bims-midbra Biomed News
on Mitochondrial dynamics in brain cells
Issue of 2021–11–28
eightteen papers selected by
Ana Paula Mendonça, University of Padova
  1. RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer's Disease.
  2. Deregulated mitochondrial microRNAs in Alzheimer's disease: Focus on synapse and mitochondria.
  3. Acetylation in Mitochondria Dynamics and Neurodegeneration.
  4. Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington's Disease.
  5. The role of protein acetylation in regulating mitochondrial fusion and fission.
  6. Mitochondria-Endoplasmic Reticulum Crosstalk in Parkinson's Disease: The Role of Brain Renin Angiotensin System Components.
  7. Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins.
  8. The PINK1 advantage: recycling mitochondria in times of trouble?
  9. The Molecular Assembly State of Drp1 Controls its Association With the Mitochondrial Recruitment Receptors Mff and MIEF1/2.
  10. Lysosomal dysfunction impairs mitochondrial quality control and is associated with neurodegeneration in TBCK encephaloneuronopathy.
  11. Mitochondrial Defects in Fibroblasts of Pathogenic MAPT Patients.
  12. Thunbergia laurifolia Leaf Extract Inhibits Glutamate-Induced Neurotoxicity and Cell Death through Mitophagy Signaling.
  13. ER-associated CTRP1 regulates mitochondrial fission via interaction with DRP1.
  14. Mitochondrial bioenergetics of astrocytes in Fragile X Syndrome: new perspectives from culture conditions and sex effects.
  15. The Mitochondrial Ca2+ import complex is altered in ADPKD.
  16. A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy.
  17. An Overview of Mitochondrial Protein Defects in Neuromuscular Diseases.
  18. Connection Lost, MAM: Errors in ER-Mitochondria Connections in Neurodegenerative Diseases.
  1. Cells. 2021 Nov 10. pii: 3113. [Epub ahead of print]10(11):
    RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer's Disease.
    Sanjay Awasthi, Ashly Hindle, Neha A Sawant, Mathew George, Murali Vijayan, Sudhir Kshirsagar, Hallie Morton, Lloyd E Bunquin, Philip T Palade, J Josh Lawrence, Hafiz Khan, Chhanda Bose, P Hemachandra Reddy, Sharda P Singh.
      The purpose of our study is to understand the role of the RALBP1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer's disease (AD) pathogenesis. The RALPB1 gene encodes the 76 kDa protein RLIP76 (Rlip). Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. We hypothesized that Rlip may play an important role in maintaining cognitive function. The aim of this study is to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype (WT) and Rlip+/- mice were analyzed for OS markers, expression of genes that regulate mitochondrial fission/fusion, and synaptic integrity. We also examined mitochondrial ultrastructure in brains obtained from these mice and further analyzed the impact of Rlip deficiency on gene networks of AD, aging, stress response, mitochondrial function, and CREB signaling. Our studies revealed a significant increase in the levels of OS markers and alterations in the expression of genes and proteins involved in mitochondrial biogenesis, dynamics and synapses in brain tissues from these mice. Furthermore, we compared the cognitive function of WT and Rlip+/- mice. Behavioral, basic motor and sensory function tests in Rlip+/- mice revealed cognitive decline, similar to AD. Gene network analysis indicated dysregulation of stress-activated gene expression, mitochondrial function and CREB signaling genes in the Rlip+/- mouse brain. Our results suggest that Rlip deficiency-associated increases in OS and mitochondrial dysfunction could contribute to the development or progression of OS-related AD processes.
    Keywords:  Alzheimer’s disease; mitochondria; mitochondrial biogenesis; mitophagy; synaptic proteins
    DOI:  https://doi.org/10.3390/cells10113113
  2. Ageing Res Rev. 2021 Nov 20. pii: S1568-1637(21)00276-2. [Epub ahead of print] 101529
    Deregulated mitochondrial microRNAs in Alzheimer's disease: Focus on synapse and mitochondria.
    Prashanth Gowda, P Hemachandra Reddy, Subodh Kumar.
