bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024‒02‒25
27 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico 
  1. The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease.
  2. Decoding the mitochondria without a code: mechanistic insights into mitochondrial DNA depletion syndromes.
  3. Mitochondrial Quantity and Quality in Age-Related Sarcopenia.
  4. Mitochondrial quality control alterations and placenta-related disorders.
  5. Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.
  6. Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.
  7. A SPLICS reporter reveals [Formula: see text]-synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation.
  8. Generation of two human induced pluripotent stem cell lines, IGIBi012-A and IGIBi013-A from Friedreich's ataxia (FRDA) patients with homozygous GAA repeat expansion in FXN gene.
  9. Variants in Human ATP Synthase Mitochondrial Genes: Biochemical Dysfunctions, Associated Diseases, and Therapies.
  10. Emerging antioxidant therapies in Friedreich's ataxia.
  11. Exposure of the inner mitochondrial membrane triggers apoptotic mitophagy.
  12. Mitochondrial Transportation, Transplantation, and Subsequent Immune Response in Alzheimer's Disease: An Update.
  13. Mitochondrial replacement techniques for treating infertility.
  14. Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis.
  15. Mitophagy regulates mitochondrial number following pharmacological induction of mitochondrial biogenesis in renal proximal tubule cells.
  16. MIMAS is a new giant multifunctional player in the mitochondrial megacomplex playground.
  17. High-dose atorvastatin therapy progressively decreases skeletal muscle mitochondrial respiratory capacity in humans.
  18. Phenotypic variation of FXN compound heterozygotes in a Friedreich ataxia cohort.
  19. An integral role of mitochondrial function in the pathophysiology of preeclampsia.
  20. Mitochondrial Dysfunction and Protein Homeostasis in Aging: Insights from a Premature-Aging Mouse Model.
  21. Mitochondrial dysfunction due to miR-210/Drd5/ROS axis is a potential mechanism of heart failure.
  22. MFN2 overexpression in skeletal muscles of young and old mice causes a mild hypertrophy without altering mitochondrial respiration and H2 O2 emission.
  23. Recurrence of Visual Loss in Recessive Leber Hereditary Optic Neuropathy: New Paradigm.
  24. Bridging the clinical-research gap: Harnessing an electronic data capture, integration, and visualization platform to systematically assess prospective patient-reported outcomes in mitochondrial medicine.
  25. Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene.
  26. In vivo mitochondria-targeted protection against uterine artery vascular dysfunction and remodelling in rodent hypoxic pregnancy.
  27. Hereditary Ataxias: From Bench to Clinic, Where Do We Stand?
  1. Int J Biol Sci. 2024 ;20(4): 1194-1217
    The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease.
    Yu Hong, Zhuoyuan Zhang, Tsering Yangzom, Anbin Chen, Bjørn Christian Lundberg, Evandro Fei Fang, Richard Siller, Gareth John Sullivan, Jiri Zeman, Charalampos Tzoulis, Laurence A Bindoff, Kristina Xiao Liang.
      Alpers' syndrome is an early-onset neurodegenerative disorder usually caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase-gamma (POLG), which is essential for mitochondrial DNA (mtDNA) replication. The disease is progressive, incurable, and inevitably it leads to death from drug-resistant status epilepticus. The neurological features of Alpers' syndrome are intractable epilepsy and developmental regression, with no effective treatment; the underlying mechanisms are still elusive, partially due to lack of good experimental models. Here, we generated the patient derived induced pluripotent stem cells (iPSCs) from one Alpers' patient carrying the compound heterozygous mutations of A467T (c.1399G>A) and P589L (c.1766C>T), and further differentiated them into cortical organoids and neural stem cells (NSCs) for mechanistic studies of neural dysfunction in Alpers' syndrome. Patient cortical organoids exhibited a phenotype that faithfully replicated the molecular changes found in patient postmortem brain tissue, as evidenced by cortical neuronal loss and depletion of mtDNA and complex I (CI). Patient NSCs showed mitochondrial dysfunction leading to ROS overproduction and downregulation of the NADH pathway. More importantly, the NAD+ precursor nicotinamide riboside (NR) significantly ameliorated mitochondrial defects in patient brain organoids. Our findings demonstrate that the iPSC model and brain organoids are good in vitro models of Alpers' disease; this first-in-its-kind stem cell platform for Alpers' syndrome enables therapeutic exploration and has identified NR as a viable drug candidate for Alpers' disease and, potentially, other mitochondrial diseases with similar causes.
    Keywords:  Alpers' disease; NAD+; NR; cortical organoids; induced pluripotent stem cells; mitochondrial function
    DOI:  https://doi.org/10.7150/ijbs.91624
  2. J Biosci. 2024 ;pii: 32. [Epub ahead of print]49
    Decoding the mitochondria without a code: mechanistic insights into mitochondrial DNA depletion syndromes.
    Ritoprova Sen, Cuckoo Teresa Jetto, Ravi Manjithaya.
      Mitochondrial DNA depletion syndromes (MDS) encompass a wide spectrum of rare genetic disorders caused by severe reduction in mitochondrial DNA (mtDNA), and exhibit heterogenous phenotypes classified as myopathic, encephalomyopathic, hepatocerebral, and neurogastrointestinal. Prognosis for such a spectrum of diseases is poor and is majorly dependent on symptomatic treatment and nutritional supplementation. Understanding the mechanistic aspect of mtDNA depletion can help bring forth a new era of medicine, moving beyond symptomatic treatment and focusing more on organelle-targeted therapies. In this review, we highlight some of the proposed mechanistic bases of mtDNA depletion and the latest therapeutic measures used to treat MDS.
