bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2021–12–19
twenty-one papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. The mining and construction of a knowledge base for gene-disease association in mitochondrial diseases.
  2. Multifaceted Roles of Mitochondrial Stress Responses under ETC Dysfunction - Repair, Destruction and Pathogenesis.
  3. Dysfunctional mitochondrial translation and combined oxidative phosphorylation deficiency in a mouse model of hepatoencephalopathy due to Gfm1 mutations.
  4. The role of mitochondrial dynamics in mtDNA maintenance.
  5. Mitochondria Dysfunction in Frontotemporal Dementia/Amyotrophic Lateral Sclerosis: Lessons From Drosophila Models.
  6. Cristae junction as a fundamental switchboard for mitochondrial ion signaling and bioenergetics.
  7. IGFBP-3 functions as a molecular switch that mediates mitochondrial and metabolic homeostasis.
  8. Mitochondrial Transfer in Cardiovascular Disease: From Mechanisms to Therapeutic Implications.
  9. Seizure Semiology, EEG, and Imaging Findings in Epilepsy Secondary to Mitochondrial Disease.
  10. Altered cardiac mitochondrial dynamics and biogenesis in rat after short-term cocaine administration.
  11. SSBP1-Disease Update: Expanding the Genetic and Clinical Spectrum, Reporting Variable Penetrance and Confirming Recessive Inheritance.
  12. Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy.
  13. Murine cerebral organoids develop network of functional neurons and hippocampal brain region identity.
  14. Lower citrate synthase activity, mitochondrial complex expression, and fewer oxidative myofibers characterize skeletal muscle from growth restricted fetal sheep.
  15. Molecular biomarkers correlate with brain grey and white matter changes in patients with mitochondrial m.3243A > G mutation.
  16. A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic tau mouse model of Alzheimer disease.
  17. Isolation of Mitochondria From Fresh Mice Lung Tissue.
  18. Autophagy in healthy aging and disease.
  19. Genetically encoded biosensors for evaluating NAD+/NADH ratio in cytosolic and mitochondrial compartments.
  20. Why do cells need oxygen? Insights from mitochondrial composition and function.
  21. MRE11-dependent instability in mitochondrial DNA fork protection activates a cGAS immune signaling pathway.
  1. Sci Rep. 2021 Dec 13. 11(1): 23909
    The mining and construction of a knowledge base for gene-disease association in mitochondrial diseases.
    Wei Wang, Junying Song, Yunhai Chuai, Fu Chen, Chunlan Song, Mingming Shu, Yayun Wang, Yunfei Li, Xinyu Zhai, Shujie Han, Shun Yao, Kexin Shen, Wei Shang, Lei Zhang.
      Mitochondrial diseases are a group of heterogeneous genetic metabolic diseases caused by mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) gene mutations. Mining the gene-disease association of mitochondrial diseases is helpful for understanding the pathogenesis of mitochondrial diseases, for carrying out early clinical diagnosis for related diseases, and for formulating better treatment strategies for mitochondrial diseases. This project researched the relationship between genes and mitochondrial diseases, combined the Malacards, Genecards, and MITOMAP disease databases to mine the knowledge on mitochondrial diseases and genes, used database integration and the sequencing method of the phenolyzer tool to integrate disease-related genes from different databases, and sorted the disease-related candidate genes. Finally, we screened 531 mitochondrial related diseases, extracted 26,723 genes directly or indirectly related to mitochondria, collected 24,602 variant sites on 1474 genes, and established a mitochondrial disease knowledge base (MitDisease) with a core of genes, diseases, and variants. This knowledge base is helpful for clinicians who want to combine the results of gene testing for diagnosis, to understand the occurrence and development of mitochondrial diseases, and to develop corresponding treatment methods.
    DOI:  https://doi.org/10.1038/s41598-021-03249-0
  2. FEBS J. 2021 Dec 16.
    Multifaceted Roles of Mitochondrial Stress Responses under ETC Dysfunction - Repair, Destruction and Pathogenesis.
    Shanshan Liu, Siqi Liu, Hui Jiang.
