bims-midneu 2021-04-18 papers

bims-midneu

Biomed News

on Mitochondrial dysfunction in neurodegeneration

Issue of 2021–04–18
33 papers selected by
Radha Desai, Merck Sharp & Dohme Corp.

Stressed mitochondria: a target to intrude alzheimer's disease.
Manganese-induced alpha-synuclein overexpression aggravates mitochondrial damage by repressing PINK1/Parkin-mediated mitophagy.
IRE1α-XBP1 Affects the Mitochondrial Function of Aβ25-35-Treated SH-SY5Y Cells by Regulating Mitochondria-Associated Endoplasmic Reticulum Membranes.
NIPSNAP protein family emerges as a sensor of mitochondrial health.
Molecular imaging of NAD+ -dependent deacetylase SIRT1 in the brain.
Mitochondrial biogenesis in developing astrocytes regulates astrocyte maturation and synapse formation.
STED and parallelized RESOLFT optical nanoscopy of the tubular endoplasmic reticulum and its mitochondrial contacts in neuronal cells.
Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.
Metabolic Profiling of Suprachiasmatic Nucleus Reveals Multifaceted Effects in an Alzheimer's Disease Mouse Model.
Frequency of mutations in PRKN, PINK1, and DJ1 in Patients With Early-Onset Parkinson Disease from neighboring countries in Central Europe.
Optogenetic delivery of trophic signals in a genetic model of Parkinson's disease.
Reducing acetylated tau is neuroprotective in brain injury.
Diabetic Encephalopathy Affecting Mitochondria and Axonal Transport Proteins.
AD Course Map charts Alzheimer's disease progression.
Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy.
eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction.
Characterization of nonmotor behavioral impairments and their neurochemical mechanisms in the MitoPark mouse model of progressive neurodegeneration in Parkinson's disease.
Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes.
Interorganelle communication, aging, and neurodegeneration.
Mitochondria: The Retina's Achilles' Heel in AMD.
An energetics perspective on geroscience: mitochondrial protonmotive force and aging.
Comment on "mt-Keima detects PINK1-PRKN mitophagy in vivo with greater sensitivity than mito-QC".
Classification of neurological diseases using multi-dimensional cerebrospinal fluid analysis.
Mitochondrial OMA1 and OPA1 as Gatekeepers of Organellar Structure/Function and Cellular Stress Response.
Nrf2 as a potential target for Parkinson's disease therapy.
Mechanisms of microRNA‑142 in mitochondrial autophagy and hippocampal damage in a rat model of epilepsy.
Depletion of mitochondrial inorganic polyphosphate (polyP) in mammalian cells causes metabolic shift from oxidative phosphorylation to glycolysis.
LncRNA MEG3 Alleviates Diabetic Cognitive Impairments by Reducing Mitochondrial-Derived Apoptosis through Promotion of FUNDC1-Related Mitophagy via Rac1-ROS Axis.
Mitochondrial DNA mutations contribute to high altitude pulmonary edema via increased oxidative stress and metabolic reprogramming during hypobaric hypoxia.
Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination.
Neuromuscular Junction Abnormalities in Mitochondrial Disease: An Observational Cohort Study.
Mitochondrial hydrogen peroxide positively regulates neuropeptide secretion during diet-induced activation of the oxidative stress response.
Dual Regeneration of Muscle and Nerve by Intramuscular Infusion of Mitochondria in a Nerve Crush Injury Model.

Mitochondrion. 2021 Apr 08. pii: S1567-7249(21)00050-7. [Epub ahead of print]

Stressed mitochondria: a target to intrude alzheimer's disease.

Vivek Kumar Sharma, Thakur Gurjeet Singh, Vineet Mehta.

  Alzheimer's disease (AD) is the inoperable, incapacitating, neuropsychiatric, and degenerative manifestation that drastically affects human life quality. The current medications target extra-neuronal senile plaques, oxidative stress, neuroinflammation, intraneuronal neurofibrillary tangles, cholinergic deficits, and excitotoxicity. Among novel pathways and targets, bioenergetic and resultant mitochondrial dysfunction has been recognized as essential factors that decide the neuronal fate and consequent neurodegeneration in AD. The crucial attributes of mitochondria, including bioenergesis, signaling, sensing, integrating, and transmitting biological signals contribute to optimum networking of neuronal dynamics and make them indispensable for cell survival. In AD, mitochondrial dysfunction and mitophagy are a preliminary and critical event that aggravates the pathological cascade. Stress is known to promote and exaggerate the neuropathological alteration during neurodegeneration and metabolic impairments, especially in the cortico-limbic system, besides adversely affecting the normal physiology and mitochondrial dynamics. Stress involves the allocation of energy resources for neuronal survival. Chronic and aggravated stress response leads to excessive release of glucocorticoids by activation of the hypothalamic-pituitary-adrenal (HPA) axis. By acting through their receptors, glucocorticoids influence adverse mitochondrial changes and alter mtDNA transcription, mtRNA expression, hippocampal mitochondrial network, and ultimately mitochondrial physiology. Chronic stress also affects mitochondrial dynamics by changing metabolic and neuro-endocrinal signalling, aggravating oxidative stress, provoking inflammatory mediators, altering tropic factors, influencing gene expression, and modifying epigenetic pathways. Thus, exploring chronic stress-induced glucocorticoid dysregulation and resultant bio-behavioral and psychosomatic mitochondrial alterations may be a feasible narrative to investigate and unravel the mysterious pathobiology of AD.

Keywords:  Alzheimer’s Disorder; Bioenergetics; Glucocorticoids; Mitochondria; Stress; mtDNA

DOI:  https://doi.org/10.1016/j.mito.2021.04.004
Food Chem Toxicol. 2021 Apr 13. pii: S0278-6915(21)00246-5. [Epub ahead of print] 112213

Manganese-induced alpha-synuclein overexpression aggravates mitochondrial damage by repressing PINK1/Parkin-mediated mitophagy.

Zhi-Qi Liu, Kuan Liu, Zhuo-Fan Liu, Lin Cong, Meng-Yu Lei, Zhuo Ma, Jing Li, Yu Deng, Wei Liu, Bin Xu.

  Chronic manganese (Mn) exposure is related to elevated risks of neurodegenerative diseases, and mitochondrial dysfunction is considered a critical pathophysiological feature of Mn neurotoxicity. Although previous research has demonstrated Mn-induced alpha-synuclein (α-Syn) overexpression, the role of α-Syn in mitochondrial dysfunction remains unclear. Here, we used Wistar rats and human neuroblastoma cells (SH-SY5Y cells) to elucidate the molecular mechanisms underlying how α-Syn overexpression induced by different doses of Mn (15, 30, and 60 mg/kg) results in mitochondrial dysfunction. We found that Mn-induced neural cell injury was associated with mitochondrial damage. Furthermore, Mn upregulated α-Syn protein levels and increased the interaction between α-Syn and mitochondria. We then used a lentivirus vector containing α-Syn shRNA to examine the effect of Mn-induced α-Syn protein on PINK1/Parkin-mediated mitophagy in SH-SY5Y cells. Our data demonstrated that the knockdown of α-Syn decreased the interaction between α-Syn and PINK1. The enhanced level of phosphorylated Parkin (p-Parkin) was due to the decrease of the interaction between α-Syn and PINK1. Moreover, the knockdown of α-Syn increased recruitment of p-Parkin to mitochondria. Collectively, these observations revealed that Mn-induced α-Syn overexpression repressed PINK1/Parkin-mediated mitophagy and exacerbated mitochondrial damage.

Keywords:  Mitophagy; Mn; Neurotoxicity; α-Syn

DOI:  https://doi.org/10.1016/j.fct.2021.112213
Front Cell Neurosci. 2021 ;15 614556

IRE1α-XBP1 Affects the Mitochondrial Function of Aβ25-35-Treated SH-SY5Y Cells by Regulating Mitochondria-Associated Endoplasmic Reticulum Membranes.

