: the European Reference Networks survey.
  4. Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.
  5. Diversities in Leigh Syndrome Associated with MT-ATP6 Gene Variants.
  6. Homozygous MFN2 variants causing severe antenatal encephalopathy with clumped mitochondria.
  7. CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature.
  8. Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.
  9. The functional significance of mitochondrial respiratory chain supercomplexes.
  10. PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.
  11. Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration.
  12. The burden of mitochondrial disease with associated seizures: systematic literature reviews of health-related quality of life, utilities, costs and healthcare resource use data.
  13. COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.
  14. Crosstalk between mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis.
  15. Carnitine acetyltransferase deficiency mediates mitochondrial dysfunction-induced cellular senescence in dermal fibroblasts.
  16. Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis.
  17. FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes.
  18. Phenotype and natural history of mitochondrial membrane protein-associated neurodegeneration.
  19. Extracellular release in the quality control of the mammalian mitochondria.
  20. Brain mitochondria in behavior: more than a powerhouse.
  21. Stimulator of Interferon Genes (STING) Triggers Adipocyte Autophagy.
  22. Apoptotic stress causes mtDNA release during senescence and drives the SASP.
  23. Autophagy protects mitochondrial health in heart failure.
  24. Adrenocortical function in patients with Single Large Scale Mitochondrial DNA Deletions: a retrospective single centre cohort study.
  25. Calcium signals tune AMPK activity and mitochondrial homeostasis in dendrites of developing neurons.
  26. Single-cell DNA methylation and 3D genome architecture in the human brain.
  27. Repeat expansions in NOP56 are a cause of spinocerebellar ataxia Type 36 in the British population.
  28. PINK1 and Parkin rescue motor defects and mitochondria dysfunction induced by a patient-derived HSPB3 mutant in Drosophila models.
  29. Low-dose atorvastatin protects skeletal muscle mitochondria in high-fat diet-fed mice with mitochondrial autophagy inhibition and fusion enhancement.
  30. Glucocerebrosidase mutations disrupt the lysosome and now the mitochondria.
  31. The roles of FGF21 and GDF15 in mediating the mitochondrial integrated stress response.
  32. Mitochondrial dysfunctions in T cells: focus on inflammatory bowel disease.
  33. Mitochondrial SOS: how mtDNA may act as a stress signal in Alzheimer's disease.
  34. Mitochondrial Fragmentation Promotes Inflammation Resolution Responses in Macrophages via Histone Lactylation.
  35. Allogeneic mitochondrial transplantation ameliorates cardiac dysfunction due to doxorubicin: An in vivo study.
  36. BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome.
  37. Illuminating the human yolk sac through single-cell omics.
  38. A single-cell multi-omic atlas spanning the adult rhesus macaque brain.
  39. The multifaceted role of mitochondria in HSC fate decisions: energy and beyond.
  40. Transcriptomic cytoarchitecture reveals principles of human neocortex organization.
  41. Mitochondrial Dysfunction and Decreased Cytochrome c in Cell and Animal Models of Machado-Joseph Disease.
  42. GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes.
  1. Elife. 2023 Oct 12. pii: RP88084. [Epub ahead of print]12
    Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes.
    Michele Brischigliaro, Alfredo Cabrera-Orefice, Susanne Arnold, Carlo Viscomi, Massimo Zeviani, Erika Fernández-Vizarra.
      Mammalian mitochondrial respiratory chain (MRC) complexes are able to associate into quaternary structures named supercomplexes (SCs), which normally coexist with non-bound individual complexes. The functional significance of SCs has not been fully clarified and the debate has been centered on whether or not they confer catalytic advantages compared with the non-bound individual complexes. Mitochondrial respiratory chain organization does not seem to be conserved in all organisms. In fact, and differently from mammalian species, mitochondria from Drosophila melanogaster tissues are characterized by low amounts of SCs, despite the high metabolic demands and MRC activity shown by these mitochondria. Here, we show that attenuating the biogenesis of individual respiratory chain complexes was accompanied by increased formation of stable SCs, which are missing in Drosophila melanogaster in physiological conditions. This phenomenon was not accompanied by an increase in mitochondrial respiratory activity. Therefore, we conclude that SC formation is necessary to stabilize the complexes in suboptimal biogenesis conditions, but not for the enhancement of respiratory chain catalysis.
    Keywords:  D. melanogaster; Drosophila; Mitochondria; OXPHOS; biochemistry; chemical biology; supercomplexes
    DOI:  https://doi.org/10.7554/eLife.88084
  2. iScience. 2023 Oct 20. 26(10): 107955
    Drosophila Mpv17 forms an ion channel and regulates energy metabolism.
    Samantha Corrà, Vanessa Checchetto, Michele Brischigliaro, Chiara Rampazzo, Emanuela Bottani, Cristina Gagliani, Katia Cortese, Cristiano De Pittà, Marco Roverso, Diego De Stefani, Sara Bogialli, Massimo Zeviani, Carlo Viscomi, Ildiko Szabò, Rodolfo Costa.
      Mutations in MPV17 are a major contributor to mitochondrial DNA (mtDNA) depletion syndromes, a group of inherited genetic conditions due to mtDNA instability. To investigate the role of MPV17 in mtDNA maintenance, we generated and characterized a Drosophila melanogaster Mpv17 (dMpv17) KO model showing that the absence of dMpv17 caused profound mtDNA depletion in the fat body but not in other tissues, increased glycolytic flux and reduced lifespan in starvation. Accordingly, the expression of key genes of glycogenolysis and glycolysis was upregulated in dMpv17 KO flies. In addition, we demonstrated that dMpv17 formed a channel in planar lipid bilayers at physiological ionic conditions, and its electrophysiological hallmarks were affected by pathological mutations. Importantly, the reconstituted channel translocated uridine but not orotate across the membrane. Our results indicate that dMpv17 forms a channel involved in translocation of key metabolites and highlight the importance of dMpv17 in energy homeostasis and mitochondrial function.
    Keywords:  model organism; molecular biology; physiology
    DOI:  https://doi.org/10.1016/j.isci.2023.107955
  3. J Neurol. 2023 Oct 13.
    Current management of primary mitochondrial disorders in EU countries: the European Reference Networks survey.
    Michelangelo Mancuso, Piervito Lopriore, Costanza Lamperti, Thomas Klopstock, Shamima Rahman, Laura Licchetta, Cornelia Kornblum, Saskia B Wortmann, Hélène Dollfus, Maria T Papadopoulou, Alexis Arzimanoglou, Maurizio Scarpa, Holm Graessner, Teresinha Evangelista.
      BACKGROUND AND PURPOSE: Primary mitochondrial diseases (PMDs) are rare diseases for which diagnosis is challenging, and management and training programs are not well defined in Europe. To capture and assess care needs, five different European Reference Networks have conducted an exploratory survey.METHODS: The survey covering multiple topics relating to PMDs was sent to all ERNs healthcare providers (HCPs) in Europe.
    RESULTS: We have collected answers from 220 members based in 24/27 European member states and seven non-European member states. Even though most of the responders are aware of neurogenetic diseases, difficulties arise in the ability to deliver comprehensive genetic testing. While single gene analysis is widely available in Europe, whole exome and genome sequencing are not easily accessible, with considerable variation between countries and average waiting time for results frequently above 6 months. Only 12.7% of responders were happy with the ICD-10 codes for classifying patients with PMDs discharged from the hospital, and more than 70% of them consider that PMDs deserve specific ICD codes to improve clinical management, including tailored healthcare, and for reimbursement reasons. Finally, 90% of responders declared that there is a need for further education and training in these diseases.
    CONCLUSIONS: This survey provides information on the current difficulties in the care of PMDs in Europe. We believe that the results of this survey are important to help rare disease stakeholders in European countries identify key care and research priorities.
    Keywords:  Europe; European Reference Networks; Mitochondrial diseases; Rare diseases; Survey
    DOI:  https://doi.org/10.1007/s00415-023-12017-1
  4. Brain. 2023 Oct 07. pii: awad340. [Epub ahead of print]
    Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.
    Camilla Aurora Franchino, Martina Brughera, Valentina Baderna, Daniele De Ritis, Alessandra Rocco, Sara Seneca, Luc Regal, Paola Podini, Maurizio D'Antonio, Camilo Toro, Angelo Quattrini, Emmanuel Scalais, Francesca Maltecca.