      Electron transport chain (ETC) dysfunction is a common feature of mitochondrial diseases and induces severe cellular stresses, including mitochondrial membrane potential (Δψm ) reduction, mitochondrial matrix acidification, metabolic derangements and proteostatic stresses. Extensive studies of ETC dysfunction in yeast, C. elegans, cultured cells and mouse models have revealed multiple mitochondrial stress response pathways. Here, we summarize the current understanding of the triggers, sensors, signaling mechanisms, and the functional outcomes of mitochondrial stress responses in different species. We highlight Δψm reduction as a major trigger of stress responses in different species, but the responses are species-specific and the outcomes are context-dependent. ETC dysfunction elicits a mitochondrial unfolded protein response (UPRmt ) to repair damaged mitochondria in C. elegans, and activates a global adaptive program to maintain Δψm in yeast. Yeast and C. elegans responses are remarkably similar at the downstream responses, although they are activated by different signaling mechanisms. UPRmt generally protects ETC-defective worms, but its constitutive activation is toxic for wildtype worms and worms carrying mutant mtDNA. In contrast to lower organisms, ETC dysfunction in mammals mainly activates a mitochondrial integrated stress response (ISRmt ) to reprogram metabolism and a PINK1-Parkin mitophagy pathway to degrade damaged mitochondria. Accumulating in vivo results suggest that the ATF4 branch of ISRmt exacerbates metabolic derangements to accelerate mitochondrial disease progression. The in vivo roles of mitophagy in mitochondrial diseases are also context-dependent. These results thus reveal the common and unique aspects of mitochondrial stress responses in different species and highlight their multifaceted roles in mitochondrial diseases.
    Keywords:  ISRmt; Mitochondrial stress response; UPRmt; mitochondrial membrane potential; mitophagy
    DOI:  https://doi.org/10.1111/febs.16323
  3. FASEB J. 2022 Jan;36(1): e22091
    Dysfunctional mitochondrial translation and combined oxidative phosphorylation deficiency in a mouse model of hepatoencephalopathy due to Gfm1 mutations.
    Miguel Molina-Berenguer, Ferran Vila-Julià, Sandra Pérez-Ramos, Maria Teresa Salcedo-Allende, Yolanda Cámara, Javier Torres-Torronteras, Ramon Martí.
      Hepatoencephalopathy due to combined oxidative phosphorylation deficiency type 1 (COXPD1) is a recessive mitochondrial translation disorder caused by mutations in GFM1, a nuclear gene encoding mitochondrial elongation factor G1 (EFG1). Patients with COXPD1 typically present hepatoencephalopathy early after birth with rapid disease progression, and usually die within the first few weeks or years of life. We have generated two different mouse models: a Gfm1 knock-in (KI) harboring the p.R671C missense mutation, found in at least 10 patients who survived more than 1 year, and a Gfm1 knock-out (KO) model. Homozygous KO mice (Gfm1-/- ) were embryonically lethal, whereas homozygous KI (Gfm1R671C / R671C ) mice were viable and showed normal growth. R671C mutation in Gfm1 caused drastic reductions in the mitochondrial EFG1 protein content in different organs. Six- to eight-week-old Gfm1R671C / R671C mice showed partial reductions of in organello mitochondrial translation and respiratory complex IV enzyme activity in the liver. Compound heterozygous Gfm1R671C /- showed a more pronounced decrease of EFG1 protein in liver and brain mitochondria, as compared with Gfm1R671C / R671C mice. At 8 weeks of age, their mitochondrial translation rates were significantly reduced in both tissues. Additionally, Gfm1R671C /- mice showed combined oxidative phosphorylation deficiency (reduced complex I and IV enzyme activities in liver and brain), and blue native polyacrylamide gel electrophoresis analysis revealed lower amounts of both affected complexes. We conclude that the compound heterozygous Gfm1R671C /- mouse presents a clear dysfunctional molecular phenotype, showing impaired mitochondrial translation and combined respiratory chain dysfunction, making it a suitable animal model for the study of COXPD1.
    Keywords:   Gfm1 ; COXPD1; animal model; elongation factor G1; mitochondria; translation
    DOI:  https://doi.org/10.1096/fj.202100819RRR
  4. J Cell Sci. 2021 Dec 15. pii: jcs258944. [Epub ahead of print]134(24):
    The role of mitochondrial dynamics in mtDNA maintenance.
    Rasha Sabouny, Timothy E Shutt.
      The dynamic nature of mitochondria, which can fuse, divide and move throughout the cell, allows these critical organelles to adapt their function in response to cellular demands, and is also important for regulating mitochondrial DNA (mtDNA). While it is established that impairments in mitochondrial fusion and fission impact the mitochondrial genome and can lead to mtDNA depletion, abnormal nucleoid organization or accumulation of deletions, it is not entirely clear how or why remodeling mitochondrial network morphology affects mtDNA. Here, we focus on recent advances in our understanding of how mitochondrial dynamics contribute to the regulation of mtDNA and discuss links to human disease.