Bingcong Chu, Maoyu Li, Xi Cao, Rulong Li, Suqin Jin, Hui Yang, Linlin Xu, Ping Wang, Jianzhong Bi.

  Background: Neurotoxicity induced by the amyloid beta (Aβ) peptide is one of the most important pathological mechanisms of Alzheimer's disease (AD). Activation of the adaptive IRE1α-XBP1 pathway contributes to the pathogenesis of AD, making it a potential target for AD therapeutics. However, the mechanism of IRE1α-XBP1 pathway involvement in AD is unclear. We, therefore, investigated the effect of the IRE1α-XBP1 axis in an in vitro AD model and explored its potential mechanism. Methods: The human neuroblastoma cell line, SH-SY5Y, was used. Cells were treated with Aβ25-35, with or without 4μ8c, an inhibitor of IRE1α. Cells were collected and analyzed by Western blotting, quantitative real-time PCR, electron microscopy, fluorescence microscopy, calcium imaging, and other biochemical assays. Results: Aβ-exposed SH-SY5Y cells showed an increased expression of XBP1s and p-IRE1α. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and calcium imaging analysis showed that the IRE1α inhibitor, 4μ8c, reduced Aβ-induced cytotoxicity. Increased levels of ATP, restoration of mitochondrial membrane potential, and decreased production of mitochondrial reactive oxygen species after Aβ treatment in the presence of 4μ8c showed that inhibiting the IRE1α-XBP1 axis effectively mitigated Aβ-induced mitochondrial dysfunction in SH-SY5Y cells. Furthermore, Aβ treatment increased the expression and interaction of IP3R, Grp75, and vdac1 and led to an increased endoplasmic reticulum (ER)-mitochondria association, malfunction of mitochondria-associated ER-membranes (MAMs), and mitochondrial dysfunction. These deficits were rescued by inhibiting the IRE1α-XBP1 axis. Conclusion: These findings demonstrate that Aβ peptide induces the activation of the IRE1α-XBP1 axis, which may aggravate cytotoxicity and mitochondrial impairment in SH-SY5Y cells by targeting MAMs. Inhibition of the IRE1α-XBP1 axis provides the protection against Aβ-induced injury in SH-SY5Y cells and may, therefore, be a new treatment strategy.

Keywords:  Alzheheimer's disease; IRE1α-XBP1; amyloid-beta-protein; cytotoxicity; mitochondria associated ER membranes; mitochondria impairment

DOI:  https://doi.org/10.3389/fncel.2021.614556
Bioessays. 2021 Apr 14. e2100014

NIPSNAP protein family emerges as a sensor of mitochondrial health.

Esmat Fathi, Jay M Yarbro, Ramin Homayouni.

  Since their discovery over two decades ago, the molecular and cellular functions of the NIPSNAP family of proteins (NIPSNAPs) have remained elusive until recently. NIPSNAPs interact with a variety of mitochondrial and cytoplasmic proteins. They have been implicated in multiple cellular processes and associated with different physiologic and pathologic conditions, including pain transmission, Parkinson's disease, and cancer. Recent evidence demonstrated a direct role for NIPSNAP1 and NIPSNAP2 proteins in regulation of mitophagy, a process that is critical for cellular health and maintenance. Importantly, NIPSNAPs contain a 110 amino acid domain that is evolutionary conserved from mammals to bacteria. However, the molecular function of the conserved NIPSNAP domain and its potential role in mitophagy have not been explored. It stands to reason that the highly conserved NIPSNAP domain interacts with a substrate that is ubiquitously present across all species and can perhaps act as a sensor for mitochondrial health.

Keywords:  Alzheimer's disease; Parkinson's disease; Sirtuin3; metabolism; mitophagy

DOI:  https://doi.org/10.1002/bies.202100014
Alzheimers Dement. 2021 Apr 15.

Molecular imaging of NAD+ -dependent deacetylase SIRT1 in the brain.

Yulong Xu, Zude Chen, Hsiao-Ying Wey, Yingxia Liang, Rudolph E Tanzi, Can Zhang, Changning Wang.

   INTRODUCTION: Aging is an inevitable physiological process and the biggest risk factor of Alzheimer's disease (AD). Developing an imaging tracer to visualize aging-related changes in the brain may provide a useful biomarker in elucidating neuroanatomical mechanisms of AD.
METHODS: We developed and characterized a new tracer that can be used to visualize SIRT1 in brains related to aging and AD by positron emission tomography imaging.
RESULTS: The SIRT1 tracer displayed desirable brain uptake and selectivity, as well as stable metabolism and proper kinetics and distribution in rodent and nonhuman primate brains. This new tracer was further validated by visualizing SIRT1 in brains of AD transgenic mice, compared to nontransgenic animals.
DISCUSSION: Our SIRT1 tracer not only enables, for the first time, the demonstration of SIRT1 in animal brains, but also allows visualization and recapitulation of AD-related SIRT1 neuropathological changes in animal brains.

Keywords:  Alzheimer's disease; SIRT1; molecular imaging; positron emission tomography; preclinical animal models

DOI:  https://doi.org/10.1002/alz.12344
Cell Rep. 2021 Apr 13. pii: S2211-1247(21)00266-7. [Epub ahead of print]35(2): 108952

Mitochondrial biogenesis in developing astrocytes regulates astrocyte maturation and synapse formation.

Tamara Zehnder, Francesco Petrelli, Jennifer Romanos, Eva C De Oliveira Figueiredo, Tommy L Lewis, Nicole Déglon, Franck Polleux, Mirko Santello, Paola Bezzi.

  The mechanisms controlling the post-natal maturation of astrocytes play a crucial role in ensuring correct synaptogenesis. We show that mitochondrial biogenesis in developing astrocytes is necessary for coordinating post-natal astrocyte maturation and synaptogenesis. The astrocytic mitochondrial biogenesis depends on the transient upregulation of metabolic regulator peroxisome proliferator-activated receptor gamma (PPARγ) co-activator 1α (PGC-1α), which is controlled by metabotropic glutamate receptor 5 (mGluR5). At tissue level, the loss or downregulation of astrocytic PGC-1α sustains astrocyte proliferation, dampens astrocyte morphogenesis, and impairs the formation and function of neighboring synapses, whereas its genetic re-expression is sufficient to restore the mitochondria compartment and correct astroglial and synaptic defects. Our findings show that the developmental enhancement of mitochondrial biogenesis in astrocytes is a critical mechanism controlling astrocyte maturation and supporting synaptogenesis, thus suggesting that astrocytic mitochondria may be a therapeutic target in the case of neurodevelopmental and psychiatric disorders characterized by impaired synaptogenesis.

Keywords:  PGC-1α; astrocyte; mGluR5; mitochondria

DOI:  https://doi.org/10.1016/j.celrep.2021.108952
Neurobiol Dis. 2021 Apr 12. pii: S0969-9961(21)00110-8. [Epub ahead of print] 105361

STED and parallelized RESOLFT optical nanoscopy of the tubular endoplasmic reticulum and its mitochondrial contacts in neuronal cells.

Martina Damenti, Giovanna Coceano, Francesca Pennacchietti, Andreas Bodén, Ilaria Testa.

