Regulation of ER-mitochondria contacts by Parkin via Mfn2 DOI Creative Commons

Valentina Basso,

Elena Marchesan, Caterina Peggion

et al.

Pharmacological Research, Journal Year: 2018, Volume and Issue: 138, P. 43 - 56

Published: Sept. 13, 2018

Parkin, an E3 ubiquitin ligase and a Parkinson's disease (PD) related gene, translocates to impaired mitochondria drives their elimination via autophagy, process known as mitophagy. Mitochondrial pro-fusion protein Mitofusins (Mfn1 Mfn2) were found be target for Parkin mediated ubiquitination. Mfns are transmembrane GTPase embedded in the outer membrane of mitochondria, which required on adjacent mediate fusion. In mammals, Mfn2 also forms complexes that capable tethering endoplasmic reticulum (ER), structural feature essential mitochondrial energy metabolism, calcium (Ca2+) transfer between organelles Ca2+ dependent cell death. Despite its fundamental physiological role, molecular mechanisms control ER-mitochondria cross talk obscure. Ubiquitination has recently emerged powerful tool modulate function, regulation subcellular localization ability interact with other proteins. is reversible mechanism, can actively controlled by opposing ubiquitination-deubiquitination events. this work we deficient cells parkin mutant human fibroblasts, tether ER decreased. We identified site ubiquitination showed non-ubiquitinatable fails restore physical functional interaction. Finally, took advantage established vivo model PD demonstrate manipulation expressing synthetic linker sufficient rescue locomotor deficit associated Drosophila PD.

Language: Английский

13 reasons why the brain is susceptible to oxidative stress DOI Creative Commons
James N. Cobley,

Maria Luisa Fiorello,

Damian M. Bailey

et al.

Redox Biology, Journal Year: 2018, Volume and Issue: 15, P. 490 - 503

Published: Feb. 3, 2018

The human brain consumes 20% of the total basal oxygen (O2) budget to support ATP intensive neuronal activity. Without sufficient O2 demands, activity fails, such that, even transient ischemia is neurodegenerative. While essentiality function clear, how oxidative stress causes neurodegeneration ambiguous. Ambiguity exists because many reasons why susceptible remain obscure. Many are erroneously understood as deleterious result adventitious derived free radical and non-radical species generation. To understand underpin stress, one must first re-cast in a positive light their deliberate generation enables achieve critical functions (e.g. synaptic plasticity) through redox signalling (i.e. functionality). Using radicals derivatives signal sensitises when goes awry negative advance mechanistic understanding, we rationalise 13 stress. Key include inter alia unsaturated lipid enrichment, mitochondria, calcium, glutamate, modest antioxidant defence, active transition metals neurotransmitter auto-oxidation. We review RNA oxidation an underappreciated cause complex interplay between each reason dictates susceptibility dynamic context neural identity dependent manner. Our discourse sets stage for investigators interrogate biochemical basis health disease.

Language: Английский

Citations

956
Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances DOI Creative Commons
Wenzhang Wang, Fanpeng Zhao,

Xiaopin Ma

et al.

Molecular Neurodegeneration, Journal Year: 2020, Volume and Issue: 15(1)

Published: May 29, 2020

Abstract Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by impaired cognitive function due to progressive loss neurons in brain. Under microscope, neuronal accumulation abnormal tau proteins and amyloid plaques are two pathological hallmarks affected brain regions. Although detailed mechanism pathogenesis AD still elusive, a large body evidence suggests that damaged mitochondria likely play fundamental roles AD. It believed healthy pool not only supports activity providing enough energy supply other related mitochondrial functions neurons, but also guards minimizing oxidative damage. In this regard, exploration multitude mechanisms altered constitutes novel promising therapeutic targets for disease. review, we will summarize recent progress underscores essential role dysfunction discuss underlying with focus on structural functional integrity including biogenesis dynamics, axonal transport, ER-mitochondria interaction, mitophagy proteostasis.

Language: Английский

Citations

895
Mitochondrial and endoplasmic reticulum calcium homeostasis and cell death DOI
Saverio Marchi, Simone Patergnani, Sonia Missiroli

et al.

Cell Calcium, Journal Year: 2017, Volume and Issue: 69, P. 62 - 72

Published: May 5, 2017

Language: Английский

Citations

576
Mitochondria at the neuronal presynapse in health and disease DOI
Michael J. Devine, Josef T. Kittler

Nature reviews. Neuroscience, Journal Year: 2018, Volume and Issue: 19(2), P. 63 - 80

Published: Jan. 19, 2018

Language: Английский

Citations

516
Endoplasmic Reticulum–Mitochondrial Contactology: Structure and Signaling Functions DOI
György Csordás, David Weaver, György Hajnóczky

et al.

Trends in Cell Biology, Journal Year: 2018, Volume and Issue: 28(7), P. 523 - 540

Published: March 24, 2018

Language: Английский

Citations

504
The role of mitochondria in amyotrophic lateral sclerosis DOI Creative Commons

Emma F. Smith,

Pamela J. Shaw, Kurt J. De Vos

et al.

