bims-midbra Biomed News
on Mitochondrial dynamics in brain cells
Issue of 2021‒11‒21
nineteen papers selected by
Ana Paula Mendonça
University of Padova
  1. New perspectives on cytoskeletal dysregulation and mitochondrial mislocalization in amyotrophic lateral sclerosis.
  2. MicroRNA-455-3p improves synaptic, cognitive functions and extends lifespan: Relevance to Alzheimer's disease.
  3. Rotenone-Induced Neurodegeneration Is Enabled by a p38-Parkin-ROS Signaling Feedback Loop.
  4. DA-9805 protects dopaminergic neurons from endoplasmic reticulum stress and inflammation.
  5. Role of Cleaved PINK1 in Neuronal Development, Synaptogenesis, and Plasticity: Implications for Parkinson's Disease.
  6. Mouse midbrain dopaminergic neurons survive loss of the PD-associated mitochondrial protein CHCHD2.
  7. Neuronal Mitochondrial Dysfunction and Bioenergetic Failure in Inflammation-Associated Depression.
  8. AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability.
  9. Sirt3-mediated mitochondrial dysfunction is involved in fluoride-induced cognitive deficits.
  10. Live imaging reveals the cellular events downstream of SARM1 activation.
  11. BH3-only proteins Puma and Beclin1 regulate autophagic death in neurons in response to Amyloid-β.
  12. Putative role of uncoupling proteins in mitochondria-nucleus communications and DNA damage response.
  13. The neuroprotective effect of increased PINK1 expression following glutamate excitotoxicity in neuronal cells.
  14. Autism spectrum disorder: A mitochondrial disorder.
  15. Serine palmitoyltransferase assembles at ER-mitochondria contact sites.
  16. Mitophagy Protects the Retina Against Anti-Vascular Endothelial Growth Factor Therapy-Driven Hypoxia via Hypoxia-Inducible Factor-1α Signaling.
  17. Mitochondrial aconitase 1 regulates age-related memory impairment via autophagy/mitophagy-mediated neural plasticity in middle-aged flies.
  18. Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders.
  19. Case report of atypical Leigh syndrome in an adolescent male with novel biallelic variants in NDUFAF5 and review of the natural history of NDUFAF5-related disorders.
  1. Transl Neurodegener. 2021 Nov 15. 10(1): 46
    New perspectives on cytoskeletal dysregulation and mitochondrial mislocalization in amyotrophic lateral sclerosis.
    Frances Theunissen, Phillip K West, Samuel Brennan, Bojan Petrović, Kosar Hooshmand, P Anthony Akkari, Matt Keon, Boris Guennewig.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective, early degeneration of motor neurons in the brain and spinal cord. Motor neurons have long axonal projections, which rely on the integrity of neuronal cytoskeleton and mitochondria to regulate energy requirements for maintaining axonal stability, anterograde and retrograde transport, and signaling between neurons. The formation of protein aggregates which contain cytoskeletal proteins, and mitochondrial dysfunction both have devastating effects on the function of neurons and are shared pathological features across several neurodegenerative conditions, including ALS, Alzheimer's disease, Parkinson's disease, Huntington's disease and Charcot-Marie-Tooth disease. Furthermore, it is becoming increasingly clear that cytoskeletal integrity and mitochondrial function are intricately linked. Therefore, dysregulations of the cytoskeletal network and mitochondrial homeostasis and localization, may be common pathways in the initial steps of neurodegeneration. Here we review and discuss known contributors, including variants in genetic loci and aberrant protein activities, which modify cytoskeletal integrity, axonal transport and mitochondrial localization in ALS and have overlapping features with other neurodegenerative diseases. Additionally, we explore some emerging pathways that may contribute to this disruption in ALS.
    Keywords:  Amyotrophic lateral sclerosis; Axonal transport; Cytoskeleton; Gut microbiome; Mitochondria; Neurodegeneration; Neurofilament
    DOI:  https://doi.org/10.1186/s40035-021-00272-z
  2. Redox Biol. 2021 Nov 09. pii: S2213-2317(21)00342-6. [Epub ahead of print]48 102182
    MicroRNA-455-3p improves synaptic, cognitive functions and extends lifespan: Relevance to Alzheimer's disease.