  The classic view of organelle cell biology is undergoing a constant revision fueled by the new insights unraveled by fluorescence nanoscopy, which enable sensitive, faster and gentler observation of specific proteins in situ. The endoplasmic reticulum (ER) is one of the most challenging structure to capture due the rapid and constant restructuring of fine sheets and tubules across the full 3D cell volume. Here we apply STED and parallelized 2D and 3D RESOLFT live imaging to uncover the tubular ER organization in the fine processes of neuronal cells with focus on mitochondria-ER contacts, which recently gained medical attention due to their role in neurodegeneration. Multi-color STED nanoscopy enables the simultaneous visualization of small transversal ER tubules crossing and constricting mitochondria all along axons and dendrites. Parallelized RESOLFT allows for dynamic studies of multiple contact sites within seconds and minutes with prolonged time-lapse imaging at ~50 nm spatial resolution. When operated in 3D super resolution mode it enables a new isotropic visualization of such contacts extending our understanding of the three-dimensional architecture of these packed structures in axons and dendrites.

Keywords:  Endoplasmic reticulum; Mitochondria-ER contacts; RESOLFT; STED; Super resolution microscopy

DOI:  https://doi.org/10.1016/j.nbd.2021.105361
Nat Commun. 2021 04 14. 12(1): 2238

Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.

Benjamin Caballero, Mathieu Bourdenx, Enrique Luengo, Antonio Diaz, Peter Dongmin Sohn, Xu Chen, Chao Wang, Yves R Juste, Susanne Wegmann, Bindi Patel, Zapporah T Young, Szu Yu Kuo, Jose Antonio Rodriguez-Navarro, Hao Shao, Manuela G Lopez, Celeste M Karch, Alison M Goate, Jason E Gestwicki, Bradley T Hyman, Li Gan, Ana Maria Cuervo.

Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression.

DOI: https://doi.org/10.1038/s41467-021-22501-9
J Alzheimers Dis. 2021 Apr 03.

Metabolic Profiling of Suprachiasmatic Nucleus Reveals Multifaceted Effects in an Alzheimer's Disease Mouse Model.

Muhamed N H Eeza, Rico Singer, Corinna Höfling, Jörg Matysik, Huub J M de Groot, Steffen Roβner, A Alia.

   BACKGROUND: Circadian rhythm disturbance is commonly observed in Alzheimer's disease (AD). In mammals, these rhythms are orchestrated by the superchiasmatic nucleus (SCN). Our previous study in the Tg2576 AD mouse model suggests that inflammatory responses, most likely manifested by low GABA production, may be one of the underlying perpetrators for the changes in circadian rhythmicity and sleep disturbance in AD. However, the mechanistic connections between SCN dysfunction, GABA modulation, and inflammation in AD is not fully understood.
OBJECTIVE: To reveal influences of amyloid pathology in Tg2576 mouse brain on metabolism in SCN and to identify key metabolic sensors that couple SCN dysfunction with GABA modulation and inflammation.
METHODS: High resolution magic angle spinning (HR-MAS) NMR in conjunction with multivariate analysis was applied for metabolic profiling in SCN of control and Tg2576 female mice. Immunohistochemical analysis was used to detect neurons, astrocytes, expression of GABA transporter 1 (GAT1) and Bmal1.
RESULTS: Metabolic profiling revealed significant metabolic deficits in SCN of Tg2576 mice. Reductions in glucose, glutamate, GABA, and glutamine provide hints toward an impaired GABAergic glucose oxidation and neurotransmitter cycling in SCN of AD mice. In addition, decreased redox co-factor NADPH and glutathione support a redox disbalance. Immunohistochemical examinations showed low expression of the core clock gene, Bmal1, especially in activated astrocytes. Moreover, decreased expression of GAT1 in astrocytes indicates low GABA recycling in this cell type.
CONCLUSION: Our results suggest that redox disbalance and compromised GABA signaling are important denominators and connectors between neuroinflammation and clock dysfunction in AD.

Keywords:  1H high-resolution magic angle spinning NMR; Alzheimer’s disease; GABA dysfunction; Tg2576 mouse model; metabolic deficit; suprachiasmatic nucleus

DOI:  https://doi.org/10.3233/JAD-201575
Parkinsonism Relat Disord. 2021 Apr 02. pii: S1353-8020(21)00119-X. [Epub ahead of print]86 48-51

Frequency of mutations in PRKN, PINK1, and DJ1 in Patients With Early-Onset Parkinson Disease from neighboring countries in Central Europe.

Łukasz M Milanowski, Jennifer A Lindemann, Dorota Hoffman-Zacharska, Alexandra I Soto-Beasley, Maria Barcikowska, Magdalena Boczarska-Jedynak, Angela Deutschlander, Gabriela Kłodowska, Jarosław Dulski, Lyuda Fedoryshyn, Andrzej Friedman, Zygmunt Jamrozik, Piotr Janik, Katherine Karpinsky, Dariusz Koziorowski, Anna Krygowska-Wajs, Barbara Jasińska-Myga, Grzegorz Opala, Anna Potulska-Chromik, Aleksander Pulyk, Irena Rektorova, Yanosh Sanotsky, Joanna Siuda, Jarosław Sławek, Katarzyna Śmiłowska, Lech Szczechowski, Monika Rudzińska-Bar, Ronald L Walton, Owen A Ross, Zbigniew K Wszolek.

   INTRODUCTION: Approximately 10% of patients with Parkinson disease (PD) present with early-onset disease (EOPD), defined as diagnosis before 50 years of age. Genetic factors are known to contribute to EOPD, with most commonly observed mutations in PRKN, PINK1, and DJ1 genes. The aim of our study was to analyze the frequency of PRKN, PINK1, and DJ1 mutations in an EOPD series from 4 neighboring European countries: Czech Republic, Germany, Poland, and Ukraine.
METHODS: Diagnosis of PD was made based on UK Brain Bank diagnostic criteria in departments experienced in movement disorders (1 from Czech Republic, 1 from Germany, 9 from Poland, and 3 from Ukraine). EOPD was defined as onset at or before 50 years of age. Of the 541 patients recruited to the study, 11 were Czech, 38 German, 476 Polish, and 16 Ukrainian. All cohorts were fully screened with Sanger sequencing for PRKN, PINK1, and DJ1 and multiplex ligation-dependent probe amplification for exon dosage.
RESULTS: PRKN homozygous or double heterozygous mutations were identified in 17 patients: 1 Czech (9.1%), 1 German (2.6%), 14 Polish (2.9%), and 1 Ukrainian (6.3%). PINK1 homozygous mutations were only identified in 3 Polish patients (0.6%). There were no homozygous or compound heterozygous DJ1 mutations in analyzed subpopulations. One novel variant in PRKN was identified in the Ukrainian series.
CONCLUSION: In the analyzed cohorts, mutations in the genes PRKN, PINK1, and DJ1 are not frequently observed.

Keywords:  Central Europe; DJ1; Early-onset Parkinson disease; PINK1; PRKN

DOI:  https://doi.org/10.1016/j.parkreldis.2021.03.026
PLoS Genet. 2021 Apr;17(4): e1009479

Optogenetic delivery of trophic signals in a genetic model of Parkinson's disease.

Alvaro Ingles-Prieto, Nikolas Furthmann, Samuel H Crossman, Alexandra-Madelaine Tichy, Nina Hoyer, Meike Petersen, Vanessa Zheden, Julia Biebl, Eva Reichhart, Attila Gyoergy, Daria E Siekhaus, Peter Soba, Konstanze F Winklhofer, Harald Janovjak.

Optogenetics has been harnessed to shed new mechanistic light on current and future therapeutic strategies. This has been to date achieved by the regulation of ion flow and electrical signals in neuronal cells and neural circuits that are known to be affected by disease. In contrast, the optogenetic delivery of trophic biochemical signals, which support cell survival and are implicated in degenerative disorders, has never been demonstrated in an animal model of disease. Here, we reengineered the human and Drosophila melanogaster REarranged during Transfection (hRET and dRET) receptors to be activated by light, creating one-component optogenetic tools termed Opto-hRET and Opto-dRET. Upon blue light stimulation, these receptors robustly induced the MAPK/ERK proliferative signaling pathway in cultured cells. In PINK1B9 flies that exhibit loss of PTEN-induced putative kinase 1 (PINK1), a kinase associated with familial Parkinson's disease (PD), light activation of Opto-dRET suppressed mitochondrial defects, tissue degeneration and behavioral deficits. In human cells with PINK1 loss-of-function, mitochondrial fragmentation was rescued using Opto-dRET via the PI3K/NF-кB pathway. Our results demonstrate that a light-activated receptor can ameliorate disease hallmarks in a genetic model of PD. The optogenetic delivery of trophic signals is cell type-specific and reversible and thus has the potential to inspire novel strategies towards a spatio-temporal regulation of tissue repair.