Neuroscience Letters, Journal Year: 2017, Volume and Issue: 710, P. 132933 - 132933

Published: June 30, 2017

Mitochondria are unique organelles that essential for a variety of cellular processes including energy metabolism, calcium homeostasis, lipid biosynthesis, and apoptosis. Mitochondrial dysfunction is prevalent feature many neurodegenerative diseases motor neuron disorders such as amyotrophic lateral sclerosis (ALS). Disruption mitochondrial structure, dynamics, bioenergetics buffering has been extensively reported in ALS patients model systems suggested to be directly involved disease pathogenesis. Here we review the alterations parameters examine common pathways dysfunction.

Language: Английский

Citations

476
Oxidative stress and cellular pathologies in Parkinson’s disease DOI Creative Commons

Lesly Puspita,

Sun Young Chung, Jaewon Shim

et al.

Molecular Brain, Journal Year: 2017, Volume and Issue: 10(1)

Published: Nov. 28, 2017

Parkinson's disease (PD) is a chronic and progressive neurodegeneration of dopamine neurons in the substantia nigra. The reason for death these unclear; however, studies have demonstrated potential involvement mitochondria, endoplasmic reticulum, α-synuclein or levels contributing to cellular oxidative stress as well PD symptoms. Even though those papers had separately described individual roles each element leading neurodegeneration, recent publications suggest that product various interactions. This review discusses role mediating separate pathological events together, ultimately result cell PD. Understanding multi-faceted relationships between events, with common denominator underlying processes, needed developing better therapeutic strategies.

Language: Английский

Citations

415
ER-mitochondria tethering by PDZD8 regulates Ca 2+ dynamics in mammalian neurons DOI Open Access
Yusuke Hirabayashi, Seok‐Kyu Kwon, Hunki Paek

et al.

Science, Journal Year: 2017, Volume and Issue: 358(6363), P. 623 - 630

Published: Nov. 2, 2017

Making the right contacts Contacts between endoplasmic reticulum (ER) and mitochondria mediate key physiological processes such as Ca 2+ exchange lipid biogenesis. wiIn yeast, ER are tethered by a complex of four proteins called ERMES. However, no functional orthologs these ERMES have been identified in metazoans. Hirabayashi et al. PDZD8 structural ortholog yeast protein MMM1 (see Perspective Lombardi Elrod). was found at ER-mitochondria contact sites required for tethering mammalian cells. In neuronal dendrites, regulated synaptically evoked dynamics, which underscores importance interorganelle membrane cell physiology. Science , this issue p. 623 ; see also 591

Language: Английский

Citations

404
Proteomic mapping of cytosol-facing outer mitochondrial and ER membranes in living human cells by proximity biotinylation DOI Creative Commons

Victoria Hung,

Stephanie S Lam,

Namrata D. Udeshi

et al.

eLife, Journal Year: 2017, Volume and Issue: 6

Published: April 25, 2017

The cytosol-facing membranes of cellular organelles contain proteins that enable signal transduction, regulation morphology and trafficking, protein import export, other specialized processes. Discovery these by traditional biochemical fractionation can be plagued with contaminants loss key components. Using peroxidase-mediated proximity biotinylation, we captured identified endogenous on the outer mitochondrial membrane (OMM) endoplasmic reticulum (ERM) living human fibroblasts. proteomes 137 634 proteins, respectively, are highly specific highlight 94 potentially novel or ER proteins. Dataset intersection candidates localized to mitochondria-ER contact sites. We found one candidate, tail-anchored, PDZ-domain-containing OMM SYNJ2BP, dramatically increases contacts rough when overexpressed. Immunoprecipitation-mass spectrometry ribosome-binding 1 (RRBP1) as SYNJ2BP's ERM binding partner. Our results power biotinylation yield insights into molecular composition function intracellular membranes.

Language: Английский

Citations

357
The ER-Mitochondria Tethering Complex VAPB-PTPIP51 Regulates Autophagy DOI Creative Commons
Patricia Gómez‐Suaga, Sébastien Paillusson,

Radu Stoica

et al.

Current Biology, Journal Year: 2017, Volume and Issue: 27(3), P. 371 - 385

Published: Jan. 26, 2017

Mitochondria form close physical associations with the endoplasmic reticulum (ER) that regulate a number of physiological functions. One mechanism by which regions ER are recruited to mitochondria involves binding protein VAPB mitochondrial PTPIP51, act as scaffolds tether two organelles. Here, we show VAPB-PTPIP51 tethers autophagy. We demonstrate overexpression or PTPIP51 tighten ER-mitochondria contacts impairs, whereas small interfering RNA (siRNA)-mediated loss loosen stimulates, autophagosome formation. Moreover, expression synthetic linker artificially and also reduces formation, this artificial rescues effects siRNA on Thus, these manipulation autophagy consequence their tethering function. Interestingly, discovered tightening impairs rapamycin- torin 1-induced, but not starvation-induced, This suggests regulation signaling is at least partly dependent upon nature autophagic stimulus. Finally, role in mediating delivery Ca2+ from stores. our findings reveal new molecular for regulating

Language: Английский

Citations

339