    Subodh Kumar, Hallie Morton, Neha Sawant, Erika Orlov, Lloyd E Bunquin, Jangampalli Adi Pradeepkiran, Razelle Alvir, P Hemachandra Reddy.
      BACKGROUND: MicroRNA-455-3p is one of the highly conserved miRNAs involved in multiple cellular functions in humans and we explored its relevance to learning and memory functions in Alzheimer's disease (AD). Our recent in vitro studies exhibited the protective role of miR-455-3p against AD toxicities in reducing full-length APP and amyloid-β (Aβ) levels, and also in reducing defective mitochondrial biogenesis, impaired mitochondrial dynamics and synaptic deficiencies. In the current study, we sought to determine the function of miR-455-3p in mouse models.METHODS: For the first time we generated both transgenic (TG) and knockout (KO) mouse models of miR-455-3p. We determined the lifespan extension, cognitive function, mitochondrial biogenesis, mitochondrial dynamics, mitochondrial morphology, dendritic spine density, synapse numbers and synaptic activity in miR-455-3p TG and KO mice.
    RESULTS: MiR-455-3p TG mice lived 5 months longer than wild-type (WT) counterparts, whereas KO mice lived 4 months shorter than WT mice. Morris water maze test showed improved cognitive behavior, spatial learning and memory in miR-455-3p TG mice relative to age-matched WT mice and miR-455-3p KO mice. Further, mitochondrial biogenesis, dynamics and synaptic activities were enhanced in miR-455-3p TG mice, while these were reduced in KO mice. Overall, overexpressed miR-455-3p in mice displayed protective effects, whereas depleted miR-455-3p in mice exhibited deleterious effects in relation to lifespan, cognitive behavior, and mitochondrial and synaptic activities.
    CONCLUSION: Both mouse models could be ideal research tools to understand the molecular basis of aging and its relevance to AD and other age-related diseases.
    Keywords:  Alzheimer's disease; MicroRNA-455-3p; Mitochondrial biogenesis; Mouse models; Synaptic activity
    DOI:  https://doi.org/10.1016/j.redox.2021.102182
  3. J Agric Food Chem. 2021 Nov 15.
    Rotenone-Induced Neurodegeneration Is Enabled by a p38-Parkin-ROS Signaling Feedback Loop.
    Jialong Chen, Mingque Li, Xueqiong Zhou, Ailun Xie, Ziwei Cai, Chunlai Fu, Yongming Peng, He Zhang, Linhua Liu.
      Rotenone, a component of pesticides, is widely used in agriculture and potentially causes Parkinson's disease (PD). However, the regulatory mechanisms of rotenone-induced PD are unclear. Here, we revealed a novel feedback mechanism of p38-Parkin-ROS regulating rotenone-induced PD. Rotenone treatment led to not only the activation of p38 but also Parkin inactivation and reactive oxygen species (ROS) overproduction in SN4741 cells. Meanwhile, p38 activation regulated Parkin phosphorylation at serine 131 to disrupt Parkin-mediated mitophagy. Notably, both p38 inhibition and Parkin overexpression decreased ROS levels. Additionally, the ROS inhibitor N-acetyl-l-cysteine (NAC) inhibited p38 and activated Parkin-mediated mitophagy. Both p38 inhibition and the ROS inhibitor NAC exerted a protective effect by restoring cell death and mitochondrial function in rotenone-induced PD models. Based on these results, the p38-Parkin-ROS signaling pathway is involved in neurodegeneration. This pathway represents a valuable treatment strategy for rotenone-induced PD, and our study provides basic research evidence for the safe use of rotenone in agriculture.
    Keywords:  Parkin; Parkinson disease; ROS; p38; rotenone
    DOI:  https://doi.org/10.1021/acs.jafc.1c04190
  4. Biomed Pharmacother. 2021 Nov 11. pii: S0753-3322(21)01175-6. [Epub ahead of print]145 112389
    DA-9805 protects dopaminergic neurons from endoplasmic reticulum stress and inflammation.
    Sora Kang, Ying Piao, Young Cheol Kang, Suyeol Lim, Youngmi Kim Pak.