DOI: https://doi.org/10.1371/journal.pgen.1009479
Cell. 2021 Apr 10. pii: S0092-8674(21)00363-9. [Epub ahead of print]

Reducing acetylated tau is neuroprotective in brain injury.

Min-Kyoo Shin, Edwin Vázquez-Rosa, Yeojung Koh, Matasha Dhar, Kalyani Chaubey, Coral J Cintrón-Pérez, Sarah Barker, Emiko Miller, Kathryn Franke, Maria F Noterman, Divya Seth, Rachael S Allen, Cara T Motz, Sriganesh Ramachandra Rao, Lara A Skelton, Machelle T Pardue, Steven J Fliesler, Chao Wang, Tara E Tracy, Li Gan, Daniel J Liebl, Jude P J Savarraj, Glenda L Torres, Hilda Ahnstedt, Louise D McCullough, Ryan S Kitagawa, H Alex Choi, Pengyue Zhang, Yuan Hou, Chien-Wei Chiang, Lang Li, Francisco Ortiz, Jessica A Kilgore, Noelle S Williams, Victoria C Whitehair, Tamar Gefen, Margaret E Flanagan, Jonathan S Stamler, Mukesh K Jain, Allison Kraus, Feixiong Cheng, James D Reynolds, Andrew A Pieper.

  Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.

Keywords:  Alzheimer’s disease; P7C3; acetylation; congenital muscular dystrophy; diflunisal; neurodegeneration; neuroprotection; omigapil; salsalate; tau; traumatic brain injury

DOI:  https://doi.org/10.1016/j.cell.2021.03.032
Basic Clin Neurosci. 2020 Nov-Dec;11(6):11(6): 781-793

Diabetic Encephalopathy Affecting Mitochondria and Axonal Transport Proteins.

Maryam Eslami Gharaati, Arezo Nahavandi, Torandokht Baluchnejad Mojarad, Mehrdad Roghani.

   Introduction: Diabetic encephalopathy is described as any cognitive and memory impairments associated with hippocampal degenerative changes, including the neurodegenerative process and decreased number of living cells. Mitochondrial diabetes (MD) appears following activation of mutant mitochondrial DNA and is a combination of diabetes and cognitive deficit. In this research, we showed the correlation of diabetic encephalopathy, dysfunctional mitochondria, and changes in the expression of axonal transport proteins (KIF5b, Dynein).
Methods: Twenty-four male Wistar rats were divided into three groups: (n=8 in each group):1. Control + saline; 2. Diabetic, and 3. Diabetic + insulin. Before starting the experiments, the animals with blood sugar lower than 150 mg/dL entered the study. Diabetes induction was carried out by Intraperitoneal (IP) Streptozotocin (STZ) administration. Fasting Blood Sugar (FBS) and body weight was checked after the first week and at the end of the eighth week. Then, behavioral studies (elevated plus maze, Y-maze, and passive avoidance learning) were performed. After behavioral studies, blood samples were taken to measure serum insulin level and HgbA1c. Next, fresh hippocampal tissue was collected. Gene expression of motor proteins was assessed by real-time PCR and mitochondrial membrane potential by rhodamine123.
Results: Our results showed the impairment of HgbA1c, serum insulin, FBS, and weight in the diabetic group (P<0.05). Behavioral tests revealed different degrees of impairment in diabetic rats (P<0.05). KIF5b mRNA expression increased in the hippocampus (P<0.05) with no change in dynein gene expression. These changes were associated with abnormal mitochondrial membrane potential (P<0.05).
Conclusion: KIF5b mRNA up-regulation in hippocampal neurons of STZ-diabetic rats is a factor that can be involved in abnormal axonal transport and decreased MMP, leading to impairment of mitochondrial function. These manifestations showed mitochondrial dysfunction in diabetes and resulted in abnormal behavioral tests and diabetic encephalopathy.

Keywords:  Axonal transport; Diabetes mellitus type 1; Dynein; KIF5b protein; Mitochondria; Mitochondrial encephalopathy

DOI:  https://doi.org/10.32598/bcn.11.6.1657.1
Sci Rep. 2021 Apr 13. 11(1): 8020

AD Course Map charts Alzheimer's disease progression.

Igor Koval, Alexandre Bône, Maxime Louis, Thomas Lartigue, Simona Bottani, Arnaud Marcoux, Jorge Samper-González, Ninon Burgos, Benjamin Charlier, Anne Bertrand, Stéphane Epelbaum, Olivier Colliot, Stéphanie Allassonnière, Stanley Durrleman.

Alzheimer's disease (AD) is characterized by the progressive alterations seen in brain images which give rise to the onset of various sets of symptoms. The variability in the dynamics of changes in both brain images and cognitive impairments remains poorly understood. This paper introduces AD Course Map a spatiotemporal atlas of Alzheimer's disease progression. It summarizes the variability in the progression of a series of neuropsychological assessments, the propagation of hypometabolism and cortical thinning across brain regions and the deformation of the shape of the hippocampus. The analysis of these variations highlights strong genetic determinants for the progression, like possible compensatory mechanisms at play during disease progression. AD Course Map also predicts the patient's cognitive decline with a better accuracy than the 56 methods benchmarked in the open challenge TADPOLE. Finally, AD Course Map is used to simulate cohorts of virtual patients developing Alzheimer's disease. AD Course Map offers therefore new tools for exploring the progression of AD and personalizing patients care.

DOI: https://doi.org/10.1038/s41598-021-87434-1
Brain. 2021 Apr 15. pii: awab056. [Epub ahead of print]

Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy.

Elena Bonora, Sanjiban Chakrabarty, Georgios Kellaris, Makiko Tsutsumi, Francesca Bianco, Christian Bergamini, Farid Ullah, Federica Isidori, Irene Liparulo, Chiara Diquigiovanni, Luca Masin, Nicola Rizzardi, Mariapia Giuditta Cratere, Elisa Boschetti, Valentina Papa, Alessandra Maresca, Giovanna Cenacchi, Rita Casadio, Pierluigi Martelli, Ivana Matera, Isabella Ceccherini, Romana Fato, Giuseppe Raiola, Serena Arrigo, Sara Signa, Angela Rita Sementa, Mariasavina Severino, Pasquale Striano, Chiara Fiorillo, Tsuyoshi Goto, Shumpei Uchino, Yoshinobu Oyazato, Hisayoshi Nakamura, Sushil K Mishra, Yu-Sheng Yeh, Takema Kato, Kandai Nozu, Jantima Tanboon, Ichiro Morioka, Ichizo Nishino, Tatsushi Toda, Yu-Ichi Goto, Akira Ohtake, Kenjiro Kosaki, Yoshiki Yamaguchi, Ikuya Nonaka, Kazumoto Iijima, Masakazu Mimaki, Hiroki Kurahashi, Anja Raams, Alyson MacInnes, Mariel Alders, Marc Engelen, Gabor Linthorst, Tom de Koning, Wilfred den Dunnen, Gerard Dijkstra, Karin van Spaendonck, Dik C van Gent, Eleonora M Aronica, Paolo Picco, Valerio Carelli, Marco Seri, Nicholas Katsanis, Floor A M Duijkers, Mariko Taniguchi-Ikeda, Roberto De Giorgio.

  Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized by predominant gut dysmotility, encephalopathy, and neuromuscular abnormalities. Bonora et al. identify a new mitochondrial recessive disorder caused by biallelic variants in the LIG3 gene encoding DNA ligase III, which is responsible for mitochondrial DNA repair. Clinical signs include gut dysmotility and neurological features such as leucoencephalopathy, epilepsy and stroke-like episodes.

Keywords:   LIG3 ; CIPO; MNGIE; mtDNA repair; mtDNA replication

DOI:  https://doi.org/10.1093/brain/awab056
Cell Rep. 2021 Apr 13. pii: S2211-1247(21)00255-2. [Epub ahead of print]35(2): 108941

eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction.

YongTian Liang, Chengji Piao, Christine B Beuschel, David Toppe, Laxmikanth Kollipara, Boris Bogdanow, Marta Maglione, Janine Lützkendorf, Jason Chun Kit See, Sheng Huang, Tim O F Conrad, Ulrich Kintscher, Frank Madeo, Fan Liu, Albert Sickmann, Stephan J Sigrist.

  Mitochondrial function declines during brain aging and is suspected to play a key role in age-induced cognitive decline and neurodegeneration. Supplementing levels of spermidine, a body-endogenous metabolite, has been shown to promote mitochondrial respiration and delay aspects of brain aging. Spermidine serves as the amino-butyl group donor for the synthesis of hypusine (Nε-[4-amino-2-hydroxybutyl]-lysine) at a specific lysine residue of the eukaryotic translation initiation factor 5A (eIF5A). Here, we show that in the Drosophila brain, hypusinated eIF5A levels decline with age but can be boosted by dietary spermidine. Several genetic regimes of attenuating eIF5A hypusination all similarly affect brain mitochondrial respiration resembling age-typical mitochondrial decay and also provoke a premature aging of locomotion and memory formation in adult Drosophilae. eIF5A hypusination, conserved through all eukaryotes as an obviously critical effector of spermidine, might thus be an important diagnostic and therapeutic avenue in aspects of brain aging provoked by mitochondrial decline.

Keywords:  CG8005; brain aging; deoxyhypusine synthase; eIF5A; eIF5A hypusination; learning and memory; locomotion; longevity; mitochondrial respiration; spermidine

DOI:  https://doi.org/10.1016/j.celrep.2021.108941
Exp Neurol. 2021 Apr 08. pii: S0014-4886(21)00122-9. [Epub ahead of print] 113716

Characterization of nonmotor behavioral impairments and their neurochemical mechanisms in the MitoPark mouse model of progressive neurodegeneration in Parkinson's disease.

R Langley Monica, Ghaisas Shivani, Palanisamy Bharathi N Ay Muhammet, Jin Huajun, Anantharam Vellareddy, Kanthasamy Arthi, G Kanthasamy Anumantha.

  Mitochondrial dysfunction has been implicated as a key player in the pathogenesis of Parkinson's disease (PD). The MitoPark mouse, a transgenic mitochondrial impairment model developed by specific inactivation of TFAM in dopaminergic neurons, spontaneously exhibits progressive motor deficits and neurodegeneration, recapitulating several features of PD. Since nonmotor symptoms are now recognized as important features of the prodromal stage of PD, we comprehensively assessed the clinically relevant motor and nonmotor deficiencies from ages 8-24 wk. in both male and female MitoPark mice and their littermate controls. As expected, motor deficits in MitoPark mice began around 12-14 wk. and became severe by 16-24 wk. Interestingly, MitoPark mice exhibited olfactory deficits in the novel and social scent tests as early as 10-12 wk. as compared to age-matched littermate controls. Additionally, male MitoPark mice showed spatial memory deficits before female mice, beginning at 8 wk. and becoming most severe at 16 wk., as determined by the Morris water maze. MitoPark mice between 16 and 24 wk. spent more time immobile in forced swim and tail suspension tests, and made fewer entries into open arms of the elevated plus maze, indicating a depressive and anxiety-like phenotype, respectively. Importantly, depressive behavior as determined by immobility in forced swim test was reversible by antidepressant treatment with desipramine. Neurochemical and mechanistic studies revealed significant changes in CREB phosphorylation, BDNF, and catecholamine levels as well as neurogenesis in key brain regions. Collectively, our results indicate that MitoPark mice progressively exhibit deficits in olfactory discrimination, cognitive learning and memory, and anxiety- and depression-like behaviors as well as key neurochemical signaling associated with nonmotor deficits in PD. Thus, MitoPark mice can serve as an invaluable model for studying motor and nonmotor deficits in addition to studying the motor deficits related to pathology in PD.

Keywords:  Behavior; MitoPark; Nonmotor; Parkinson's disease

DOI:  https://doi.org/10.1016/j.expneurol.2021.113716
Genome Med. 2021 Apr 12. 13(1): 55

Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes.

Zheng Yie Yap, Yo Han Park, Saskia B Wortmann, Adam C Gunning, Shlomit Ezer, Sukyeong Lee, Lita Duraine, Ekkehard Wilichowski, Kate Wilson, Johannes A Mayr, Matias Wagner, Hong Li, Usha Kini, Emily Davis Black, Kristin G Monaghan, James R Lupski, Sian Ellard, Dominik S Westphal, Tamar Harel, Wan Hee Yoon.

   BACKGROUND: ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans.
METHODS: To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants.
RESULTS: We report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. The variants included four missense variants inherited in trans to loss-of-function alleles (p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val)), a homozygous missense variant p.(Arg327Pro), and a heterozygous non-frameshift indel p.(Lys568del). Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy. Drosophila studies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles leading to early developmental lethality. Further, we showed that Phe50Leu, Gly236Val, and Arg327Pro cause neurogenesis defects. On the contrary, Leu77Val and Arg170Trp are partial loss-of-function alleles that cause progressive locomotion defects and whose expression leads to an increase in autophagy and mitophagy in adult muscles.
CONCLUSION: Our findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation.

Keywords:  AAA+ protein; ATAD3A; Autophagy; Autosomal recessive; Disease; Drosophila; Mitochondria; Neurogenesis

DOI:  https://doi.org/10.1186/s13073-021-00873-3
Genes Dev. 2021 Apr 01. 35(7-8): 449-469

Interorganelle communication, aging, and neurodegeneration.

Maja Petkovic, Caitlin E O'Brien, Yuh Nung Jan.

  Our cells are comprised of billions of proteins, lipids, and other small molecules packed into their respective subcellular organelles, with the daunting task of maintaining cellular homeostasis over a lifetime. However, it is becoming increasingly evident that organelles do not act as autonomous discrete units but rather as interconnected hubs that engage in extensive communication through membrane contacts. In the last few years, our understanding of how these contacts coordinate organelle function has redefined our view of the cell. This review aims to present novel findings on the cellular interorganelle communication network and how its dysfunction may contribute to aging and neurodegeneration. The consequences of disturbed interorganellar communication are intimately linked with age-related pathologies. Given that both aging and neurodegenerative diseases are characterized by the concomitant failure of multiple cellular pathways, coordination of organelle communication and function could represent an emerging regulatory mechanism critical for long-term cellular homeostasis. We anticipate that defining the relationships between interorganelle communication, aging, and neurodegeneration will open new avenues for therapeutics.

Keywords:  aging; cellular homeostasis; communication; contact sites; endolysosomal pathway; interorganelle communication; lipid metabolism; mitochondria; neurodegeneration

DOI:  https://doi.org/10.1101/gad.346759.120
Adv Exp Med Biol. 2021 ;1256 237-264

Mitochondria: The Retina's Achilles' Heel in AMD.

Deborah A Ferrington, M Cristina Kenney, Shari R Atilano, James B Hurley, Emily E Brown, John D Ash.

