bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023–01–22
twenty papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7.
  2. Cardiovascular Research in Friedreich Ataxia: Unmet Needs and Opportunities.
  3. Insulin Resistance in Mitochondrial Diabetes.
  4. Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14).
  5. Generation of two mother-child pairs of iPSCs from maternally inherited Leigh syndrome patients with m.8993 T > G and m.9176 T > G MT-ATP6 mutations.
  6. Emerging role of mitophagy in heart failure: from molecular mechanism to targeted therapy.
  7. SIRT6 is a key regulator of mitochondrial function in the brain.
  8. CoQ Regulates Brown Adipose Tissue Respiration and Uncoupling Protein 1 Expression.
  9. Peanut AhmTERF1 Regulates Root Growth by Modulating Mitochondrial Abundance.
  10. A wearable motion capture suit and machine learning predict disease progression in Friedreich's ataxia.
  11. Mitochondrial stress and mitokines in aging.
  12. NMN: The NAD Precursor at the Intersection Between Axon Degeneration and Anti-ageing Therapies.
  13. Mitochondria in Cell-Based Therapy for Stroke.
  14. Gene therapy for liver diseases - progress and challenges.
  15. Liver-directed gene therapy for ornithine aminotransferase deficiency.
  16. Leber Mitochondrial Optic Neuropathy in Pediatric Females With Focus on Very Early Onset Cases.
  17. Sarcopenia: investigation of metabolic changes and its associated mechanisms.
  18. Age-Related Dysfunction in Proteostasis and Cellular Quality Control in the Development of Sarcopenia.
  19. HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy.
  20. Enhancement of mitochondrial function using NO releasing nanoparticles; a potential approach for therapy of Alzheimer's diseases.
  1. Nat Cell Biol. 2023 Jan 19.
    Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7.
    Soni Deshwal, Mashun Onishi, Takashi Tatsuta, Tim Bartsch, Eileen Cors, Katharina Ried, Kathrin Lemke, Hendrik Nolte, Patrick Giavalisco, Thomas Langer.
      Coenzyme Q (or ubiquinone) is a redox-active lipid that serves as universal electron carrier in the mitochondrial respiratory chain and antioxidant in the plasma membrane limiting lipid peroxidation and ferroptosis. Mechanisms allowing cellular coenzyme Q distribution after synthesis within mitochondria are not understood. Here we identify the cytosolic lipid transfer protein STARD7 as a critical factor of intracellular coenzyme Q transport and suppressor of ferroptosis. Dual localization of STARD7 to the intermembrane space of mitochondria and the cytosol upon cleavage by the rhomboid protease PARL ensures the synthesis of coenzyme Q in mitochondria and its transport to the plasma membrane. While mitochondrial STARD7 preserves coenzyme Q synthesis, oxidative phosphorylation function and cristae morphogenesis, cytosolic STARD7 is required for the transport of coenzyme Q to the plasma membrane and protects against ferroptosis. A coenzyme Q variant competes with phosphatidylcholine for binding to purified STARD7 in vitro. Overexpression of cytosolic STARD7 increases ferroptotic resistance of the cells, but limits coenzyme Q abundance in mitochondria and respiratory cell growth. Our findings thus demonstrate the need to coordinate coenzyme Q synthesis and cellular distribution by PARL-mediated STARD7 processing and identify PARL and STARD7 as promising targets to interfere with ferroptosis.
    DOI:  https://doi.org/10.1038/s41556-022-01071-y
  2. JACC Basic Transl Sci. 2022 Dec;7(12): 1267-1283
    Cardiovascular Research in Friedreich Ataxia: Unmet Needs and Opportunities.
    R Mark Payne.
      Friedreich Ataxia (FRDA) is an autosomal recessive disease in which a mitochondrial protein, frataxin, is severely decreased in its expression. In addition to progressive ataxia, patients with FRDA often develop a cardiomyopathy that can be hypertrophic. This cardiomyopathy is unlike the sarcomeric hypertrophic cardiomyopathies in that the hypertrophy is associated with massive mitochondrial proliferation within the cardiomyocyte rather than contractile protein overexpression. This is associated with atrial arrhythmias, apoptosis, and fibrosis over time, and patients often develop heart failure leading to premature death. The differences between this mitochondrial cardiomyopathy and the more common contractile protein hypertrophic cardiomyopathies can be a source of misunderstanding in the management of these patients. Although imaging studies have revealed much about the structure and function of the heart in this disease, we still lack an understanding of many important clinical and fundamental molecular events that determine outcome of the heart in FRDA. This review will describe the current basic and clinical understanding of the FRDA heart, and most importantly, identify major gaps in our knowledge that represent new directions and opportunities for research.
