bims-midbra 2022-01-16 papers

bims-midbra

Biomed News

on Mitochondrial dynamics in brain cells

Issue of 2022–01–16
nine papers selected by
Ana Paula Mendonça, University of Padova

Broad activation of the Parkin pathway induces synaptic mitochondrial deficits in early tauopathy.
Mitochondrial repair as potential pharmacological target in cerebral ischemia.
Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons.
Accumulation of APP-CTF induces mitophagy dysfunction in the iNSCs model of Alzheimer's disease.
Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia.
Studies on Regulation of Global Protein Profile and Cellular Bioenergetics of Differentiating SH-SY5Y Cells.
Bicalutamide Exhibits Potential to Damage Kidney via Destroying Complex I and Affecting Mitochondrial Dynamics.
Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease.
Covering the Role of PGC-1α in the Nervous System.

Brain. 2022 Jan 12. pii: awab243. [Epub ahead of print]

Broad activation of the Parkin pathway induces synaptic mitochondrial deficits in early tauopathy.

Yu Young Jeong, Sinsuk Han, Nuo Jia, Mingyang Zhang, Preethi Sheshadri, Prasad Tammineni, Jasmine Cheung, Marialaina Nissenbaum, Sindhuja S Baskar, Kelvin Kwan, David J Margolis, Peng Jiang, Alexander Kusnecov, Qian Cai.

  Mitochondrial defects are a hallmark of early pathophysiology in Alzheimer's disease, with pathologically phosphorylated tau reported to induce mitochondrial toxicity. Mitophagy constitutes a key pathway in mitochondrial quality control by which damaged mitochondria are targeted for autophagy. However, few details are known regarding the intersection of mitophagy and pathologies in tauopathy. Here, by applying biochemical and cell biological approaches including time-lapse confocal imaging in live tauopathy neurons, combined with gene rescue experiments via stereotactic injections of adeno-associated virus particles into tauopathy mouse brains, electrophysiological recordings and behavioural tests, we demonstrate for the first time that mitochondrial distribution deficits at presynaptic terminals are an early pathological feature in tauopathy brains. Furthermore, Parkin-mediated mitophagy is extensively activated in tauopathy neurons, which accelerates mitochondrial Rho GTPase 1 (Miro1) turnover and consequently halts Miro1-mediated mitochondrial anterograde movement towards synaptic terminals. As a result, mitochondrial supply at tauopathy synapses is disrupted, impairing synaptic function. Strikingly, increasing Miro1 levels restores the synaptic mitochondrial population by enhancing mitochondrial anterograde movement and thus reverses tauopathy-associated synaptic failure. In tauopathy mouse brains, overexpression of Miro1 markedly elevates synaptic distribution of mitochondria and protects against synaptic damage and neurodegeneration, thereby counteracting impairments in learning and memory as well as synaptic plasticity. Taken together, our study reveals that activation of the Parkin pathway triggers an unexpected effect-depletion of mitochondria from synaptic terminals, a characteristic feature of early tauopathy. We further provide new mechanistic insights into how parkin activation-enhanced Miro1 degradation and impaired mitochondrial anterograde transport drive tauopathy-linked synaptic pathogenesis and establish a foundation for future investigations into new therapeutic strategies to prevent synaptic deterioration in Alzheimer's disease and other tauopathies.

Keywords:  Alzheimer’s disease; Parkin-mediated mitophagy; mitochondrial anterograde transport; synaptic mitochondrial deficits; tauopathy

DOI:  https://doi.org/10.1093/brain/awab243
Mitochondrion. 2022 Jan 06. pii: S1567-7249(22)00001-0. [Epub ahead of print]63 23-31

Mitochondrial repair as potential pharmacological target in cerebral ischemia.

Ms Mandeep Kaur, Dr Saurabh Sharma.