  3. Int J Mol Sci. 2024 Feb 08. pii: 2052. [Epub ahead of print]25(4):
    Mitochondrial Quantity and Quality in Age-Related Sarcopenia.
    Emanuele Marzetti, Riccardo Calvani, Hélio José Coelho-Júnior, Francesco Landi, Anna Picca.
      Sarcopenia, the age-associated decline in skeletal muscle mass and strength, is a condition with a complex pathophysiology. Among the factors underlying the development of sarcopenia are the progressive demise of motor neurons, the transition from fast to slow myosin isoform (type II to type I fiber switch), and the decrease in satellite cell number and function. Mitochondrial dysfunction has been indicated as a key contributor to skeletal myocyte decline and loss of physical performance with aging. Several systems have been implicated in the regulation of muscle plasticity and trophism such as the fine-tuned and complex regulation between the stimulator of protein synthesis, mechanistic target of rapamycin (mTOR), and the inhibitor of mTOR, AMP-activated protein kinase (AMPK), that promotes muscle catabolism. Here, we provide an overview of the molecular mechanisms linking mitochondrial signaling and quality with muscle homeostasis and performance and discuss the main pathways elicited by their imbalance during age-related muscle wasting. We also discuss lifestyle interventions (i.e., physical exercise and nutrition) that may be exploited to preserve mitochondrial function in the aged muscle. Finally, we illustrate the emerging possibility of rescuing muscle tissue homeostasis through mitochondrial transplantation.
    Keywords:  DAMPs; extracellular vesicles; inflammaging; metabolism; mitochondrial DNA; mitochondrial biogenesis; mitochondrial transplantation; mitophagy; muscle aging; muscle plasticity
    DOI:  https://doi.org/10.3390/ijms25042052
  4. Front Physiol. 2024 ;15 1344951
    Mitochondrial quality control alterations and placenta-related disorders.
    Yamei Wu, Meng Li, Hao Ying, Ying Gu, Yunlong Zhu, Yanfang Gu, Lu Huang.
      Mitochondria are ubiquitous in eukaryotic cells. Normal maintenance of function is the premise and basis for various physiological activities. Mitochondrial dysfunction is commonly observed in a wide range of pathological conditions, such as neurodegenerative, metabolic, cardiovascular, and various diseases related to foetal growth and development. The placenta is a highly energy-dependent organ that acts as an intermediary between the mother and foetus and functions to maintain foetal growth and development. Recent studies have demonstrated that mitochondrial dysfunction is associated with placental disorders. Defects in mitochondrial quality control mechanisms may lead to preeclampsia and foetal growth restriction. In this review, we address the quality control mechanisms of mitochondria and the relevant pathologies of mitochondrial dysfunction in placenta-related diseases, such as preeclampsia and foetal growth restriction. This review also investigates the relation between mitochondrial dysfunction and placental disorders.
    Keywords:  foetal growth restriction; mitochondria; mitochondrial dysfunction; placenta; preeclampsia
    DOI:  https://doi.org/10.3389/fphys.2024.1344951
  5. Cell Rep. 2024 Feb 19. pii: S2211-1247(24)00133-5. [Epub ahead of print]43(3): 113805
    Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.
    Jon V Busto, Iniyan Ganesan, Hannah Mathar, Conny Steiert, Eva F Schneider, Sebastian P Straub, Lars Ellenrieder, Jiyao Song, Sebastian B Stiller, Philipp Lübbert, Ritwika Chatterjee, Jana Elsaesser, Laura Melchionda, Christina Schug, Fabian den Brave, Uwe Schulte, Till Klecker, Claudine Kraft, Bernd Fakler, Thomas Becker, Nils Wiedemann.
      The majority of mitochondrial precursor proteins are imported through the Tom40 β-barrel channel of the translocase of the outer membrane (TOM). The sorting and assembly machinery (SAM) is essential for β-barrel membrane protein insertion into the outer membrane and thus required for the assembly of the TOM complex. Here, we demonstrate that the α-helical outer membrane protein Mco6 co-assembles with the mitochondrial distribution and morphology protein Mdm10 as part of the SAM machinery. MCO6 and MDM10 display a negative genetic interaction, and a mco6-mdm10 yeast double mutant displays reduced levels of the TOM complex. Cells lacking Mco6 affect the levels of Mdm10 and show assembly defects of the TOM complex. Thus, this work uncovers a role of the SAMMco6 complex for the biogenesis of the mitochondrial outer membrane.
    Keywords:  CP: Cell biology; ERMES complex; Mdm10; SAM complex; TOM complex; mitochondria; outer membrane; protein import; protein translocation; β-barrel protein
    DOI:  https://doi.org/10.1016/j.celrep.2024.113805
  6. Cell Rep. 2024 Feb 21. pii: S2211-1247(24)00100-1. [Epub ahead of print]43(3): 113772
    Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.
    Patrick Horten, Kuo Song, Joshua Garlich, Robert Hardt, Lilia Colina-Tenorio, Susanne E Horvath, Uwe Schulte, Bernd Fakler, Martin van der Laan, Thomas Becker, Rosemary A Stuart, Nikolaus Pfanner, Heike Rampelt.
      The mitochondrial inner membrane plays central roles in bioenergetics and metabolism and contains several established membrane protein complexes. Here, we report the identification of a mega-complex of the inner membrane, termed mitochondrial multifunctional assembly (MIMAS). Its large size of 3 MDa explains why MIMAS has escaped detection in the analysis of mitochondria so far. MIMAS combines proteins of diverse functions from respiratory chain assembly to metabolite transport, dehydrogenases, and lipid biosynthesis but not the large established supercomplexes of the respiratory chain, ATP synthase, or prohibitin scaffold. MIMAS integrity depends on the non-bilayer phospholipid phosphatidylethanolamine, in contrast to respiratory supercomplexes whose stability depends on cardiolipin. Our findings suggest that MIMAS forms a protein-lipid mega-assembly in the mitochondrial inner membrane that integrates respiratory biogenesis and metabolic processes in a multifunctional platform.