  Strong experimental evidence from studies in human donor retinas and animal models supports the idea that the retinal pathology associated with age-related macular degeneration (AMD) involves mitochondrial dysfunction and consequent altered retinal metabolism. This chapter provides a brief overview of mitochondrial structure and function, summarizes evidence for mitochondrial defects in AMD, and highlights the potential ramifications of these defects on retinal health and function. Discussion of mitochondrial haplogroups and their association with AMD brings to light how mitochondrial genetics can influence disease outcome. As one of the most metabolically active tissues in the human body, there is strong evidence that disruption in key metabolic pathways contributes to AMD pathology. The section on retinal metabolism reviews cell-specific metabolic differences and how the metabolic interdependence of each retinal cell type creates a unique ecosystem that is disrupted in the diseased retina. The final discussion includes strategies for therapeutic interventions that target key mitochondrial pathways as a treatment for AMD.

Keywords:  Age-related macular degeneration; Ecosystem model; Metabolism; Mitochondria; Proteomics; mtDNA

DOI:  https://doi.org/10.1007/978-3-030-66014-7_10
Geroscience. 2021 Apr 17.

An energetics perspective on geroscience: mitochondrial protonmotive force and aging.

Brandon J Berry, Matt Kaeberlein.

  Mitochondria are organelles that provide energy to cells through ATP production. Mitochondrial dysfunction has long been postulated to mediate cellular declines that drive biological aging. Many well-characterized hallmarks of aging may involve underlying energetic defects that stem from loss of mitochondrial function with age. Why and how mitochondrial function declines with age is an open question and one that has been difficult to answer. Mitochondria are powered by an electrochemical gradient across the inner mitochondrial membrane known as the protonmotive force (PMF). This gradient decreases with age in several experimental models. However, it is unclear if a diminished PMF is a cause or a consequence of aging. Herein, we briefly review and define mitochondrial function, we summarize how PMF changes with age in several models, and we highlight recent studies that implicate PMF in aging biology. We also identify barriers that must be addressed for the field to progress. Emerging technology permits more precise in vivo study of mitochondria that will allow better understanding of cause and effect in metabolic models of aging. Once cause and effect can be discerned more precisely, energetics approaches to combat aging may be developed to prevent or reverse functional decline.

Keywords:  AMPK; Autophagy; Membrane potential; Metabolism; mTOR

DOI:  https://doi.org/10.1007/s11357-021-00365-7
Autophagy. 2021 Apr 05. 1-3

Comment on "mt-Keima detects PINK1-PRKN mitophagy in vivo with greater sensitivity than mito-QC".

Ian G Ganley, Alexander J Whitworth, Thomas G McWilliams.

DOI: https://doi.org/10.1080/15548627.2021.1907269
Brain. 2021 Apr 12. pii: awab147. [Epub ahead of print]

Classification of neurological diseases using multi-dimensional cerebrospinal fluid analysis.

Catharina C Gross, Andreas Schulte-Mecklenbeck, Lohith Madireddy, Marc Pawlitzki, Christine Strippel, Saskia Räuber, Julia Krämer, Leoni Rolfes, Tobias Ruck, Carolin Beuker, Antje Schmidt-Pogoda, Lisa Lohmann, Tilman Schneider-Hohendorf, Tim Hahn, Nicholas Schwab, Jens Minnerup, Nico Melzer, Luisa Klotz, Sven G Meuth, Gerd Meyer Zu Hörste, Sergio E Baranzini, Heinz Wiendl.

  Although cerebrospinal fluid (CSF) analysis routinely enables diagnosis of neurological diseases, it is mainly used for gross distinction between infectious, autoimmune inflammatory, and degenerative central nervous system (CNS) disorders. To investigate, whether a multi-dimensional cellular blood and CSF characterization can support the diagnosis of clinically similar neurological diseases, we analyzed 546 patients with autoimmune neuro-inflammatory, degenerative, or vascular conditions in a cross-sectional retrospective study. By combining feature selection with dimensionality reduction and machine learning approaches we identified pan-disease parameters altered across all autoimmune neuro-inflammatory CNS-diseases and differentiating them from other neurological conditions and inter-autoimmunity classifiers sub-differentiating variants of CNS-directed autoimmunity. Pan-disease as well as diseases-specific changes formed a continuum, reflecting clinical disease evolution. A validation cohort of 231 independent patients confirmed that combining multiple parameters into composite scores can assist classification of neurological patients. Overall, we show that an integrated analysis of blood and CSF parameters improves differential diagnosis of neurological diseases, thereby facilitating early treatment decisions.

Keywords:  CNS autoimmunity; CSF; differential diagnosis; immune profile; multiple sclerosis

DOI:  https://doi.org/10.1093/brain/awab147
Front Cell Dev Biol. 2021 ;9 626117

Mitochondrial OMA1 and OPA1 as Gatekeepers of Organellar Structure/Function and Cellular Stress Response.

Robert Gilkerson, Patrick De La Torre, Shaynah St Vallier.

  Mammalian mitochondria are emerging as a critical stress-responsive contributor to cellular life/death and developmental outcomes. Maintained as an organellar network distributed throughout the cell, mitochondria respond to cellular stimuli and stresses through highly sensitive structural dynamics, particularly in energetically demanding cell settings such as cardiac and muscle tissues. Fusion allows individual mitochondria to form an interconnected reticular network, while fission divides the network into a collection of vesicular organelles. Crucially, optic atrophy-1 (OPA1) directly links mitochondrial structure and bioenergetic function: when the transmembrane potential across the inner membrane (ΔΨm) is intact, long L-OPA1 isoforms carry out fusion of the mitochondrial inner membrane. When ΔΨm is lost, L-OPA1 is cleaved to short, fusion-inactive S-OPA1 isoforms by the stress-sensitive OMA1 metalloprotease, causing the mitochondrial network to collapse to a fragmented population of organelles. This proteolytic mechanism provides sensitive regulation of organellar structure/function but also engages directly with apoptotic factors as a major mechanism of mitochondrial participation in cellular stress response. Furthermore, emerging evidence suggests that this proteolytic mechanism may have critical importance for cell developmental programs, particularly in cardiac, neuronal, and stem cell settings. OMA1's role as a key mitochondrial stress-sensitive protease motivates exciting new questions regarding its mechanistic regulation and interactions, as well as its broader importance through involvement in apoptotic, stress response, and developmental pathways.

Keywords:  OMA1; OPA1; apoptosis; development; mitochondria

DOI:  https://doi.org/10.3389/fcell.2021.626117
J Mol Med (Berl). 2021 Apr 12.

Nrf2 as a potential target for Parkinson's disease therapy.

Yingcai Niu, Jing Zhang, Miaoxian Dong.

  Parkinson's disease (PD) is a complex neurodegenerative disorder featuring both motor and nonmotor symptoms associated with a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Conventionally, PD treatment options have focused on dopamine replacement and provide only symptomatic relief. However, disease-modifying therapies are still unavailable. Mechanistically, genetic and environmental factors can produce oxidative stress which has been implicated as a core contributor to the initiation and progression of PD through the degeneration of dopaminergic neurons. Importantly, nuclear factor erythroid 2-related factor 2 (Nrf2) is essential for maintaining redox homeostasis by binding to the antioxidant response element which exists in the promoter regions of most genes coding for antioxidant enzymes. Furthermore, protein kinase C, mitogen-activated protein kinases, and phosphotidylinositol 3-kinase have been implicated in the regulation of Nrf2 activity during PD. Here, we review the evidence supporting the regulation of Nrf2 through Keap1-dependent and Keap1-independent mechanisms. We also address that targeting Nrf2 may provide a therapeutic option to mitigate oxidative stress-associated PD. Finally, we discuss currently known classes of small molecule activators of Nrf2, including Nrf2-activating compounds in PD.