  Cerebral ischemia and its consequences like transient ischemic attack, aneurysm and stroke are the common and devastating conditions which remain the leading cause of mortality after coronary heart disease in developed countries and are the greatest cause of disability, leaving 50% of survivors permanently disabled. Despite recognition of risk factors and mechanisms involved in the pathology of the disease, treatment of ischemic disorders is limited to thrombolytic drugs like recombinant tissue plasminogen activator (rt-PA) and clinical rendition of the neuroprotective agents have not been so successful. Recent studies evidenced the role of mitochondrial dysfunction in neuronal damage that occurred after cerebral ischemia. This review article will focus on the various fundamental mechanisms responsible for neuronal damage because of mitochondrial dysfunction including cell signaling pathways, autophagy, apoptosis/necrosis, generation of reactive oxygen species, calcium overload, the opening of membrane permeability transition pore (mPTP), mitochondrial dynamics and biogenesis. Recent studies have concerned the significant role of mitochondrial biogenesis in mitochondrial repair and transfer of healthy mitochondria from astrocytes to the damaged neurons, providing neuroprotection and neural recovery following ischemia. Novel and influential studies have evidenced the significant role of mitochondria transfer and mitochondrial transplantation in reviving cell energy and in replacement of impaired or dysfunctional mitochondria with healthy mitochondria after ischemic episode. This review article will focus on recent advances in mitochondrial interventions and exogenous therapeutic modalities like mitochondria transfer technique, employment of stem cells, mitochondrial transplantation, miRNA inhibition and mitochondrial-targeted Sirtuin1 activator for designing novel and promising treatment for cerebral ischemia induced pathological states.

Keywords:  Cerebral ischemia; Mitochondrial transfer; Mitochondrial transplantation; Mitochondrial dysfunction; Mitophagy; Reactive oxygen species; miRNA inhibition

DOI:  https://doi.org/10.1016/j.mito.2022.01.001
Brain. 2022 Jan 13. pii: awab488. [Epub ahead of print]

Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons.

Zhenyu Chen, Eric Chai, Yongchao Mou, Ricardo H Roda, Craig Blackstone, Xue-Jun Li.

  Hereditary spastic paraplegias (HSPs) are characterized by lower limb spasticity resulting from degeneration of long corticospinal axons. SPG11 is one of the most common autosomal recessive HSPs, and the SPG11 protein spatacsin forms a complex with the SPG15 protein spastizin and heterotetrameric AP5 adaptor protein complex, which includes the SPG48 protein AP5Z1. Using the integration-free episomal method, we established SPG11 patient-specific induced pluripotent stem cells (iPSCs) from patient fibroblasts. We differentiated SPG11 iPSCs, as well as SPG48 iPSCs previously established, into cortical projection neurons (PNs) and examined protective effects by targeting mitochondrial dynamics using P110, a peptide that selectively inhibits mitochondrial fission GTPase Drp1. P110 treatment mitigates mitochondrial fragmentation, improves mitochondrial motility, and restores mitochondrial health and ATP levels in SPG11 and SPG48 neurons. Neurofilament (NF) aggregations are increased in SPG11 and SPG48 axons, and these are also suppressed by P110. Similarly, P110 mitigates NF disruption in both SPG11 and SPG48 knockdown cortical PNs, confirming the contribution of HSP gene deficiency to subsequent NF and mitochondrial defects. Strikingly, NF aggregations in SPG11 and SPG48 deficient neurons double stain with ubiquitin and autophagy related proteins, resembling the pathological hallmark observed in SPG11 autopsy brain sections. To confirm the cause-effect relationship between the SPG11 mutations and disease phenotypes, we knocked-in SPG11 disease mutations to human embryonic stem cells (hESCs) and differentiated these stem cells into cortical PNs. Reduced ATP levels and accumulated NF aggregations along axons are observed, and both are mitigated by P110. Furthermore, rescue experiment with expression of wildtype SPG11 in cortical PNs derived from both SPG11 patient iPSCs and SPG11 disease mutation knock-in hESCs leads to rescue of mitochondrial dysfunction and NF aggregations in these SPG11 neurons. Finally, in SPG11 and SPG48 long-term cultures, increased release of phosphoNF-H, a biomarker for nerve degeneration, is significantly reduced by inhibiting mitochondrial fission pharmacologically using P110 and genetically using Drp1 shRNA. Taken together, our results demonstrate that impaired mitochondrial dynamics underlie both cytoskeletal disorganization and axonal degeneration in SPG11 and SPG48 neurons, highlighting the importance of targeting these pathologies therapeutically.