    Keywords:  CP: Metabolism; CP: Molecular biology; membrane protein complex; metabolism; metabolite carriers; mitochondria; phosphatidylethanolamine; phospholipids; protein assembly; respiratory chain
    DOI:  https://doi.org/10.1016/j.celrep.2024.113772
  7. Nat Commun. 2024 Feb 19. 15(1): 1516
    A SPLICS reporter reveals [Formula: see text]-synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation.
    Flavia Giamogante, Lucia Barazzuol, Francesca Maiorca, Elena Poggio, Alessandra Esposito, Anna Masato, Gennaro Napolitano, Alessio Vagnoni, Tito Calì, Marisa Brini.
      Mitochondrial and lysosomal activities are crucial to maintain cellular homeostasis: optimal coordination is achieved at their membrane contact sites where distinct protein machineries regulate organelle network dynamics, ions and metabolites exchange. Here we describe a genetically encoded SPLICS reporter for short- and long- juxtapositions between mitochondria and lysosomes. We report the existence of narrow and wide lysosome-mitochondria contacts differently modulated by mitophagy, autophagy and genetic manipulation of tethering factors. The overexpression of α-synuclein (α-syn) reduces the apposition of mitochondria/lysosomes membranes and affects their privileged Ca2+ transfer, impinging on TFEB nuclear translocation. We observe enhanced TFEB nuclear translocation in α-syn-overexpressing cells. We propose that α-syn, by interfering with mitochondria/lysosomes tethering impacts on local Ca2+ regulated pathways, among which TFEB mediated signaling, and in turn mitochondrial and lysosomal function. Defects in mitochondria and lysosome represent a common hallmark of neurodegenerative diseases: targeting their communication could open therapeutic avenues.
    DOI:  https://doi.org/10.1038/s41467-024-46007-2
  8. Stem Cell Res. 2024 Feb 10. pii: S1873-5061(24)00038-2. [Epub ahead of print]76 103340
    Generation of two human induced pluripotent stem cell lines, IGIBi012-A and IGIBi013-A from Friedreich's ataxia (FRDA) patients with homozygous GAA repeat expansion in FXN gene.
    Istaq Ahmad, Himanshi Kapoor, Achal Kumar Srivastava, Mohammed Faruq.
      Friedreich's ataxia is a neurodegenerative disorder caused by the hyper expansion of (GAA-TTC)n triplet repeats in the first intron of the FXN gene. Here, we generated iPSC lines from two individuals with FRDA, both of whom have homozygous GAA repeat expansion in the first intron of FXN gene. Both iPSC lines demonstrated characteristics of pluripotency, including expression of pluripotency markers, stable karyotypes and ability to develop into all three germ layers, and presence of GAA repeat expansion with reduced FXN mRNA expression. These iPSC lines will serve as invaluable tools for investigating the pathophysiology and phenotypes of FRDA.
    DOI:  https://doi.org/10.1016/j.scr.2024.103340
  9. Int J Mol Sci. 2024 Feb 13. pii: 2239. [Epub ahead of print]25(4):
    Variants in Human ATP Synthase Mitochondrial Genes: Biochemical Dysfunctions, Associated Diseases, and Therapies.
    Valentina Del Dotto, Francesco Musiani, Alessandra Baracca, Giancarlo Solaini.
      Mitochondrial ATP synthase (Complex V) catalyzes the last step of oxidative phosphorylation and provides most of the energy (ATP) required by human cells. The mitochondrial genes MT-ATP6 and MT-ATP8 encode two subunits of the multi-subunit Complex V. Since the discovery of the first MT-ATP6 variant in the year 1990 as the cause of Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) syndrome, a large and continuously increasing number of inborn variants in the MT-ATP6 and MT-ATP8 genes have been identified as pathogenic. Variants in these genes correlate with various clinical phenotypes, which include several neurodegenerative and multisystemic disorders. In the present review, we report the pathogenic variants in mitochondrial ATP synthase genes and highlight the molecular mechanisms underlying ATP synthase deficiency that promote biochemical dysfunctions. We discuss the possible structural changes induced by the most common variants found in patients by considering the recent cryo-electron microscopy structure of human ATP synthase. Finally, we provide the state-of-the-art of all therapeutic proposals reported in the literature, including drug interventions targeting mitochondrial dysfunctions, allotopic gene expression- and nuclease-based strategies, and discuss their potential translation into clinical trials.
    Keywords:  ATP synthase; ATP6; ATP8; F1Fo-ATPase modeling; mitochondria; mt-DNA; mutations; therapy
    DOI:  https://doi.org/10.3390/ijms25042239
  10. Front Pharmacol. 2024 ;15 1359618
    Emerging antioxidant therapies in Friedreich's ataxia.
    Fred Jonathan Edzeamey, Zenouska Ramchunder, Charareh Pourzand, Sara Anjomani Virmouni.