      AFG3L2 is a mitochondrial protease exerting protein quality control in the inner mitochondrial membrane (IMM). Heterozygous AFG3L2 mutations cause Spinocerebellar Ataxia type 28 (SCA28) or Dominant Optic Atrophy type 12 (DOA12), while biallelic AFG3L2 mutations result in the rare and severe Spastic Ataxia type 5 (SPAX5). The clinical spectrum of SPAX5 includes childhood-onset cerebellar ataxia, spasticity, dystonia, and myoclonic epilepsy. We previously reported that the absence or mutation of AFG3L2 leads to the accumulation of mitochondria-encoded proteins, causing the over-activation of the stress-sensitive protease OMA1, which over-processes OPA1, leading to mitochondrial fragmentation. Recently, OMA1 has been identified as the pivotal player communicating mitochondrial stress to the cytosol via a pathway involving the IMM protein DELE1 and the cytosolic kinase HRI, thus eliciting the integrated stress response (ISR). In general, the ISR reduces global protein synthesis and drives the expression of cytoprotective genes that allow cells to endure proteotoxic stress. However, the relevance of the OMA1-DELE1-HRI axis in vivo, and especially in a human CNS disease context, has been poorly documented so far. In this work, we demonstrated that mitochondrial proteotoxicity in the absence/mutation of AFG3L2 activates the OMA1-DELE1-HRI pathway eliciting the ISR. We indeed found enhanced OMA1-dependent processing of DELE1 upon depletion of AFG3L2. Also, in both skin fibroblasts from SPAX5 patients (including a novel case) and in the cerebellum of Afg3l2-/- mice we detected increased phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2α), increased levels of ATF4 and strong upregulation of its downstream targets (Chop, Chac1, Ppp1r15a and Ffg21). Silencing of DELE1 or HRI in SPAX5 fibroblasts (where OMA1 is overactivated at basal state) reduces eIF2α phosphorylation and affects cell growth. In agreement, pharmacological potentiation of ISR via Sephin-1, a drug that selectively inhibits the stress-induced eIF2alpha phosphatase GADD34 (encoded by Ppp1r15a), improved cell growth of SPAX5 fibroblasts, and cell survival and dendritic arborization ex vivo in primary Afg3l2-/- Purkinje neurons (PNs). Notably, Sephin-1 treatment in vivo extended the life span of Afg3l2-/- mice, improved PN morphology, mitochondrial ultrastructure and respiratory capacity. These data indicate that activation of the OMA1-DELE1-HRI pathway is protective in the context of SPAX5. Pharmacological tuning of the ISR may represent a future therapeutic strategy for SPAX5 and other cerebellar ataxias caused by impaired mitochondrial proteostasis.
    Keywords:  OMA1; integrated stress response; spastic ataxia type 5
    DOI:  https://doi.org/10.1093/brain/awad340
  5. Endocr Metab Immune Disord Drug Targets. 2023 Oct 04.
    Diversities in Leigh Syndrome Associated with MT-ATP6 Gene Variants.
    Sara Martins, Maria João Santos, Marta Simões, Sandra Jacinto, Cristina Martins Halpern, Juliette Dupont, Luísa Diogo, Manuela Grazina.
      INTRODUCTION: Leigh syndrome (LS) is clinically and genetically heterogeneous and presents defective mitochondrial bioenergetics. Patients present neurological symptoms and imagiological features that may result in early death [1]. The LS has been associated with mitochondrial DNA (mtDNA) variants, e.g., m.8993T>G (L156R) and m.8993T>C (L156P), in the MT-ATP6 gene. They lead to the substitution of a highly conserved amino acid in subunit 6 of ATP synthase, affecting the F0 domain and ATP synthesis [1-3]. We present five cases with m.8993T>G and a family harbouring m.8993T>C+m.1555A>G (proband and four relatives).METHODS: Our laboratory received 48 samples from LS-suspected patients. The samples (various tissues) were assessed for bioenergetics (activity of mitochondrial respiratory chain (MRC) complexes, ubiquinone content) and genetic analyses (mtDNA copy number, Sequencing and PCR-RFLP) by established protocols.
    RESULTS/CASE REPORT: Bioenergetics were assessed in 5 patients (various tissues) with varying levels of MRC/ATP synthase impairment. Six cases had a mtDNA pathogenic variant in the 8993 nucleotide associated with LS. Five cases presented the m.8993T>G variant, one of which (P5) possibly de novo. This variant was homoplasmy (P1-3) or very high heteroplasmy (P4/5, 90-95%). Of the four patients with bioenergetics assessment, three (P1/3/4) had deficiencies of MRC complexes, and P5 had small deficits. The other case (familial, proband and 4 relatives) presented a combination of m.1555A>G (homoplasmy) and m.8993T>C (heteroplasmy) variants. The proband presents m.8993T>C in 95% heteroplasmy and 85-35% in three relatives. All have m.1555A>G in homoplasmy, including the fourth relative without m.8993T>C. A deficiency (31%) was found in complex V activity in muscle for proband.
    CONCLUSION: We present a case series of patients harbouring pathogenic variants in the 8993 nucleotide of mtDNA, which have been associated with LS and impairment of MRC's complex V. These cases highlight the variability in clinical symptoms and their severity, as well as genetic heterogeneity within LS. Many patients will not present a classic pathogenic variant and there are many cases of asymptomatic relatives (carriers). It is important to get a broader view of the cases - classical methods and multiple tissue analysis are still valuable tools for the comprehensive characterization of patients.
    Keywords:  Leigh syndrome; disease heterogeneity; methodology; mitochondrial cytopathies; mtDNA; pathogenic sequence variants
    DOI:  https://doi.org/10.2174/0118715303273271230928060000
  6. Brain. 2023 Oct 07. pii: awad347. [Epub ahead of print]
    Homozygous MFN2 variants causing severe antenatal encephalopathy with clumped mitochondria.
    Arnaud Chevrollier, Adeline Alice Bonnard, Lyse Ruaud, Naïg Gueguen, Laurence Perrin, Valérie Desquiret-Dumas, Fabien Guimiot, Pierre-Hadrien Becker, Jonathan Levy, Pascal Reynier, Pauline Gaignard.
      Pathogenic variants in MFN2 gene are commonly associated with autosomal dominant (CMT2A2A) or recessive (CMT2A2B) Charcot-Marie-Tooth disease, with possible involvement of the central nervous system. Here, we present a case of severe antenatal encephalopathy with lissencephaly, polymicrogyria and cerebellar atrophy. Whole Genome Analysis revealed a homozygous deletion c.1717-274_1734 del (NM_014874.4) in MFN2 gene, leading to exon 16 skipping and in-frame loss of 50 amino acids (p.Gln574_Val624del), removing the proline rich domain and the transmembrane domain 1 (TM1). MFN2 is a transmembrane GTPase located on the mitochondrial outer membrane (MOM) that contributes to mitochondrial fusion, shaping large mitochondrial networks within cells. In silico modelling showed that the loss of the TM1 domain resulted in a drastically altered topological insertion of the protein in the MOM. Fetus fibroblasts, investigated by fluorescent cell imaging, electron microscopy and time lapse recording, showed a sharp alteration of the mitochondrial network, with clumped mitochondria and clusters of tethered mitochondria unable to fuse. Multiple deficiencies of respiratory chain complexes with severe impairment of complex I were also evidenced in patient fibroblasts, without involvement of mitochondrial DNA instability. This is the first reported case of a severe developmental defect due to MFN2 deficiency with clumped mitochondria.
    Keywords:  early onset; mitochondrial dynamics; mitochondrial fusion; neurological disorders
    DOI:  https://doi.org/10.1093/brain/awad347
  7. Hum Mol Genet. 2023 Oct 10. pii: ddad161. [Epub ahead of print]
    CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature.
    Mario K Shammas, Yu Nie, Alexandra Gilsrud, Xiaoping Huang, Derek P Narendra, Patrick F Chinnery.
      Mutations affecting the mitochondrial intermembrane space protein CHCHD10 cause human disease, but it is not known why different amino acid substitutions cause markedly different clinical phenotypes, including amyotrophic lateral sclerosis-frontotemporal dementia, spinal muscular atrophy Jokela-type, isolated autosomal dominant mitochondrial myopathy and cardiomyopathy. CHCHD10 mutations have been associated with deletions of mitochondrial DNA (mtDNA deletions), raising the possibility that these explain the clinical variability. Here, we sequenced mtDNA obtained from hearts, skeletal muscle, livers and spinal cords of WT and Chchd10 G58R or S59L knockin mice to characterize the mtDNA deletion signatures of the two mutant lines. We found that the deletion levels were higher in G58R and S59L mice than in WT mice in some tissues depending on the Chchd10 genotype, and the deletion burden increased with age. Furthermore, we observed that the spinal cord was less prone to the development of mtDNA deletions than the other tissues examined. Finally, in addition to accelerating the rate of naturally occurring deletions, Chchd10 mutations also led to the accumulation of a novel set of deletions characterized by shorter direct repeats flanking the deletion breakpoints. Our results indicate that Chchd10 mutations in mice induce tissue-specific deletions which may also contribute to the clinical phenotype associated with these mutations in humans.
    Keywords:  miochondrial DNA; mitochondria; mtDNA deletions; neurodegeneration
    DOI:  https://doi.org/10.1093/hmg/ddad161
  8. EMBO Rep. 2023 Oct 11. e57228
    Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.