Keywords:  Antioxidants; Keap1; Nrf2; Oxidative stress; Parkinson’s disease

DOI:  https://doi.org/10.1007/s00109-021-02071-5
Int J Mol Med. 2021 Jun;pii: 98. [Epub ahead of print]47(6):

Mechanisms of microRNA‑142 in mitochondrial autophagy and hippocampal damage in a rat model of epilepsy.

Du Xiao, Jingdan Lv, Zhigang Zheng, Yi Liu, Yonggen Zhang, Cuizhu Luo, Liu Qi, Bing Qin, Chao Liu.

Researchers have confirmed the microRNA (miRNA/miR)‑epilepsy association in rodent models of human epilepsy via a comprehensive database. However, the mechanisms of miR‑142 in epilepsy have not been extensively studied. In the present study, a rat model of epilepsy was first established by an injection of lithium chloride‑pilocarpine and the successful establishment of the model was verified via electroencephalogram monitoring. The levels of miR‑142, phosphatase and tensin homolog deleted on chromosome 10 (PTEN)‑induced putative kinase 1 (PINK1), marker proteins of mitochondrial autophagy, and apoptosis‑related proteins were measured. Additionally, the pathological changes in the hippocampus, the ultrastructure of the mitochondria, and degeneration and the apoptosis of neurons were observed using different staining methods. The malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in the hippocampus, mitochondrial membrane potential (MTP) and reactive oxygen species (ROS) generation were detected. Furthermore, the targeting association between miR‑142 and PINK1 was predicted and verified. Consequently, apoptosis increased, and mitochondrial autophagy decreased, in the hippocampus of epileptic rats. Following miR‑142 inhibition, the epileptic rats exhibited an increased Bax expression, a decreased Bcl‑2 expression, upregulated marker protein levels of mitochondrial autophagy, a reduced MDA content, an enhanced SOD activity, an increased MTP and decreased ROS generation. PINK1 is a target gene of miR‑142, and its overexpression protected against hippocampal damage. Taken together, the results of the present study demonstrated that miR‑142 inhibition promotes mitochondrial autophagy and reduces hippocampal damage in epileptic rats by targeting PINK1. These findings may provide useful information for the treatment of epilepsy.

DOI: https://doi.org/10.3892/ijmm.2021.4931
Biochem J. 2021 Apr 12. pii: BCJ20200975. [Epub ahead of print]

Depletion of mitochondrial inorganic polyphosphate (polyP) in mammalian cells causes metabolic shift from oxidative phosphorylation to glycolysis.

Maria E Solesio, Lihan Xie, Brendan McIntyre, Mathew Ellenberger, Erna Mitaishvili, Siddharth Bhadra-Lobo, Lisa F Bettcher, Jason N Bazil, Daniel Raftery, Ursula Jakob, Evgeny V Pavlov.

  Inorganic polyphosphate (polyP) is a linear polymer composed of up to a few hundred orthophosphates linked together by high-energy phosphoanhydride bonds, identical to those found in ATP. In mammalian mitochondria, polyP has been implicated in multiple processes, including energy metabolism, ion channels function, and the regulation of calcium signaling. However, the specific mechanisms of all these effects of polyP within the organelle remain poorly understood. The central goal of this study was to investigate how mitochondrial polyP participates in the regulation of the mammalian cellular energy metabolism. To accomplish this, we created HEK293 cells depleted of mitochondrial polyP, through the stable expression of the polyP hydrolyzing enzyme (scPPX). We found that these cells have significantly reduced rates of oxidative phosphorylation (OXPHOS), while their rates of glycolysis were elevated. Consistent with this, metabolomics assays confirmed increased levels of metabolites involved in glycolysis in these cells, compared with the wild-type samples. At the same time, key respiratory parameters of the isolated mitochondria were unchanged, suggesting that respiratory chain activity is not affected by the lack of mitochondrial polyP. However, we detected that mitochondria from cells that lack mitochondrial polyP are more fragmented when compared with those from wild-type cells. Based on these results, we propose that mitochondrial polyP plays an important role as a regulator of the metabolic switch between OXPHOS and glycolysis.

Keywords:  glycolysis; inorganic polyphosphates; mitochondrial bioenergetics; oxidative phosphorylation; polyP

DOI:  https://doi.org/10.1042/BCJ20200975
ACS Chem Neurosci. 2021 Apr 12.

LncRNA MEG3 Alleviates Diabetic Cognitive Impairments by Reducing Mitochondrial-Derived Apoptosis through Promotion of FUNDC1-Related Mitophagy via Rac1-ROS Axis.

Zhihua Wang, Pingping Xia, Jie Hu, Yan Huang, Fan Zhang, Longyan Li, E Wang, Qulian Guo, Zhi Ye.

  Mitochondrial dysfunction and elevated ROS generation are predominant contributors of neuronal death that is responsible for the diabetes-related cognitive impairments. Emerging evidence has demonstrated that long noncoding RNA-MEG3 can serve as an important regulator in the pathogenesis of diabetes. However, the underlying mechanisms remain to be further clarified. Here, it was observed that MEG3 was significantly down-regulated in STZ (streptozotocin)-induced diabetic rats. MEG3 overexpression noticeably improved diabetes-induced cognitive dysfunctions, accompanied by the abatement of Rac1 activation and ROS production, as well as the inhibition of mitochondria-associated apoptosis. Furthermore, either MEG3 overexpression or Rac1 inhibition promoted FUNDC1 dephosphorylation and suppressed oxidative stress and neuro-inflammation. Similarly, in vitro studies confirmed that hyperglycemia also down-regulated MEG3 expression in PC12 cells. MEG3 reintroduction protected PC12 cells against hyperglycemia-triggered neurotoxicity by improving mitochondrial fitness and repressing mitochondria-mediated apoptosis. Moreover, these neuroprotective effects of MEG3 relied on FUNDC1-related mitophagy, since silencing of FUNDC1 abolished these beneficial outcomes. Additionally, MEG3 rescued HG-induced neurotoxicity was involved in inhibiting Rac1 expression via interaction with Rac1 3'UTR. Conversely, knockdown of MEG3 showed opposite effects. NSC23766, a specific inhibitor of Rac1, fully abolished harmful effects of MEG3 depletion. Consistently, knockdown of Rac1 potentiated FUNDC1-associated mitophagy. Meanwhile, colocalization of Rac1 and FUNDC1 was found in mitochondria under hyperglycemia, which was interrupted by MEG3 overexpression. Furthermore, silencing of Rac1 promoted PGAM5 expression, and FUNDC1 strongly interacted with LC3 in Rac1-deleted cells. Altogether, our findings suggested that the Rac1/ROS axis may be a downstream signaling pathway for MEG3-induced neuroprotection, which was involved in FUNDC1-associated mitophagy.

Keywords:  FUNDC1; MEG3; Rac1; cognitive dysfunctions; diabetes; mitophagy

DOI:  https://doi.org/10.1021/acschemneuro.0c00682
Biochim Biophys Acta Bioenerg. 2021 Apr 13. pii: S0005-2728(21)00064-5. [Epub ahead of print] 148431

Mitochondrial DNA mutations contribute to high altitude pulmonary edema via increased oxidative stress and metabolic reprogramming during hypobaric hypoxia.

Swati Sharma, Yamini Singh, Rajat Sandhir, Sayar Singh, Lilly Ganju, Bhuvnesh Kumar, Rajeev Varshney.