    Keywords:  CMR, cardiac magnetic resonance; FDA, U.S. Food and Drug Administration; FRDA, Friedreich ataxia; Friedreich ataxia; GAA, triplet expansion in first intron of the Friedreich ataxia gene; HF, heart failure; LV, left ventricle; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; RV, right ventricle; cardiomyopathy; frataxin; heart; mitochondria
    DOI:  https://doi.org/10.1016/j.jacbts.2022.04.005
  3. Biomolecules. 2023 Jan 07. pii: 126. [Epub ahead of print]13(1):
    Insulin Resistance in Mitochondrial Diabetes.
    Chika Takano, Erika Ogawa, Satoshi Hayakawa.
      Mitochondrial diabetes (MD) is generally classified as a genetic defect of β-cells. The main pathophysiology is insulin secretion failure in pancreatic β-cells due to impaired mitochondrial ATP production. However, several reports have mentioned the presence of insulin resistance (IR) as a clinical feature of MD. As mitochondrial dysfunction is one of the important factors causing IR, we need to focus on IR as another pathophysiology of MD. In this special issue, we first briefly summarized the insulin signaling and molecular mechanisms of IR. Second, we overviewed currently confirmed pathogenic mitochondrial DNA (mtDNA) mutations from the MITOMAP database. The variants causing diabetes were mostly point mutations in the transfer RNA (tRNA) of the mitochondrial genome. Third, we focused on these variants leading to the recently described "tRNA modopathies" and reviewed the clinical features of patients with diabetes. Finally, we discussed the pathophysiology of MD caused by mtDNA mutations and explored the possible mechanism underlying the development of IR. This review should be beneficial to all clinicians involved in diagnostics and therapeutics related to diabetes and mitochondrial diseases.
    Keywords:  insulin resistance; mitochondrial DNA mutation; mitochondrial diabetes; transfer RNA modopathy
    DOI:  https://doi.org/10.3390/biom13010126
  4. Elife. 2023 Jan 16. pii: e82555. [Epub ahead of print]12
    Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14).
    Guang Lin, Burak Tepe, Geoff McGrane, Regine C Tipon, Gist Croft, Leena Panwala, Amanda Hope, Agnes J H Liang, Zhongyuan Zuo, Seul Kee Byeon, Lily Wang, Akhilesh Pandey, Hugo J Bellen.
      Infantile Neuroaxonal Dystrophy (INAD) is caused by recessive variants in PLA2G6 and is a lethal pediatric neurodegenerative disorder. Loss of the Drosophila homolog of PLA2G6, leads to ceramide accumulation, lysosome expansion, and mitochondrial defects. Here, we report that retromer function, ceramide metabolism, the endolysosomal pathway, and mitochondrial morphology are affected in INAD patient-derived neurons. We show that in INAD mouse models the same features are affected in Purkinje cells, arguing that the neuropathological mechanisms are evolutionary conserved and that these features can be used as biomarkers. We tested 20 drugs that target these pathways and found that Ambroxol, Desipramine, Azoramide, and Genistein alleviate neurodegenerative phenotypes in INAD flies and INAD patient-derived NPCs. We also develop an AAV-based gene therapy approach that delays neurodegeneration and prolongs lifespan in an INAD mouse model.
    Keywords:  D. melanogaster; human; mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.82555
  5. Stem Cell Res. 2023 Jan 17. pii: S1873-5061(23)00016-8. [Epub ahead of print]67 103030
    Generation of two mother-child pairs of iPSCs from maternally inherited Leigh syndrome patients with m.8993 T > G and m.9176 T > G MT-ATP6 mutations.
    Marie-Thérèse Henke, Annika Zink, Sebastian Diecke, Alessandro Prigione, Markus Schuelke.
      We generated two pairs of mother-child iPSCs lines for Maternally Inherited Leigh Syndrome (MILS) carrying the m.8993 T > G and m.9176 T > G mutations in the MT-ATP6 gene. We delivered reprogramming factors OCT4, SOX2, KLF4, and c-MYC via Sendai virus. All iPSCs lines had a normal karyotype, expressed pluripotency markers, and differentiated into the three germ layers. Both patient-iPSCs retained the same degrees of heteroplasmy as their source fibroblasts (>97.0 %). In maternal iPSCs, the heteroplasmy remained 0.0 % in the case of the m.8993 T > G mutation and dropped from 55.0 % to 1.0 % in the case of m.9176 T > G mutation.