      Parkinson's disease (PD) is a multifactorial neurodegenerative disease with damages to mitochondria and endoplasmic reticulum (ER), followed by neuroinflammation. We previously reported that a triple herbal extract DA-9805 in experimental PD toxin-models had neuroprotective effects by alleviating mitochondrial damage and oxidative stress. In the present study, we investigated whether DA-9805 could suppress ER stress and neuroinflammation in vitro and/or in vivo. Pre-treatment with DA-9805 (1 μg/ml) attenuated upregulation of glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and cleaved caspase-3 in SH-SY5Y neuroblastoma cells treated with thapsigargin (1 µg/ml) or tunicamycin (2 µg/ml). In addition, DA-9805 prevented the production of IL-1β, IL-6, TNF-α and nitric oxide through inhibition of NF-κB activation in BV2 microglial cells stimulated with lipopolysaccharides (LPS). Intraperitoneal injection of LPS (10 mg/kg) into mice can induce acute neuroinflammation and dopaminergic neuronal cell death. Oral administration of DA-9805 (10 or 30 mg/kg/day for 3 days before LPS injection) prevented loss of dopaminergic neurons and activation of microglia and astrocytes in the substantia nigra in LPS-injected mouse models. Taken together, these results indicate that DA-9805 can effectively prevent ER stress and neuroinflammation, suggesting that DA-9805 is a multitargeting and disease-modifying therapeutic candidate for PD.
    Keywords:  ER stress; Herbal medicine; Mitochondria; Neuroinflammation; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.biopha.2021.112389
  5. Front Neurosci. 2021 ;15 769331
    Role of Cleaved PINK1 in Neuronal Development, Synaptogenesis, and Plasticity: Implications for Parkinson's Disease.
    Smijin K Soman, Ruben K Dagda.
      Mitochondrial dysfunction plays a significant role in the pathogenesis of Parkinson's disease (PD). Consistent with this concept, loss of function mutations in the serine/threonine kinase- PINK1 (PTEN-induced putative kinase-1) causes autosomal recessive early onset PD. While the functional role of f-PINK1 (full-length PINK1) in clearing dysfunctional mitochondria via mitophagy is extensively documented, our understanding of specific physiological roles that the non-mitochondrial pool of PINK1 imparts in neurons is more limited. PINK1 is proteolytically processed in the intermembrane space and matrix of the mitochondria into functional cleaved products (c-PINK1) that are exported to the cytosol. While it is clear that posttranslational processing of PINK1 depends on the mitochondria's oxidative state and structural integrity, the functional roles of c-PINK1 in modulating neuronal functions are poorly understood. Here, we review the diverse roles played by c-PINK1 in modulating various neuronal functions. Specifically, we describe the non-canonical functional roles of PINK1, including but not limited to: governing mitochondrial movement, neuronal development, neuronal survival, and neurogenesis. We have published that c-PINK1 stimulates neuronal plasticity and differentiation via the PINK1-PKA-BDNF signaling cascade. In addition, we provide insight into how mitochondrial membrane potential-dependent processing of PINK1 confers conditional retrograde signaling functions to PINK1. Further studies delineating the role of c-PINK1 in neurons would increase our understanding regarding the role played by PINK1 in PD pathogenesis.
    Keywords:  BDNF (brain derived neurotrophic factor); PKA signaling; Parkinson’s disease; cleaved PINK1; mitochondrial retrograde signaling; neuronal plasticity and neurogenesis
    DOI:  https://doi.org/10.3389/fnins.2021.769331
  6. Hum Mol Genet. 2021 Nov 15. pii: ddab329. [Epub ahead of print]
    Mouse midbrain dopaminergic neurons survive loss of the PD-associated mitochondrial protein CHCHD2.
    Mai K Nguyen, Kevin McAvoy, Szu-Chi Liao, Zak Doric, Iris Lo, Huihui Li, Giovanni Manfredi, Ken Nakamura.