    Conor T Ronayne, Thomas D Jackson, Christopher F Bennett, Elizabeth A Perry, Noa Kantorovic, Pere Puigserver.
      Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations is redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. One method to rescue this cell death vulnerability is the inhibition of mitochondrial translation using tetracyclines. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that tetracyclines inhibit the mitochondrial ribosome and promote survival through suppression of endoplasmic reticulum (ER) stress. Tetracyclines increase mitochondrial levels of the mitoribosome quality control factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) and promote its recruitment to the mitoribosome large subunit, where MALSU1 is necessary for tetracycline-induced survival and suppression of ER stress. Glucose starvation induces ER stress to activate the unfolded protein response and IRE1α-mediated cell death that is inhibited by tetracyclines. These studies establish a new interorganelle communication whereby inhibition of the mitoribosome signals to the ER to promote survival, implicating basic mechanisms of cell survival and treatment of mitochondrial diseases.
    Keywords:  IRE1α; MALSU1; mitochondrial disease; mitoribosome; tetracyclines
    DOI:  https://doi.org/10.15252/embr.202357228
  9. EMBO Rep. 2023 Oct 12. e57092
    The functional significance of mitochondrial respiratory chain supercomplexes.
    Andreas Kohler, Antoni Barrientos, Flavia Fontanesi, Martin Ott.
      The mitochondrial respiratory chain (MRC) is a key energy transducer in eukaryotic cells. Four respiratory chain complexes cooperate in the transfer of electrons derived from various metabolic pathways to molecular oxygen, thereby establishing an electrochemical gradient over the inner mitochondrial membrane that powers ATP synthesis. This electron transport relies on mobile electron carries that functionally connect the complexes. While the individual complexes can operate independently, they are in situ organized into large assemblies termed respiratory supercomplexes. Recent structural and functional studies have provided some answers to the question of whether the supercomplex organization confers an advantage for cellular energy conversion. However, the jury is still out, regarding the universality of these claims. In this review, we discuss the current knowledge on the functional significance of MRC supercomplexes, highlight experimental limitations, and suggest potential new strategies to overcome these obstacles.
    Keywords:  Mitochondria; bioenergetics; electron transfer; respiratory chain; supercomplexes
    DOI:  https://doi.org/10.15252/embr.202357092
  10. Nat Commun. 2023 Oct 13. 14(1): 6431
    PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.
    Natalie M Niemi, Lia R Serrano, Laura K Muehlbauer, Catherine E Balnis, Lianjie Wei, Andrew J Smith, Keri-Lyn Kozul, Merima Forny, Olivia M Connor, Edrees H Rashan, Evgenia Shishkova, Kathryn L Schueler, Mark P Keller, Alan D Attie, Jonathan R Friedman, Julia K Pagan, Joshua J Coon, David J Pagliarini.
      PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass and metabolic capacity with elevated hepatic triglyceride accumulation. Pptc7 knockout animals exhibit increased expression of the mitophagy receptors BNIP3 and NIX, and Pptc7-/- mouse embryonic fibroblasts (MEFs) display a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs, including multiple sites on BNIP3 and NIX, and our molecular studies demonstrate that PPTC7 can directly interact with and dephosphorylate these proteins. These data suggest that Pptc7 deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that PPTC7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for PPTC7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.
    DOI:  https://doi.org/10.1038/s41467-023-42069-w
  11. Int J Mol Sci. 2023 Sep 22. pii: 14421. [Epub ahead of print]24(19):
    Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration.
    Hariprasath Ragupathy, Manasvi Vukku, Sandeep Kumar Barodia.
      Neurodegeneration is an age-dependent progressive phenomenon with no defined cause. Aging is the main risk factor for neurodegenerative diseases. During aging, activated microglia undergo phenotypic alterations that can lead to neuroinflammation, which is a well-accepted event in the pathogenesis of neurodegenerative diseases. Several common mechanisms are shared by genetically or pathologically distinct neurodegenerative diseases, such as excitotoxicity, mitochondrial deficits and oxidative stress, protein misfolding and translational dysfunction, autophagy and microglia activation. Progressive loss of the neuronal population due to increased oxidative stress leads to neurodegenerative diseases, mostly due to the accumulation of dysfunctional mitochondria. Mitochondrial dysfunction and excessive neuroinflammatory responses are both sufficient to induce pathology in age-dependent neurodegeneration. Therefore, mitochondrial quality control is a key determinant for the health and survival of neuronal cells in the brain. Research has been primarily focused to demonstrate the significance of neuronal mitochondrial health, despite the important contributions of non-neuronal cells that constitute a significant portion of the brain volume. Moreover, mitochondrial morphology and function are distinctly diverse in different tissues; however, little is known about their molecular diversity among cell types. Mitochondrial dynamics and quality in different cell types markedly decide the fate of overall brain health; therefore, it is not justifiable to overlook non-neuronal cells and their significant and active contribution in facilitating overall neuronal health. In this review article, we aim to discuss the mitochondrial quality control of different cell types in the brain and how important and remarkable the diversity and highly synchronized connecting property of non-neuronal cells are in keeping the neurons healthy to control neurodegeneration.
    Keywords:  astrocytes; microglia; mitochondria; neurons; oligodendrocytes; oxidative stress
    DOI:  https://doi.org/10.3390/ijms241914421
  12. Orphanet J Rare Dis. 2023 Oct 11. 18(1): 320
    The burden of mitochondrial disease with associated seizures: systematic literature reviews of health-related quality of life, utilities, costs and healthcare resource use data.
    Enrico Bertini, Emily Gregg, Chris Bartlett, Vij Senthilnathan, Mick Arber, Deborah Watkins, Sara Graziadio, Ioannis Tomazos.
      BACKGROUND: Mitochondrial disease is a degenerative, progressive, heterogeneous group of genetic disorders affecting children and adults. Mitochondrial disease is associated with morbidity and mortality, with predominantly neurological and neuromuscular symptoms including dystonia, weakness, encephalopathy, developmental delay and seizures. Seizures are one of the most common and severe manifestations of mitochondrial disease. These seizures are typically refractory to common anti-seizure therapies. There are no approved disease-modifying treatments for mitochondrial disease. Our objective was to conduct two systematic literature reviews to identify health-related quality of life (HRQoL), utilities, costs and healthcare resource use data in mitochondrial disease with associated seizures.METHODS: A range of databases and information sources were searched up to July 2022 to identify eligible studies. Search strategies included a range of variant terms for mitochondrial disease and HRQoL, utilities, cost and healthcare resource use outcomes. Two reviewers independently assessed articles against the eligibility criteria; studies were extracted by one reviewer and checked by a second. Risk of bias was assessed for studies reporting HRQoL data. Results were narratively assessed.
    RESULTS: Seven studies were eligible for the HRQoL and utilities review. The studies used different tools to report data, and despite the variability in methods, HRQoL scores across the studies showed moderate/severe disease in patients with mitochondrial disease with associated seizures. Parents of patients with mitochondrial disease with associated seizures were characterised by high total parenting stress. No studies reported utilities data. Two case reports and one retrospective review of medical records of children who died in hospital were eligible for the costs and resource use review. These provided limited information on the duration of hospital stay, in an intensive care unit (ICU), on mechanical ventilation. No studies reported costs data.
    CONCLUSION: These reviews highlight the limited HRQoL, utilities, costs and resource use data and the variability of instruments used in mitochondrial disease with associated seizures. However, the data available indicate that mitochondrial disease with associated seizures affects patients' and caregivers' HRQoL alike. No robust conclusion can be drawn on the impact of mitochondrial disease with associated seizures on hospital or ICU length of stay. Trial registration PROSPERO: CRD42022345005.
    Keywords:  Costs; Disease burden; Epilepsy; Health state utility values; Health-related quality of life; Healthcare resource use; Mitochondrial diseases; Seizures; Systematic literature reviews; Utilities
    DOI:  https://doi.org/10.1186/s13023-023-02945-6
  13. Nat Metab. 2023 Oct 09.
    COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.
    Sukanya Guhathakurta, Niyazi Umut Erdogdu, Juliane J Hoffmann, Iga Grzadzielewska, Alexander Schendzielorz, Janine Seyfferth, Christoph U Mårtensson, Mauro Corrado, Adam Karoutas, Bettina Warscheid, Nikolaus Pfanner, Thomas Becker, Asifa Akhtar.
      Reversible acetylation of mitochondrial proteins is a regulatory mechanism central to adaptive metabolic responses. Yet, how such functionally relevant protein acetylation is achieved remains unexplored. Here we reveal an unprecedented role of the MYST family lysine acetyltransferase MOF in energy metabolism via mitochondrial protein acetylation. Loss of MOF-KANSL complex members leads to mitochondrial defects including fragmentation, reduced cristae density and impaired mitochondrial electron transport chain complex IV integrity in primary mouse embryonic fibroblasts. We demonstrate COX17, a complex IV assembly factor, as a bona fide acetylation target of MOF. Loss of COX17 or expression of its non-acetylatable mutant phenocopies the mitochondrial defects observed upon MOF depletion. The acetylation-mimetic COX17 rescues these defects and maintains complex IV activity even in the absence of MOF, suggesting an activatory role of mitochondrial electron transport chain protein acetylation. Fibroblasts from patients with MOF syndrome who have intellectual disability also revealed respiratory defects that could be restored by alternative oxidase, acetylation-mimetic COX17 or mitochondrially targeted MOF. Overall, our findings highlight the critical role of MOF-KANSL complex in mitochondrial physiology and provide new insights into MOF syndrome.