    DOI:  https://doi.org/10.1016/j.scr.2023.103030
  6. Cell Cycle. 2023 Jan 19. 1-13
    Emerging role of mitophagy in heart failure: from molecular mechanism to targeted therapy.
    Yu Liu, Yizhou Wang, Yingfei Bi, Zhiqiang Zhao, Shuai Wang, Shanshan Lin, Zhihua Yang, Xianliang Wang, Jingyuan Mao.
      Heart failure is defined as a drop in heart's pump function, accounting for reduced blood output and venous stasis, and constitutes the end stage of various cardiovascular diseases. Although mild mitochondrial dysfunction may hinder cardiomyocyte metabolism and impair myocardial function, severe mitochondrial injury is accompanied by cardiomyocyte apoptosis, leading to irreversible damage of the heart. Selective autophagy of mitochondria, or mitophagy, serves to rapidly remove dysfunctional mitochondria and restore the health of the mitochondrial population within cells by allowing reutilization of degradative substrates such as amino acids, fatty acids, and nucleotides. Although mitophagy represents a protective program that prevents the accumulation of poorly structured or damaged mitochondria, excessive mitophagy leads to mitochondrial population decline, impaired oxidative phosphorylation, and decreased ATP production. In this review, we first discuss the molecular underpinnings of mitophagy and the roles of different mitophagy adaptors. Then, the multiple and complex influence of mitophagy on heart failure is summarized. Finally, novel pharmacological strategies targeting mitophagy to relieve heart failure are briefly summarized.
    Keywords:  Bnip3; FUNDC1; Heart failure; Parkin; mitophagy
    DOI:  https://doi.org/10.1080/15384101.2023.2167949
  7. Cell Death Dis. 2023 Jan 18. 14(1): 35
    SIRT6 is a key regulator of mitochondrial function in the brain.
    Dmitrii Smirnov, Ekaterina Eremenko, Daniel Stein, Shai Kaluski, Weronika Jasinska, Claudia Cosentino, Barbara Martinez-Pastor, Yariv Brotman, Raul Mostoslavsky, Ekaterina Khrameeva, Debra Toiber.
      The SIRT6 deacetylase has been implicated in DNA repair, telomere maintenance, glucose and lipid metabolism and, importantly, it has critical roles in the brain ranging from its development to neurodegeneration. Here, we combined transcriptomics and metabolomics approaches to characterize the functions of SIRT6 in mouse brains. Our analysis reveals that SIRT6 is a central regulator of mitochondrial activity in the brain. SIRT6 deficiency in the brain leads to mitochondrial deficiency with a global downregulation of mitochondria-related genes and pronounced changes in metabolite content. We suggest that SIRT6 affects mitochondrial functions through its interaction with the transcription factor YY1 that, together, regulate mitochondrial gene expression. Moreover, SIRT6 target genes include SIRT3 and SIRT4, which are significantly downregulated in SIRT6-deficient brains. Our results demonstrate that the lack of SIRT6 leads to decreased mitochondrial gene expression and metabolomic changes of TCA cycle byproducts, including increased ROS production, reduced mitochondrial number, and impaired membrane potential that can be partially rescued by restoring SIRT3 and SIRT4 levels. Importantly, the changes we observed in SIRT6-deficient brains are also occurring in aging human brains and particularly in patients with Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis disease. Overall, our results suggest that the reduced levels of SIRT6 in the aging brain and neurodegeneration initiate mitochondrial dysfunction by altering gene expression, ROS production, and mitochondrial decay.
    DOI:  https://doi.org/10.1038/s41419-022-05542-w
  8. Antioxidants (Basel). 2022 Dec 22. pii: 14. [Epub ahead of print]12(1):
    CoQ Regulates Brown Adipose Tissue Respiration and Uncoupling Protein 1 Expression.
    Ching-Fang Chang, Amanda L Gunawan, Irene Liparulo, Peter-James H Zushin, Ambre M Bertholet, Yuriy Kirichok, Andreas Stahl.