      Mutations in the mitochondrial protein CHCHD2 cause autosomal-dominant PD characterized by the preferential loss of substantia nigra dopamine (DA) neurons. Therefore, understanding the function of CHCHD2 in neurons may provide vital insights into how mitochondrial dysfunction contributes to neurodegeneration in PD. To investigate the normal requirement and function of CHCHD2 in neurons, we first examined CHCHD2 levels, and showed that DA neurons have higher CHCHD2 levels than other neuron types, both in vivo and in co-culture. We then generated mice with either a targeted deletion of CHCHD2 in DA neurons, or a deletion in the brain or total body. All three models were viable, and loss of CHCHD2 in the brain did not cause degeneration of DA neurons. Mice lacking CHCHD2 in DA neurons did display sex-specific changes to locomotor activity, but we did not observe differences in assays of muscle strength, exercise endurance, or motor coordination. Furthermore, mitochondria derived from mice lacking CHCHD2 did not display abnormalities in OXPHOS function. Lastly, resilience to CHCHD2 deletion could not be explained by functional complementation by its paralog CHCHD10, as deletion of both CHCHD10 and CHCHD2 did not cause degeneration of DA neurons in the midbrain. These findings support the hypothesis that pathogenic CHCHD2 mutations cause PD through a toxic gain-of-function, rather than loss-of-function mechanism.
    DOI:  https://doi.org/10.1093/hmg/ddab329
  7. Front Neurosci. 2021 ;15 725547
    Neuronal Mitochondrial Dysfunction and Bioenergetic Failure in Inflammation-Associated Depression.
    Angela Maria Casaril, Robert Dantzer, Carlos Bas-Orth.
      Depression is a leading cause of disability and affects more than 4% of the population worldwide. Even though its pathophysiology remains elusive, it is now well accepted that peripheral inflammation might increase the risk of depressive episodes in a subgroup of patients. However, there is still insufficient knowledge about the mechanisms by which inflammation induces alterations in brain function. In neurodegenerative and neuroinflammatory diseases, extensive studies have reported that inflammation negatively impacts mitochondrial health, contributing to excitotoxicity, oxidative stress, energy deficits, and eventually neuronal death. In addition, damaged mitochondria can release a wide range of damage-associated molecular patterns that are potent activators of the inflammatory response, creating a feed-forward cycle between oxidative stress, mitochondrial impairment, inflammation, and neuronal dysfunction. Surprisingly, the possible involvement of this vicious cycle in the pathophysiology of inflammation-associated depression remains understudied. In this mini-review we summarize the research supporting the association between neuroinflammation, mitochondrial dysfunction, and bioenergetic failure in inflammation-associated depression to highlight the relevance of further studies addressing this crosstalk.
    Keywords:  bioenergetics; depression; inflammation; mitochondria; neurons
    DOI:  https://doi.org/10.3389/fnins.2021.725547
  8. Autophagy. 2021 Nov 19. 1-11
    AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability.
    Martina Di Rienzo, Alessandra Romagnoli, Fabiola Ciccosanti, Giulia Refolo, Veronica Consalvi, Giuseppe Arena, Enza Maria Valente, Mauro Piacentini, Gian Maria Fimia.
      PINK1 accumulation at the outer mitochondrial membrane (OMM) is a key event required to signal depolarized mitochondria to the autophagy machinery. How this early step is, in turn, modulated by autophagy proteins remains less characterized. Here, we show that, upon mitochondrial depolarization, the proautophagic protein AMBRA1 is recruited to the OMM and interacts with PINK1 and ATAD3A, a transmembrane protein that mediates mitochondrial import and degradation of PINK1. Downregulation of AMBRA1 expression results in reduced levels of PINK1 due to its enhanced degradation by the mitochondrial protease LONP1, which leads to a decrease in PINK1-mediated ubiquitin phosphorylation and mitochondrial PRKN/PARKIN recruitment. Notably, ATAD3A silencing rescues defective PINK1 accumulation in AMBRA1-deficient cells upon mitochondrial damage. Overall, our findings underline an upstream contribution of AMBRA1 in the control of PINK1-PRKN mitophagy by interacting with ATAD3A and promoting PINK1 stability. This novel regulatory element may account for changes of PINK1 levels in neuropathological conditions.