      Alzheimer's disease (AD) is the most common cause of dementia and is currently one of the biggest public health concerns in the world. Mitochondrial dysfunction in neurons is one of the major hallmarks of AD. Emerging evidence suggests that mitochondrial miRNAs potentially play important roles in the mitochondrial dysfunctions, focusing on synapse in AD progression. In this meta-analysis paper, a comprehensive literature review was conducted to identify and discuss the (1) role of mitochondrial miRNAs that regulate mitochondrial and synaptic functions; (2) the role of various factors such as mitochondrial dynamics, biogenesis, calcium signaling, biological sex, and aging on synapse and mitochondrial function; (3) how synapse damage and mitochondrial dysfunctions contribute to AD; (4) the structure and function of synapse and mitochondria in the disease process; (5) latest research developments in synapse and mitochondria in healthy and disease states; and (6) therapeutic strategies that improve synaptic and mitochondrial functions in AD. Specifically, we discussed how differences in the expression of mitochondrial miRNAs affect ATP production, oxidative stress, mitophagy, bioenergetics, mitochondrial dynamics, synaptic activity, synaptic plasticity, neurotransmission, and synaptotoxicity in neurons observed during AD. However, more research is needed to confirm the locations and roles of individual mitochondrial miRNAs in the development of AD.
    Keywords:  Alzheimer’s disease; Bioenergetics; MicroRNAs; Mitochondria; Synapse; Synaptic activity
    DOI:  https://doi.org/10.1016/j.arr.2021.101529
  3. Cells. 2021 Nov 05. pii: 3031. [Epub ahead of print]10(11):
    Acetylation in Mitochondria Dynamics and Neurodegeneration.
    Jaylyn Waddell, Aditi Banerjee, Tibor Kristian.
      Mitochondria are a unique intracellular organelle due to their evolutionary origin and multifunctional role in overall cellular physiology and pathophysiology. To meet the specific spatial metabolic demands within the cell, mitochondria are actively moving, dividing, or fusing. This process of mitochondrial dynamics is fine-tuned by a specific group of proteins and their complex post-translational modifications. In this review, we discuss the mitochondrial dynamics regulatory enzymes, their adaptor proteins, and the effect of acetylation on the activity of fusion and fission machinery as a ubiquitous response to metabolic stresses. Further, we discuss the role of intracellular cytoskeleton structures and their post-translational modifications in the modulation of mitochondrial fusion and fission. Finally, we review the role of mitochondrial dynamics dysregulation in the pathophysiology of acute brain injury and the treatment strategies based on modulation of NAD+-dependent deacetylation.
    Keywords:  acetylation; dynamics; mitochondria; tubulin
    DOI:  https://doi.org/10.3390/cells10113031
  4. Cells. 2021 Nov 15. pii: 3172. [Epub ahead of print]10(11):
    Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington's Disease.
    Tatiana Brustovetsky, Rajesh Khanna, Nickolay Brustovetsky.
      Mitochondrial morphology and motility (mitochondrial dynamics) play a major role in the proper functioning of distant synapses. In Huntington's disease (HD), mitochondria become fragmented and less motile, but the mechanisms leading to these changes are not clear. Here, we found that collapsin response mediator protein 2 (CRMP2) interacted with Drp1 and Miro 2, proteins involved in regulating mitochondrial dynamics. CRMP2 interaction with these proteins inversely correlated with CRMP2 phosphorylation. CRMP2 was hyperphosphorylated in postmortem brain tissues of HD patients, in human neurons derived from induced pluripotent stem cells from HD patients, and in cultured striatal neurons from HD mouse model YAC128. At the same time, CRMP2 interaction with Drp1 and Miro 2 was diminished in HD neurons. The CRMP2 hyperphosphorylation and dissociation from Drp1 and Miro 2 correlated with increased fission and suppressed motility. (S)-lacosamide ((S)-LCM), a small molecule that binds to CRMP2, decreased its phosphorylation at Thr 509/514 and Ser 522 and rescued CRMP2's interaction with Drp1 and Miro 2. This was accompanied by reduced mitochondrial fission and enhanced mitochondrial motility. Additionally, (S)-LCM exerted a neuroprotective effect in YAC128 cultured neurons. Thus, our data suggest that CRMP2 may regulate mitochondrial dynamics in a phosphorylation-dependent manner and modulate neuronal survival in HD.