Keywords:  axonal degeneration; cortical projection neuron; cytoskeletal organization; hereditary spastic paraplegias; mitochondrial dynamics

DOI:  https://doi.org/10.1093/brain/awab488
Cell Death Discov. 2022 Jan 10. 8(1): 1

Accumulation of APP-CTF induces mitophagy dysfunction in the iNSCs model of Alzheimer's disease.

Seung-Eun Lee, Daekee Kwon, Nari Shin, Dasom Kong, Nam Gyo Kim, Hee-Yeong Kim, Min-Ji Kim, Soon Won Choi, Kyung-Sun Kang.

Mitochondrial dysfunction is associated with familial Alzheimer's disease (fAD), and the accumulation of damaged mitochondria has been reported as an initial symptom that further contributes to disease progression. In the amyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by β-secretase to generate a C-terminal fragment, which is then cleaved by γ-secretase to produce amyloid-beta (Aβ). The accumulation of Aβ and its detrimental effect on mitochondrial function are well known, yet the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) contributing to this pathology have rarely been reported. We demonstrated the effects of APP-CTFs-related pathology using induced neural stem cells (iNSCs) from AD patient-derived fibroblasts. APP-CTFs accumulation was demonstrated to mainly occur within mitochondrial domains and to be both a cause and a consequence of mitochondrial dysfunction. APP-CTFs accumulation also resulted in mitophagy failure, as validated by increased LC3-II and p62 and inconsistent PTEN-induced kinase 1 (PINK1)/E3 ubiquitin ligase (Parkin) recruitment to mitochondria and failed fusion of mitochondria and lysosomes. The accumulation of APP-CTFs and the causality of impaired mitophagy function were also verified in AD patient-iNSCs. Furthermore, we confirmed this pathological loop in presenilin knockout iNSCs (PSEN KO-iNSCs) because APP-CTFs accumulation is due to γ-secretase blockage and similarly occurs in presenilin-deficient cells. In the present work, we report that the contribution of APP-CTFs accumulation is associated with mitochondrial dysfunction and mitophagy failure in AD patient-iNSCs as well as PSEN KO-iNSCs.

DOI: https://doi.org/10.1038/s41420-021-00796-3
Aging Cell. 2022 Jan 13. e13549

Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia.

Patricia Gomez-Suaga, Gábor M Mórotz, Andrea Markovinovic, Sandra M Martín-Guerrero, Elisavet Preza, Natalia Arias, Keith Mayl, Afra Aabdien, Vesela Gesheva, Agnes Nishimura, Ambra Annibali, Younbok Lee, Jacqueline C Mitchell, Selina Wray, Christopher Shaw, Wendy Noble, Christopher C J Miller.

  Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mechanisms by which the expansions cause disease are not properly understood but a favoured route involves its translation into dipeptide repeat (DPR) polypeptides, some of which are neurotoxic. However, the precise targets for mutant C9orf72 and DPR toxicity are not fully clear, and damage to several neuronal functions has been described. Many of these functions are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. ER-mitochondria signalling requires close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 'tethering' proteins. Here, we show that ER-mitochondria signalling and the VAPB-PTPIP51 tethers are disrupted in neurons derived from induced pluripotent stem (iPS) cells from patients carrying ALS/FTD pathogenic C9orf72 expansions and in affected neurons in mutant C9orf72 transgenic mice. In these mice, disruption of the VAPB-PTPIP51 tethers occurs prior to disease onset suggesting that it contributes to the pathogenic process. We also show that neurotoxic DPRs disrupt the VAPB-PTPIP51 interaction and ER-mitochondria contacts and that this may involve activation of glycogen synthase kinases-3β (GSK3β), a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that these DPRs disrupt delivery of Ca2+ from ER stores to mitochondria, which is a primary function of the VAPB-PTPIP51 tethers. This delivery regulates a number of key neuronal functions that are damaged in ALS/FTD including bioenergetics, autophagy and synaptic function. Our findings reveal a new molecular target for mutant C9orf72-mediated toxicity.

