bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022‒09‒18
sixteen papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico
  1. OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy.
  2. The relationship of alpha-synuclein to mitochondrial dynamics and quality control.
  3. Preventive migraine treatment in mitochondrial diseases: a case report of erenumab efficacy and literature review.
  4. Mitochondrial autophagy in the sleeping brain.
  5. Sensing local energetics to acutely regulate mitophagy in skeletal muscle.
  6. Activation of a type I interferon response associated with acute frataxin knockdown in iPSC-derived cardiomyocytes.
  7. Calcium homeostasis in the control of mitophagy.
  8. Qualitative exploration of the lived experience of adults diagnosed with primary mitochondrial disease.
  9. Next generation sequencing of Tunisian Leigh syndrome patients reveals novel variations: impact for diagnosis and treatment.
  10. The emergent role of mitochondrial surveillance in cellular health.
  11. Regulation of mitochondrial dynamic equilibrium by physical exercise in sarcopenia: A systematic review.
  12. A promissing mouse model for Friedreich Ataxia progressing like human patients.
  13. Metabolic reprogramming in the OPA1-deficient cells.
  14. Overexpression of UCP3 decreases mitochondrial efficiency in mouse skeletal muscle in vivo.
  15. Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST.
  16. Changing trends in the development of AAV-based gene therapies: a meta-analysis of past and present therapies.
  1. Cell Metab. 2022 Sep 08. pii: S1550-4131(22)00360-6. [Epub ahead of print]
    OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy.
    Sofia Ahola, Pablo Rivera Mejías, Steffen Hermans, Srikanth Chandragiri, Patrick Giavalisco, Hendrik Nolte, Thomas Langer.
      Cardiomyopathy and heart failure are common manifestations in mitochondrial disease caused by deficiencies in the oxidative phosphorylation (OXPHOS) system of mitochondria. Here, we demonstrate that the cardiac-specific loss of the assembly factor Cox10 of the cytochrome c oxidase causes mitochondrial cardiomyopathy in mice, which is associated with OXPHOS deficiency, lysosomal defects, and an aberrant mitochondrial morphology. Activation of the mitochondrial peptidase Oma1 in Cox10-/- mice results in mitochondrial fragmentation and induction of the integrated stress response (ISR) along the Oma1-Dele1-Atf4 signaling axis. Ablation of Oma1 or Dele1 in Cox10-/- mice aggravates cardiomyopathy. ISR inhibition impairs the cardiac glutathione metabolism, limits the selenium-dependent accumulation of the glutathione peroxidase Gpx4, and increases lipid peroxidation in the heart, ultimately culminating in ferroptosis. Our results demonstrate a protective role of the Oma1-Dele1-mediated ISR in mitochondrial cardiomyopathy and link ferroptosis to OXPHOS deficiency and mitochondrial disease.
    Keywords:  Atf4; Dele1; Gpx4; Oma1; cardiomyopathy; ferroptosis; glutathione; integrated stress response; mitochondria; selenium
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.017
  2. Front Mol Neurosci. 2022 ;15 947191
    The relationship of alpha-synuclein to mitochondrial dynamics and quality control.
    Naomi J Thorne, David A Tumbarello.
      Maintenance of mitochondrial health is essential for neuronal survival and relies upon dynamic changes in the mitochondrial network and effective mitochondrial quality control mechanisms including the mitochondrial-derived vesicle pathway and mitophagy. Mitochondrial dysfunction has been implicated in driving the pathology of several neurodegenerative diseases, including Parkinson's disease (PD) where dopaminergic neurons in the substantia nigra are selectively degenerated. In addition, many genes with PD-associated mutations have defined functions in organelle quality control, indicating that dysregulation in mitochondrial quality control may represent a key element of pathology. The most well-characterized aspect of PD pathology relates to alpha-synuclein; an aggregation-prone protein that forms intracellular Lewy-body inclusions. Details of how alpha-synuclein exerts its toxicity in PD is not completely known, however, dysfunctional mitochondria have been observed in both PD patients and models of alpha-synuclein pathology. Accordingly, an association between alpha-synuclein and mitochondrial function has been established. This relates to alpha-synuclein's role in mitochondrial transport, dynamics, and quality control. Despite these relationships, there is limited research defining the direct mechanisms linking alpha-synuclein to mitochondrial dynamics and quality control. In this review, we will discuss the current literature addressing this association and provide insight into the proposed mechanisms promoting these functional relationships. We will also consider some of the alternative mechanisms linking alpha-synuclein with mitochondrial dynamics and speculate what the relationship between alpha-synuclein and mitochondria might mean both physiologically and in relation to PD.