    Keywords:  CRMP2; Huntington’s disease; mitochondria; morphology; motility; neuron
    DOI:  https://doi.org/10.3390/cells10113172
  5. Biochem Soc Trans. 2021 Nov 23. pii: BST20210798. [Epub ahead of print]
    The role of protein acetylation in regulating mitochondrial fusion and fission.
    Golam M Uddin, Rafa Abbas, Timothy E Shutt.
      The dynamic processes of mitochondrial fusion and fission determine the shape of mitochondria, which can range from individual fragments to a hyperfused network, and influence mitochondrial function. Changes in mitochondrial shape can occur rapidly, allowing mitochondria to adapt to specific cues and changing cellular demands. Here, we will review what is known about how key proteins required for mitochondrial fusion and fission are regulated by their acetylation status, with acetylation promoting fission and deacetylation enhancing fusion. In particular, we will examine the roles of NAD+ dependant sirtuin deacetylases, which mediate mitochondrial acetylation, and how this post-translational modification provides an exquisite regulatory mechanism to co-ordinate mitochondrial function with metabolic demands of the cell.
    Keywords:  acetylation/deacetylation; fission; fusion; mitochondria; sirtuins
    DOI:  https://doi.org/10.1042/BST20210798
  6. Biomolecules. 2021 Nov 10. pii: 1669. [Epub ahead of print]11(11):
    Mitochondria-Endoplasmic Reticulum Crosstalk in Parkinson's Disease: The Role of Brain Renin Angiotensin System Components.
    Tuladhar Sunanda, Bipul Ray, Arehally M Mahalakshmi, Abid Bhat, Luay Rashan, Wiramon Rungratanawanich, Byoung-Joon Song, Musthafa Mohamed Essa, Meena Kishore Sakharkar, Saravana Babu Chidambaram.
      The past few decades have seen an increased emphasis on the involvement of the mitochondrial-associated membrane (MAM) in various neurodegenerative diseases, particularly in Parkinson's disease (PD) and Alzheimer's disease (AD). In PD, alterations in mitochondria, endoplasmic reticulum (ER), and MAM functions affect the secretion and metabolism of proteins, causing an imbalance in calcium homeostasis and oxidative stress. These changes lead to alterations in the translocation of the MAM components, such as IP3R, VDAC, and MFN1 and 2, and consequently disrupt calcium homeostasis and cause misfolded proteins with impaired autophagy, distorted mitochondrial dynamics, and cell death. Various reports indicate the detrimental involvement of the brain renin-angiotensin system (RAS) in oxidative stress, neuroinflammation, and apoptosis in various neurodegenerative diseases. In this review, we attempted to update the reports (using various search engines, such as PubMed, SCOPUS, Elsevier, and Springer Nature) demonstrating the pathogenic interactions between the various proteins present in mitochondria, ER, and MAM with respect to Parkinson's disease. We also made an attempt to speculate the possible involvement of RAS and its components, i.e., AT1 and AT2 receptors, angiotensinogen, in this crosstalk and PD pathology. The review also collates and provides updated information on the role of MAM in calcium signaling, oxidative stress, neuroinflammation, and apoptosis in PD.
    Keywords:  ER stress; ER–mitochondria crosstalk; brain renin angiotensin system; mitochondrial dysfunction; mitochondrial-associated membrane (MAM)
    DOI:  https://doi.org/10.3390/biom11111669
  7. Nat Commun. 2021 Nov 25. 12(1): 6914
    Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins.
    Topaz Altman, Ariel Ionescu, Amjad Ibraheem, Dominik Priesmann, Tal Gradus-Pery, Luba Farberov, Gayster Alexandra, Natalia Shelestovich, Ruxandra Dafinca, Noam Shomron, Florence Rage, Kevin Talbot, Michael E Ward, Amir Dori, Marcus Krüger, Eran Perlson.
      Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of ~95% of amyotrophic lateral sclerosis (ALS) patients, but the contribution of axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show TDP-43 accumulation in intra-muscular nerves from ALS patients and in axons of human iPSC-derived motor neurons of ALS patient, as well as in motor neurons and neuromuscular junctions (NMJs) of a TDP-43 mislocalization mouse model. In axons, TDP-43 is hyper-phosphorylated and promotes G3BP1-positive ribonucleoprotein (RNP) condensate assembly, consequently inhibiting local protein synthesis in distal axons and NMJs. Specifically, the axonal and synaptic levels of nuclear-encoded mitochondrial proteins are reduced. Clearance of axonal TDP-43 or dissociation of G3BP1 condensates restored local translation and resolved TDP-43-derived toxicity in both axons and NMJs. These findings support an axonal gain of function of TDP-43 in ALS, which can be targeted for therapeutic development.
    DOI:  https://doi.org/10.1038/s41467-021-27221-8
  8. Autophagy. 2021 Nov 23. 1-2
    The PINK1 advantage: recycling mitochondria in times of trouble?
    Zak Doric, Huihui Li, Ken Nakamura.
      Parkinson disease remains a debilitating neurodegenerative disorder, despite the discovery of multiple causative genes that account for familial forms. Prominent among these are PRKN/Parkin and PINK1, whose protein products participate in mitochondrial turnover, or mitophagy. But our poor understanding of the basic biological mechanisms driven by those genes in neurons limits our ability to target them therapeutically. Here, we summarize our recent findings enabled by a new platform to track individual mitochondria in neurons. Our analysis delineates the steps of PINK1- and PRKN-dependent mitochondrial turnover, including the unexplored fates of mitochondria after fusion with lysosomes. These studies reveal unexpected mechanisms of mitochondrial quality control, which may contribute to the reliance of neurons on PINK1 under conditions of stress.
    Keywords:  Mitophagy; PARKIN; PINK1; Parkinson’s disease; mitochondrial turnover
    DOI:  https://doi.org/10.1080/15548627.2021.1998872
  9. Front Cell Dev Biol. 2021 ;9 706687
    The Molecular Assembly State of Drp1 Controls its Association With the Mitochondrial Recruitment Receptors Mff and MIEF1/2.
    Rong Yu, Shao-Bo Jin, Maria Ankarcrona, Urban Lendahl, Monica Nistér, Jian Zhao.
      Drp1 is a central player in mitochondrial fission and is recruited to mitochondria by Mff and MIEFs (MIEF1 and MIEF2), but little is known about how its assembly state affects Drp1 mitochondrial recruitment and fission. Here, we used in vivo chemical crosslinking to explore the self-assembly state of Drp1 and how it regulates the association of Drp1 with MIEFs and Mff. We show that in intact mammalian cells Drp1 exists as a mixture of multiple self-assembly forms ranging from the minimal, probably tetrameric, self-assembly subunit to several higher order oligomers. Precluding mitochondria-bound Drp1 in Mff/MIEF1/2-deficient cells does not affect the oligomerization state of Drp1, while conversely forced recruitment of Drp1 to mitochondria by MIEFs or Mff facilitates Drp1 oligomerization. Mff preferentially binds to higher order oligomers of Drp1, whereas MIEFs bind to a wider-range of Drp1 assembly subunits, including both lower and higher oligomeric states. Mff only recruits active forms of Drp1, while MIEFs are less selective and recruit both active and inactive Drp1 as well as oligomerization- or GTPase-deficient Drp1 mutants to mitochondria. Moreover, all the fission-incompetent Drp1 mutants tested (except the monomeric mutant K668E) affect Drp1-driven mitochondrial dynamics via incorporation of the mutants into the native oligomers to form function-deficient Drp1 assemblies. We here confirm that MIEFs also serve as a platform facilitating the binding of Drp1 to Mff and loss of MIEFs severely impairs the interaction between Drp1 and Mff. Collectively, our findings suggest that Mff and MIEFs respond differently to the molecular assembly state of Drp1 and that the extent of Drp1 oligomerization regulates mitochondrial dynamics.