    DOI:  https://doi.org/10.1038/s42255-023-00904-w
  14. J Biomed Sci. 2023 Oct 12. 30(1): 86
    Crosstalk between mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis.
    Lei Liu, Yanjun Li, Guo Chen, Quan Chen.
      Mitochondrial mass and quality are tightly regulated by two essential and opposing mechanisms, mitochondrial biogenesis (mitobiogenesis) and mitophagy, in response to cellular energy needs and other cellular and environmental cues. Great strides have been made to uncover key regulators of these complex processes. Emerging evidence has shown that there exists a tight coordination between mitophagy and mitobiogenesis, and their defects may cause many human diseases. In this review, we will first summarize the recent advances made in the discovery of molecular regulations of mitobiogenesis and mitophagy and then focus on the mechanism and signaling pathways involved in the simultaneous regulation of mitobiogenesis and mitophagy in the response of tissue or cultured cells to energy needs, stress, or pathophysiological conditions. Further studies of the crosstalk of these two opposing processes at the molecular level will provide a better understanding of how the cell maintains optimal cellular fitness and function under physiological and pathophysiological conditions, which holds promise for fighting aging and aging-related diseases.
    Keywords:  Aging; Aging-related diseases; Mitochondrial biogenesis; Mitochondrial quality; Mitophagy; Mitophagy receptors
    DOI:  https://doi.org/10.1186/s12929-023-00975-7
  15. Aging Cell. 2023 Oct 13. e14000
    Carnitine acetyltransferase deficiency mediates mitochondrial dysfunction-induced cellular senescence in dermal fibroblasts.
    Min Ji Song, Chi-Hyun Park, Haesoo Kim, Sangbum Han, Si Hyung Lee, Dong Hun Lee, Jin Ho Chung.
      Aging is accompanied by impaired mitochondrial function and accumulation of senescent cells. Mitochondrial dysfunction contributes to senescence by increasing the levels of reactive oxygen species and compromising energy metabolism. Senescent cells secrete a senescence-associated secretory phenotype (SASP) and stimulate chronic low-grade inflammation, ultimately inducing inflammaging. Mitochondrial dysfunction and cellular senescence are two closely related hallmarks of aging; however, the key driver genes that link mitochondrial dysfunction and cellular senescence remain unclear. Here, we aimed to elucidate a novel role of carnitine acetyltransferase (CRAT) in the development of mitochondrial dysfunction and cellular senescence in dermal fibroblasts. Transcriptomic analysis of skin tissues from young and aged participants showed significantly decreased CRAT expression in intrinsically aged skin. CRAT downregulation in human dermal fibroblasts recapitulated mitochondrial changes in senescent cells and induced SASP secretion. Specifically, CRAT knockdown caused mitochondrial dysfunction, as indicated by increased oxidative stress, disruption of mitochondrial morphology, and a metabolic shift from oxidative phosphorylation to glycolysis. Mitochondrial damage induced the release of mitochondrial DNA into the cytosol, which activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NF-ĸB pathways to induce SASPs. Consistently, fibroblast-specific CRAT-knockout mice showed increased skin aging phenotypes in vivo, including decreased cell proliferation, increased SASP expression, increased inflammation, and decreased collagen density. Our results suggest that CRAT deficiency contributes to aging by mediating mitochondrial dysfunction-induced senescence.
    Keywords:  carnitine acetyltransferase; cellular senescence; mitochondrial dysfunction; oxidative stress; skin aging
    DOI:  https://doi.org/10.1111/acel.14000
  16. Mol Cell. 2023 Oct 08. pii: S1097-2765(23)00753-0. [Epub ahead of print]
    Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis.
    Yi Fu, Olivia Sacco, Emily DeBitetto, Evgeny Kanshin, Beatrix Ueberheide, Agnel Sfeir.
      Mitochondrial DNA double-strand breaks (mtDSBs) lead to the degradation of circular genomes and a reduction in copy number; yet, the cellular response in human cells remains elusive. Here, using mitochondrial-targeted restriction enzymes, we show that a subset of cells with mtDSBs exhibited defective mitochondrial protein import, reduced respiratory complexes, and loss of membrane potential. Electron microscopy confirmed the altered mitochondrial membrane and cristae ultrastructure. Intriguingly, mtDSBs triggered the integrated stress response (ISR) via the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) by DELE1 and heme-regulated eIF2α kinase (HRI). When ISR was inhibited, the cells experienced intensified mitochondrial defects and slower mtDNA recovery post-breakage. Lastly, through proteomics, we identified ATAD3A-a membrane-bound protein interacting with nucleoids-as potentially pivotal in relaying signals from impaired genomes to the inner mitochondrial membrane. In summary, our study delineates the cascade connecting damaged mitochondrial genomes to the cytoplasm and highlights the significance of the ISR in maintaining mitochondrial homeostasis amid genome instability.
    Keywords:  ATAD3A; double-strand breaks; integrated stress response; mitochondrial DNA; protein import
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.026
  17. Nat Commun. 2023 10 10. 14(1): 6344
    FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes.
    Jiamin Qiu, Feng Yue, Peipei Zhu, Jingjuan Chen, Fan Xu, Lijia Zhang, Kun Ho Kim, Madigan M Snyder, Nanjian Luo, Hao-Wei Xu, Fang Huang, W Andy Tao, Shihuan Kuang.
      Cold stimulation dynamically remodels mitochondria in brown adipose tissue (BAT) to facilitate non-shivering thermogenesis in mammals, but what regulates mitochondrial plasticity is poorly understood. Comparing mitochondrial proteomes in response to cold revealed FAM210A as a cold-inducible mitochondrial inner membrane protein. An adipocyte-specific constitutive knockout of Fam210a (Fam210aAKO) disrupts mitochondrial cristae structure and diminishes the thermogenic activity of BAT, rendering the Fam210aAKO mice vulnerable to lethal hypothermia under acute cold exposure. Induced knockout of Fam210a in adult adipocytes (Fam210aiAKO) does not affect steady-state mitochondrial structure under thermoneutrality, but impairs cold-induced mitochondrial remodeling, leading to progressive loss of cristae and reduction of mitochondrial density. Proteomics reveals an association between FAM210A and OPA1, whose cleavage governs cristae dynamics and mitochondrial remodeling. Mechanistically, FAM210A interacts with mitochondrial protease YME1L and modulates its activity toward OMA1 and OPA1 cleavage. These data establish FAM210A as a key regulator of mitochondrial cristae remodeling in BAT and shed light on the mechanism underlying mitochondrial plasticity in response to cold.
    DOI:  https://doi.org/10.1038/s41467-023-41988-y
  18. Brain. 2023 Oct 13. pii: awad357. [Epub ahead of print]
    Phenotype and natural history of mitochondrial membrane protein-associated neurodegeneration.
    Vassilena Iankova, Peter Sparber, Mohammad Rohani, Petr Dusek, Boriana Büchner, Ivan Karin, Susanne A Schneider, Juan M Gorriz, Tomasz Kmiec, Thomas Klopstock.
      Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an ultraorphan neurogenetic disease from the group of Neurodegeneration with Brain Iron Accumulation (NBIA) disorders. Here we report cross-sectional and longitudinal data to define the phenotype, to assess disease progression, and to estimate sample sizes for clinical trials. We enrolled patients with genetically confirmed MPAN from the Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON) registry and cohort study, and from additional sites. Linear mixed-effect modelling (LMEM) was used to calculate annual progression rates for Unified Parkinson's Disease Rating Scale (UPDRS), Barry-Albright Dystonia (BAD) Scale, Schwab and England Activities of Daily Living (SE-ADL) scale, and the Pediatric Quality of Life Inventory (PedsQL). We investigated 85 MPAN patients cross-sectionally, with functional outcome data collected in 45. Median age at onset was 9 years and the median diagnostic delay was 5 years. The most common findings were gait disturbance (99%), pyramidal involvement (95%), dysarthria (90%), vision disturbances (82%), with all but dysarthria presenting early in the disease course. After 16 years into disease, 50% of patients were wheelchair dependent. LMEM showed an annual progression rate of 4.5 points in total UPDRS. The total BAD scale showed no significant progression over time. The SE-ADL scale, the patient- reported and the parent-reported PedsQL showed a decline of 3.9%, 2.14 and 2.05 points respectively. No patient subpopulations were identified based on longitudinal trajectories. Interpretation: Our cross-sectional results define order of onset and frequency of symptoms in MPAN, which will inform the diagnostic process, help shorten the diagnostic delay, and aid in counselling patients, parents, and caregivers. Our longitudinal findings define the natural history of MPAN, reveal the most responsive outcomes, and highlight the need for an MPAN-specific rating approach. Our sample size estimations inform the design of upcoming clinical trials.