    Keywords:  Parkinson’s disease; lysosome; membrane trafficking; mitochondria; mitochondrial quality control; vesicle transport
    DOI:  https://doi.org/10.3389/fnmol.2022.947191
  3. Neurol Sci. 2022 Sep 13.
    Preventive migraine treatment in mitochondrial diseases: a case report of erenumab efficacy and literature review.
    Guido Primiano, Eleonora Rollo, Marina Romozzi, Paolo Calabresi, Serenella Servidei, Catello Vollono.
      Migraine is a common condition in mitochondrial diseases, with a higher prevalence than in the general population. Although several clinical studies support the hypothesis that mitochondrial dysfunction plays a central role in the pathophysiology of migraine, currently there are few data in the literature regarding the efficacy and safety of drugs for the treatment and prophylaxis for this condition in patients with primary mitochondrial disorders. We report a 37-year-old woman affected by mitochondrial disease with progressive external ophthalmoplegia phenotype (PEO) associated with POLG mutation effectively treated with erenumab, in the absence of side effects. Monoclonal antibodies against the calcitonin gene-related peptide (CGRP) or against its receptor are innovative and specific therapies for migraine prophylaxis. This class of drugs is particularly suitable for subjects, such as those suffering from genetically determined mitochondrial dysfunction, in which pharmacological management can represent a challenge due to the nature of these neurogenetic disorders and/or the frequently associated comorbidities.
    Keywords:  CGRP; Case report; Erenumab; Migraine; Mitochondrial diseases; POLG
    DOI:  https://doi.org/10.1007/s10072-022-06391-3
  4. Front Cell Dev Biol. 2022 ;10 956394
    Mitochondrial autophagy in the sleeping brain.
    Sofia Mauri, Mariavittoria Favaro, Greta Bernardo, Gabriella M Mazzotta, Elena Ziviani.
      A significant percentage of the mitochondrial mass is replaced on a daily basis via mechanisms of mitochondrial quality control. Through mitophagy (a selective type of autophagy that promotes mitochondrial proteostasis) cells keep a healthy pool of mitochondria, and prevent oxidative stress and inflammation. Furthermore, mitophagy helps adapting to the metabolic demand of the cells, which changes on a daily basis. Core components of the mitophagy process are PINK1 and Parkin, which mutations are linked to Parkinson's Disease. The crucial role of PINK1/Parkin pathway during stress-induced mitophagy has been extensively studied in vitro in different cell types. However, recent advances in the field allowed discovering that mitophagy seems to be only slightly affected in PINK1 KO mice and flies, putting into question the physiological relevance of this pathway in vivo in the whole organism. Indeed, several cell-specific PINK1/Parkin-independent mitophagy pathways have been recently discovered, which appear to be activated under physiological conditions such as those that promote mitochondrial proteome remodeling during differentiation or in response to specific physiological stimuli. In this Mini Review we want to summarize the recent advances in the field, and add another level of complexity by focusing attention on a potentially important aspect of mitophagy regulation: the implication of the circadian clock. Recent works showed that the circadian clock controls many aspects of mitochondrial physiology, including mitochondrial morphology and dynamic, respiratory activity, and ATP synthesis. Furthermore, one of the essential functions of sleep, which is controlled by the clock, is the clearance of toxic metabolic compounds from the brain, including ROS, via mechanisms of proteostasis. Very little is known about a potential role of the clock in the quality control mechanisms that maintain the mitochondrial repertoire healthy during sleep/wake cycles. More importantly, it remains completely unexplored whether (dys)function of mitochondrial proteostasis feedbacks to the circadian clockwork.
    Keywords:  Parkinson’s disease; animal models; circadian rhythms; mitophagy; proteostasis
    DOI:  https://doi.org/10.3389/fcell.2022.956394
  5. Front Cell Dev Biol. 2022 ;10 987317
    Sensing local energetics to acutely regulate mitophagy in skeletal muscle.