    Keywords:  Drp1; Drp1 mutation; MIEF1; MIEF2; Mff; mitochondria; mitochondrial dynamics; oligomerization
    DOI:  https://doi.org/10.3389/fcell.2021.706687
  10. Brain Commun. 2021 ;3(4): fcab215
    Lysosomal dysfunction impairs mitochondrial quality control and is associated with neurodegeneration in TBCK encephaloneuronopathy.
    Jesus A Tintos-Hernández, Adrian Santana, Kierstin N Keller, Xilma R Ortiz-González.
      Biallelic variants in the TBCK gene cause intellectual disability with remarkable clinical variability, ranging from static encephalopathy to progressive neurodegeneration (TBCK-Encephaloneuronopathy). The biological factors underlying variable disease penetrance remain unknown. Since previous studies had suggested aberrant autophagy, we tested whether mitophagy and mitochondrial function are altered in TBCK -/- fibroblasts derived from patients exhibiting variable clinical severity. Our data show significant accumulation of mitophagosomes, reduced mitochondrial respiratory capacity and mitochondrial DNA content, suggesting impaired mitochondrial quality control. Furthermore, the degree of mitochondrial dysfunction correlates with a neurodegenerative clinical course. Since mitophagy ultimately depends on lysosomal degradation, we also examined lysosomal function. Our data show that lysosomal proteolytic function is significantly reduced in TBCK -/- fibroblasts. Moreover, acidifying lysosomal nanoparticles rescue the mitochondrial respiratory defects in fibroblasts, suggesting impaired mitochondrial quality control secondary to lysosomal dysfunction. Our data provide insight into the disease mechanisms of TBCK Encephaloneuronopathy and the potential relevance of mitochondrial function as a biomarker beyond primary mitochondrial disorders. It also supports the benefit of lysosomal acidification strategies for disorders of impaired lysosomal degradation affecting mitochondrial quality control.
    Keywords:  intellectual disability; lysosome; mitochondria; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.1093/braincomms/fcab215
  11. Front Cell Dev Biol. 2021 ;9 765408
    Mitochondrial Defects in Fibroblasts of Pathogenic MAPT Patients.
    Vinita Bharat, Chung-Han Hsieh, Xinnan Wang.
      Mutations in MAPT gene cause multiple neurological disorders, including frontal temporal lobar degeneration and parkinsonism. Increasing evidence indicates impaired mitochondrial homeostasis and mitophagy in patients and disease models of pathogenic MAPT. Here, using MAPT patients' fibroblasts as a model, we report that disease-causing MAPT mutations compromise early events of mitophagy. By employing biochemical and mitochondrial assays we discover that upon mitochondrial depolarization, the recruitment of LRRK2 and Parkin to mitochondria and degradation of the outer mitochondrial membrane protein Miro1 are disrupted. Using high resolution electron microscopy, we reveal that the contact of mitochondrial membranes with ER and cytoskeleton tracks is dissociated following mitochondrial damage. This membrane dissociation is blocked by a pathogenic MAPT mutation. Furthermore, we provide evidence showing that tau protein, which is encoded by MAPT gene, interacts with Miro1 protein, and this interaction is abolished by pathogenic MAPT mutations. Lastly, treating fibroblasts of a MAPT patient with a small molecule promotes Miro1 degradation following depolarization. Altogether, our results show molecular defects in a peripheral tissue of patients and suggest that targeting mitochondrial quality control may have a broad application for future therapeutic intervention.
    Keywords:  ER; FTLD; MAPT; Miro; mitochondria; mitophagy; parkinsonism; tau
    DOI:  https://doi.org/10.3389/fcell.2021.765408
  12. Antioxidants (Basel). 2021 Oct 25. pii: 1678. [Epub ahead of print]10(11):
    Thunbergia laurifolia Leaf Extract Inhibits Glutamate-Induced Neurotoxicity and Cell Death through Mitophagy Signaling.
    Wudtipong Vongthip, Chanin Sillapachaiyaporn, Kyu-Won Kim, Monruedee Sukprasansap, Tewin Tencomnao.