    Keywords:  MPAN; NBIA; mitochondrial membrane protein-associated neurodegeneration; neurodegeneration with brain iron accumulation
    DOI:  https://doi.org/10.1093/brain/awad357
  19. J Biomed Sci. 2023 Oct 08. 30(1): 85
    Extracellular release in the quality control of the mammalian mitochondria.
    Kuei-Hsiang Pan, Hung Chang, Wei Yuan Yang.
      Mammalian cells release a wealth of materials to their surroundings. Emerging data suggest these materials can even be mitochondria with perturbed morphology and aberrant function. These dysfunctional mitochondria are removed by migrating cells through membrane shedding. Neuronal cells, cardiomyocytes, and adipocytes send dysfunctional mitochondria into the extracellular space for nearby cells to degrade. Various studies also indicate that there is an interplay between intracellular mitochondrial degradation pathways and mitochondrial release in handling dysfunctional mitochondria. These observations, in aggregate, suggest that extracellular release plays a role in quality-controlling mammalian mitochondria. Future studies will help delineate the various types of molecular machinery mammalian cells use to release dysfunctional mitochondria. Through the studies, we will better understand how mammalian cells choose between intracellular degradation and extracellular release for the quality control of mitochondria.
    Keywords:  Autophagy; Extracellular vesicles; Mitochondria; Mitophagy; Organelle quality control
    DOI:  https://doi.org/10.1186/s12929-023-00979-3
  20. Trends Endocrinol Metab. 2023 Oct 05. pii: S1043-2760(23)00197-2. [Epub ahead of print]
    Brain mitochondria in behavior: more than a powerhouse.
    Alexia Crockett, Fiona Hollis.
      Rosenberg and colleagues developed a miniaturized assay of mitochondrial content and energy transformation capacity that allowed them to assess mitochondrial features and activities across the brain in male mice. Their findings provide a comprehensive brain-wide map of mitochondrial associations with stress-induced behaviors and highlight mitochondria as dynamic, spatially-organized organelles.
    Keywords:  behavior; brain bioenergetics; mitochondria; stress
    DOI:  https://doi.org/10.1016/j.tem.2023.09.008
  21. Cells. 2023 Sep 24. pii: 2345. [Epub ahead of print]12(19):
    Stimulator of Interferon Genes (STING) Triggers Adipocyte Autophagy.
    Kornél Z Varga, Katalin Gyurina, Ádám Radványi, Tibor Pál, László Sasi-Szabó, Haidong Yu, Enikő Felszeghy, Tamás Szabó, Tamás Röszer.
      Innate immune signaling in adipocytes affects systemic metabolism. Cytosolic nucleic acid sensing has been recently shown to stimulate thermogenic adipocyte differentiation and protect from obesity; however, DNA efflux from adipocyte mitochondria is a potential proinflammatory signal that causes adipose tissue dysfunction and insulin resistance. Cytosolic DNA activates the stimulator of interferon response genes (STING), a key signal transducer which triggers type I interferon (IFN-I) expression; hence, STING activation is expected to induce IFN-I response and adipocyte dysfunction. However, we show herein that mouse adipocytes had a diminished IFN-I response to STING stimulation by 2'3'-cyclic-GMP-AMP (cGAMP). We also show that cGAMP triggered autophagy in murine and human adipocytes. In turn, STING inhibition reduced autophagosome number, compromised the mitochondrial network and caused inflammation and fat accumulation in adipocytes. STING hence stimulates a process that removes damaged mitochondria, thereby protecting adipocytes from an excessive IFN-I response to mitochondrial DNA efflux. In summary, STING appears to limit inflammation in adipocytes by promoting mitophagy under non-obesogenic conditions.
    Keywords:  STING; adipocyte; immunity; inflammation; interferons; mitochondria
    DOI:  https://doi.org/10.3390/cells12192345
  22. Nature. 2023 Oct 11.
    Apoptotic stress causes mtDNA release during senescence and drives the SASP.
    Stella Victorelli, Hanna Salmonowicz, James Chapman, Helene Martini, Maria Grazia Vizioli, Joel S Riley, Catherine Cloix, Ella Hall-Younger, Jair Machado Espindola-Netto, Diana Jurk, Anthony B Lagnado, Lilian Sales Gomez, Joshua N Farr, Dominik Saul, Rebecca Reed, George Kelly, Madeline Eppard, Laura C Greaves, Zhixun Dou, Nicholas Pirius, Karolina Szczepanowska, Rebecca A Porritt, Huijie Huang, Timothy Y Huang, Derek A Mann, Claudio Akio Masuda, Sundeep Khosla, Haiming Dai, Scott H Kaufmann, Emmanouil Zacharioudakis, Evripidis Gavathiotis, Nathan K LeBrasseur, Xue Lei, Alva G Sainz, Viktor I Korolchuk, Peter D Adams, Gerald S Shadel, Stephen W G Tait, João F Passos.
      Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.
    DOI:  https://doi.org/10.1038/s41586-023-06621-4
  23. Heart Fail Rev. 2023 Oct 12.
    Autophagy protects mitochondrial health in heart failure.
    Yating Tang, Wenlong Xu, Yu Liu, Jiajun Zhou, Kai Cui, Yanmei Chen.
      The progression of heart failure is reported to be strongly associated with homeostatic imbalance, such as mitochondrial dysfunction and abnormal autophagy, in the cardiomyocytes. Mitochondrial dysfunction triggers autophagic and cardiac dysfunction. In turn, abnormal autophagy impairs mitochondrial function and leads to apoptosis or autophagic cell death under certain circumstances. These events often occur concomitantly, forming a vicious cycle that exacerbates heart failure. However, the role of the crosstalk between mitochondrial dysfunction and abnormal autophagy in the development of heart failure remains obscure and the underlying mechanisms are mainly elusive. The potential role of the link between mitochondrial dysfunction and abnormal autophagy in heart failure progression has recently garnered attention. This review summarized recent advances of the interactions between mitochondria and autophagy during the development of heart failure.
    Keywords:  Autophagy; Heart failure; Mitochondria health; Mitochondria-targeted therapeutics; Mitochondrial quality control
    DOI:  https://doi.org/10.1007/s10741-023-10354-x
  24. Eur J Endocrinol. 2023 Oct 10. pii: lvad137. [Epub ahead of print]
    Adrenocortical function in patients with Single Large Scale Mitochondrial DNA Deletions: a retrospective single centre cohort study.
    Barbara Siri, Annamaria D'Alessandro, Arianna Maiorana, Ottavia Porzio, Lucilla Ravà, Carlo Dionisi-Vici, Marco Cappa, Diego Martinelli.
      OBJECTIVE: Single Large Scale Mitochondrial DNA Deletions (SLSMDs), Pearson Syndrome (PS) and Kearns-Sayre Syndrome (KSS), are systemic diseases with multiple endocrine abnormalities. The adrenocortical function has not been systematically investigated with a few anecdotal reports of overt adrenal insufficiency (AI). The study aimed to assess the adrenocortical function in a large cohort of SLSMDs.DESIGN AND METHODS: A retrospective monocentric longitudinal study involved a cohort of 18 SLSMDs patients. Adrenocortical function was evaluated by baseline adrenocorticotrophic hormone (ACTH) and cortisol measurements and by high- (HDT) and low-dose (LDT) ACTH stimulation tests and compared with 92 healthy controls (HC).
    RESULTS: Baseline adrenocortical function was impaired in 39% of patients and by the end of the study 66% of PS and 25% of KSS showed an insufficient increase after ACTH stimulation, with cortisol deficiency due to primary AI in most PS and subclinical AI in KSS. Symptomatic AI was recorded in 44% of patients.Peak cortisol levels after ACTH stimulation tests were significantly lower in patients than in HC (p<0.0001), with a more reduced response to LDT vs HDT (p<0.05).
    CONCLUSIONS: Our study highlights that cortisol deficiency due to primary AI represents a relevant part of the clinical spectrum in SLSMDs, with more severe impairment in PS than in KSS. Basal and after-stimulus assessment of adrenocortical axis should be early and regularly investigated to identify any degree of adrenocortical dysfunction. The study allowed the elaboration of a diagnostic process designed for the diagnosis, treatment, and follow-up of adrenocortical abnormalities in SLSMDs.
    Keywords:  ACTH stimulation tests; Single large scale mtDNA deletions; glucocorticoid replacement therapy; primary adrenal insufficiency
    DOI:  https://doi.org/10.1093/ejendo/lvad137
  25. Development. 2023 Oct 12. pii: dev.201930. [Epub ahead of print]
    Calcium signals tune AMPK activity and mitochondrial homeostasis in dendrites of developing neurons.