    Keywords:  Autophagy; LONP1; PRKN/PARKIN; TOMM complex; ubiquitin phosphorylation
    DOI:  https://doi.org/10.1080/15548627.2021.1997052
  9. Food Chem Toxicol. 2021 Nov 12. pii: S0278-6915(21)00698-0. [Epub ahead of print] 112665
    Sirt3-mediated mitochondrial dysfunction is involved in fluoride-induced cognitive deficits.
    Dongmei Wang, Luyang Cao, Shunji Pan, Gang Wang, Lewei Wang, Ningyao Cao, Xueqin Hao.
      Excessive fluoride is capable of inducing cognitive deficits, but the mechanisms remain elusive. This study aimed to investigate the effects and underlying mechanisms of fluoride on mitochondrial dysfunction and neurobiological alterations, as well as cognitive impairment. C57BL/6 mice were orally administered 25, 50, and 100 mg/L NaF for 90 days. Cultured human neuroblastoma SH-SY5Y cells were exposed to NaF (110 mg/L) for 24 h in the presence or absence of Sirt3 overexpression. The results demonstrated that chronic exposure to high fluoride induced cognitive deficits and neural/synaptic injury in mice. Fluoride reduced mitochondrial antioxidant enzyme activities and SOD2 acetylation by downregulating Sirt3 expression in the brains of mice and NaF-treated SH-SY5Y cells. Moreover, fluoride lowered mtDNA transcription and induced mitochondrial dysfunction along with increased FoxO3A acetylation in the brains of mice and NaF-treated SH-SY5Y cells. Subsequent experiments revealed that overexpression of Sirt3 significantly attenuated the adverse effects of fluoride on radical scavenging capabilities and mtDNA transcription, as well as mitochondrial function in SH-SY5Y cells. These results suggest that chronic long-term fluoride exposure evokes neural/synaptic injury and cognitive impairment through mitochondrial dysfunction and its associated oxidative stress, which is, at least partly, mediated by Sirt3 inhibition in the mouse brain.
    Keywords:  Mitochondrial dysfunction; NaF; Neurotoxicity; SOD2 acetylation; Sirt3/FoxO3A
    DOI:  https://doi.org/10.1016/j.fct.2021.112665
  10. Elife. 2021 Nov 15. pii: e71148. [Epub ahead of print]10
    Live imaging reveals the cellular events downstream of SARM1 activation.
    Kwang Woo Ko, Laura Devault, Yo Sasaki, Jeffrey Milbrandt, Aaron DiAntonio.
      SARM1 is an inducible NAD+ hydrolase that triggers axon loss and neuronal cell death in the injured and diseased nervous system. While SARM1 activation and enzyme function are well defined, the cellular events downstream of SARM1 activity but prior to axonal demise are much less well understood. Defects in calcium, mitochondria, ATP, and membrane homeostasis occur in injured axons, but the relationships among these events have been difficult to disentangle because prior studies analyzed large collections of axons in which cellular events occur asynchronously. Here we used live imaging of mouse sensory neurons with single axon resolution to investigate the cellular events downstream of SARM1 activity. Our studies support a model in which SARM1 NADase activity leads to an ordered sequence of events from loss of cellular ATP, to defects in mitochondrial movement and depolarization, followed by calcium influx, externalization of phosphatidylserine, and loss of membrane permeability prior to catastrophic axonal self-destruction.
    Keywords:  mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.71148
  11. Cell Death Discov. 2021 Nov 15. 7(1): 356
    BH3-only proteins Puma and Beclin1 regulate autophagic death in neurons in response to Amyloid-β.
    Akash Saha, Suraiya Saleem, Paidi Ramesh Kumar, Subhas C Biswas.