    Anna S Nichenko, Kalyn S Specht, Siobhan M Craige, Joshua C Drake.
      The energetic requirements of skeletal muscle to sustain movement, as during exercise, is met largely by mitochondria, which form an intricate, interconnected reticulum. Maintenance of a healthy mitochondrial reticulum is essential for skeletal muscle function, suggesting quality control pathways are spatially governed. Mitophagy, the process by which damaged and/or dysfunctional regions of the mitochondrial reticulum are removed and degraded, has emerged as an integral part of the molecular response to exercise. Upregulation of mitophagy in response to acute exercise is directly connected to energetic sensing mechanisms through AMPK. In this review, we discuss the connection of mitophagy to muscle energetics and how AMPK may spatially control mitophagy through multiple potential means.
    Keywords:  AMPK; energetic stress; mitochondria; mitophagy; reactive oxygen species
    DOI:  https://doi.org/10.3389/fcell.2022.987317
  6. Dis Model Mech. 2022 Sep 15. pii: dmm.049497. [Epub ahead of print]
    Activation of a type I interferon response associated with acute frataxin knockdown in iPSC-derived cardiomyocytes.
    M Grazia Cotticelli, Shujuan Xia, Rachel Truitt, Nicolai M Doliba, Andrea V Rozo, John W Tobias, Taehee Lee, Justin Chen, Jill S Napierala, Marek Napierala, Wenli Yang, Robert B Wilson.
      Friedreich ataxia, the most common hereditary ataxia, is a neuro- and cardio-degenerative disorder caused, in most cases, by decreased expression of the mitochondrial protein frataxin. Cardiomyopathy is the leading cause of premature death. Frataxin functions in the biogenesis of iron-sulfur clusters, which are prosthetic groups that are found in proteins involved in many biological processes. To study the changes associated with decreased frataxin in human cardiomyocytes, we developed a novel isogenic model by acutely knocking down frataxin, post-differentiation, in cardiomyocytes derived from induced pluripotent stem cells. Transcriptome analysis of four biological replicates identified severe mitochondrial dysfunction and a type I interferon response as the pathways most affected by frataxin knockdown. We confirmed that in iPSC-derived cardiomyocytes, loss of frataxin leads to mitochondrial dysfunction. The type I interferon response was activated in multiple cell types following acute frataxin knockdown and was caused, at least in part, by release of mitochondrial DNA into the cytosol, activating the cGAS-STING sensor pathway.
    Keywords:  Cardiomyopathy; Friedreich; Innate Immunity; Interferon; mtDNA
    DOI:  https://doi.org/10.1242/dmm.049497
  7. Antioxid Redox Signal. 2022 Sep 16.
    Calcium homeostasis in the control of mitophagy.
    Mariasole Perrone, Simone Patergnani, Tommaso Di Mambro, Laura Palumbo, Mariusz Więckowski, Carlotta Giorgi, Paolo Pinton.
      SIGNIFICANCE: Maintenance of mitochondrial quality is essential for cellular homeostasis. Among processes responsible for preserving healthy mitochondria, mitophagy selectively eliminates dysfunctional mitochondria by targeting them to the autophagosome for degradation. Alterations in mitophagy lead to the accumulation of damaged mitochondria, which plays an essential role in several diseases like carcinogenesis and tumor progression, neurodegenerative disorders, and autoimmune and cardiovascular pathologies.RECENT ADVANCES: Calcium (Ca2+) plays a fundamental role in cell life, modulating several pathways, such as gene expression, proliferation, differentiation, metabolism, cell death, and survival. Indeed, because it is involved in all these events, Ca2+ is the most versatile intracellular second messenger. Being a process that limits cellular degeneration, mitophagy participates in cellular fate decisions. Several mitochondrial parameters, such as membrane potential, structure, and reactive oxygen species, can trigger the activation of mitophagic machinery. These parameters regulate not only mitophagy but also the mitochondrial Ca2+ uptake.
    CRITICAL ISSUES: Ca2+ handling is fundamental in regulating ATP production by mitochondria and mitochondrial quality control processes. Despite the growing literature about the link between Ca2+ and mitophagy, the mechanism by which Ca2+ homeostasis regulates mitophagy is still debated.