      Oxidative stress plays a crucial role in neurodegeneration. Therefore, reducing oxidative stress in the brain is an important strategy to prevent neurodegenerative disorders. Thunbergia laurifolia (Rang-jued) is well known as an herbal tea in Thailand. Here, we aimed to determine the protective effects of T. laurifolia leaf extract (TLE) on glutamate-induced oxidative stress toxicity and mitophagy-mediated cell death in mouse hippocampal cells (HT-22). Our results reveal that TLE possesses a high level of bioactive antioxidants by LC-MS technique. We found that the pre-treatment of cells with TLE prevented glutamate-induced neuronal death in a concentration-dependent manner. TLE reduced the intracellular ROS and maintained the mitochondrial membrane potential caused by glutamate. Moreover, TLE upregulated the gene expression of antioxidant enzymes (SOD1, SOD2, CAT, and GPx). Interestingly, glutamate also induced the activation of the mitophagy process. However, TLE could reverse this activity by inhibiting autophagic protein (LC3B-II/LC3B-I) activation and increasing a specific mitochondrial protein (TOM20). Our results suggest that excessive glutamate can cause neuronal death through mitophagy-mediated cell death signaling in HT-22 cells. Our findings indicate that TLE protects cells from neuronal death by stimulating the endogenous antioxidant enzymes and inhibiting glutamate-induced oxidative toxicity via the mitophagy-autophagy pathway. TLE might have potential as an alternative or therapeutic approach in neurodegenerative diseases.
    Keywords:  Thunbergia laurifolia; autophagy; glutamate; mitophagy; neurodegenerative diseases; oxidative stress
    DOI:  https://doi.org/10.3390/antiox10111678
  13. Exp Mol Med. 2021 Nov 26.
    ER-associated CTRP1 regulates mitochondrial fission via interaction with DRP1.
    Seong Keun Sonn, Seungwoon Seo, Jaemoon Yang, Ki Sook Oh, Hsiuchen Chen, David C Chan, Kunsoo Rhee, Kyung S Lee, Young Yang, Goo Taeg Oh.
      C1q/TNF-related protein 1 (CTRP1) is a CTRP family member that has collagenous and globular C1q-like domains. The secreted form of CTRP1 is known to be associated with cardiovascular and metabolic diseases, but its cellular roles have not yet been elucidated. Here, we showed that cytosolic CTRP1 localizes to the endoplasmic reticulum (ER) membrane and that knockout or depletion of CTRP1 leads to mitochondrial fission defects, as demonstrated by mitochondrial elongation. Mitochondrial fission events are known to occur through an interaction between mitochondria and the ER, but we do not know whether the ER and/or its associated proteins participate directly in the entire mitochondrial fission event. Interestingly, we herein showed that ablation of CTRP1 suppresses the recruitment of DRP1 to mitochondria and provided evidence suggesting that the ER-mitochondrion interaction is required for the proper regulation of mitochondrial morphology. We further report that CTRP1 inactivation-induced mitochondrial fission defects induce apoptotic resistance and neuronal degeneration, which are also associated with ablation of DRP1. These results demonstrate for the first time that cytosolic CTRP1 is an ER transmembrane protein that acts as a key regulator of mitochondrial fission, providing new insight into the etiology of metabolic and neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s12276-021-00701-z
  14. Am J Physiol Cell Physiol. 2021 Nov 24.
    Mitochondrial bioenergetics of astrocytes in Fragile X Syndrome: new perspectives from culture conditions and sex effects.
    Gregory G Vandenberg, Aasritha Thotakura, Angela L Scott.