      Alzheimer's disease (AD) is characterized by accumulation of senile amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles causing progressive loss of synapse and neuronal death. Out of the various neuron death modalities, autophagy and apoptosis are reported to be the major death paradigms in AD. However, how these two processes lead to neuronal loss is still inconspicuous. Here we report that under Aβ toxicity, aberrant autophagy is induced with inefficient autophagic flux in neurons. Simultaneous activation of both autophagy and apoptosis are seen in primary cortical neurons as well as in transgenic mice brains. We found that induction of autophagy by rapamycin is detrimental for neurons; whereas downregulation of Beclin1, an important autophagy inducing protein, provides significant protection in Aβ treated neuronal cells by blocking cytochrome-c release from the mitochondria. We further report that downregulation of Puma, a BH3-only pro-apoptotic protein, inhibits the induction of aberrant autophagy and also ameliorates the autophagy flux under the influence of Aβ. Notably, stereotactic administration of shRNAs against Puma and Beclin1 in adult Aβ-infused rat brains inhibits both apoptotic and autophagic pathways. The regulation of both of the death processes is brought about by the direct interaction between Puma and Beclin1 upon Aβ treatment. We conclude that both Beclin1 and Puma play essential roles in the neuronal death caused by the induction of aberrant autophagy in AD and targeting their interaction could be vital to understand the crosstalk of autophagy and apoptosis as well as to develop a potential therapeutic strategy in AD.
    DOI:  https://doi.org/10.1038/s41420-021-00748-x
  12. J Biosci. 2021 ;pii: 99. [Epub ahead of print]46
    Putative role of uncoupling proteins in mitochondria-nucleus communications and DNA damage response.
    Yahan Niu, Chang Liu, Rui Zhang, Ying Jing, Donghai Li.
      Mitochondria-nucleus communications and DNA damage response (DDR) play roles in cellular stress and closely associate with a range of diseases. Mitochondrial uncoupling proteins (UCPs) are capable of uncoupling mitochondrial oxidative phosphorylation and protecting against oxidative stress. However, the potential role of UCPs in DDR and DDR-related mitochondria-nucleus communications remains unknown. The review deduces UCPs functions in mitochondria-nucleus communications implicated in metabolite regulation (e.g., reactive oxygen species) and Ca2+ signaling, and in DDR (e.g., base excision repair, double-strand DNA break repair, mitophagy and nuclear DNA degradation). Represented are shared microRNAs that regulate UCPs and DDR. It would provide novel insight into UCPs-mediated mitochondria-nucleus communications and DDR, and potentially promote drug target identification, drug discovery and clinical therapy of DDR-related diseases.
  13. Neuroscience. 2021 Nov 16. pii: S0306-4522(21)00579-0. [Epub ahead of print]
    The neuroprotective effect of increased PINK1 expression following glutamate excitotoxicity in neuronal cells.
    Ya-Nan Dou, Xiuquan Wu, Xiaowei Fei, Zhou Fei.
      Ischemic injury in patients with stroke often leads to neuronal damage and mitochondrial dysfunction. Neuronal injury caused by ischemia can be partly attributed to glutamate (L-Glu) excitotoxicity. Previous studies have shown that PTEN-induced kinase 1 (PINK1) plays a neuroprotective role in ischemic brain injury by regulating mitochondrial integrity and function. However, there are few reports on the expression of PINK1 in L-Glu excitotoxicity models, its effect on neuronal survival, and whether PINK1 plays a protective role in stroke by regulating mitophagy. In the present study, different concentrations of L-Glu inhibited the viability of neurons. After L-Glu treatment at different times, the mRNA level, protein level, and cellular fluorescence intensity of PINK1 first increased and then decreased. Compared with normal cells, cells with low PINK1 expression enhanced the inhibitory effect of L-Glu on neuronal activity, while those with high PINK1 expression showed a protective effect on neurons by alleviating mitochondrial membrane potential loss. In addition, RAP (an autophagy activator) could increase the co-localization of the mitophagy-related proteins light chain 3 (LC3) and Tom20, whereas 3-MA (an autophagy inhibitor) exerted the opposite effect. Finally, we found that L-Glu could induce the expression of PINK1/Parkin/ LC3 in neurons at both mRNA and protein levels, while RAP could further increase their expression, and 3-MA decreased their expression. Taken together, PINK1 protects against L-Glu-induced neuronal injury by protecting mitochondrial function, and the potential protective mechanism may be closely related to the enhancement of mitophagy mediated by the PINK1/Parkin signaling pathway.
    Keywords:  Glutamate excitotoxicity; Ischemic stroke; LC3; Mitophagy; PINK1; Parkin
    DOI:  https://doi.org/10.1016/j.neuroscience.2021.11.020
  14. Iran J Child Neurol. 2021 ;15(4): 115-117
    Autism spectrum disorder: A mitochondrial disorder.