      Coenzyme Q (CoQ, aka ubiquinone) is a key component of the mitochondrial electron transport chain (ETC) and membrane-incorporated antioxidant. CoQ10 deficiencies encompass a heterogeneous spectrum of clinical phenotypes and can be caused by hereditary mutations in the biosynthesis pathway or result from pharmacological interventions such as HMG-CoA Reductase inhibitors, and statins, which are widely used to treat hypercholesterolemia and prevent cardiovascular disease. How CoQ deficiency affects individual tissues and cell types, particularly mitochondrial-rich ones such as brown adipose tissue (BAT), has remained poorly understood. Here we show that pharmacological and genetic models of BAT CoQ deficiency show altered respiration that can only in part be explained by classical roles of CoQ in the respiration chain. Instead, we found that CoQ strongly impacts brown and beige adipocyte respiration via the regulation of uncoupling protein 1 (UCP1) expression. CoQ deficiency in BAT robustly decreases UCP1 protein levels and uncoupled respiration unexpectedly, resulting in increased inner mitochondrial membrane potential and decreased ADP/ATP ratios. Suppressed UCP1 expression was also observed in a BAT-specific in vivo model of CoQ deficiency and resulted in enhanced cold sensitivity. These findings demonstrate an as yet unappreciated role of CoQ in the transcriptional regulation of key thermogenic genes and functions.
    Keywords:  Coenzyme Q; brown adipose tissue; mitochondrial function; thermogenesis
    DOI:  https://doi.org/10.3390/antiox12010014
  9. Genes (Basel). 2023 Jan 13. pii: 209. [Epub ahead of print]14(1):
    Peanut AhmTERF1 Regulates Root Growth by Modulating Mitochondrial Abundance.
    Limei Li, Xiaoyun Li, Chen Yang, Ling Li.
      Mitochondria are responsible for energy generation, as well as key metabolic and signaling pathways, and thus affect the entire developmental process of plants as well as their responses to stress. In metazoans, mitochondrial transcription termination factors (mTERFs) are known to regulate mitochondrial transcription. mTERFs have also been discovered in plants, but only a few of these proteins have been explored for their biological functions. Here, we report a role in root growth for mitochondria-associated protein AhmTERF1 in peanut (Arachis hypogaea L.). Overexpressing AhmTERF1 significantly stimulated the growth of peanut hairy roots and transgenic Arabidopsis. Surprisingly, AhmTERF1 is predominantly expressed in the root meristem where it increases mitochondrial abundance. AhmTERF1 binding to mtDNA was enriched in the RRN18 and RRN26 regions, suggesting it is related to the accumulation of mitochondrial ribosomes. Peanut is one of the main oil crops and the important source of edible oil and AhmTERF1 likely affects agronomic traits related to root growth in different peanut cultivars. We propose that peanut AhmTERF1 is an important protein for root growth due to its role in regulating mitochondrial abundance.
    Keywords:  AhmTERF1; mitochondria; peanut; root
    DOI:  https://doi.org/10.3390/genes14010209
  10. Nat Med. 2023 Jan 19.
    A wearable motion capture suit and machine learning predict disease progression in Friedreich's ataxia.
    Balasundaram Kadirvelu, Constantinos Gavriel, Sathiji Nageshwaran, Jackson Ping Kei Chan, Suran Nethisinghe, Stavros Athanasopoulos, Valeria Ricotti, Thomas Voit, Paola Giunti, Richard Festenstein, A Aldo Faisal.
      Friedreich's ataxia (FA) is caused by a variant of the Frataxin (FXN) gene, leading to its downregulation and progressively impaired cardiac and neurological function. Current gold-standard clinical scales use simplistic behavioral assessments, which require 18- to 24-month-long trials to determine if therapies are beneficial. Here we captured full-body movement kinematics from patients with wearable sensors, enabling us to define digital behavioral features based on the data from nine FA patients (six females and three males) and nine age- and sex-matched controls, who performed the 8-m walk (8-MW) test and 9-hole peg test (9 HPT). We used machine learning to combine these features to longitudinally predict the clinical scores of the FA patients, and compared these with two standard clinical assessments, Spinocerebellar Ataxia Functional Index (SCAFI) and Scale for the Assessment and Rating of Ataxia (SARA). The digital behavioral features enabled longitudinal predictions of personal SARA and SCAFI scores 9 months into the future and were 1.7 and 4 times more precise than longitudinal predictions using only SARA and SCAFI scores, respectively. Unlike the two clinical scales, the digital behavioral features accurately predicted FXN gene expression levels for each FA patient in a cross-sectional manner. Our work demonstrates how data-derived wearable biomarkers can track personal disease trajectories and indicates the potential of such biomarkers for substantially reducing the duration or size of clinical trials testing disease-modifying therapies and for enabling behavioral transcriptomics.