    FUTURE DIRECTIONS: Several studies have revealed that excessive mitophagy together with altered mitochondrial Ca2+ uptake leads to different dysfunctions in numerous diseases. Thus, therapeutic modulation of these pathways is considered promising treatments.
    DOI:  https://doi.org/10.1089/ars.2022.0122
  8. JIMD Rep. 2022 Sep;63(5): 494-507
    Qualitative exploration of the lived experience of adults diagnosed with primary mitochondrial disease.
    Kathleen D Valverde, Elizabeth M McCormick, Marni J Falk.
      Primary mitochondrial disease (PMD) encompasses a heterogeneous group of energy deficiency disorders that are typically progressive, with affected individuals experiencing an average of 16 multisystem symptoms. Clinical trials are emerging, but current treatment options remain limited. In PMD, the effect of specific disease factors and their relationship to meaning-based coping has not been studied. Given the connection between prognostic uncertainty and psychological distress in other patient populations, we explored the lived experience of adults with PMD. Adults with PMD caused by pathogenic variant(s) in nuclear or mitochondrial genes impairing mitochondrial function were interviewed. Interview questions addressed the lived experience with PMD, diagnostic journey, practical learnings at the time of diagnosis, suggestions for supportive information to provide at diagnosis, diagnosis impact on daily living and self-care, and sources of support and hope. Focus group transcripts were analyzed using thematic analysis. Four themes (diagnostic challenges, adaptations to daily living, social implications, and meaning-based coping) and several subthemes (the importance of being hopeful and benefit finding) emerged. Most participants reported strong family support (9/14) and identified a benefit (9/14) derived from their PMD diagnosis, while (5/14) did not identify any benefits. Benefit finding, reframing, and maintaining a positive attitude emerged as common coping in adults living with PMD. Understanding how adults with PMD cope is essential to provide anticipatory guidance and ongoing support for those struggling with their disease diagnosis, progression, and broader life impact. Our findings suggest that adult PMD patients prefer healthcare providers to inquire about their emotional well-being and meaning based coping with PMD.
    Keywords:  benefit finding; chronic illness; lived experience; meaning based coping; resiliency
    DOI:  https://doi.org/10.1002/jmd2.12316
  9. Biosci Rep. 2022 Sep 12. pii: BSR20220194. [Epub ahead of print]
    Next generation sequencing of Tunisian Leigh syndrome patients reveals novel variations: impact for diagnosis and treatment.
    Meriem Hechmi, Majida Charif, Ichraf Kraoua, Meriem Fassatoui, Hamza Dallali, Valerie Desquiret-Dumas, Céline Bris, David Goudenège, Cyrine Drissi, Saïd Galai, Slah Ouerhani, Vincent Procaccio, Patrizia Amati-Bonneau, Sonia Abdelhak, Ilhem Ben Youssef-Turki, Guy Lenaers, Rym Kefi.
      Mitochondrial cytopathies, among which the Leigh syndrome (LS), are caused by variants either in the mitochondrial or the nuclear genome, affecting the oxidative phosphorylation process. The aim of this study consisted in defining the molecular diagnosis of a group of Tunisian patients with LS. Six children, belonging to five Tunisian families, with clinical and imaging presentations suggestive of LS were recruited. Whole mitochondrial DNA and targeted next generation sequencing of a panel of 281 nuclear genes involved in mitochondrial physiology were performed. Bioinformatic analyses were achieved in order to identify deleterious variations. A single m.10197G>A (p.Ala47Thr) variant was found in the mitochondrial MT-ND3 gene in one patient, while the others were related to autosomal homozygous variants: two c.1412delA (p.Gln471ArgfsTer42) and c.1264A>G (p.Thr422Ala) in SLC19A3, one c.454C>G (p.Pro152Ala) in SLC25A19 and one c.122G>A (p.Gly41Asp) in ETHE1. Our findings demonstrate the usefulness of genomic investigations to improve LS diagnosis in consanguineous populations, and further allow for treating the patients harboring variants in SLC19A3 and SLC25A19 that contribute to thiamine transport, by thiamine and biotin supplementation. Considering the Tunisian genetic background, the newly identified variants could be screened in patients with similar clinical presentation in related populations.