    Keywords:  Fission; Fusion; Mitochondria; Mitochondrial dynamics; Mitophagy; mtDNA
    DOI:  https://doi.org/10.1242/jcs.258944
  5. Front Neurosci. 2021 ;15 786076
    Mitochondria Dysfunction in Frontotemporal Dementia/Amyotrophic Lateral Sclerosis: Lessons From Drosophila Models.
    Sharifah Anoar, Nathaniel S Woodling, Teresa Niccoli.
      Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by declining motor and cognitive functions. Even though these diseases present with distinct sets of symptoms, FTD and ALS are two extremes of the same disease spectrum, as they show considerable overlap in genetic, clinical and neuropathological features. Among these overlapping features, mitochondrial dysfunction is associated with both FTD and ALS. Recent studies have shown that cells derived from patients' induced pluripotent stem cells (iPSC)s display mitochondrial abnormalities, and similar abnormalities have been observed in a number of animal disease models. Drosophila models have been widely used to study FTD and ALS because of their rapid generation time and extensive set of genetic tools. A wide array of fly models have been developed to elucidate the molecular mechanisms of toxicity for mutations associated with FTD/ALS. Fly models have been often instrumental in understanding the role of disease associated mutations in mitochondria biology. In this review, we discuss how mutations associated with FTD/ALS disrupt mitochondrial function, and we review how the use of Drosophila models has been pivotal to our current knowledge in this field.
    Keywords:  ALS; Drosophila; FTD; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.3389/fnins.2021.786076
  6. Cell Calcium. 2021 Dec 10. pii: S0143-4160(21)00171-8. [Epub ahead of print]101 102517
    Cristae junction as a fundamental switchboard for mitochondrial ion signaling and bioenergetics.
    Benjamin Gottschalk, Corina T Madreiter-Sokolowski, Wolfgang F Graier.
      OPA1 and MICU1 are both involved in the regulation of mitochondrial Ca2+ uptake and the stabilization of the cristae junction, which separates the inner mitochondrial membrane into the interboundary membrane and the cristae membrane. In this mini-review, we focus on the synergetic control of OPA1 and MICU1 on the cristae junction that serves as a fundamental regulator of multiple mitochondrial functions. In particular, we point to the critical role of an adaptive cristae junction permeability in mitochondrial Ca2+ signaling, spatial H+ gradients and mitochondrial membrane potential, metabolic activity, and apoptosis. These characteristics bear on a distinct localization of the oxidative phosphorylation machinery, the FoF1-ATPase, and mitochondrial Ca2+uniporter (MCU) within sections of the inner mitochondrial membrane isolated by the cristae junction and regulated by proteins like OPA1 and MICU1. We specifically focus on the impact of MICU1-regulated cristae junction on the activity and distribution of MCU within the complex ultrastructure of mitochondria.
    DOI:  https://doi.org/10.1016/j.ceca.2021.102517
  7. FASEB J. 2022 Jan;36(1): e22062
    IGFBP-3 functions as a molecular switch that mediates mitochondrial and metabolic homeostasis.
    Whitney L Stuard, Rossella Titone, Danielle M Robertson.
      Mitochondrial dysfunction or loss of homeostasis is a central hallmark of many human diseases. Mitochondrial homeostasis is mediated by multiple quality control mechanisms including mitophagy, a form of selective autophagy that recycles terminally ill or dysfunctional mitochondria in order to preserve mitochondrial integrity. Our prior studies have shown that members of the insulin-like growth factor (IGF) family localize to the mitochondria and may play important roles in mediating mitochondrial health in the corneal epithelium, an integral tissue that is required for the maintenance of optical transparency and vision. Importantly, the IGF-binding protein-3, IGFBP-3, is secreted by corneal epithelial cells in response to stress and functions to mediate intracellular receptor trafficking in this cell type. In this study, we demonstrate a novel role for IGFBP-3 in mitochondrial homeostasis through regulation of the short isoform (s)BNIP3L/NIX mitophagy receptor in corneal epithelial cells and extend this finding to non-ocular epithelial cells. We further show that IGFBP-3-mediated control of mitochondrial homeostasis is associated with alterations in lamellar cristae morphology and mitochondrial dynamics. Interestingly, both loss and gain of function of IGFBP-3 drive an increase in mitochondrial respiration. This increase in respiration is associated with nuclear accumulation of IGFBP-3. Taken together, these findings support a novel role for IGFBP-3 as a key mediator of mitochondrial health in mucosal epithelia through the regulation of mitophagy and mitochondrial morphology.
    Keywords:  autophagy; insulin-like growth factor type 1 receptor; mTOR; metabolism; mitochondria
    DOI:  https://doi.org/10.1096/fj.202100710RR
  8. Front Cardiovasc Med. 2021 ;8 771298
    Mitochondrial Transfer in Cardiovascular Disease: From Mechanisms to Therapeutic Implications.