    DOI:  https://doi.org/10.1038/s41591-022-02159-6
  11. Aging Cell. 2023 Jan 15. e13770
    Mitochondrial stress and mitokines in aging.
    Johannes Burtscher, Afsaneh Soltany, Nishant P Visavadiya, Martin Burtscher, Grégoire P Millet, Kayvan Khoramipour, Andy V Khamoui.
      Mitokines are signaling molecules that enable communication of local mitochondrial stress to other mitochondria in distant cells and tissues. Among those molecules are FGF21, GDF15 (both expressed in the nucleus) and several mitochondrial-derived peptides, including humanin. Their responsiveness to mitochondrial stress induces mitokine-signaling in response for example to exercise, following mitochondrial challenges in skeletal muscle. Such signaling is emerging as an important mediator of exercise-derived and dietary strategy-related molecular and systemic health benefits, including healthy aging. A compensatory increase in mitokine synthesis and secretion could preserve mitochondrial function and overall cellular vitality. Conversely, resistance against mitokine actions may also develop. Alterations of mitokine-levels, and therefore of mitokine-related inter-tissue cross talk, are associated with general aging processes and could influence the development of age-related chronic metabolic, cardiovascular and neurological diseases; whether these changes contribute to aging or represent "rescue factors" remains to be conclusively shown. The aim of the present review is to summarize the expanding knowledge on mitokines, the potential to modulate them by lifestyle and their involvement in aging and age-related diseases. We highlight the importance of well-balanced mitokine-levels, the preventive and therapeutic properties of maintaining mitokine homeostasis and sensitivity of mitokine signaling but also the risks arising from the dysregulation of mitokines. While reduced mitokine levels may impair inter-organ crosstalk, also excessive mitokine concentrations can have deleterious consequences and are associated with conditions such as cancer and heart failure. Preservation of healthy mitokine signaling levels can be achieved by regular exercise and is associated with an increased lifespan.
    Keywords:  FGF21; GDF15; humanin; mitochondria-derived peptides; mitochondrial stress response; mitohormesis; mitokines
    DOI:  https://doi.org/10.1111/acel.13770
  12. Neurosci Res. 2023 Jan 16. pii: S0168-0102(23)00004-4. [Epub ahead of print]
    NMN: The NAD Precursor at the Intersection Between Axon Degeneration and Anti-ageing Therapies.
    Andrea Loreto, Christina Antoniou, Elisa Merlini, Jonathan Gilley, Michael P Coleman.
      The past 20 years of research on axon degeneration has revealed fine details on how NAD biology controls axonal survival. Extensive data demonstrate that the NAD precursor NMN binds to and activates the pro-degenerative enzyme SARM1, so a failure to convert sufficient NMN into NAD leads to toxic NMN accumulation and axon degeneration. This involvement of NMN brings the axon degeneration field to an unexpected overlap with research into ageing and extending healthy lifespan. A decline in NAD levels throughout life, at least in some tissues, is believed to contribute to age-related functional decay and boosting NAD production with supplementation of NMN or other NAD precursors has gained attention as a potential anti-ageing therapy. Recent years have witnessed an influx of NMN-based products and related molecules on the market, sold as food supplements, with many people taking these supplements daily. While several clinical trials are ongoing to check the safety profiles and efficacy of NAD precursors, sufficient data to back their therapeutic use are still lacking. Here, we discuss NMN supplementation, SARM1 and anti-ageing strategies, with an important question in mind: considering that NMN accumulation can lead to axon degeneration, how is this compatible with its beneficial effect in ageing and are there circumstances in which NMN lementation could become harmful?
    Keywords:  Ageing; Axon degeneration; Lifespan; NAM, NAD, SARM1; NMN; NMNAT; NR; Programmed axon death
    DOI:  https://doi.org/10.1016/j.neures.2023.01.004
  13. Antioxidants (Basel). 2023 Jan 12. pii: 178. [Epub ahead of print]12(1):
    Mitochondria in Cell-Based Therapy for Stroke.