    Akane Hatsuda, Junko Kurisu, Kazuto Fujishima, Ayano Kawaguchi, Nobuhiko Ohno, Mineko Kengaku.
      Dendritic outgrowth in immature neurons is enhanced by neuronal activity and is considered one of the mechanisms of neural circuit optimization. It is known that calcium signals affect transcriptional regulation and cytoskeletal remodeling necessary for dendritic outgrowth. Here we demonstrate that activity-dependent calcium signaling also controls mitochondrial homeostasis via AMP-activated protein kinase (AMPK) in growing dendrites of differentiating hippocampal neurons. We found that the inhibition of neuronal activity induces dendritic hypotrophy with abnormally elongated mitochondria. In growing dendrites, AMPK is activated by neuronal activity and dynamically oscillates in synchrony with calcium spikes, and this AMPK oscillation is inhibited by CaMKK2 knockdown. AMPK activation leads to phosphorylation of MFF and ULK1, which initiate mitochondrial fission and mitophagy, respectively. Dendritic mitochondria in AMPK-depleted neurons exhibit impaired fission and mitophagy and display multiple signs of dysfunction. Genetic inhibition of fission leads to dendritic hypoplasia reminiscent of AMPK deficient neurons. Thus, AMPK activity is finely tuned by the calcium-CaMKK2 pathway and regulates mitochondrial homeostasis by facilitating removal of damaged components of mitochondria in growing neurons during normal brain development.
    Keywords:  AMPK; Dendritogenesis; Hippocampal neurons; Mitochondria; Neuronal activity
    DOI:  https://doi.org/10.1242/dev.201930
  26. Science. 2023 Oct 13. 382(6667): eadf5357
    Single-cell DNA methylation and 3D genome architecture in the human brain.
    Wei Tian, Jingtian Zhou, Anna Bartlett, Qiurui Zeng, Hanqing Liu, Rosa G Castanon, Mia Kenworthy, Jordan Altshul, Cynthia Valadon, Andrew Aldridge, Joseph R Nery, Huaming Chen, Jiaying Xu, Nicholas D Johnson, Jacinta Lucero, Julia K Osteen, Nora Emerson, Jon Rink, Jasper Lee, Yang E Li, Kimberly Siletti, Michelle Liem, Naomi Claffey, Carolyn O'Connor, Anna Marie Yanny, Julie Nyhus, Nick Dee, Tamara Casper, Nadiya Shapovalova, Daniel Hirschstein, Song-Lin Ding, Rebecca Hodge, Boaz P Levi, C Dirk Keene, Sten Linnarsson, Ed Lein, Bing Ren, M Margarita Behrens, Joseph R Ecker.
      Delineating the gene-regulatory programs underlying complex cell types is fundamental for understanding brain function in health and disease. Here, we comprehensively examined human brain cell epigenomes by probing DNA methylation and chromatin conformation at single-cell resolution in 517 thousand cells (399 thousand neurons and 118 thousand non-neurons) from 46 regions of three adult male brains. We identified 188 cell types and characterized their molecular signatures. Integrative analyses revealed concordant changes in DNA methylation, chromatin accessibility, chromatin organization, and gene expression across cell types, cortical areas, and basal ganglia structures. We further developed single-cell methylation barcodes that reliably predict brain cell types using the methylation status of select genomic sites. This multimodal epigenomic brain cell atlas provides new insights into the complexity of cell-type-specific gene regulation in adult human brains.
    DOI:  https://doi.org/10.1126/science.adf5357
  27. Brain Commun. 2023 ;5(5): fcad244
    Repeat expansions in NOP56 are a cause of spinocerebellar ataxia Type 36 in the British population.
    Genomics England Research Consortium
      Spinocerebellar ataxias form a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by progressive cerebellar ataxia. Their prevalence varies among populations and ethnicities. Spinocerebellar ataxia 36 is caused by a GGCCTG repeat expansion in the first intron of the NOP56 gene and is characterized by late-onset ataxia, sensorineural hearing loss and upper and lower motor neuron signs, including tongue fasciculations. Spinocerebellar ataxia 36 has been described mainly in East Asian and Western European patients and was thought to be absent in the British population. Leveraging novel bioinformatic tools to detect repeat expansions from whole-genome sequencing, we analyse the NOP56 repeat in 1257 British patients with hereditary ataxia and in 7506 unrelated controls. We identify pathogenic repeat expansions in five families (seven patients), representing the first cohort of White British descent patients with spinocerebellar ataxia 36. Employing in silico approaches using whole-genome sequencing data, we found an 87 kb shared haplotype in among the affected individuals from five families around the NOP56 repeat region, although this block was also shared between several controls, suggesting that the repeat arises on a permissive haplotype. Clinically, the patients presented with slowly progressive cerebellar ataxia with a low rate of hearing loss and variable rates of motor neuron impairment. Our findings show that the NOP56 expansion causes ataxia in the British population and that spinocerebellar ataxia 36 can be suspected in patients with a late-onset, slowly progressive ataxia, even without the findings of hearing loss and tongue fasciculation.
    Keywords:  NOP56; SCA36; repeat expansion; spinocerebellar ataxia; whole-genome sequencing
    DOI:  https://doi.org/10.1093/braincomms/fcad244
  28. Biochem Biophys Res Commun. 2023 Sep 29. pii: S0006-291X(23)01134-8. [Epub ahead of print]682 71-76
    PINK1 and Parkin rescue motor defects and mitochondria dysfunction induced by a patient-derived HSPB3 mutant in Drosophila models.
    Ji Eun Han, Kyong-Hwa Kang, Hyunjin Kim, Young Bin Hong, Byung-Ok Choi, Hyongjong Koh.
      Small heat shock proteins (sHSPs) are ATP-independent molecular chaperones with the α-crystalline domain that is critical to their chaperone activity. Within the sHSP family, three (HSPB1, HSPB3, and HSPB8) proteins are linked with inherited peripheral neuropathies, including distal hereditary motor neuropathy (dHMN) and Charco-Marie-Tooth disease (CMT). In this study, we introduced the HSPB3 Y118H (HSPB3Y118H) mutant gene identified from the CMT2 family in Drosophila. With a missense mutation on its α-crystalline domain, this human HSPB3 mutant gene induced a loss of motor activity accompanied by reduced mitochondrial membrane potential in fly neuronal tissues. Moreover, mitophagy, a critical mechanism of mitochondrial quality control, is downregulated in fly motor neurons expressing HSPB3Y118H. Surprisingly, PINK1 and Parkin, the core regulators of mitophagy, successfully rescued these motor and mitochondrial abnormalities in HSPB3 mutant flies. Results from the first animal model of HSPB3 mutations suggest that mitochondrial dysfunction plays a critical role in HSPB3-associated human pathology.
    Keywords:  Charcot-Marie-Tooth disease; Distal hereditary motor neuropathies; Drosophila; HSPB3; PINK1; Parkin
    DOI:  https://doi.org/10.1016/j.bbrc.2023.09.092
  29. Eur J Pharmacol. 2023 Oct 06. pii: S0014-2999(23)00597-6. [Epub ahead of print] 176085
    Low-dose atorvastatin protects skeletal muscle mitochondria in high-fat diet-fed mice with mitochondrial autophagy inhibition and fusion enhancement.
    Peng Zheng, Qian Zhang, Wenjing Ma, Ran Hu, Yilu Gu, Zhiping Bian, Di Yang, Xiangjian Chen, Hengfang Wu.
      Despite the great clinical benefits of statins in cardiovascular diseases, their widespread use may lead to adverse muscle reactions associated with mitochondrial dysfunction. Some studies have demonstrated that statins provide substantial improvement to skeletal muscle health in mice. Our previous study found that oral treatment with atorvastatin (Ator, 3 mg/kg) protected myocardial mitochondria in high-fat diet (HFD)-fed mice. Therefore, this study aimed to explore the influence of low-dose Ator (3 mg/kg) on mitochondria in skeletal muscle under cholesterol overload. Male C57BL/6J mice were fed a HFD for 18 weeks and orally administered Ator (3 mg/kg) during the last 12 weeks. Ator treatment had no effects on elevated serum cholesterol and glucose levels in HFD-fed mice. Serum creatine kinase levels and the cross-sectional area of muscle cells were not affected by HFD feeding or Ator treatment. Increased expression of PINK1-LC3 II (activated mitophagy), MFN2 (fusion), and PGC-1α (biogenesis) proteins was induced in the skeletal muscles of HFD-fed mice. Treatment with Ator inhibited PINK1 and LC3 II protein expression, but further promoted MFN1, MFN2, and OPA1 expression. The impairments in mitochondrial quality and morphology in HFD-fed mice was attenuated by treatment with Ator. Furthermore, Ator treatment enhanced glucose oxidation capacity and restored ATP production in the skeletal muscles of HFD-fed mice. The study reveals that low-dose Ator has a protective effect on muscle mitochondria in mice, likely through inhibiting mitophagy and enhancing mitochondrial fusion. This suggests that skeletal muscle mitochondria may be one of low-dose Ator-mediated protective targets.