    Josef Finsterer.
      
    Keywords:  Abnormal behaviour; Autism; MTDNA; Mitochondrial; Respiratory Chain
    DOI:  https://doi.org/10.22037/ijcn.v16i2.33066
  15. Life Sci Alliance. 2022 Feb;pii: e202101278. [Epub ahead of print]5(2):
    Serine palmitoyltransferase assembles at ER-mitochondria contact sites.
    Mari J Aaltonen, Irina Alecu, Tim König, Steffany Al Bennett, Eric A Shoubridge.
      The accumulation of sphingolipid species in the cell contributes to the development of obesity and neurological disease. However, the subcellular localization of sphingolipid-synthesizing enzymes is unclear, limiting the understanding of where and how these lipids accumulate inside the cell and why they are toxic. Here, we show that SPTLC2, a subunit of the serine palmitoyltransferase (SPT) complex, catalyzing the first step in de novo sphingolipid synthesis, localizes dually to the ER and the outer mitochondrial membrane. We demonstrate that mitochondrial SPTLC2 interacts and forms a complex in trans with the ER-localized SPT subunit SPTLC1. Loss of SPTLC2 prevents the synthesis of mitochondrial sphingolipids and protects from palmitate-induced mitochondrial toxicity, a process dependent on mitochondrial ceramides. Our results reveal the in trans assembly of an enzymatic complex at an organellar membrane contact site, providing novel insight into the localization of sphingolipid synthesis and the composition and function of ER-mitochondria contact sites.
    DOI:  https://doi.org/10.26508/lsa.202101278
  16. Front Cell Dev Biol. 2021 ;9 727822
    Mitophagy Protects the Retina Against Anti-Vascular Endothelial Growth Factor Therapy-Driven Hypoxia via Hypoxia-Inducible Factor-1α Signaling.
    Yimeng Sun, Feng Wen, Chun Yan, Lishi Su, Jiawen Luo, Wei Chi, Shaochong Zhang.
      Anti-VEGF drugs are first-line treatments for retinal neovascular diseases, but these anti-angiogenic agents may also aggravate retinal damage by inducing hypoxia. Mitophagy can protect against hypoxia by maintaining mitochondrial quality, thereby sustaining metabolic homeostasis and reducing reactive oxygen species (ROS) generation. Here we report that the anti-VEGF agent bevacizumab upregulated the hypoxic cell marker HIF-1α in photoreceptors, Müller cells, and vascular endothelial cells of oxygen-induced retinopathy (OIR) model mice, as well as in hypoxic cultured 661W photoreceptors, MIO-MI Müller cells, and human vascular endothelial cells. Bevacizumab also increased expression of mitophagy-related proteins, and mitophagosome formation both in vivo and in vitro, but did not influence cellular ROS production or apoptosis rate. The HIF-1α inhibitor LW6 blocked mitophagy, augmented ROS production, and triggered apoptosis. Induction of HIF-1α and mitophagy were associated with upregulation of BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3) and FUN14 domain containing 1 (FUNDC1), and overexpression of these proteins in culture reversed the effects of HIF-1α inhibition. These findings suggest that bevacizumab does induce retinal hypoxia, but that concomitant activation of the HIF-1α-BNIP3/FUNDC1 signaling pathway also induces mitophagy, which can mitigate the deleterious effects by reducing oxidative stress secondary. Promoting HIF-1α-BNIP3/FUNDC1-mediated mitophagy may enhance the safety of anti-VEGF therapy for retinal neovascular diseases and indicate new explanation and possible new target of the anti-VEGF therapy with suboptimal effect.
    Keywords:  anti-VEGF; bevacizumab; hypoxia; mitophagy; retina; retinal neovascular disease
    DOI:  https://doi.org/10.3389/fcell.2021.727822
  17. Aging Cell. 2021 Nov 19. e13520
    Mitochondrial aconitase 1 regulates age-related memory impairment via autophagy/mitophagy-mediated neural plasticity in middle-aged flies.
    Yun-Ho Cho, Gye-Hyeong Kim, Joong-Jean Park.