    Molly Monsour, Jonah Gordon, Gavin Lockard, Adam Alayli, Cesar V Borlongan.
      Despite a relatively developed understanding of the pathophysiology underlying primary and secondary mechanisms of cell death after ischemic injury, there are few established treatments to improve stroke prognoses. A major contributor to secondary cell death is mitochondrial dysfunction. Recent advancements in cell-based therapies suggest that stem cells may be revolutionary for treating stroke, and the reestablishment of mitochondrial integrity may underlie these therapeutic benefits. In fact, functioning mitochondria are imperative for reducing oxidative damage and neuroinflammation following stroke and reperfusion injury. In this review, we will discuss the role of mitochondria in establishing the anti-oxidative effects of stem cell therapies for stroke.
    Keywords:  mitochondria; neuroinflammation; oxidation; reactive oxygen species; stem cell; stroke
    DOI:  https://doi.org/10.3390/antiox12010178
  14. Nat Rev Gastroenterol Hepatol. 2023 Jan 16.
    Gene therapy for liver diseases - progress and challenges.
    Nerea Zabaleta, Carmen Unzu, Nicholas D Weber, Gloria Gonzalez-Aseguinolaza.
      Gene therapy is poised to revolutionize modern medicine, with seemingly unlimited potential for treating and curing genetic disorders. For otherwise incurable indications, including most inherited metabolic liver disorders, gene therapy provides a realistic therapeutic option. In this Review, we discuss gene supplementation and gene editing involving the use of recombinant adeno-associated virus (rAAV) vectors for the treatment of inherited liver diseases, including updates on several ongoing clinical trials that are producing promising results. Clinical testing has been essential in highlighting many key translational challenges associated with this transformative therapy. In particular, the interaction of a patient's immune system with the vector raises issues of safety and the duration of treatment efficacy. Furthermore, several serious adverse events after the administration of high doses of rAAVs suggest greater involvement of innate immune responses and pre-existing hepatic conditions than initially anticipated. Finally, permanent modification of the host genome associated with rAAV genome integration and gene editing raises concerns about the risk of oncogenicity that require careful evaluation. We summarize the main progress, challenges and pathways forward for gene therapy for liver diseases.
    DOI:  https://doi.org/10.1038/s41575-022-00729-0
  15. EMBO Mol Med. 2023 Jan 17. e17033
    Liver-directed gene therapy for ornithine aminotransferase deficiency.
    Iolanda Boffa, Elena Polishchuk, Lucia De Stefano, Fabio Dell'Aquila, Edoardo Nusco, Elena Marrocco, Matteo Audano, Silvia Pedretti, Marianna Caterino, Ilaria Bellezza, Margherita Ruoppolo, Nico Mitro, Barbara Cellini, Alberto Auricchio, Nicola Brunetti-Pierri.
      Gyrate atrophy of choroid and retina (GACR) is a chorioretinal degeneration caused by pathogenic variants in the gene encoding ornithine aminotransferase (OAT), an enzyme mainly expressed in liver. Affected patients have increased ornithine concentrations in blood and other body fluids and develop progressive constriction of vision fields leading to blindness. Current therapies are unsatisfactory and better treatments are highly needed. In two mouse models of OAT deficiency that recapitulates biochemical and retinal changes of GACR, we investigated the efficacy of an intravenously injected serotype 8 adeno-associated (AAV8) vector expressing OAT under the control of a hepatocyte-specific promoter. Following injections, OAT-deficient mice showed reductions of ornithine concentrations in blood and eye cups compared with control mice injected with a vector expressing green fluorescent protein. AAV-injected mice showed improved electroretinogram response and partial restoration of retinal structure up to one-year post-injection. In summary, hepatic OAT expression by AAV8 vector was effective at correction of hyperornithinemia and improved function and structure of the retina. In conclusion, this study provides proof-of-concept of efficacy of liver-directed AAV-mediated gene therapy of GACR.
    Keywords:  AAV; gyrate atrophy of choroid and retina; inherited metabolic diseases; liver gene therapy; ornithine aminotransferase
    DOI:  https://doi.org/10.15252/emmm.202217033
  16. J Child Neurol. 2023 Jan 19. 8830738221149962
    Leber Mitochondrial Optic Neuropathy in Pediatric Females With Focus on Very Early Onset Cases.
    Sara Tagliani, Cristina Malaventura, Chiara Ceccato, Francesco Parmeggiani, Agnese Suppiej.