    Jun Chen, Jinjie Zhong, Lin-Lin Wang, Ying-Ying Chen.
      Mitochondrial dysfunction has been proven to play a critical role in the pathogenesis of cardiovascular diseases. The phenomenon of intercellular mitochondrial transfer has been discovered in the cardiovascular system. Studies have shown that cell-to-cell mitochondrial transfer plays an essential role in regulating cardiovascular system development and maintaining normal tissue homeostasis under physiological conditions. In pathological conditions, damaged cells transfer dysfunctional mitochondria toward recipient cells to ask for help and take up exogenous functional mitochondria to alleviate injury. In this review, we summarized the mechanism of mitochondrial transfer in the cardiovascular system and outlined the fate and functional role of donor mitochondria. We also discussed the advantage and challenges of mitochondrial transfer strategies, including cell-based mitochondrial transplantation, extracellular vesicle-based mitochondrial transplantation, and naked mitochondrial transplantation, for the treatment of cardiovascular disorders. We hope this review will provide perspectives on mitochondrial-targeted therapeutics in cardiovascular diseases.
    Keywords:  cardiovascular disease; extracellular vesicles; mitochondria; mitochondrial transfer; mitochondrial transplantation; tunneling nanotubes
    DOI:  https://doi.org/10.3389/fcvm.2021.771298
  9. Front Neurol. 2021 ;12 779052
    Seizure Semiology, EEG, and Imaging Findings in Epilepsy Secondary to Mitochondrial Disease.
    Anthony L Fine, Greta Liebo, Ralitza H Gavrilova, Jeffrey W Britton.
      Background: Identification of an underlying mitochondrial disorder can be challenging due to the significant phenotypic variability between and within specific disorders. Epilepsy can be a presenting symptom with several mitochondrial disorders. In this study, we evaluated clinical, electrophysiologic, and imaging features in patients with epilepsy and mitochondrial disorders to identify common features, which could aid in earlier identification of a mitochondrial etiology. Methods: This is a retrospective case series from January 2011 to December 2019 at a tertiary referral center of patients with epilepsy and a genetically confirmed diagnosis of a mitochondrial disorder. A total of 164 patients were reviewed with 20 patients fulfilling inclusion criteria. Results: A total of 20 patients (14 females, 6 males) aged 0.5-61 years with epilepsy and genetically confirmed mitochondrial disorders were identified. Status epilepticus occurred in 15 patients, with focal status epilepticus in 13 patients, including 9 patients with visual features. Abnormalities over the posterior cerebral regions were seen in 66% of ictal recordings and 44% of imaging studies. All the patients were on nutraceutical supplementation with no significant change in disease progression seen. At last follow-up, eight patients were deceased and the remainder had moderate-to-severe disability. Discussion: In this series of patients with epilepsy and mitochondrial disorders, we found increased propensity for seizures arising from the posterior cerebral regions. Over time, electroencephalogram (EEG) and imaging abnormalities increasingly occurred over the posterior cerebral regions. Focal seizures and focal status epilepticus with visual symptoms were common. Additional study is needed on nutraceutical supplementation in mitochondrial disorders.
    Keywords:  EEG; epilepsy; genetic; mitochondria; neuroimaging
    DOI:  https://doi.org/10.3389/fneur.2021.779052
  10. Sci Rep. 2021 Dec 16. 11(1): 24129
    Altered cardiac mitochondrial dynamics and biogenesis in rat after short-term cocaine administration.
    Shuheng Wen, Kana Unuma, Takeshi Funakoshi, Toshihiko Aki, Koichi Uemura.
      Abuse of the potent psychostimulant cocaine is widely established to have cardiovascular consequences. The cardiotoxicity of cocaine is mainly associated with oxidative stress and mitochondrial dysfunction. Mitochondrial dynamics and biogenesis, as well as the mitochondrial unfolded protein response (UPRmt), guarantee cardiac mitochondrial homeostasis. Collectively, these mechanisms act to protect against stress, injury, and the detrimental effects of chemicals on mitochondria. In this study, we examined the effects of cocaine on cardiac mitochondrial dynamics, biogenesis, and UPRmt in vivo. Rats administered cocaine via the tail vein at a dose of 20 mg/kg/day for 7 days showed no structural changes in the myocardium, but electron microscopy revealed a significant increase in the number of cardiac mitochondria. Correspondingly, the expressions of the mitochondrial fission gene and mitochondrial biogenesis were increased after cocaine administration. Significant increase in the expression and nuclear translocation of activating transcription factor 5, the major active regulator of UPRmt, were observed after cocaine administration. Accordingly, our findings show that before any structural changes are observable in the myocardium, cocaine alters mitochondrial dynamics, elevates mitochondrial biogenesis, and induces the activation of UPRmt. These alterations might reflect cardiac mitochondrial compensation to protect against the cardiotoxicity of cocaine.