      Fragile X syndrome is a genetic disorder that is characterized by a range of cognitive and behavioural deficits, including mild-moderate intellectual disability. The disease is characterized by an X-linked mutation of the Fmr1 gene, which causes silencing of the gene coding for FMRP, a translational regulator integral for neurodevelopment. Mitochondrial dysfunction has been recently associated with FXS, with reports of increases in oxidative stress markers, reactive oxygen species, and lipid peroxidation being present in brain tissue. Astrocytes, a prominent glial cell within the CNS, plays a large role in regulating oxidative homeostasis within the developing brain and dysregulation of astrocyte redox balance in FXS may contribute to oxidative stress. Astrocyte function and mitochondrial bioenergetics is significantly influenced by oxygen availability as well as circulating sex hormones; yet these parameters are rarely considered during in vitro experimentation. Given that the brain normally develops in a range of hypoxic conditions and FXS is a sex-linked genetic disorder, we investigated how different oxygen levels (normoxic versus hypoxic) and biological sex affected mitochondrial bioenergetics of astrocytes in FXS. Our results show demonstrate that both mitochondrial respiration capacity and reactive oxygen species emission are altered with Fmr1 deletion in astrocytes and these changes were dependent upon both sexual dimorphism and oxygen availability.
    Keywords:  Fragile X Syndrome; astrocyte; mitochondrial respiration; reactive oxygen species; tissue culture
    DOI:  https://doi.org/10.1152/ajpcell.00130.2021
  15. Cell Calcium. 2021 Nov 19. pii: S0143-4160(21)00155-X. [Epub ahead of print]101 102501
    The Mitochondrial Ca2+ import complex is altered in ADPKD.
    Murali K Yanda, Vartika Tomar, Robert Cole, William B Guggino, Liudmila Cebotaru.
      Mutations in either of the polycystic kidney disease genes, PKD1 or PKD2, engender the growth of cysts, altering renal function. Cystic growth is supported by major changes in cellular metabolism, some of which involve the mitochondrion, a major storage site for Ca2+ and a key organelle in cellular Ca2+ signaling. The goal here was to understand the role of components of the mitochondrial Ca2+ uptake complex in PC1-mutant cells in autosomal dominant polycystic kidney disease (ADPKD). We found that the mitochondrial Ca2+ uniporter (MCU) and voltage-dependent anion channels 1& 3 (VDAC) were down-regulated in different mouse and cell models of ADPKD along with the Ca2+-dependent enzyme, pyruvate dehydrogenase phosphatase (PDHX). The release of Ca2+ from the endoplasmic reticulum, and Ca2+ uptake by the mitochondria were upregulated in PC1(polycystin)-null cells. We also observed an enhanced staining with MitoTracker Red CMXRos in PC1-null cultured cells than in PC1-containing cells and a substantially higher increase in response to ER Ca2+ release. Increased colocalization of the Ca2+ sensitive dye, rhodamine2, with MitoTracker Green suggested an increase Ca2+ entry into the mitochondria in PC1 null cells subsequent to Ca2+ release from the ER or from Ca2+ entry from the extracellular solution. These data clearly demonstrate abnormal release of Ca2+ by the ER and corresponding alterations in Ca2+ uptake by the mitochondria in PC1-null cells. Importantly, inhibiting mitochondrial Ca2+ uptake with the specific inhibitor Ru360 inhibited cyst growth and altered both apoptosis and cell proliferation. We further show that the decrease in mitochondrial proteins and abnormally high Ca2+ signaling can be reversed by application of the cystic fibrosis (CFTR) corrector, VX-809. We conclude that enhanced Ca2+ signaling and alterations in proteins association with the mitochondrial Ca2+ uptake complex are associated with malfunction of PC1. Finally, our results identify novel therapeutic targets for treating ADPKD.
    Keywords:  Adult onset polycystic kidney disease; CFTR modulators; Calcium; Mitochondria
    DOI:  https://doi.org/10.1016/j.ceca.2021.102501
  16. Redox Biol. 2021 Nov 11. pii: S2213-2317(21)00346-3. [Epub ahead of print]48 102186
    A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy.
    Akbar Zeb, Vinay Choubey, Ruby Gupta, Malle Kuum, Dzhamilja Safiulina, Annika Vaarmann, Nana Gogichaishvili, Mailis Liiv, Ivar Ilves, Kaido Tämm, Vladimir Veksler, Allen Kaasik.