      The aim of this study was to describe the phenotype of Leber hereditary optic neuropathy occurring in pediatric females. This disease generally affects young adult males, but it can occur also in females, and research data in this population is lacking. The very early onset can challenge the diagnosis and delay treatment. We searched PubMed through February 2021 and identified 226 pediatric females with genetically confirmed Leber hereditary optic neuropathy and added a new case of a 3-year-old female. The male-female ratio was 1.8:1; the mean onset age in females was 11 years with the onset at 3 years of age occurring in 3 females only. Acute onset with mild visual impairment was the most common presentation, associated with optic disc edema in 16%. Differential diagnoses are pseudotumor cerebri, optic nerve drusen and optic neuritis. The outcome is poor with partial recovery in 50%, despite some receiving Idebenone therapy.
    Keywords:  children; mitochondrial disorder; neuro-ophthalmology; neuropathy; pseudotumor cerebri
    DOI:  https://doi.org/10.1177/08830738221149962
  17. Skelet Muscle. 2023 Jan 19. 13(1): 2
    Sarcopenia: investigation of metabolic changes and its associated mechanisms.
    Jair Marques, Engy Shokry, Olaf Uhl, Lisa Baber, Fabian Hofmeister, Stefanie Jarmusch, Martin Bidlingmaier, Uta Ferrari, Berthold Koletzko, Michael Drey.
       BACKGROUND: Sarcopenia is one of the most predominant musculoskeletal diseases of the elderly, defined as age-related progressive and generalized loss of muscle mass with a simultaneous reduction in muscle strength and/or function. Using metabolomics, we aimed to examine the association between sarcopenia and the plasma metabolic profile of sarcopenic patients, measured using a targeted HPLC-MS/MS platform.
    METHODS: Plasma samples from 22 (17 men) hip fracture patients undergoing surgery (8 sarcopenic, age 81.4+6.3, and 14 non-sarcopenic, age 78.4±8.1) were analyzed. T test, fold change, orthogonal partial least squares discriminant analysis, and sparse partial least squares discriminant analysis were used for mining significant features. Metabolite set enrichment analysis and mediation analysis by PLSSEM were thereafter performed.
    RESULTS: Using a univariate analysis for sarcopenia z score, the amino acid citrulline was the only metabolite with a significant group difference after FDR correction. Positive trends were observed between the sarcopenia z score and very long-chain fatty acids as well as dicarboxylic acid carnitines. Multivariate analysis showed citrulline, non-esterified fatty acid 26:2, and decanedioyl carnitine as the top three metabolites according to the variable importance in projection using oPLS-DA and loadings weight by sPLS-DA. Metabolite set enrichment analysis showed carnitine palmitoyltransferase deficiency (II) as the highest condition related to the metabolome.
    CONCLUSIONS: We observed a difference in the plasma metabolic profile in association with different measures of sarcopenia, which identifies very long-chain fatty acids, Carn.DC and citrulline as key variables associated with the disease severity. These findings point to a potential link between sarcopenia and mitochondrial dysfunction and portraits a number of possible biochemical pathways which might be involved in the disease pathogenesis.
    Keywords:  Energy metabolism; Fatty acid metabolism; Fatty acid oxidation; Lipid metabolism; Metabolomics; Mitochondrial metabolism; Sarcopenia
    DOI:  https://doi.org/10.1186/s13395-022-00312-w
  18. Cells. 2023 Jan 07. pii: 249. [Epub ahead of print]12(2):
    Age-Related Dysfunction in Proteostasis and Cellular Quality Control in the Development of Sarcopenia.
    Hector G Paez, Christopher R Pitzer, Stephen E Alway.
      Sarcopenia is a debilitating skeletal muscle disease that accelerates in the last decades of life and is characterized by marked deficits in muscle strength, mass, quality, and metabolic health. The multifactorial causes of sarcopenia have proven difficult to treat and involve a complex interplay between environmental factors and intrinsic age-associated changes. It is generally accepted that sarcopenia results in a progressive loss of skeletal muscle function that exceeds the loss of mass, indicating that while loss of muscle mass is important, loss of muscle quality is the primary defect with advanced age. Furthermore, preclinical models have suggested that aged skeletal muscle exhibits defects in cellular quality control such as the degradation of damaged mitochondria. Recent evidence suggests that a dysregulation of proteostasis, an important regulator of cellular quality control, is a significant contributor to the aging-associated declines in muscle quality, function, and mass. Although skeletal muscle mammalian target of rapamycin complex 1 (mTORC1) plays a critical role in cellular control, including skeletal muscle hypertrophy, paradoxically, sustained activation of mTORC1 recapitulates several characteristics of sarcopenia. Pharmaceutical inhibition of mTORC1 as well as caloric restriction significantly improves muscle quality in aged animals, however, the mechanisms controlling cellular proteostasis are not fully known. This information is important for developing effective therapeutic strategies that mitigate or prevent sarcopenia and associated disability. This review identifies recent and historical understanding of the molecular mechanisms of proteostasis driving age-associated muscle loss and suggests potential therapeutic interventions to slow or prevent sarcopenia.