    DOI:  https://doi.org/10.1038/s41598-021-03631-y
  11. Invest Ophthalmol Vis Sci. 2021 Dec 01. 62(15): 12
    SSBP1-Disease Update: Expanding the Genetic and Clinical Spectrum, Reporting Variable Penetrance and Confirming Recessive Inheritance.
    Genomics England Research Consortium
       Purpose: To report novel genotypes and expand the phenotype spectrum of SSBP1-disease and explore potential disease mechanism.
    Methods: Five families with previously unsolved optic atrophy and retinal dystrophy underwent whole genome sequencing as part of the National Institute for Health Research BioResource Rare-Diseases and the UK's 100,000 Genomes Project. In silico analysis and protein modelling was performed on the identified variants. Deep phenotyping including retinal imaging and International Society for Clinical Electrophysiology of Vision standard visual electrophysiology was performed.
    Results: Seven individuals from five unrelated families with bilateral optic atrophy and/or retinal dystrophy with extraocular signs and symptoms in some are described. In total, 6 SSBP1 variants were identified including the previously unreported variants: c.151A>G, p.(Lys51Glu), c.335G>A p.(Gly112Glu), and c.380G>A, p.(Arg127Gln). One individual was found to carry biallelic variants (c.380G>A p.(Arg127Gln); c.394A>G p.(Ile132Val)) associated with likely autosomal recessive SSBP1-disease. In silico analysis predicted all variants to be pathogenic and Three-dimensional protein modelling suggested possible disease mechanisms via decreased single-stranded DNA binding affinity or impaired higher structure formation.
    Conclusions: SSBP1 is essential for mitochondrial DNA replication and maintenance, with defects leading to a spectrum of disease that includes optic atrophy and/or retinal dystrophy, occurring with or without extraocular features. This study provides evidence of intrafamilial variability and confirms the existence of an autosomal recessive inheritance in SSBP1-disease consequent upon a previously unreported genotype.
    DOI:  https://doi.org/10.1167/iovs.62.15.12
  12. Brain Commun. 2021 ;3(4): fcab245
    Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy.
    Italian Undiagnosed Diseases Network
      The vacuolar H+-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in ATP6V0A1, the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four individuals. Here, we identified 17 individuals from 14 unrelated families with both with new and previously characterized variants in this gene, representing the largest cohort to date. Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals carried de novo missense variants and showed severe developmental and epileptic encephalopathy. The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction and severe developmental defect in Caenorhabditis elegans. Altogether, our findings further expand the neurological phenotype associated with variants in this gene and provide a direct link with endolysosomal acidification in the pathophysiology of ATP6V0A1-related conditions.
    Keywords:  Caenorhabditis elegans disease modelling; V-ATPase; epileptic encephalopathy; lysosomal disease; organelle acidification
    DOI:  https://doi.org/10.1093/braincomms/fcab245
  13. iScience. 2021 Dec 17. 24(12): 103438
    Murine cerebral organoids develop network of functional neurons and hippocampal brain region identity.
    Francesca Ciarpella, Raluca Georgiana Zamfir, Alessandra Campanelli, Elisa Ren, Giulia Pedrotti, Emanuela Bottani, Andrea Borioli, Davide Caron, Marzia Di Chio, Sissi Dolci, Annika Ahtiainen, Giorgio Malpeli, Giovanni Malerba, Rita Bardoni, Guido Fumagalli, Jari Hyttinen, Francesco Bifari, Gemma Palazzolo, Gabriella Panuccio, Giulia Curia, Ilaria Decimo.
      Brain organoids are in vitro three-dimensional (3D) self-organized neural structures, which can enable disease modeling and drug screening. However, their use for standardized large-scale drug screening studies is limited by their high batch-to-batch variability, long differentiation time (10-20 weeks), and high production costs. This is particularly relevant when brain organoids are obtained from human induced pluripotent stem cells (iPSCs). Here, we developed, for the first time, a highly standardized, reproducible, and fast (5 weeks) murine brain organoid model starting from embryonic neural stem cells. We obtained brain organoids, which progressively differentiated and self-organized into 3D networks of functional neurons with dorsal forebrain phenotype. Furthermore, by adding the morphogen WNT3a, we generated brain organoids with specific hippocampal region identity. Overall, our results showed the establishment of a fast, robust and reproducible murine 3D in vitro brain model that may represent a useful tool for high-throughput drug screening and disease modeling.