      Age-related memory impairment (AMI) occurs in many species, including humans. The underlying mechanisms are not fully understood. In wild-type Drosophila (w1118 ), AMI appears in the form of a decrease in learning (3-min memory) from middle age (30 days after eclosion [DAE]). We performed in vivo, DNA microarray, and behavioral screen studies to identify genes controlling both lifespan and AMI and selected mitochondrial Acon1 (mAcon1). mAcon1 expression in the head of w1118 decreased with age. Neuronal overexpression of mAcon1 extended its lifespan and improved AMI. Neuronal or mushroom body expression of mAcon1 regulated the learning of young (10 DAE) and middle-aged flies. Interestingly, acetyl-CoA and citrate levels increased in the heads of middle-aged and neuronal mAcon1 knockdown flies. Acetyl-CoA, as a cellular energy sensor, is related to autophagy. Autophagy activity and efficacy determined by the positive and negative changes in the expression levels of Atg8a-II and p62 were proportional to the expression level of mAcon1. Levels of the presynaptic active zone scaffold protein Bruchpilot were inversely proportional to neuronal mAcon1 levels in the whole brain. Furthermore, mAcon1 overexpression in Kenyon cells induced mitophagy labeled with mt-Keima and improved learning ability. Both processes were blocked by pink1 knockdown. Taken together, our results imply that the regulation of learning and AMI by mAcon1 occurs via autophagy/mitophagy-mediated neural plasticity.
    Keywords:  aconitase; age-related memory disorders; autophagy; mitochondria; mitophagy; neural plasticity
    DOI:  https://doi.org/10.1111/acel.13520
  18. Elife. 2021 Nov 19. pii: e70905. [Epub ahead of print]10
    Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders.
    Queen Square Genomics
      SARM1, a protein with critical NADase activity, is a central executioner in a conserved programme of axon degeneration. We report seven rare missense or in-frame microdeletion human SARM1 variant alleles in patients with amyotrophic lateral sclerosis (ALS) or other motor nerve disorders that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activity of these seven variants is similar to that of SARM1 lacking the entire ARM domain and greatly exceeds the activity of wild-type SARM1, even in the presence of nicotinamide mononucleotide (NMN), its physiological activator. This rise in constitutive activity alone is enough to promote neuronal degeneration in response to otherwise non-harmful, mild stress. Importantly, these strong gain-of-function alleles are completely patient-specific in the cohorts studied and show a highly significant association with disease at the single gene level. These findings of disease-associated coding variants that alter SARM1 function build on previously reported genome-wide significant association with ALS for a neighbouring, more common SARM1 intragenic single nucleotide polymorphism (SNP) to support a contributory role of SARM1 in these disorders. A broad phenotypic heterogeneity and variable age-of-onset of disease among patients with these alleles also raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.
    Keywords:  genetics; genomics; human; neuroscience
    DOI:  https://doi.org/10.7554/eLife.70905
  19. Am J Med Genet A. 2021 Nov 19.
    Case report of atypical Leigh syndrome in an adolescent male with novel biallelic variants in NDUFAF5 and review of the natural history of NDUFAF5-related disorders.
    Nicole R Legro, Ashutosh Kumar, Ermal Aliu.
      NDUFAF5 encodes a Complex I assembly factor which is critical to the modification of a core subunit, NDUFS7, in early Complex I factor assembly. Mutations in NDUFAF5 have been previously shown to cause Complex I deficiency leading to mitochondrial respiratory chain impairment. More than 15 individuals affected by variants in NDUFAF5 have been described; however, there is phenotypic heterogeneity within this cohort. Some individuals display features of classical Leigh syndrome with early onset neurodegeneration whereas others live into early adulthood with progressive neurological deficits. Here, we present a clinical report of a 17-year-old African American individual with compound heterozygous mutations in NDUFAF5. The individual presented with childhood onset bilateral optic atrophy and developed progressive neuromuscular decline with relatively preserved cognition over time.
    Keywords:  Complex I; Leigh syndrome; NDUFAF5; mitochondrial disease
    DOI:  https://doi.org/10.1002/ajmg.a.62568
This page is being maintained by Thomas Krichel. It was last updated on 2021‒11‒29 at 11:22:20.