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Abstract

Evidence suggests a striking causal relationship between changes in quality control of neuronal mitochondria and numerous devastating human neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Contrary to replicating mammalian cells with a metabolism essentially glycolytic, post-mitotic neurons are distinctive owing to (i) their exclusive energetic dependence from mitochondrial metabolism and (ii) their polarized shape, which entails compartmentalized and distinct energetic needs. Here, we review the recent findings on mitochondrial dynamics and mitophagy in differentiated neurons focusing on how the exceptional characteristics of neuronal populations in their morphology and bioenergetics needs make them quite different to other cells in controlling the intracellular turnover of these organelles.

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Nix is a selective autophagy receptor for mitochondrial clearance.

Ivana Novak, Vladimir Kirkin, David G McEwan … (2010)

Autophagy is the cellular homeostatic pathway that delivers large cytosolic materials for degradation in the lysosome. Recent evidence indicates that autophagy mediates selective removal of protein aggregates, organelles and microbes in cells. Yet, the specificity in targeting a particular substrate to the autophagy pathway remains poorly understood. Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins, ubiquitin-like modifiers that are required for the growth of autophagosomal membranes. In cultured cells, Nix recruits GABARAP-L1 to damaged mitochondria through its amino-terminal LC3-interacting region. Furthermore, ablation of the Nix:LC3/GABARAP interaction retards mitochondrial clearance in maturing murine reticulocytes. Thus, Nix functions as an autophagy receptor, which mediates mitochondrial clearance after mitochondrial damage and during erythrocyte differentiation.

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Impaired balance of mitochondrial fission and fusion in Alzheimer's disease.

Xinglong Wang, Bo Su, Hyoung-gon Lee … (2009)

Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) neurons. In this study, we explored the involvement of an abnormal mitochondrial dynamics by investigating the changes in the expression of mitochondrial fission and fusion proteins in AD brain and the potential cause and consequence of these changes in neuronal cells. We found that mitochondria were redistributed away from axons in the pyramidal neurons of AD brain. Immunoblot analysis revealed that levels of DLP1 (also referred to as Drp1), OPA1, Mfn1, and Mfn2 were significantly reduced whereas levels of Fis1 were significantly increased in AD. Despite their differential effects on mitochondrial morphology, manipulations of these mitochondrial fission and fusion proteins in neuronal cells to mimic their expressional changes in AD caused a similar abnormal mitochondrial distribution pattern, such that mitochondrial density was reduced in the cell periphery of M17 cells or neuronal process of primary neurons and correlated with reduced spine density in the neurite. Interestingly, oligomeric amyloid-beta-derived diffusible ligands (ADDLs) caused mitochondrial fragmentation and reduced mitochondrial density in neuronal processes. More importantly, ADDL-induced synaptic change (i.e., loss of dendritic spine and postsynaptic density protein 95 puncta) correlated with abnormal mitochondrial distribution. DLP1 overexpression, likely through repopulation of neuronal processes with mitochondria, prevented ADDL-induced synaptic loss, suggesting that abnormal mitochondrial dynamics plays an important role in ADDL-induced synaptic abnormalities. Based on these findings, we suggest that an altered balance in mitochondrial fission and fusion is likely an important mechanism leading to mitochondrial and neuronal dysfunction in AD brain.

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PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65

Chandana Kondapalli, Agne Kazlauskaite, Ning Zhang … (2012)

Summary Missense mutations in PTEN-induced kinase 1 (PINK1) cause autosomal-recessive inherited Parkinson's disease (PD). We have exploited our recent discovery that recombinant insect PINK1 is catalytically active to test whether PINK1 directly phosphorylates 15 proteins encoded by PD-associated genes as well as proteins reported to bind PINK1. We have discovered that insect PINK1 efficiently phosphorylates only one of these proteins, namely the E3 ligase Parkin. We have mapped the phosphorylation site to a highly conserved residue within the Ubl domain of Parkin at Ser65. We show that human PINK1 is specifically activated by mitochondrial membrane potential (Δψm) depolarization, enabling it to phosphorylate Parkin at Ser65. We further show that phosphorylation of Parkin at Ser65 leads to marked activation of its E3 ligase activity that is prevented by mutation of Ser65 or inactivation of PINK1. We provide evidence that once activated, PINK1 autophosphorylates at several residues, including Thr257, which is accompanied by an electrophoretic mobility band-shift. These results provide the first evidence that PINK1 is activated following Δψm depolarization and suggest that PINK1 directly phosphorylates and activates Parkin. Our findings indicate that monitoring phosphorylation of Parkin at Ser65 and/or PINK1 at Thr257 represent the first biomarkers for examining activity of the PINK1-Parkin signalling pathway in vivo. Our findings also suggest that small molecule activators of Parkin that mimic the effect of PINK1 phosphorylation may confer therapeutic benefit for PD.

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Journal

Journal ID (nlm-ta): Front Aging Neurosci

Journal ID (iso-abbrev): Front Aging Neurosci

Journal ID (publisher-id): Front. Aging Neurosci.

Title: Frontiers in Aging Neuroscience

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-4365

Publication date (Electronic): 18 February 2014

Publication date Collection: 2014

Volume: 6

Electronic Location Identifier: 18

Affiliations

[1] ¹Institute of Translational Pharmacology – National Research Council Rome, Italy

[2] ²European Brain Research Institute Rome, Italy

[3] ³Institute of Biomembrane and Bioenergetics – National Research Council Bari, Italy

[4] ⁴Clinical Department of Medical, Surgical and Health Science, University of Trieste Trieste, Italy

[5] ⁵Department of Medicine and Surgery, University of Salerno Baronissi, Italy

Author notes

Edited by: Antonio Camins, University of Barcelona, Spain

Reviewed by: Daniel Ortuño-Sahagun, Centro Universitario de Ciencias Biológicas y Agropecuarias, Mexico; Nibaldo C. Inestrosa, Pontifical Catholic University of Chile, Chile; Alberto Lazarowski, University of Buenos Aires, Argentina

*Correspondence: Giuseppina Amadoro, Institute of Translational Pharmacology – National Research Council, Via Fosso del Cavaliere 100, 00133 Rome, Italy e-mail: g.amadoro@ 123456inmm.cnr.it

^† Giuseppina Amadoro, Veronica Corsetti, and Fulvio Florenzano have contributed equally to this work.

This article was submitted to the journal Frontiers in Aging Neuroscience.

Article

DOI: 10.3389/fnagi.2014.00018

PMC ID: 3927396

PubMed ID: 24600391

SO-VID: a6c44f3d-1371-4d0d-97e3-e904cb769b4e

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 23 October 2013

Date accepted : 27 January 2014

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Figures: 4, Tables: 1, Equations: 0, References: 216, Pages: 18, Words: 0

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Morphological and bioenergetic demands underlying the mitophagy in post-mitotic neurons: the pink–parkin pathway

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Most cited references 140

Nix is a selective autophagy receptor for mitochondrial clearance.

Impaired balance of mitochondrial fission and fusion in Alzheimer's disease.

PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65

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