    Keywords:  Leigh syndrome; NGS; North Africa; Tunisia; mitochondrial cytopathies
    DOI:  https://doi.org/10.1042/BSR20220194
  10. Aging Cell. 2022 Sep 11. e13710
    The emergent role of mitochondrial surveillance in cellular health.
    Elissa Tjahjono, Daniel R Kirienko, Natalia V Kirienko.
      Mitochondrial dysfunction is one of the primary causatives for many pathologies, including neurodegenerative diseases, cancer, metabolic disorders, and aging. Decline in mitochondrial functions leads to the loss of proteostasis, accumulation of ROS, and mitochondrial DNA damage, which further exacerbates mitochondrial deterioration in a vicious cycle. Surveillance mechanisms, in which mitochondrial functions are closely monitored for any sign of perturbations, exist to anticipate possible havoc within these multifunctional organelles with primitive origin. Various indicators of unhealthy mitochondria, including halted protein import, dissipated membrane potential, and increased loads of oxidative damage, are on the top of the lists for close monitoring. Recent research also indicates a possibility of reductive stress being monitored as part of a mitochondrial surveillance program. Upon detection of mitochondrial stress, multiple mitochondrial stress-responsive pathways are activated to promote the transcription of numerous nuclear genes to ameliorate mitochondrial damage and restore compromised cellular functions. Co-expression occurs through functionalization of transcription factors, allowing their binding to promoter elements to initiate transcription of target genes. This review provides a comprehensive summary of the intricacy of mitochondrial surveillance programs and highlights their roles in our cellular life. Ultimately, a better understanding of these surveillance mechanisms is expected to improve healthspan.
    Keywords:  aging; mitochondria; mitochondrial membrane transport proteins; mitophagy; physiological stress; reactive oxygen species; surveillance
    DOI:  https://doi.org/10.1111/acel.13710
  11. J Orthop Translat. 2022 Jul;35 37-52
    Regulation of mitochondrial dynamic equilibrium by physical exercise in sarcopenia: A systematic review.
    Yu-Feng Long, Simon Kwoon-Ho Chow, Can Cui, Ronald Man Yeung Wong, Ling Qin, Sheung-Wai Law, Wing-Hoi Cheung.
      Background: Sarcopenia is a hallmark of the ageing process, which is characterized by the decline in muscle mass and strength. Growing evidence indicates that mitochondria dysfunction play core roles in this process. Meanwhile, physical exercise is regarded as one of the efficiency therapies to attenuate sarcopenia via regulating mitochondrial function during ageing. However, the specific mechanisms among exercise, mitochondrial function and sarcopenia are still unclear. The aim of this systematic review is to delineate the effects of physical exercise on mitochondria during ageing in order to explore potential target for rescuing sarcopenia.Methods: A systematic literature search was performed in PubMed, Embase and Web of Science. Information was extracted from the included studies for review.
    Results: In this review, 16 pre-clinical studies were included and 105 clinical studies that were not mechanistic research were excluded. 16 pre-clinical studies provided evidence that physical exercise could affect mitochondrial quality control to attenuate sarcopenia. Most of the included studies described the important role of mitochondrial dynamic equilibrium in sarcopenia and showed that effective physical exercise could influence mitochondrial biogenesis, fusion, fission and mitophagy to attenuate sarcopenia in aged animal.
    Conclusions: This systematic review provides an up-to-date sequential overview and highlights the link in the potential mitochondria-related target and physical exercise in aged animal.
    Translation of this article: Currently, there is no standard treatment method for sarcopenia. This systematic review revealed the underlying mechanisms for how physical exercise improved muscle performance via regulating mitochondrial dynamic equilibrium, which could provide scientific support for using exercise as a timely intervention for sarcopenia. Additionally, this systematic review allows a better understanding of mitochondrial dynamic equilibrium and exercise for future development of new therapeutic interventions to attenuate sarcopenia.
    Keywords:  Apoptosis; Mitochondria; Physical exercise; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.jot.2022.06.003
  12. Behav Brain Res. 2022 Sep 08. pii: S0166-4328(22)00375-8. [Epub ahead of print] 114107
    A promissing mouse model for Friedreich Ataxia progressing like human patients.