    Keywords:  Biological sciences; Cell biology; Developmental biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2021.103438
  14. Am J Physiol Regul Integr Comp Physiol. 2021 Dec 15.
    Lower citrate synthase activity, mitochondrial complex expression, and fewer oxidative myofibers characterize skeletal muscle from growth restricted fetal sheep.
    Jane Stremming, Eileen Chang, Leslie A Knaub, Michael L Armstrong, Peter R Baker, Stephanie R Wesolowski, Nichole Reisdorph, Jane E B Reusch, Laura D Brown.
      Skeletal muscle from the late gestation sheep fetus with intrauterine growth restriction (IUGR) has evidence of reduced oxidative metabolism. Using a sheep model of placental insufficiency and IUGR, we tested the hypothesis that by late gestation, IUGR fetal skeletal muscle has reduced capacity for oxidative phosphorylation due to intrinsic deficits in mitochondrial respiration. We measured mitochondrial respiration in permeabilized muscle fibers from biceps femoris (BF) and soleus (SOL) from control and IUGR fetal sheep. Using muscles including BF, SOL, tibialis anterior (TA), and flexor digitorum superficialis (FDS), we measured citrate synthase (CS) activity, mitochondrial complex subunit abundance, fiber type distribution, and gene expression of regulators of mitochondrial biosynthesis. Ex vivo mitochondrial respiration was similar in control and IUGR muscle. However, CS activity was lower in IUGR BF and TA, indicating lower mitochondrial content, and protein expression of individual mitochondrial complex subunits was lower in IUGR TA and BF in a muscle specific pattern. IUGR TA, BF, and FDS also had lower expression of type I oxidative fibers. Fiber type shifts that support glycolytic instead of oxidative metabolism may be advantageous for the IUGR fetus in a hypoxic and nutrient deficient environment, whereas these adaptions may be maladaptive in postnatal life.
    Keywords:  fetal growth restriction; fetal programming; fiber type; mitochondria; nucleotides
    DOI:  https://doi.org/10.1152/ajpregu.00222.2021
  15. Mol Genet Metab. 2021 Nov 30. pii: S1096-7192(21)00830-1. [Epub ahead of print]
    Molecular biomarkers correlate with brain grey and white matter changes in patients with mitochondrial m.3243A > G mutation.
    Stefania Evangelisti, Laura Ludovica Gramegna, Chiara La Morgia, Lidia Di Vito, Alessandra Maresca, Lia Talozzi, Claudio Bianchini, Micaela Mitolo, David Neil Manners, Leonardo Caporali, Maria Lucia Valentino, Rocco Liguori, Valerio Carelli, Raffaele Lodi, Claudia Testa, Caterina Tonon.
       INTRODUCTION: The mitochondrial DNA (mtDNA) m.3243A > G mutation in the MT-TL1 gene results in a multi-systemic disease, that is commonly associated with neurodegenerative changes in the brain.
    METHODS: Seventeen patients harboring the m3243A > G mutation were enrolled (age 43.1 ± 11.4 years, 10 M/7F). A panel of plasma biomarkers including lactate acid, alanine, L-arginine, fibroblast growth factor 21 (FGF-21), growth/differentiation factor 15 (GDF-15) and circulating cell free -mtDNA (ccf-mtDNA), as well as blood, urine and muscle mtDNA heteroplasmy were evaluated. Patients also underwent a brain standardized MR protocol that included volumetric T1-weighted images and diffusion-weighted MRI. Twenty sex- and age-matched healthy controls were included. Voxel-wise analysis was performed on T1-weighted and diffusion imaging, respectively with VBM (voxel-based morphometry) and TBSS (Tract-based Spatial Statistics). Ventricular lactate was also evaluated by 1H-MR spectroscopy.
    RESULTS: A widespread cortical gray matter (GM) loss was observed, more severe (p < 0.001) in the bilateral calcarine, insular, frontal and parietal cortex, along with infratentorial cerebellar cortex. High urine mtDNA mutation load, high levels of plasma lactate and alanine, low levels of plasma arginine, high levels of serum FGF-21 and ventricular lactate accumulation significantly (p < 0.05) correlated with the reduced brain GM density. Widespread microstructural alterations were highlighted in the white matter, significantly (p < 0.05) correlated with plasma alanine and arginine levels, with mtDNA mutation load in urine, with high level of serum GDF-15 and with high content of plasma ccf-mtDNA.
    CONCLUSIONS: Our results suggest that the synergy of two pathogenic mechanisms, mtDNA-related mitochondrial respiratory deficiency and defective nitric oxide metabolism, contributes to the brain neurodegeneration in m.3243A > G patients.