    Keywords:  Atorvastatin; High cholesterol; High-fat diet; Mitochondria; Mitochondrial quality-control network; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.ejphar.2023.176085
  30. Nat Commun. 2023 Oct 11. 14(1): 6383
    Glucocerebrosidase mutations disrupt the lysosome and now the mitochondria.
    Andrés D Klein, Tiago Fleming Outeiro.
      
    DOI:  https://doi.org/10.1038/s41467-023-42107-7
  31. Front Endocrinol (Lausanne). 2023 ;14 1264530
    The roles of FGF21 and GDF15 in mediating the mitochondrial integrated stress response.
    Jayashree Jena, Luis Miguel García-Peña, Renata O Pereira.
      Various models of mitochondrial stress result in induction of the stress-responsive cytokines fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). This is an adaptive mechanism downstream of the mitochondrial integrated stress response frequently associated with improvements in systemic metabolic health. Both FGF21 and GDF15 have been shown to modulate energy balance and glucose homeostasis, and their pharmacological administration leads to promising beneficial effects against obesity and associated metabolic diseases in pre-clinical models. Furthermore, endogenous upregulation of FGF21 and GDF15 is associated with resistance to diet-induced obesity (DIO), improved glucose homeostasis and increased insulin sensitivity. In this review, we highlight several studies on transgenic mouse models of mitochondrial stress and will compare the specific roles played by FGF21 and GDF15 on the systemic metabolic adaptations reported in these models.
    Keywords:  FGF21; GDF15; energy balance; integrated stress response; metabolic health; mitochondrial stress
    DOI:  https://doi.org/10.3389/fendo.2023.1264530
  32. Front Immunol. 2023 ;14 1219422
    Mitochondrial dysfunctions in T cells: focus on inflammatory bowel disease.
    Hoyul Lee, Jae-Han Jeon, Eun Soo Kim.
      Mitochondria has emerged as a critical ruler of metabolic reprogramming in immune responses and inflammation. In the context of colitogenic T cells and IBD, there has been increasing research interest in the metabolic pathways of glycolysis, pyruvate oxidation, and glutaminolysis. These pathways have been shown to play a crucial role in the metabolic reprogramming of colitogenic T cells, leading to increased inflammatory cytokine production and tissue damage. In addition to metabolic reprogramming, mitochondrial dysfunction has also been implicated in the pathogenesis of IBD. Studies have shown that colitogenic T cells exhibit impaired mitochondrial respiration, elevated levels of mROS, alterations in calcium homeostasis, impaired mitochondrial biogenesis, and aberrant mitochondria-associated membrane formation. Here, we discuss our current knowledge of the metabolic reprogramming and mitochondrial dysfunctions in colitogenic T cells, as well as the potential therapeutic applications for treating IBD with evidence from animal experiments.
    Keywords:  IBD - inflammatory bowel disease; T cell; immunometabolism; inflammation; mitochondria; treatment
    DOI:  https://doi.org/10.3389/fimmu.2023.1219422
  33. Alzheimers Res Ther. 2023 Oct 11. 15(1): 171
    Mitochondrial SOS: how mtDNA may act as a stress signal in Alzheimer's disease.
    Isabelle K Gorham, Robert C Barber, Harlan P Jones, Nicole R Phillips.
      BACKGROUND: Alterations in mitochondrial DNA (mtDNA) levels have been observed in Alzheimer's disease and are an area of research that shows promise as a useful biomarker. It is well known that not only are the mitochondria a key player in producing energy for the cell, but they also are known to interact in other important intracellular processes as well as extracellular signaling and communication. BODY: This mini review explores how cells use mtDNA as a stress signal, particularly in Alzheimer's disease. We investigate the measurement of these mtDNA alterations, the mechanisms of mtDNA release, and the immunological effects from the release of these stress signals.CONCLUSION: Literature indicates a correlation between the release of mtDNA in Alzheimer's disease and increased immune responses, showing promise as a potential biomarker. However, several questions remain unanswered and there is great potential for future studies in this area.
    Keywords:  Alzheimer’s Disease; Inflammation; Mitochondria; Oxidative Stress; mtDNA
    DOI:  https://doi.org/10.1186/s13195-023-01322-6
  34. Mol Cell Biol. 2023 ;43(10): 531-546
    Mitochondrial Fragmentation Promotes Inflammation Resolution Responses in Macrophages via Histone Lactylation.
    Leah I Susser, My-Anh Nguyen, Michele Geoffrion, Christina Emerton, Mireille Ouimet, Mireille Khacho, Katey J Rayner.
      During the inflammatory response, macrophage phenotypes can be broadly classified as pro-inflammatory/classically activated "M1", or pro-resolving/alternatively "M2" macrophages. Although the classification of macrophages is general and assumes there are distinct phenotypes, in reality macrophages exist across a spectrum and must transform from a pro-inflammatory state to a proresolving state following an inflammatory insult. To adapt to changing metabolic needs of the cell, mitochondria undergo fusion and fission, which have important implications for cell fate and function. We hypothesized that mitochondrial fission and fusion directly contribute to macrophage function during the pro-inflammatory and proresolving phases. In the present study, we find that mitochondrial length directly contributes to macrophage phenotype, primarily during the transition from a pro-inflammatory to a proresolving state. Phenocopying the elongated mitochondrial network (by disabling the fission machinery using siRNA) leads to a baseline reduction in the inflammatory marker IL-1β, but a normal inflammatory response to LPS, similar to control macrophages. In contrast, in macrophages with a phenocopied fragmented phenotype (by disabling the fusion machinery using siRNA) there is a heightened inflammatory response to LPS and increased signaling through the ATF4/c-Jun transcriptional axis compared to control macrophages. Importantly, macrophages with a fragmented mitochondrial phenotype show increased expression of proresolving mediator arginase 1 and increased phagocytic capacity. Promoting mitochondrial fragmentation caused an increase in cellular lactate, and an increase in histone lactylation which caused an increase in arginase 1 expression. These studies demonstrate that a fragmented mitochondrial phenotype is critical for the proresolving response in macrophages and specifically drive epigenetic changes via lactylation of histones following an inflammatory insult.
    Keywords:  fission; fusion; histone lactylation; inflammation resolution; macrophages; mitochondrial metabolism
    DOI:  https://doi.org/10.1080/10985549.2023.2253131
  35. Biomed Pharmacother. 2023 Oct 07. pii: S0753-3322(23)01449-X. [Epub ahead of print]168 115651
    Allogeneic mitochondrial transplantation ameliorates cardiac dysfunction due to doxorubicin: An in vivo study.
    Farshid Maleki, Shahram Rabbani, Reza Shirkoohi, Mohsen Rezaei.
      Damage to the mitochondria may lead to serious conditions that are difficult to treat. Doxorubicin is one of the most widely used chemotherapeutic drugs for the treatment of malignancies in children and adults, and reportedly causes damage to the mitochondria. Unfortunately, the dangerous cardiac side effects of doxorubicin appear when the patient is in the midst of a vigorous fight against the disease, either by taking doxorubicin alone or in combination with other drugs. This study aimed to determine whether exogenous healthy and functional mitochondria are internalized by cells, can it help the survival of these cells, and can reduce cardiotoxicity. For this purpose, isolated, pure, and functional exogenous mitochondria were injected into the tail vein of a rat model of doxorubicin-induced cardiotoxicity. After that, the heart function of the rats and their antioxidant status, inflammatory markers, and histopathological examination were investigated. Our findings show that intravenous mitochondrial transplantation provided efficient mitochondrial uptake and reduced cardiotoxicity by reducing ROS production, lipid peroxidation, and inflammation. In addition, the levels of ATP and antioxidant enzymes increased after mitochondrial transplantation; therefore all of these complex processes resulted in the reduction of apoptosis and necrosis in rat heart tissue. These promising results open the way to more effective cancer treatment without the side effects of related drugs. Transplanting exogenous mitochondria probably enhances the cell's mitochondrial network, potentially treating mitochondria-related disorders such as cardiovascular and neurodegenerative diseases, although the exact relationship between mitochondrial damage and these conditions remains unclear.
    Keywords:  Cardiotoxicity; Chemotherapy; Doxorubicin; Mitochondrial transplantation; Oxidative stress
    DOI:  https://doi.org/10.1016/j.biopha.2023.115651
  36. Nucleic Acids Res. 2023 Oct 12. pii: gkad842. [Epub ahead of print]
    BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome.
    Hui Zhong, Alexandre Janer, Oleh Khalimonchuk, Hana Antonicka, Eric A Shoubridge, Antoni Barrientos.