    Catherine Gérard, Annabelle Fortin Archambault, Camille Bouchard, Jacques P Tremblay.
      Friedreich Ataxia (FRDA) is a genetic disease caused by an expended GAA repeat in the FXN gene leading to a reduction in frataxin protein production. Frataxin is an essential protein involved in mitochondrial iron-sulfur-cluster formation, its absence affecting numerous cellular rections. In patients, the disease leads to a progressive neuromuscular degeneration and, most of the time, death from heart failure. In order to determine if a treatment is effective or not, it is essential to have the mouse model, which best reflects all of the characteristics of this disease. Many groups were working on the creation of mouse models by decreasing the mouse frataxin or knocking it out, by introducing a transgene with a human frataxin with long GAA repeat. Most of the mouse models are limited to one problem, either neurologic or cardiac symptoms, and, for those who have both, generally these symptoms are too severe and mice have a very short life span, which does not reflect the human disease's progression. Jackson Laboratories Inc. developed a new mouse model that has 800 GAA repeats. We demonstrate here that these mice accurately reflect the human disease with a progressive neuromuscular degeneration highlighted by the two beam tests and the beginning of heart hypertrophy at 26 weeks. YG8-800 mice are thus currently a promising mouse model for FRDA.
    Keywords:  Friedreich Ataxia; behavior test; cardiac hypertrophy; frataxin; mouse model
    DOI:  https://doi.org/10.1016/j.bbr.2022.114107
  13. Cell Mol Life Sci. 2022 Sep 14. 79(10): 517
    Metabolic reprogramming in the OPA1-deficient cells.
    Wenting Dai, Zhichao Wang, Qiong A Wang, David Chan, Lei Jiang.
      OPA1, a dynamin-related GTPase mutated in autosomal dominant optic atrophy, is essential for the fusion of the inner mitochondrial membrane. Although OPA1 deficiency leads to impaired mitochondrial morphology, the role of OPA1 in central carbon metabolism remains unclear. Here, we aim to explore the functional role and metabolic mechanism of OPA1 in cell fitness beyond the control of mitochondrial fusion. We applied [U-13C]glucose and [U-13C]glutamine isotope tracing techniques to OPA1-knockout (OPA1-KO) mouse embryonic fibroblasts (MEFs) compared to OPA1 wild-type (OPA1-WT) controls. Furthermore, the resulting tracing data were integrated by metabolic flux analysis to understand the underlying metabolic mechanism through which OPA1 deficiency reprograms cellular metabolism. OPA1-deficient MEFs were depleted of intracellular citrate, which was consistent with the decreased oxygen consumption rate in these cells with mitochondrial fission that is not balanced by mitochondrial fusion. Whereas oxidative glucose metabolism was impaired, OPA1-deficient cells activated glutamine-dependent reductive carboxylation and subsequently relied on this reductive metabolism to produce cytosolic citrate as a predominant acetyl-CoA source for de novo fatty acid synthesis. Prevention of cytosolic glutamine reductive carboxylation by GSK321, an inhibitor of isocitrate dehydrogenase 1 (IDH1), largely repressed lipid synthesis and blocked cell proliferation in OPA1-deficient MEFs. Our data support that, when glucose oxidation failed to support lipogenesis and proliferation in cells with unbalanced mitochondrial fission, OPA1 deficiency stimulated metabolic anaplerosis into glutamine-dependent reductive carboxylation in an IDH1-mediated manner.
    Keywords:  Cell growth; Citrate; De novo lipogenesis; OPA1 dysfunction; Oxidative metabolism; Reductive carboxylation
    DOI:  https://doi.org/10.1007/s00018-022-04542-5
  14. FEBS Lett. 2022 Sep 16.
    Overexpression of UCP3 decreases mitochondrial efficiency in mouse skeletal muscle in vivo.
    Roberto Codella, Tiago C Alves, Douglas E Befroy, Cheol Soo Choi, Livio Luzi, Douglas L Rothman, Richard G Kibbey, Gerald I Shulman.