      Friedreich's ataxia (FRDA) is a rare childhood neurologic disorder, affecting 1 in 50,000 Caucasians. The disease is caused by the abnormal expansion of the GAA repeat sequence in intron 1 of the FXN gene, leading to the reduced expression of the mitochondrial protein frataxin. The disease is characterised by progressive neurodegeneration, hypertrophic cardiomyopathy, diabetes mellitus and musculoskeletal deformities. The reduced expression of frataxin has been suggested to result in the downregulation of endogenous antioxidant defence mechanisms and mitochondrial bioenergetics, and the increase in mitochondrial iron accumulation thereby leading to oxidative stress. The confirmation of oxidative stress as one of the pathological signatures of FRDA led to the search for antioxidants which can be used as therapeutic modality. Based on this observation, antioxidants with different mechanisms of action have been explored for FRDA therapy since the last two decades. In this review, we bring forth all antioxidants which have been investigated for FRDA therapy and have been signed off for clinical trials. We summarise their various target points in FRDA disease pathway, their performances during clinical trials and possible factors which might have accounted for their failure or otherwise during clinical trials. We also discuss the limitation of the studies completed and propose possible strategies for combinatorial therapy of antioxidants to generate synergistic effect in FRDA patients.
    Keywords:  Friedreich’s ataxia; antioxidants; clinical trials; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.3389/fphar.2024.1359618
  11. Cell Death Differ. 2024 Feb 23.
    Exposure of the inner mitochondrial membrane triggers apoptotic mitophagy.
    Tahnee L Saunders, Simon P Windley, Gediminas Gervinskas, Katherine R Balka, Caitlin Rowe, Rachael Lane, Maximilien Tailler, Thanh Ngoc Nguyen, Georg Ramm, Michael Lazarou, Dominic De Nardo, Benjamin T Kile, Kate McArthur.
      During apoptosis mediated by the intrinsic pathway, BAX/BAK triggers mitochondrial permeabilization and the release of cytochrome-c, followed by a dramatic remodelling of the mitochondrial network that results in mitochondrial herniation and the subsequent release of pro-inflammatory mitochondrial components. Here, we show that mitochondrial herniation and subsequent exposure of the inner mitochondrial membrane (IMM) to the cytoplasm, initiates a unique form of mitophagy to deliver these damaged organelles to lysosomes. IMM-induced mitophagy occurs independently of canonical PINK1/Parkin signalling and is driven by ubiquitination of the IMM. Our data suggest IMM-induced mitophagy is an additional safety mechanism that cells can deploy to contain damaged mitochondria. It may have particular relevance in situations where caspase activation is incomplete or inhibited, and in contexts where PINK1/Parkin-mitophagy is impaired or overwhelmed.
    DOI:  https://doi.org/10.1038/s41418-024-01260-2
  12. Mol Neurobiol. 2024 Feb 17.
    Mitochondrial Transportation, Transplantation, and Subsequent Immune Response in Alzheimer's Disease: An Update.
    Pegah Javadpour, Fatemeh Abbaszadeh, Abolhassan Ahmadiani, Mohsen Rezaei, Rasoul Ghasemi.
      Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by memory impairment and a progressive decline in cognitive function. Mitochondrial dysfunction has been identified as an important contributor to the development of AD, leading to oxidative stress and energy deficits within the brain. While current treatments for AD aim to alleviate symptoms, there is an urgent need to target the underlying mechanisms. The emerging field of mitotherapy, which involves the transplantation of healthy mitochondria into damaged cells, has gained substantial attention and has shown promising results. However, research in the context of AD remains limited, necessitating further investigations. In this review, we summarize the mitochondrial pathways that contribute to the progression of AD. Additionally, we discuss mitochondrial transfer among brain cells and mitotherapy, with a focus on different administration routes, various sources of mitochondria, and potential modifications to enhance transplantation efficacy. Finally, we review the limited available evidence regarding the immune system's response to mitochondrial transplantation in damaged brain regions.
    Keywords:  Alzheimer’s disease; Energy metabolism; Mitochondria; Mitochondrial transplantation; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s12035-024-04009-7
  13. J Med Ethics. 2024 Feb 21. pii: jme-2023-109660. [Epub ahead of print]
    Mitochondrial replacement techniques for treating infertility.
    Esther Braun.
      Mitochondrial replacement techniques (MRTs) usually aim to prevent the genetic transmission of maternally inherited mitochondrial diseases. Until now, only the UK and Australia have implemented specific legal regulations of MRTs. In both countries, clinical trials on these techniques are only permissible for cases with a high risk of severe mitochondrial disease in the offspring. However, these techniques can also be applied to treat infertility, especially for older women with impaired oocyte quality. In some countries without legal regulation of these techniques, MRTs are already offered for this purpose. Yet, this application of MRTs has received insufficient attention in the bioethical literature so far.In this paper, I examine whether there are ethical reasons to prohibit trials on MRTs in the context of infertility when they are permitted for preventing mitochondrial disease. Allowing MRTs in one context but not the other might be justified either because their application in the context of mitochondrial disease (1) is supported by a more convincing evidence base, (2) has a higher potential benefit or (3) has a lower risk. I compare both applications of MRTs with respect to these three factors. I conclude that there is no convincing reason to prohibit clinical trials on MRTs for infertility when they are permitted in the context of mitochondrial disease.
    Keywords:  Embryos and Fetuses; Ethics- Medical; Fertilization in Vitro; Genetic Engineering; Reproductive Medicine
    DOI:  https://doi.org/10.1136/jme-2023-109660
  14. Nat Commun. 2024 Feb 22. 15(1): 1637
    Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis.
    Ji Geng, Shuangxi Li, Yu Li, Zhihao Wu, Sunil Bhurtel, Suman Rimal, Danish Khan, Rani Ohja, Onn Brandman, Bingwei Lu.