  High altitude pulmonary edema (HAPE) is experienced by non-acclimatized sea level individuals on exposure to high altitude hypoxic conditions. Available evidence suggests that genetic factors and perturbed mitochondrial redox status may play an important role in HAPE pathophysiology. However, the precise mechanism has not been fully understood. In the present study, sequencing of mitochondrial DNA (mtDNA) from HAPE subjects and acclimatized controls was performed to identify pathogenic mutations and to determine their role in HAPE. Hypobaric hypoxia induced oxidative stress and metabolic alterations were also assessed in HAPE subjects. mtDNA copy number, mitochondrial oxidative phosphorylation (mtOXPHOS) activity, mitochondrial biogenesis were measured to determine mitochondrial functions. The data revealed that the mutations in Complex I genes affects the secondary structure of protein in HAPE subjects. Further, increased oxidative stress during hypobaric hypoxia, reduced mitochondrial biogenesis and mtOXPHOS activity induced metabolic reprogramming that might contribute to mitochondrial dysfunctions in HAPE individuals. Haplogroup analysis suggests that mtDNA haplogroup H2a2a1 has potential contribution in the pathobiology of HAPE in lowlanders. This study suggests contribution of altered mitochondrial functions in HAPE susceptibility.

Keywords:  HAPE; Hypobaric hypoxia; Mitochondria; Oxidative phosphorylation; Oxidative stress; mtDNA

DOI:  https://doi.org/10.1016/j.bbabio.2021.148431
J Cell Biol. 2021 Jun 07. pii: e202006043. [Epub ahead of print]220(6):

Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination.

Yumiko Oshima, Etienne Cartier, Liron Boyman, Nicolas Verhoeven, Brian M Polster, Weiliang Huang, Maureen Kane, W Jonathan Lederer, Mariusz Karbowski.

Here, we report that acute reduction in mitochondrial translation fidelity (MTF) causes ubiquitination of the inner mitochondrial membrane (IMM) proteins, including TRAP1 and CPOX, which occurs selectively in mitochondria with a severed outer mitochondrial membrane (OMM). Ubiquitinated IMM recruits the autophagy machinery. Inhibiting autophagy leads to increased accumulation of mitochondria with severed OMM and ubiquitinated IMM. This process occurs downstream of the accumulation of cytochrome c/CPOX in a subset of mitochondria heterogeneously distributed throughout the cell ("mosaic distribution"). Formation of mosaic mitochondria, OMM severing, and IMM ubiquitination require active mitochondrial translation and mitochondrial fission, but not the proapoptotic proteins Bax and Bak. In contrast, in Parkin-overexpressing cells, MTF reduction does not lead to the severing of the OMM or IMM ubiquitination, but it does induce Drp1-independent ubiquitination of the OMM. Furthermore, high-cytochrome c/CPOX mitochondria are preferentially targeted by Parkin, indicating that in the context of reduced MTF, they are mitophagy intermediates regardless of Parkin expression. In sum, Parkin-deficient cells adapt to mitochondrial proteotoxicity through a Drp1-mediated mechanism that involves the severing of the OMM and autophagy targeting ubiquitinated IMM proteins.

DOI: https://doi.org/10.1083/jcb.202006043
Neurol Clin Pract. 2021 Apr;11(2): 97-104

Neuromuscular Junction Abnormalities in Mitochondrial Disease: An Observational Cohort Study.

Luis P Braz, Yi Shiau Ng, Gráinne S Gorman, Andrew M Schaefer, Robert McFarland, Robert W Taylor, Doug M Turnbull, Roger G Whittaker.

Objective: To determine the prevalence of neuromuscular junction (NMJ) abnormalities in patients with mitochondrial disease.
Methods: Eighty patients with genetically proven mitochondrial disease were recruited from a national center for mitochondrial disease in the United Kingdom. Participants underwent detailed clinical and neurophysiologic testing including single-fiber electromyography.
Results: The overall prevalence of neuromuscular transmission defects was 25.6%. The highest prevalence was in patients with pathogenic dominant RRM2B variants (50%), but abnormalities were found in a wide range of mitochondrial genotypes. The presence of NMJ abnormalities was strongly associated with coexistent myopathy, but not with neuropathy. Furthermore, 15% of patients with NMJ abnormality had no evidence of either myopathy or neuropathy.
Conclusions: NMJ transmission defects are common in mitochondrial disease. In some patients, NMJ dysfunction occurs in the absence of obvious pre- or post-synaptic pathology, suggesting that the NMJ may be specifically affected.

DOI: https://doi.org/10.1212/CPJ.0000000000000795
Nat Commun. 2021 Apr 16. 12(1): 2304

Mitochondrial hydrogen peroxide positively regulates neuropeptide secretion during diet-induced activation of the oxidative stress response.

Qi Jia, Derek Sieburth.

Mitochondria play a pivotal role in the generation of signals coupling metabolism with neurotransmitter release, but a role for mitochondrial-produced ROS in regulating neurosecretion has not been described. Here we show that endogenously produced hydrogen peroxide originating from axonal mitochondria (mtH2O2) functions as a signaling cue to selectively regulate the secretion of a FMRFamide-related neuropeptide (FLP-1) from a pair of interneurons (AIY) in C. elegans. We show that pharmacological or genetic manipulations that increase mtH2O2 levels lead to increased FLP-1 secretion that is dependent upon ROS dismutation, mitochondrial calcium influx, and cysteine sulfenylation of the calcium-independent PKC family member PKC-1. mtH2O2-induced FLP-1 secretion activates the oxidative stress response transcription factor SKN-1/Nrf2 in distal tissues and protects animals from ROS-mediated toxicity. mtH2O2 levels in AIY neurons, FLP-1 secretion and SKN-1 activity are rapidly and reversibly regulated by exposing animals to different bacterial food sources. These results reveal a previously unreported role for mtH2O2 in linking diet-induced changes in mitochondrial homeostasis with neuropeptide secretion.

DOI: https://doi.org/10.1038/s41467-021-22561-x
Neurosurgery. 2021 Apr 16. pii: nyab105. [Epub ahead of print]

Dual Regeneration of Muscle and Nerve by Intramuscular Infusion of Mitochondria in a Nerve Crush Injury Model.

Meei-Ling Sheu, Chiung-Chyi Shen, Hsi-Kai Tsou, Meng Yin Yang, Hong-Lin Su, Jason Sheehan, Ming-Hong Chang, Hong-Shiu Chen, Hung-Chuan Pan.

   BACKGROUND: Peripheral nerve injuries result in muscle denervation and apoptosis of the involved muscle, which subsequently reduces mitochondrial content and causes muscle atrophy. The local injection of mitochondria has been suggested as a useful tool for restoring the function of injured nerves or the brain.
OBJECTIVE: To determine outcomes following the administration of isolated mitochondria into denervated muscle after nerve injury that have not been investigated.
METHODS: Muscle denervation was conducted in a sciatic nerve crushed by a vessel clamp and the denervated gastrocnemius muscle was subjected to 195 μg hamster green fluorescent protein (GFP)-mitochondria intramuscular infusion for 10 min.
RESULTS: The mitochondria were homogeneously distributed throughout the denervated muscle after intramuscular infusion. The increases in caspase 3, 8-oxo-dG, Bad, Bax, and ratio of Bax/Bcl-2 levels in the denervated muscle were attenuated by mitochondrial infusion, and the downregulation of Bcl-2 expression was prevented by mitochondrial infusion. In addition, the decrease in the expression of desmin and the acetylcholine receptor was counteracted by mitochondrial infusion; this effect paralleled the amount of distributed mitochondria. The restoration of the morphology of injured muscles and nerves was augmented by the local infusion of mitochondria. Mitochondrial infusion also led to improvements in sciatic functional indexes, compound muscle action potential amplitudes, and conduction latencies as well as the parameters of CatWalk (Noldus) gait analysis.
CONCLUSION: The local infusion of mitochondria can successfully prevent denervated muscle atrophy and augment nerve regeneration by reducing oxidative stress in denervated muscle.

Keywords:  Denervated muscle; Mitochondria transplantation; Nerve crush injury

DOI:  https://doi.org/10.1093/neuros/nyab105