Keywords:   C9orf72 ; GSK3β; PTPIP51; VAPB; amyotrophic lateral sclerosis; endoplasmic reticulum; frontotemporal dementia; mitochondria

DOI:  https://doi.org/10.1111/acel.13549
Mol Neurobiol. 2022 Jan 13.

Studies on Regulation of Global Protein Profile and Cellular Bioenergetics of Differentiating SH-SY5Y Cells.

Anuj Pandey, Sana Sarkar, Sanjeev Kumar Yadav, Smriti Singh Yadav, Saripella Srikrishna, Mohammad Haris Siddiqui, Devendra Parmar, Sanjay Yadav.

  The SH-SY5Y cells differentiated by sequential exposure of retinoic acid (RA) and brain-derived neurotrophic growth factor (BDNF) are a well-employed cellular model for studying the mechanistic aspects of neural development and neurodegeneration. Earlier studies from our lab have identified dramatic upregulation (77 miRNAs) and downregulation (17 miRNAs) of miRNAs in SH-SY5Y cells differentiated with successive exposure of RA + BDNF and demonstrated the essential role of increased levels of P53 proteins in coping with the differentiation-induced changes in protein levels. In continuation to our earlier studies, we have performed unbiased LC-MS/MS global protein profiling of naïve and differentiated SH-SY5Y cells and analyzed the identified proteins in reference to miRNAs identified in our earlier studies to identify the cellular events regulated by both identified miRNAs and proteins. Analysis of LC-MS/MS data has shown a significant increase and decrease in levels of 215 and 163 proteins, respectively, in differentiated SH-SY5Y cells. Integrative analysis of miRNA identified in our previous studies and protein identified in the present study is carried out to discover novel miRNA-protein regulatory modules to elucidate miRNA-protein regulatory relationships of differentiating neurons. In silico network analysis of miRNAs and proteins deregulated upon SH-SY5Y differentiation identified cell cycle, synapse formation, axonogenesis, differentiation, neuron projection, and neurotransmission, as the topmost involved pathways. Further, measuring mitochondrial dynamics and cellular bioenergetics using qPCR and Seahorse XFp Flux Analyzer, respectively, showed that differentiated cells possess increased mitochondrial dynamics and OCR relative to undifferentiated cells. In summary, our studies have identified a novel set of proteins deregulated during neuronal differentiation and establish the role of miRNAs identified in earlier studies in the regulation of proteins identified by LC-MS/MS-based global profiling of differentiating neurons, which will help in future studies related to neural development and neurodegeneration.

Keywords:  Differentiation; Mitochondrial bioenergetics; Mitochondrial dynamics; Proteomics; microRNA

DOI:  https://doi.org/10.1007/s12035-021-02667-5
J Clin Med. 2021 Dec 27. pii: 135. [Epub ahead of print]11(1):

Bicalutamide Exhibits Potential to Damage Kidney via Destroying Complex I and Affecting Mitochondrial Dynamics.

Kuan-Chou Chen, Chang-Rong Chen, Chang-Yu Chen, Chiung-Chi Peng, Robert Y Peng.

  Bicalutamide (Bic) is an androgen deprivation therapy (ADT) for treating prostate cancer, while ADT is potentially associated with acute kidney injury. Previously, we recognized Bic induced renal mitochondria dysfunction in vitro and in vivo via the ROS -HIF1α pathway. Whether OXPHOS complex, as well as mitochondrial dynamics, can be influenced by Bic via modulation of peroxisome proliferator-activated receptor coactivator 1α (PGC1α), NADPH oxidase 4 (Nox4), mitofusins 1/2 (MFN 1/2), optic atrophy 1 (OPA1), and sirtuins (SIRTs) has not been documented. Renal mesangial cell line was treated with Bic (30~60 μM) for the indicated time. SIRTs, complex I, mitochondrial dynamics- and oxidative stress-related proteins were analyzed. Bic dose-dependently reduced mitochondrial potential, but dose- and time-dependently suppressed translocase of the outer mitochondrial membrane member 20 (Tomm 20), complex I activity. Nox4 and glutathione lead to decreased NAD+/NADH ratio, with upregulated superoxide dismutase 2. SIRT1 was initially stimulated and then suppressed, while SIRT3 was time- and dose-dependently downregulated. PGC1α, MFN2, and OPA1 were all upregulated, with MFN1 and pro-fission dynamin-related protein I downregulated. Bic exhibits potential to damage mitochondria via destroying complex I, complex I activity, and mitochondrial dynamics. Long-term treatment with Bic should be carefully followed up.