      Uncoupling protein-3 (UCP3) is a mitochondrial transmembrane protein highly expressed in muscle that has been implicated in regulating the efficiency of mitochondrial oxidative phosphorylation. Increasing UCP3 expression in skeletal muscle enhances proton leak across the inner mitochondrial membrane and increases oxygen consumption in isolated mitochondria, but its precise function in vivo has yet to be fully elucidated. To examine whether muscle-specific overexpression of UCP3 modulates muscle mitochondrial oxidation in vivo, rates of ATP synthesis were assessed by 31 P magnetic resonance spectroscopy (MRS) and rates of mitochondrial oxidative metabolism were measured by assessing the rate of [2-13 C]acetate incorporation into muscle [4-13 C]- , [3-13 C]-glutamate and [4-13 C]-glutamine by high resolution 13 C/1 H MRS. Using this approach we found that overexpression of UCP3 in skeletal muscle was accompanied by increased muscle mitochondrial inefficiency in vivo as reflected by a 42% reduction in the ratio of ATP synthesis to mitochondrial oxidation.
    Keywords:  magnetic resonance spectroscopy; mitochondrial efficiency; mitochondrial uncoupling; muscle energy metabolism
    DOI:  https://doi.org/10.1002/1873-3468.14494
  15. Mov Disord. 2022 Sep 14.
    Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST.
    Alisa Mo, Afshin Saffari, Melanie Kellner, Marion Döbler-Neumann, Catherine Jordan, Siddharth Srivastava, Bo Zhang, Mustafa Sahin, John K Fink, Linsley Smith, Jennifer E Posey, Katharine E Alter, Camilo Toro, Craig Blackstone, Ariane G Soldatos, Michelle Christie, Rebecca Schüle, Darius Ebrahimi-Fakhari.
      BACKGROUND: Familial hereditary spastic paraplegia (HSP)-SPAST (SPG4) typically presents with a pure HSP phenotype.OBJECTIVE: The aim of this study was to delineate the genotypic and phenotypic spectrum of children with de novo HSP-SPAST.
    METHODS: This study used a systematic cross-sectional analysis of clinical and molecular features.
    RESULTS: We report the clinical and molecular spectrum of 40 patients with heterozygous pathogenic de novo variants in SPAST (age range: 2.2-27.7 years). We identified 19 unique variants (16/40 carried the same recurrent variant, p.Arg499His). Symptom onset was in early childhood (median: 11.0 months, interquartile range: 6.0 months) with significant motor and speech delay, followed by progressive ascending spasticity, dystonia, neurogenic bladder dysfunction, gastrointestinal dysmotility, and epilepsy. The mean Spastic Paraplegia Rating Scale score was 32.8 ± 9.7 (standard deviation).
    CONCLUSIONS: These results confirm that de novo variants in SPAST lead to a severe and complex form of HSP that differs from classic familial pure HSP-SPAST. Clinicians should be aware of this syndrome in the differential diagnosis for cerebral palsy. © 2022 International Parkinson and Movement Disorder Society.
    Keywords:  SPAST; cerebral palsy; childhood-onset movement disorders; hereditary spastic paraplegia; neurogenetics
    DOI:  https://doi.org/10.1002/mds.29225
  16. Gene Ther. 2022 Sep 12.
    Changing trends in the development of AAV-based gene therapies: a meta-analysis of past and present therapies.
    Tamara Burdett, Samir Nuseibeh.
      Gene therapy has seen a transformation from a proof-of-concept approach to a clinical reality over the past several decades, with adeno-associated virus (AAV)-mediated gene therapy emerging as the leading platform for in vivo gene transfer. A systematic review of AAV-based gene therapies in clinical development was conducted herein to determine why only a handful of AAV-based gene therapy products have achieved market approval. The indication to be treated, route of administration and vector design were investigated as critical factors and assessed for their impact on clinical safety and efficacy. A shift in recent years towards high-dose systemic administration for the treatment of metabolic, neurological and haematological diseases was identified, with intravenous administration demonstrating the highest efficacy and safety risks in clinical trials. Recent years have seen a decline in favour of traditional AAV serotypes and promoters, accompanied by an increase in favour and higher clinical success rate for novel capsids and tissue-specific promoters. Furthermore, a meta-analysis was performed to identify factors that may inhibit the translation of therapeutic efficacy from preclinical large animal studies to first-in-human clinical trials and a detrimental effect on clinical efficacy was associated with alterations to administration routes.
    DOI:  https://doi.org/10.1038/s41434-022-00363-0
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