      Translational control exerts immediate effect on the composition, abundance, and integrity of the proteome. Ribosome-associated quality control (RQC) handles ribosomes stalled at the elongation and termination steps of translation, with ZNF598 in mammals and Hel2 in yeast serving as key sensors of translation stalling and coordinators of downstream resolution of collided ribosomes, termination of stalled translation, and removal of faulty translation products. The physiological regulation of RQC in general and ZNF598 in particular in multicellular settings is underexplored. Here we show that ZNF598 undergoes regulatory K63-linked ubiquitination in a CNOT4-dependent manner and is upregulated upon mitochondrial stresses in mammalian cells and Drosophila. ZNF598 promotes resolution of stalled ribosomes and protects against mitochondrial stress in a ubiquitination-dependent fashion. In Drosophila models of neurodegenerative diseases and patient cells, ZNF598 overexpression aborts stalled translation of mitochondrial outer membrane-associated mRNAs, removes faulty translation products causal of disease, and improves mitochondrial and tissue health. These results shed lights on the regulation of ZNF598 and its functional role in mitochondrial and tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41467-024-45525-3
  15. Front Pharmacol. 2024 ;15 1344075
    Mitophagy regulates mitochondrial number following pharmacological induction of mitochondrial biogenesis in renal proximal tubule cells.
    Kevin A Hurtado, Rick G Schnellmann.
      Background: Mitochondrial biogenesis (MB) induction through the activation of the 5-Hydroxytriptamine (5-HT) 1F receptor (HTR1F) is a promising mechanism for the treatment of diseases characterized by mitochondrial dysfunction, such as acute kidney injury (AKI). While several studies report pharmacological activation of MB in the proximal tubule, it is unclear how the proximal tubule regulates itself once the pharmacological activation is removed. Mitophagy is the process of selective mitochondria degradation. We hypothesize that mitophagy decreases mitochondrial number after pharmacological stimulation and restore mitochondrial homeostasis. Methods: Renal proximal tubules were treated at time 0hr with LY344864 or vehicle for 24 h and then removed. LY344864, a selective HTR1F agonist, induces MB in renal proximal tubules as previously reported (Gibbs et al., Am J Physiol Renal Physiol, 2018, 314(2), F260-F268). Vehicle and pharmacological reagents were added at the 24 h time point. Electron microscopy was used to assess mitochondrial morphology, number, and autolysosomes. Seahorse Bioscience XF-96 extracellular flux analyzer was used to measure maximal mitochondrial oxygen consumption rates (FCCP-OCR), a functional marker of MB. Results: LY344864 treatment increased FCCP-OCR, phosphorylation of protein kinase B (AKT), peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α), and mitochondrial number after 24 h. These endpoints decreased to baseline 24 h after LY344864 removal. Treatment with ROC-325, an autophagy inhibitor, increased Sequestosome-1 (SQSTM1/P62) and microtubule-associated protein-1 light chain 3 (LC3B) after 24 h of treatment. Also, ROC-325 treatment sustained the elevated mitochondrial number after LY344864 pre-treatment and removal. Conclusion: These data revealed that inhibition of autophagy extends elevated mitochondrial number and function by preventing the lysosomal degradation of mitochondria after the removal of LY344864.
    Keywords:  HTR1F; autophagy; mitochondrial biogenesis; mitophagy; proximal tubule
    DOI:  https://doi.org/10.3389/fphar.2024.1344075
  16. Cell Rep. 2024 Feb 21. pii: S2211-1247(24)00202-X. [Epub ahead of print]43(3): 113874
    MIMAS is a new giant multifunctional player in the mitochondrial megacomplex playground.
    Kostas Tokatlidis.
      Mitochondria are rich in multi-protein assemblies that are usually dedicated to one function. In this issue of Cell Reports, Horten et al.1 describe a 3-nanometer megacomplex in the mitochondrial inner membrane, which serves multiple functions integrating mitochondria biogenesis and metabolism.
    DOI:  https://doi.org/10.1016/j.celrep.2024.113874
  17. JCI Insight. 2024 Feb 22. pii: e174125. [Epub ahead of print]9(4):
    High-dose atorvastatin therapy progressively decreases skeletal muscle mitochondrial respiratory capacity in humans.
    Terence E Ryan, Maria J Torres, Chien-Te Lin, Angela H Clark, Patricia M Brophy, Cheryl A Smith, Cody D Smith, E Matthew Morris, John P Thyfault, P Darrell Neufer.
      BACKGROUNDWhile the benefits of statin therapy on atherosclerotic cardiovascular disease are clear, patients often experience mild to moderate skeletal myopathic symptoms, the mechanism for which is unknown. This study investigated the potential effect of high-dose atorvastatin therapy on skeletal muscle mitochondrial function and whole-body aerobic capacity in humans.METHODSEight overweight (BMI, 31.9 ± 2.0) but otherwise healthy sedentary adults (4 females, 4 males) were studied before (day 0) and 14, 28, and 56 days after initiating atorvastatin (80 mg/d) therapy.RESULTSMaximal ADP-stimulated respiration, measured in permeabilized fiber bundles from muscle biopsies taken at each time point, declined gradually over the course of atorvastatin treatment, resulting in > 30% loss of skeletal muscle mitochondrial oxidative phosphorylation capacity by day 56. Indices of in vivo muscle oxidative capacity (via near-infrared spectroscopy) decreased by 23% to 45%. In whole muscle homogenates from day 0 biopsies, atorvastatin inhibited complex III activity at midmicromolar concentrations, whereas complex IV activity was inhibited at low nanomolar concentrations.CONCLUSIONThese findings demonstrate that high-dose atorvastatin treatment elicits a striking progressive decline in skeletal muscle mitochondrial respiratory capacity, highlighting the need for longer-term dose-response studies in different patient populations to thoroughly define the effect of statin therapy on skeletal muscle health.FUNDINGNIH R01 AR071263.