    Keywords:  aging; anabolic resistance; atrophy; autophagy; caloric restriction; dynapenia; mTORC1; mitochondria; mitophagy; muscle protein synthesis; rapamycin; sarcopenia; skeletal muscle; ubiquitin proteasome
    DOI:  https://doi.org/10.3390/cells12020249
  19. EMBO Mol Med. 2023 Jan 16. e16525
    HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy.
    Yang Kong, Pei-Kang Liu, Yao Li, Nicholas D Nolan, Peter M J Quinn, Chun-Wei Hsu, Laura A Jenny, Jin Zhao, Xuan Cui, Ya-Ju Chang, Katherine J Wert, Janet R Sparrow, Nan-Kai Wang, Stephen H Tsang.
      Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. This study provided the pathogenic and molecular basis for DFO-related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO-related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2α and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2α and preserving mitochondrial dysfunction by α-ketoglutarate (AKG) protects the RPE against lesions both in vitro and in vivo. This supported our observation that AKG supplementation alleviates visual impairment in a patient undergoing DFO-chelation therapy. Overall, our study established a significant role of iron deficiency in initiating DFO-related RPE atrophy. Inhibiting HIF2α and rescuing mitochondrial function by AKG protect RPE cells and can potentially ameliorate patients' visual function.
    Keywords:  HIF2α upregulation; RPE atrophy; iron deficiency; mitochondrial deficit; α-ketoglutarate
    DOI:  https://doi.org/10.15252/emmm.202216525
  20. Eur J Pharm Biopharm. 2023 Jan 11. pii: S0939-6411(23)00006-1. [Epub ahead of print]
    Enhancement of mitochondrial function using NO releasing nanoparticles; a potential approach for therapy of Alzheimer's diseases.
    Mirna Samir, Reham M Abdelkader, Maryam Shetab Boushehri, Samar Mansour, Alf Lamprecht, Salma N Tammam.
      Alzheimer's disease (AD) is the most common type of dementia. Increasing evidence is showing the important role of mitochondrial dysfunction in AD. Mitochondria based oxidative stress, decrease in respiratory chain activity and ATP production are all associated with AD, hence indicating that the enhancement of mitochondrial function and biogenesis present a promising therapeutic approach for AD. Nitric oxide (NO) is an initiator of mitochondrial biogenesis. However, its gaseous nature and very short half-life limit the realization of its therapeutic potential. Additionally, its uncontrolled in-vivo distribution results in generalized vasodilation, hypotension among other off-target effects. Diazeniumdiolates (NONOates) are NO donors that release NO in physiological temperature and pH. Their encapsulation within a hydrophobic matrix carrier system could control the release of NO, and at the same time enable its delivery to the brain. In this work, PAPANONOate (PN) a NO donor was encapsulated in small (92 ± 7 nm) poly (lactic-co-glycolic acid) (PLGA) NPs. These NPs did not induce hemolysis upon intravenous administration and were able to accumulate in the brains of lipopolysaccharides (LPS) induced neurodegeneration mouse models. The encapsulation of PN within a hydrophobic PLGA matrix enabled the sustained release of NO from NPs (≈ 3 folds slower relative to free PN) and successfully delivered PN to brain. As a result, PN-NPs but not free PN resulted in an enhancement in memory in cognition in animals with neurodegeneration as determined by the Y-maze test. The enhancement in cognition was a result of increased mitochondria function as indicated by the increased production of ATP and Cytochrome C oxidase enzyme activity.
    Keywords:  Alzheimer’s disease; PLGA nanoparticles; brain targeting; mitochondrial activity; neurodegeneration; nitric oxide
    DOI:  https://doi.org/10.1016/j.ejpb.2023.01.006
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