      The human mitochondrial ribosome contains three [2Fe-2S] clusters whose assembly pathway, role, and implications for mitochondrial and metabolic diseases are unknown. Here, structure-function correlation studies show that the clusters play a structural role during mitoribosome assembly. To uncover the assembly pathway, we have examined the effect of silencing the expression of Fe-S cluster biosynthetic and delivery factors on mitoribosome stability. We find that the mitoribosome receives its [2Fe-2S] clusters from the GLRX5-BOLA3 node. Additionally, the assembly of the small subunit depends on the mitoribosome biogenesis factor METTL17, recently reported containing a [4Fe-4S] cluster, which we propose is inserted via the ISCA1-NFU1 node. Consistently, fibroblasts from subjects suffering from 'multiple mitochondrial dysfunction' syndrome due to mutations in BOLA3 or NFU1 display previously unrecognized attenuation of mitochondrial protein synthesis that contributes to their cellular and pathophysiological phenotypes. Finally, we report that, in addition to their structural role, one of the mitoribosomal [2Fe-2S] clusters and the [4Fe-4S] cluster in mitoribosome assembly factor METTL17 sense changes in the redox environment, thus providing a way to regulate organellar protein synthesis accordingly.
    DOI:  https://doi.org/10.1093/nar/gkad842
  37. Nat Rev Immunol. 2023 Oct 09.
    Illuminating the human yolk sac through single-cell omics.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-023-00957-8
  38. Sci Adv. 2023 Oct 13. 9(41): eadh1914
    A single-cell multi-omic atlas spanning the adult rhesus macaque brain.
    Cayo Biobank Research Unit
      Cataloging the diverse cellular architecture of the primate brain is crucial for understanding cognition, behavior, and disease in humans. Here, we generated a brain-wide single-cell multimodal molecular atlas of the rhesus macaque brain. Together, we profiled 2.58 M transcriptomes and 1.59 M epigenomes from single nuclei sampled from 30 regions across the adult brain. Cell composition differed extensively across the brain, revealing cellular signatures of region-specific functions. We also identified 1.19 M candidate regulatory elements, many previously unidentified, allowing us to explore the landscape of cis-regulatory grammar and neurological disease risk in a cell type-specific manner. Altogether, this multi-omic atlas provides an open resource for investigating the evolution of the human brain and identifying novel targets for disease interventions.
    DOI:  https://doi.org/10.1126/sciadv.adh1914
  39. Exp Hematol. 2023 Oct 11. pii: S0301-472X(23)01736-8. [Epub ahead of print]
    The multifaceted role of mitochondria in HSC fate decisions: energy and beyond.
    Marie-Dominique Filippi.
      Hematopoietic stem cells (HSCs) have the properties to self-renew and/or differentiate into all mature blood cell lineages. The fate decisions to generate progeny that retain stemness properties or that commit to differentiation is a fundamental process to maintain tissue homeostasis and must be tightly regulated in order to prevent HSC overgrowth or exhaustion. HSC fate decisions are inherently coupled to cell division. The transition from quiescence to activation is accompanied by major metabolic and mitochondrial changes that are important for cell cycle entry for balanced decisions between self-renewal and differentiation. In this review, we discuss the current understanding of the role of mitochondrial metabolism in HSC transition from quiescence to activation and fate decisions.
    DOI:  https://doi.org/10.1016/j.exphem.2023.10.001
  40. Science. 2023 Oct 13. 382(6667): eadf6812
    Transcriptomic cytoarchitecture reveals principles of human neocortex organization.
    Nikolas L Jorstad, Jennie Close, Nelson Johansen, Anna Marie Yanny, Eliza R Barkan, Kyle J Travaglini, Darren Bertagnolli, Jazmin Campos, Tamara Casper, Kirsten Crichton, Nick Dee, Song-Lin Ding, Emily Gelfand, Jeff Goldy, Daniel Hirschstein, Katelyn Kiick, Matthew Kroll, Michael Kunst, Kanan Lathia, Brian Long, Naomi Martin, Delissa McMillen, Trangthanh Pham, Christine Rimorin, Augustin Ruiz, Nadiya Shapovalova, Soraya Shehata, Kimberly Siletti, Saroja Somasundaram, Josef Sulc, Michael Tieu, Amy Torkelson, Herman Tung, Edward M Callaway, Patrick R Hof, C Dirk Keene, Boaz P Levi, Sten Linnarsson, Partha P Mitra, Kimberly Smith, Rebecca D Hodge, Trygve E Bakken, Ed S Lein.
      Variation in cytoarchitecture is the basis for the histological definition of cortical areas. We used single cell transcriptomics and performed cellular characterization of the human cortex to better understand cortical areal specialization. Single-nucleus RNA-sequencing of 8 areas spanning cortical structural variation showed a highly consistent cellular makeup for 24 cell subclasses. However, proportions of excitatory neuron subclasses varied substantially, likely reflecting differences in connectivity across primary sensorimotor and association cortices. Laminar organization of astrocytes and oligodendrocytes also differed across areas. Primary visual cortex showed characteristic organization with major changes in the excitatory to inhibitory neuron ratio, expansion of layer 4 excitatory neurons, and specialized inhibitory neurons. These results lay the groundwork for a refined cellular and molecular characterization of human cortical cytoarchitecture and areal specialization.
    DOI:  https://doi.org/10.1126/science.adf6812
  41. Cells. 2023 Oct 03. pii: 2397. [Epub ahead of print]12(19):
    Mitochondrial Dysfunction and Decreased Cytochrome c in Cell and Animal Models of Machado-Joseph Disease.
    Filipa Almeida, Ildete L Ferreira, Luana Naia, Daniela Marinho, Ana Catarina Vilaça-Ferreira, Marta D Costa, Sara Duarte-Silva, Patrícia Maciel, A Cristina Rego.
      Mitochondrial dysfunction has been described in many neurodegenerative disorders; however, there is less information regarding mitochondrial deficits in Machado-Joseph disease (MJD), a polyglutamine (polyQ) disorder caused by CAG repeat expansion in the ATXN3 gene. In the present study, we characterized the changes in mitochondrial function and biogenesis markers in two MJD models, CMVMJD135 (MJD135) transgenic mice at a fully established phenotype stage and tetracycline-regulated PC6-3 Q108 cell line expressing mutant ataxin-3 (mATXN3). We detected mATXN3 in the mitochondrial fractions of PC6-3 Q108 cells, suggesting the interaction of expanded ATXN3 with the organelle. Interestingly, in both the cerebella of the MJD135 mouse model and in PC6-3 Q108 cells, we found decreased mitochondrial respiration, ATP production and mitochondrial membrane potential, strongly suggesting mitochondrial dysfunction in MJD. Also, in PC6-3 Q108 cells, an additional enhanced glycolytic flux was observed. Supporting the functional deficits observed in MJD mitochondria, MJD135 mouse cerebellum and PC6-3 Q108 cells showed reduced cytochrome c mRNA and protein levels. Overall, our findings show compromised mitochondrial function associated with decreased cytochrome c levels in both cell and animal models of MJD.
    Keywords:  Machado–Joseph disease; calcium handling; mitochondrial membrane potential; mitochondrial transcription; oxygen consumption
    DOI:  https://doi.org/10.3390/cells12192397
  42. Elife. 2023 Oct 11. pii: e86452. [Epub ahead of print]12
    GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes.
    Jayashree Jena, Luis Miguel García-Peña, Eric T Weatherford, Alex Marti, Sarah H Bjorkman, Kevin Kato, Jivan Koneru, Jason H Chen, Randy J Seeley, E Dale Abel, Renata O Pereira.
      We previously reported that mice lacking the protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) display induction of the activating transcription factor 4 (ATF4), which promotes fibroblast growth factor 21 (FGF21) secretion as a batokine. FGF21 increases metabolic rates under baseline conditions but is dispensable for the resistance to diet-induced obesity (DIO) reported in OPA1 BKO mice (Pereira et al., 2021). To determine alternative mediators of this phenotype, we performed transcriptome analysis, which revealed increased levels of growth differentiation factor 15 (GDF15), along with increased protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) levels in BAT. To investigate whether ATF4 induction was mediated by PERK and evaluate the contribution of GDF15 to the resistance to DIO, we selectively deleted PERK or GDF15 in OPA1 BKO mice. Mice with reduced OPA1 and PERK levels in BAT had preserved ISR activation. Importantly, simultaneous deletion of OPA1 and GDF15 partially reversed the resistance to DIO and abrogated the improvements in glucose tolerance. Furthermore, GDF15 was required to improve cold-induced thermogenesis in OPA1 BKO mice. Taken together, our data indicate that PERK is dispensable to induce the ISR, but GDF15 contributes to the resistance to DIO, and is required for glucose homeostasis and thermoregulation in OPA1 BKO mice by increasing energy expenditure.
    Keywords:  GDF15; PERK; biochemistry; brown adipose tissue; chemical biology; integrated stress response; mitochondrial stress; mouse
    DOI:  https://doi.org/10.7554/eLife.86452
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