    Keywords:  Bioenergetics; Mitochondria; Muscle biology; Skeletal muscle
    DOI:  https://doi.org/10.1172/jci.insight.174125
  18. Ann Clin Transl Neurol. 2024 Feb 23.
    Phenotypic variation of FXN compound heterozygotes in a Friedreich ataxia cohort.
    Megan M Shen, Christian Rummey, David R Lynch.
      OBJECTIVE: Most individuals with Friedreich ataxia (FRDA) have homozygous GAA triplet repeat expansions in the FXN gene, correlating with a typical phenotype of ataxia and cardiomyopathy. A minority are compound heterozygotes carrying a GAA expansion on one allele and a mutation on the other. The study aim was to examine phenotypic variation among compound heterozygotes.METHODS: Data on FXN mutations were obtained from the Friedreich Ataxia Clinical Outcome Measures Study (FA-COMS). We compared clinical features in a single-site FA-COMS cohort of 51 compound heterozygous and 358 homozygous patients, including quantitative measures of cardiac, neurologic, and visual disease progression.
    RESULTS: Non-GAA repeat mutations were associated with reduced cardiac disease, and patients with minimal/no function mutations otherwise had a typical FRDA phenotype but with significantly more severe progression. The partial function mutation group was characterized by relative sparing of bulbar and upper limb function, as well as particularly low cardiac involvement. Other clinical features in this group, including optic atrophy and diabetes mellitus, varied widely depending on the specific type of partial function mutation.
    INTERPRETATION: These data support that the typical FRDA phenotype is driven by frataxin deficiency, especially severe in compound heterozygotes with minimal/no function mutations, whereas the heterogeneous presentations of those with partial function mutations may indicate other contributing factors to FRDA pathogenesis.
    DOI:  https://doi.org/10.1002/acn3.52027
  19. Mol Biol Rep. 2024 Feb 23. 51(1): 330
    An integral role of mitochondrial function in the pathophysiology of preeclampsia.
    Hiroshi Kobayashi, Chiharu Yoshimoto, Sho Matsubara, Hiroshi Shigetomi, Shogo Imanaka.
      Preeclampsia (PE) is associated with high maternal and perinatal morbidity and mortality. The development of effective treatment strategies remains a major challenge due to the limited understanding of the pathogenesis. In this review, we summarize the current understanding of PE research, focusing on the molecular basis of mitochondrial function in normal and PE placentas, and discuss perspectives on future research directions. Mitochondria integrate numerous physiological processes such as energy production, cellular redox homeostasis, mitochondrial dynamics, and mitophagy, a selective autophagic clearance of damaged or dysfunctional mitochondria. Normal placental mitochondria have evolved innovative survival strategies to cope with uncertain environments (e.g., hypoxia and nutrient starvation). Cytotrophoblasts, extravillous trophoblast cells, and syncytiotrophoblasts all have distinct mitochondrial morphology and function. Recent advances in molecular studies on the spatial and temporal changes in normal mitochondrial function are providing valuable insight into PE pathogenesis. In PE placentas, hypoxia-mediated mitochondrial fission may induce activation of mitophagy machinery, leading to increased mitochondrial fragmentation and placental tissue damage over time. Repair mechanisms in mitochondrial function restore placental function, but disruption of compensatory mechanisms can induce apoptotic death of trophoblast cells. Additionally, molecular markers associated with repair or compensatory mechanisms that may influence the development and progression of PE are beginning to be identified. However, contradictory results have been obtained regarding some of the molecules that control mitochondrial biogenesis, dynamics, and mitophagy in PE placentas. In conclusion, understanding how the mitochondrial morphology and function influence cell fate decisions of trophoblast cells is an important issue in normal as well as pathological placentation biology. Research focusing on mitochondrial function will become increasingly important for elucidating the pathogenesis and effective treatment strategies of PE.
    Keywords:  Biogenesis; Dynamics; Mitochondria; Mitophagy; Preeclampsia
    DOI:  https://doi.org/10.1007/s11033-024-09285-z
  20. Biomolecules. 2024 Jan 30. pii: 162. [Epub ahead of print]14(2):
    Mitochondrial Dysfunction and Protein Homeostasis in Aging: Insights from a Premature-Aging Mouse Model.
    Jaime M Ross, Lars Olson, Giuseppe Coppotelli.
      Mitochondrial dysfunction has been implicated in aging and age-related disorders. Disturbed-protein homeostasis and clearance of damaged proteins have also been linked to aging, as well as to neurodegenerative diseases, cancers, and metabolic disorders. However, since mitochondrial oxidative phosphorylation, ubiquitin-proteasome, and autophagy-lysosome systems are tightly interdependent, it is not understood whether the facets observed in aging are the causes or consequences of one or all of these failed processes. We therefore used prematurely aging mtDNA-mutator mice and normally aging wild-type littermates to elucidate whether mitochondrial dysfunction per se is sufficient to impair cellular protein homeostasis similarly to that which is observed in aging. We found that both mitochondrial dysfunction and normal aging affect the ubiquitin-proteasome system in a tissue-dependent manner, whereas only normal aging markedly impairs the autophagy-lysosome system. Thus, our data show that the proteostasis network control in the prematurely aging mtDNA-mutator mouse differs in certain aspects from that found in normal aging. Taken together, our findings suggest that severe mitochondrial dysfunction drives an aging phenotype associated with the impairment of certain components of the protein homeostasis machinery, while others, such as the autophagy-lysosome system, are not affected or only minimally affected. Taken together, this shows that aging is a multifactorial process resulting from alterations of several integrated biological processes; thus, manipulating one process at the time might not be sufficient to fully recapitulate all changes associated with normal aging.