    Keywords:  Brain gray matter atrophy; Brain white matter microstructure; M.3243A > G mutation; MR neuroimaging; Molecular biomarkers
    DOI:  https://doi.org/10.1016/j.ymgme.2021.11.012
  16. Hum Mol Genet. 2021 Dec 17. pii: ddab360. [Epub ahead of print]
    A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic tau mouse model of Alzheimer disease.
    Ramesh Kandimalla, Maria Manczak, Jangampalli Adi Pradeepkiran, Hallie Morton, P Hemachandra Reddy.
      The purpose of our study is to understand the impact of a partial dynamin-related protein 1 (Drp1) on cognitive behavior, mitophagy, autophagy, and mitochondrial and synaptic activities in transgenic Tau mice in Alzheimer's disease (ad). Our lab reported increased levels of Aβ and P-Tau, and abnormal interactions between Aβ and Drp1, P-Tau, and Drp1 induced increased mitochondrial fragmentation and reduced fusion and synaptic activities in ad. These abnormal interactions, result in the proliferation of dysfunctional mitochondria in ad neurons. Recent research on mitochondria revealed that fission protein Drp1 is largely implicated in mitochondrial dynamics in ad. To determine the impact of reduced Drp1 in ad, we recently crossed transgenic Tau mice with Drp1 heterozygote knockout (Drp1+/-) mice and generated double mutant (P301LDrp1+/-) mice. In the current study, we assessed cognitive behavior, mRNA and protein levels of mitophagy, autophagy, mitochondrial biogenesis, dynamics and synaptic genes, mitochondrial morphology & mitochondrial function, dendritic spines in Tau mice relative to double mutant mice. When compared to Tau mice, double mutant mice did better on Morris Maze (reduced latency to find hidden platform, increased swimming speed and time spent on quadrant) and rotarod (stayed a longer period of time) tests. Both mRNA and proteins levels autophagy, mitophagy, mitochondrial biogenesis and synaptic proteins were increased in double mutant mice compared to Tau (P301L) mice. Dendritic spines were significantly increased; mitochondrial number is reduced and length is increased in double mutant mice. Based on these observations, we conclude that reduced Drp1 is beneficial in a symptomatic-transgenic Tau (P301L) mice.
    Keywords:  Mitochondria Alzheimer’s disease Mitophagy Autophagy Dynamin-related protein 1 Oxidative stress Mitochondrial biogenesis
    DOI:  https://doi.org/10.1093/hmg/ddab360
  17. Front Physiol. 2021 ;12 748261
    Isolation of Mitochondria From Fresh Mice Lung Tissue.
    Dayene de Assis Fernandes Caldeira, Dahienne Ferreira de Oliveira, João Paulo Cavalcanti-de-Albuquerque, Jose Hamilton Matheus Nascimento, Walter Araujo Zin, Leonardo Maciel.
      Direct analysis of isolated mitochondria enables a better understanding of lung dysfunction. Despite well-defined mitochondrial isolation protocols applicable to other tissues, such as the brain, kidney, heart, and liver, a robust and reproductive protocol has not yet been advanced for the lung. We describe a protocol for the isolation of mitochondria from lung tissue aiming for functional analyses of mitochondrial O2 consumption, transmembrane potential, reactive oxygen species (ROS) formation, ATP production, and swelling. We compared our protocol to that used for heart mitochondrial function that is well-established in the literature, and achieved similar results.
    Keywords:  ATP; O2-consumption; ROS; lung mitochondria isolation; mitochondrial assessment
    DOI:  https://doi.org/10.3389/fphys.2021.748261
  18. Nat Aging. 2021 Aug;1(8): 634-650
    Autophagy in healthy aging and disease.
    Yahyah Aman, Tomas Schmauck-Medina, Malene Hansen, Richard I Morimoto, Anna Katharina Simon, Ivana Bjedov, Konstantinos Palikaras, Anne Simonsen, Terje Johansen, Nektarios Tavernarakis, David C Rubinsztein, Linda Partridge, Guido Kroemer, John Labbadia, Evandro F Fang.
      Autophagy is a fundamental cellular process that eliminates molecules and subcellular elements, including nucleic acids, proteins, lipids and organelles, via lysosome-mediated degradation to promote homeostasis, differentiation, development and survival. While autophagy is intimately linked to health, the intricate relationship among autophagy, aging and disease remains unclear. This Review examines several emerging features of autophagy and postulates how they may be linked to aging as well as to the development and progression of disease. In addition, we discuss current preclinical evidence arguing for the use of autophagy modulators as suppressors of age-related pathologies such as neurodegenerative diseases. Finally, we highlight key questions and propose novel research avenues that will likely reveal new links between autophagy and the hallmarks of aging. Understanding the precise interplay between autophagy and the risk of age-related pathologies across organisms will eventually facilitate the development of clinical applications that promote long-term health.