Keywords:  NADPH oxidase 4 (Nox4); PGC1α; bicalutamide; complex I NDUFB8; glutathione (GSH); mitofusins 1/2 (MFN 1/2); optic atrophy 1 (OPA1); sirtuins (SIRTs)1/3; superoxide dismutase 2 (SOD2)

DOI:  https://doi.org/10.3390/jcm11010135
Hum Mol Genet. 2022 Jan 13. pii: ddac002. [Epub ahead of print]

Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease.

Florian A Schober, Jia Xin Tang, Kate Sergeant, Marco F Moedas, Charlotte M Zierz, David Moore, Conrad Smith, David Lewis, Nishan Guha, Sila Hopton, Gavin Falkous, Amanda Lam, Angela Pyle, Joanna Poulton, Gráinne S Gorman, Robert W Taylor, Christoph Freyer, Anna Wredenberg.

The SLC25A26 gene encodes a mitochondrial inner membrane carrier that transports S-adenosylmethionine (SAM) into the mitochondrial matrix in exchange for S-adenosylhomocysteine (SAH). SAM is the predominant methyl-group donor for most cellular methylation processes, of which SAH is produced as a by-product. Pathogenic, bi-allelic SLC25A26 variants are a recognised cause of mitochondrial disease in children, with a severe neonatal-onset caused by decreased SAM transport activity. Here, we describe two, unrelated adult cases, one of whom presented with recurrent episodes of severe abdominal pain and metabolic decompensation with lactic acidosis. Both patients had exercise intolerance and mitochondrial myopathy associated with bi-allelic variants in SLC25A26 which led to marked respiratory chain deficiencies and mitochondrial histopathological abnormalities in skeletal muscle that are comparable to those previously described in early-onset cases. We demonstrate using both mouse and fruit fly models that impairment of SAH, rather than SAM, transport across the mitochondrial membrane is likely the cause of this milder, late-onset phenotype. Our findings associate a novel pathomechanism with a known disease-causing protein and highlight the quests of precision medicine in optimising diagnosis, therapeutic intervention, and prognosis.

DOI: https://doi.org/10.1093/hmg/ddac002
Cells. 2021 Dec 30. pii: 111. [Epub ahead of print]11(1):

Covering the Role of PGC-1α in the Nervous System.

Zuzanna Kuczynska, Erkan Metin, Michal Liput, Leonora Buzanska.

  The peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a well-known transcriptional coactivator involved in mitochondrial biogenesis. PGC-1α is implicated in the pathophysiology of many neurodegenerative disorders; therefore, a deep understanding of its functioning in the nervous system may lead to the development of new therapeutic strategies. The central nervous system (CNS)-specific isoforms of PGC-1α have been recently identified, and many functions of PGC-1α are assigned to the particular cell types of the central nervous system. In the mice CNS, deficiency of PGC-1α disturbed viability and functioning of interneurons and dopaminergic neurons, followed by alterations in inhibitory signaling and behavioral dysfunction. Furthermore, in the ALS rodent model, PGC-1α protects upper motoneurons from neurodegeneration. PGC-1α is engaged in the generation of neuromuscular junctions by lower motoneurons, protection of photoreceptors, and reduction in oxidative stress in sensory neurons. Furthermore, in the glial cells, PGC-1α is essential for the maturation and proliferation of astrocytes, myelination by oligodendrocytes, and mitophagy and autophagy of microglia. PGC-1α is also necessary for synaptogenesis in the developing brain and the generation and maintenance of synapses in postnatal life. This review provides an outlook of recent studies on the role of PGC-1α in various cells in the central nervous system.

Keywords:  PGC-1α; central nervous system; mitochondrial biogenesis

DOI:  https://doi.org/10.3390/cells11010111