    Keywords:  aging; autophagy; mitochondrial dysfunction; ubiquitin–proteasome system
    DOI:  https://doi.org/10.3390/biom14020162
  21. Int J Cardiol. 2024 Feb 20. pii: S0167-5273(24)00343-7. [Epub ahead of print] 131897
    Mitochondrial dysfunction due to miR-210/Drd5/ROS axis is a potential mechanism of heart failure.
    Zhihuan Luo, Xiaofang Gong, Yongpan Liu, Kun Hao, Jinlong Jiang, Luyuan Yao.
      
    Keywords:  Drd5; Heart failure; Mitochondrial dysfunction; ROS; miR-210
    DOI:  https://doi.org/10.1016/j.ijcard.2024.131897
  22. Acta Physiol (Oxf). 2024 Feb 23. e14119
    MFN2 overexpression in skeletal muscles of young and old mice causes a mild hypertrophy without altering mitochondrial respiration and H2 O2 emission.
    Marina Cefis, Manon Dargegen, Vincent Marcangeli, Shima Taherkhani, Maude Dulac, Jean-Philippe Leduc-Gaudet, Dominique Mayaki, Sabah N A Hussain, Gilles Gouspillou.
      AIM: Sarcopenia, the aging-related loss of muscle mass and function, is a debilitating process negatively impacting the quality of life of affected individuals. Although the mechanisms underlying sarcopenia are incompletely understood, impairments in mitochondrial dynamics, including mitochondrial fusion, have been proposed as a contributing factor. However, the potential of upregulating mitochondrial fusion proteins to alleviate the effects of aging on skeletal muscles remains unexplored. We therefore hypothesized that overexpressing Mitofusin 2 (MFN2) in skeletal muscle in vivo would mitigate the effects of aging on muscle mass and improve mitochondrial function.METHODS: MFN2 was overexpressed in young (7 mo) and old (24 mo) male mice for 4 months through intramuscular injections of an adeno-associated viruses. The impacts of MFN2 overexpression on muscle mass and fiber size (histology), mitochondrial respiration, and H2 O2 emission (Oroboros fluororespirometry), and various signaling pathways (qPCR and western blotting) were investigated.
    RESULTS: MFN2 overexpression increased muscle mass and fiber size in both young and old mice. No sign of fibrosis, necrosis, or inflammation was found upon MFN2 overexpression, indicating that the hypertrophy triggered by MFN2 overexpression was not pathological. MFN2 overexpression even reduced the proportion of fibers with central nuclei in old muscles. Importantly, MFN2 overexpression had no impact on muscle mitochondrial respiration and H2 O2 emission in both young and old mice. MFN2 overexpression attenuated the increase in markers of impaired autophagy in old muscles.
    CONCLUSION: MFN2 overexpression may be a viable approach to mitigate aging-related muscle atrophy and may have applications for other muscle disorders.
    Keywords:  autophagy; mitochondria; mitochondrial dynamics; mitochondrial fusion; mitofusin 2; sarcopenia; skeletal muscle aging
    DOI:  https://doi.org/10.1111/apha.14119
  23. J Neuroophthalmol. 2024 Feb 21.
    Recurrence of Visual Loss in Recessive Leber Hereditary Optic Neuropathy: New Paradigm.
    Piero Barboni, Marco Battista, Luigi Brotto, Paolo Nucci, Lisa Checchin, Francesco Bandello, Claudio Fiorini, Danara Ormanbekova, Valerio Carelli, Maria Lucia Cascavilla, Leonardo Caporali.
      
    DOI:  https://doi.org/10.1097/WNO.0000000000002117
  24. Mol Genet Metab. 2024 Feb 16. pii: S1096-7192(24)00233-6. [Epub ahead of print]142(1): 108348
    Bridging the clinical-research gap: Harnessing an electronic data capture, integration, and visualization platform to systematically assess prospective patient-reported outcomes in mitochondrial medicine.
    Laura E MacMullen, Ibrahim George-Sankoh, Katelynn Stanley, Elizabeth M McCormick, Colleen C Muraresku, Amy Goldstein, Zarazuela Zolkipli-Cunningham, Marni J Falk.
      PURPOSE: Optimizing individualized clinical care in heterogeneous rare disorders, such as primary mitochondrial disease (PMD), will require gaining more comprehensive and objective understanding of the patient experience by longitudinally tracking quantifiable patient-specific outcomes and integrating subjective data with clinical data to monitor disease progression and targeted therapeutic effects.METHODS: Electronic surveys of patient (and caregiver) reported outcome (PRO) measures were administered in REDCap within clinical domains commonly impaired in patients with PMD in the context of their ongoing routine care, including quality of life, fatigue, and functional performance. Descriptive statistics, group comparisons, and inter-measure correlations were used to evaluate system feasibility, utility of PRO results, and consistency across outcome measure domains. Real-time tracking and visualization of longitudinal individual-level and cohort-level data were facilitated by a customized data integration and visualization system, MMFP-Tableau.
    RESULTS: An efficient PRO electronic capture and analysis system was successfully implemented within a clinically and genetically heterogeneous rare disease clinical population spanning all ages. Preliminary data analyses demonstrated the flexibility of this approach for a range of PROs, as well as the value of selected PRO scales to objectively capture qualitative functional impairment in four key clinical domains. High inter-measure reliability and correlation were observed. Between-group analyses revealed that adults with PMD reported significantly worse quality of life and greater fatigue than did affected children, while PMD patients with nuclear gene disorders reported lower functioning relative to those with an mtDNA gene disorder in several clinical domains.
    CONCLUSION: Incorporation of routine electronic data collection, integration, visualization, and analysis of relevant PROs for rare disease patients seen in the clinical setting was demonstrated to be feasible, providing prospective and quantitative data on key clinical domains relevant to the patient experience. Further work is needed to validate specific PROs in diverse PMD patients and cohorts, and to formally evaluate the clinical impact and utility of harnessing integrated data systems to objectively track and integrate quantifiable PROs in the context of rare disease patient clinical care.