      When ROS production exceeds the cellular antioxidant capacity, the cell needs to eliminate the defective mitochondria responsible for excessive ROS production. It has been proposed that the removal of these defective mitochondria involves mitophagy, but the mechanism of this regulation remains unclear. Here, we demonstrate that moderate mitochondrial superoxide and hydrogen peroxide production oxidates KEAP1, thus breaking the interaction between this protein and PGAM5, leading to the inhibition of its proteasomal degradation. Accumulated PGAM5 interferes with the processing of the PINK1 in the mitochondria leading to the accumulation of PINK1 on the outer mitochondrial membrane. In turn, PINK1 promotes Parkin recruitment to mitochondria and sensitizes mitochondria for autophagic removal. We also demonstrate that inhibitors of the KEAP1-PGAM5 protein-protein interaction (including CPUY192018) mimic the effect of mitochondrial ROS and sensitize mitophagy machinery, suggesting that these inhibitors could be used as pharmacological regulators of mitophagy. Together, our results show that KEAP1/PGAM5 complex senses mitochondrially generated superoxide/hydrogen peroxide to induce mitophagy.
    Keywords:  Mitophagy; NRF2/KEAP1 pathway; Neurodegenerative diseases; Oxidative stress; PINK1/Parkin pathway
    DOI:  https://doi.org/10.1016/j.redox.2021.102186
  17. Biomolecules. 2021 Nov 04. pii: 1633. [Epub ahead of print]11(11):
    An Overview of Mitochondrial Protein Defects in Neuromuscular Diseases.
    Federica Marra, Paola Lunetti, Rosita Curcio, Francesco Massimo Lasorsa, Loredana Capobianco, Vito Porcelli, Vincenza Dolce, Giuseppe Fiermonte, Pasquale Scarcia.
      Neuromuscular diseases (NMDs) are dysfunctions that involve skeletal muscle and cause incorrect communication between the nerves and muscles. The specific causes of NMDs are not well known, but most of them are caused by genetic mutations. NMDs are generally progressive and entail muscle weakness and fatigue. Muscular impairments can differ in onset, severity, prognosis, and phenotype. A multitude of possible injury sites can make diagnosis of NMDs difficult. Mitochondria are crucial for cellular homeostasis and are involved in various metabolic pathways; for this reason, their dysfunction can lead to the development of different pathologies, including NMDs. Most NMDs due to mitochondrial dysfunction have been associated with mutations of genes involved in mitochondrial biogenesis and metabolism. This review is focused on some mitochondrial routes such as the TCA cycle, OXPHOS, and β-oxidation, recently found to be altered in NMDs. Particular attention is given to the alterations found in some genes encoding mitochondrial carriers, proteins of the inner mitochondrial membrane able to exchange metabolites between mitochondria and the cytosol. Briefly, we discuss possible strategies used to diagnose NMDs and therapies able to promote patient outcome.
    Keywords:  Leigh syndrome; MELAS; MERF; OXPHOS; mitochondrial carrier family; mitochondrial metabolism; myopathy; neuromuscular diseases; neuromuscular junction; therapy
    DOI:  https://doi.org/10.3390/biom11111633
  18. Brain Sci. 2021 Oct 28. pii: 1437. [Epub ahead of print]11(11):
    Connection Lost, MAM: Errors in ER-Mitochondria Connections in Neurodegenerative Diseases.
    Ashu Johri, Abhishek Chandra.
      Mitochondria associated membranes (MAMs), as the name suggests, are the membranes that physically and biochemically connect mitochondria with endoplasmic reticulum. MAMs not only structurally but also functionally connect these two important organelles within the cell which were previously thought to exist independently. There are multiple points of communication between ER-mitochondria and MAMs play an important role in both ER and mitochondria functions such as Ca2+ homeostasis, proteostasis, mitochondrial bioenergetics, movement, and mitophagy. The number of disease-related proteins and genes being associated with MAMs has been continually on the rise since its discovery. There is an overwhelming overlap between the biochemical functions of MAMs and processes affected in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Thus, MAMs have received well-deserving and much delayed attention as modulators for ER-mitochondria communication and function. This review briefly discusses the recent progress made in this now fast developing field full of promise for very exciting future therapeutic discoveries.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; mitochondria associated membranes (MAMs)
    DOI:  https://doi.org/10.3390/brainsci11111437
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