    DOI:  https://doi.org/10.1038/s43587-021-00098-4
  19. Cell Rep Methods. 2021 Nov 22. pii: 100116. [Epub ahead of print]1(7):
    Genetically encoded biosensors for evaluating NAD+/NADH ratio in cytosolic and mitochondrial compartments.
    Qingxun Hu, Dan Wu, Matthew Walker, Pei Wang, Rong Tian, Wang Wang.
      The ratio of oxidized to reduced NAD (NAD+/NADH) sets intracellular redox balance and antioxidant capacity. Intracellular NAD is compartmentalized and the mitochondrial NAD+/NADH ratio is intricately linked to cellular function. Here, we report the monitoring of the NAD+/NADH ratio in mitochondrial and cytosolic compartments in live cells by using a modified genetic biosensor (SoNar). The fluorescence signal of SoNar targeted to mitochondria (mt-SoNar) or cytosol (ct-SoNar) responded linearly to physiological NAD+/NADH ratios in situ. NAD+/NADH ratios in cytosol versus mitochondria responded rapidly, but differently, to acute metabolic perturbations, indicating distinct NAD pools. Subcellular NAD redox balance regained homeostasis via communications through malate-aspartate shuttle. Mitochondrial and cytosolic NAD+/NADH ratios are influenced by NAD+ precursor levels and are distinctly regulated under pathophysiological conditions. Compartment-targeted biosensors and real-time imaging allow assessment of subcellular NAD+/NADH redox signaling in live cells, enabling future mechanistic research of NAD redox in cell biology and disease development.
    DOI:  https://doi.org/10.1016/j.crmeth.2021.100116
  20. Cell Biol Int. 2021 Dec 17.
    Why do cells need oxygen? Insights from mitochondrial composition and function.
    Kelath Murali Manoj, Daniel Andrew Gideon, Laurent Jaeken.
      Mitochondrial membrane-embedded redox proteins are classically perceived as deterministic 'electron transport chain' (ETC) arrays cum proton pumps; and oxygen is seen as an 'immobile terminal electron acceptor'. This is untenable because: (1) there are little free protons to be pumped out of the matrix; (2) proton pumping would be highly endergonic; (3) ETC-chemiosmosis-rotary ATP synthesis proposal is 'irreducibly complex'/'non-evolvable' and does not fit with mitochondrial architecture or structural/distribution data of the concerned proteins/components; (4) a plethora of experimental observations do not conform to the postulates/requisites; e.g. there is little evidence for viable proton-pumps/pH-gradient in mitochondria, trans-membrane potential (TMP) is non-fluctuating/non-trappable, oxygen is seen to give copious 'diffusible reactive (oxygen) species' (DRS/DROS) in milieu, etc. Quite contrarily, the newly proposed murburn model's tenets agree with known principles of energetics/kinetics, and build on established structural data and reported observations. In this purview, oxygen is needed to make DRS, the principal component of mitochondrial function. Complex V and porins respectively serve as proton-inlet and turgor-based water-exodus portals, thereby achieving organellar homeostasis. Complexes I to IV possess ADP-binding sites and their redox-centres react/interact with O2 /DRS. At/around these complexes, DRS cross-react or activate/oxidize ADP/Pi via fast thermogenic one-electron reaction(s), condensing to form two-electron stabilized products (H2 O2 /H2 O/ATP). The varied architecture and distribution of components in mitochondria validate DRS as the- (i) the coupling agent of oxidative reactions and phosphorylations, and (ii) the primary reason for manifestation of TMP in steady-state. Explorations along the new precepts stand to provide greater insights on mitochondrial function and pathophysiology. This article is protected by copyright. All rights reserved.
    Keywords:  energetics; homeostasis; mitochondrial physiology; murburn concept; thermogenesis
    DOI:  https://doi.org/10.1002/cbin.11746
  21. Sci Adv. 2021 Dec 17. 7(51): eabf9441
    MRE11-dependent instability in mitochondrial DNA fork protection activates a cGAS immune signaling pathway.
    Jessica W Luzwick, Eszter Dombi, Rebecca A Boisvert, Sunetra Roy, Soyoung Park, Selvi Kunnimalaiyaan, Steffi Goffart, Detlev Schindler, Katharina Schlacher.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciadv.abf9441
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