    Keywords:  Data integration; Data visualization; Fatigue; Function; Mitochondrial diseases; Patient reported outcome measures; Personalized medicine; Quality of life
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108348
  25. J Hum Genet. 2024 Feb 19.
    Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene.
    Emma Matthews, Ella F Whittle, Faraan Khan, Meriel McEntagart, Christopher J Carroll.
      Only five children with pathogenic PMPCB gene variants have been described and all carried missense variants. Clinical features included a Leigh-like syndrome of developmental regression, basal ganglia lesions and ataxia with or without dystonia and epilepsy. Three of the five died in childhood and none was older than age six when described. We report the first splice site variant in the PMPCB gene in a 39-year old individual who experienced developmental regression and ataxia following otitis media in childhood. A minigene assay confirms this variant results in aberrant splicing and skipping of exon 12.
    DOI:  https://doi.org/10.1038/s10038-024-01226-9
  26. J Physiol. 2024 Feb 21.
    In vivo mitochondria-targeted protection against uterine artery vascular dysfunction and remodelling in rodent hypoxic pregnancy.
    Zhongchao Wang, Emily J Camm, Anna Maria Nuzzo, Ana-Mishel Spiroski, Katie L Skeffington, Thomas J Ashmore, Alessandro Rolfo, Tullia Todros, Angela Logan, Jin Ma, Michael P Murphy, Youguo Niu, Dino A Giussani.
      Gestational hypoxia adversely affects uterine artery function, increasing complications. However, an effective therapy remains unidentified. Here, we show in rodent uterine arteries that hypoxic pregnancy promotes hypertrophic remodelling, increases constrictor reactivity via protein kinase C signalling, and triggers compensatory dilatation via nitric oxide-dependent mechanisms and stimulation of large conductance Ca2+ -activated K+ -channels. Maternal in vivo oral treatment with the mitochondria-targeted antioxidant MitoQ in hypoxic pregnancy normalises uterine artery reactivity and prevents vascular remodelling. From days 6-20 of gestation (term ∼22 days), female Wistar rats were randomly assigned to normoxic or hypoxic (13-14% O2 ) pregnancy ± daily maternal MitoQ treatment (500 µm in drinking water). At 20 days of gestation, maternal, placental and fetal tissue was frozen to determine MitoQ uptake. The uterine arteries were harvested and, in one segment, constrictor and dilator reactivity was determined by wire myography. Another segment was fixed for unbiased stereological analysis of vessel morphology. Maternal administration of MitoQ in both normoxic and hypoxic pregnancy crossed the placenta and was present in all tissues analysed. Hypoxia increased uterine artery constrictor responses to norepinephrine, angiotensin II and the protein kinase C activator, phorbol 12,13-dibutyrate. Hypoxia enhanced dilator reactivity to sodium nitroprusside, the large conductance Ca2+ -activated K+ -channel activator NS1619 and ACh via increased nitric oxide-dependent mechanisms. Uterine arteries from hypoxic pregnancy showed increased wall thickness and MitoQ treatment in hypoxic pregnancy prevented all effects on uterine artery reactivity and remodelling. The data support mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy. KEY POINTS: Dysfunction and remodelling of the uterine artery are strongly implicated in many pregnancy complications, including advanced maternal age, maternal hypertension of pregnancy, maternal obesity, gestational diabetes and pregnancy at high altitude. Such complications not only have immediate adverse effects on the growth of the fetus, but also they can also increase the risk of cardiovascular disease in the mother and offspring. Despite this, there is a significant unmet clinical need for therapeutics that treat uterine artery vascular dysfunction in adverse pregnancy. Here, we show in a rodent model of gestational hypoxia that in vivo oral treatment of the mitochondria-targeted antioxidant MitoQ protects against uterine artery vascular dysfunction and remodelling, supporting the use of mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy.
    Keywords:  chronic hypoxia; fetal growth restriction; pre-eclampsia; uterine PI
    DOI:  https://doi.org/10.1113/JP286178
  27. Cells. 2024 Feb 09. pii: 319. [Epub ahead of print]13(4):
    Hereditary Ataxias: From Bench to Clinic, Where Do We Stand?
    Federica Pilotto, Andrea Del Bondio, Hélène Puccio.
      Cerebellar ataxias are a wide heterogeneous group of movement disorders. Within this broad umbrella of diseases, there are both genetics and sporadic forms. The clinical presentation of these conditions can exhibit a diverse range of symptoms across different age groups, spanning from pure cerebellar manifestations to sensory ataxia and multisystemic diseases. Over the last few decades, advancements in our understanding of genetics and molecular pathophysiology related to both dominant and recessive ataxias have propelled the field forward, paving the way for innovative therapeutic strategies aimed at preventing and arresting the progression of these diseases. Nevertheless, the rarity of certain forms of ataxia continues to pose challenges, leading to limited insights into the etiology of the disease and the identification of target pathways. Additionally, the lack of suitable models hampers efforts to comprehensively understand the molecular foundations of disease's pathophysiology and test novel therapeutic interventions. In the following review, we describe the epidemiology, symptomatology, and pathological progression of hereditary ataxia, including both the prevalent and less common forms of these diseases. Furthermore, we illustrate the diverse molecular pathways and therapeutic approaches currently undergoing investigation in both pre-clinical studies and clinical trials. Finally, we address the existing and anticipated challenges within this field, encompassing both basic research and clinical endeavors.
    Keywords:  ataxia; cerebellum; therapy
    DOI:  https://doi.org/10.3390/cells13040319
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