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Interaction of α‑Synuclein with ATP Synthase: Switching Role from Physiological to Pathological Timir Tripathi*,† and Krishnananda Chattopadhyay*,‡ †
ACS Chem. Neurosci. Downloaded from pubs.acs.org by 185.89.101.117 on 08/23/18. For personal use only.
Molecular and Structural Biophysics Laboratory, Department of Biochemistry, North-Eastern Hill University, Shillong 793022, India ‡ CSIR-Indian Institute of Chemical Biology, 4, Raja SC Mallick Rd, Poddar Nagar, Jadavpur, Kolkata, West Bengal 700032, India ABSTRACT: The most abundantly present protein found in Lewy bodies, which is the pathological hallmark of Parkinson’s disease, is α-synuclein. Native monomeric α-synuclein is localized within mitochondria, interacts with ATP synthase subunit, and enhances ATP synthase efficiency and mitochondrial function. Recently, an advanced study shows that the interaction of αsynuclein oligomer with ATP synthase switches its role from physiological to pathological, which leads to mitochondrial dysfunction. KEYWORDS: ATP synthase, α-synuclein, monomer, oligomer, permeability transition pore physiology, and dynamic fluorescent imaging to distinguish between the functional mechanisms of interaction of oligomeric α-synuclein with that of monomeric species. It is observed that the oligomeric α-synuclein induces mitochondrial dysfunction in whole cells. In addition, conformationspecific filament antibody is used, raised against aggregated αsynuclein, to confirm that the oligomers interact with the mitochondrial ATP synthase. The results of super-resolution microscopy and proximity ligation assay have demonstrated colocalization of aggregated α-synuclein and the ATP synthase of rodent and human neurons. Since α-synuclein oligomers are strong inducers of cellular reactive oxygen species (ROS), they have tested whether aggregates of α-synuclein are naturally redox-active. It is found that the oligomers generate ROS as an intrinsic property and are able to oxidize the inner mitochondrial lipid membrane. As ROS can mediate direct oxidation of proteins, redox proteomics is used to investigate the oxidative posttranslational modifications (PTMs) of the ATP synthase in mitochondrial fractions treated either with monomers or oligomers. These results have shown significant oligomer-dependent oxidative PTMs of methionine residues in the β-subunit of ATP synthase. Then, they have studied the effect of α-synuclein on isolated mitochondria and it was seen that within isolated mitochondria, the α-synuclein oligomers induce PTP opening as a direct effect of interaction of αsynuclein oligomers. The oxidation events increase the PTP opening, causing mitochondrial swelling, and eventually cell death. Thus, the α-synuclein oligomer-induced toxicity is dependent on PTP opening. Significantly, the inhibition of oligomer-induced oxidation stops the pathological induction of PTP. Neurons, derived from inducible pluripotent stem cells bearing SNCA triplication are found to generate α-synuclein aggregates, which interact with the ATP synthase and induce PTP opening, leading to neuronal death.
he presence of fibrillar aggregates called Lewy bodies, formed by the deposition of an intrinsically disordered protein α-synuclein,1 is believed to be the histological hallmark of Parkinson’s disease (PD). Mitochondrial dysfunction is considered another important process of PD pathogenicity, although how these two processes (protein aggregation and mitochondrial dysfunction) modulate each other is not apprehended. The physiological function of α-synuclein is also not known. New insights into these unsolved issues are provided by a collaborative study between scientists at the UCL Institute of Neurology and the Francis Crick Institue, UK and other institutions in their recent analyses. It is a recognized aspect that α-synuclein can bind the inner mitochondrial membrane, suggesting that it has a possible physiological role in mitochondrial metabolism.2,3 By using biochemical experiments, in concomitance with live-cell imaging and mitochondrial respiration analysis, Ludtmann et al., in 2016,4 showed that the monomeric α-synuclein interacts with ATP synthase subunit and improves its function, which implies that it is involved in mitochondrial metabolism. In general, they suggested that monomeric α-synuclein directly interacts with the α-subunit of ATP synthase and positively regulates ATP synthase activity, thereby regulating mitochondrial respiration and bioenergetics. A recent study by the same group demonstrates that an antagonistic effect is ensued by the interaction of oligomeric αsynuclein with ATP synthase.5 The β-sheet-rich α-synuclein oligomers interact with ATP synthase and induce mitochondrial dysfunction in PD. Following their interaction, oligomeric α-synuclein impairs respiration and induces oxidation of the βsubunit of ATP synthase and stimulates mitochondrial lipid peroxidation. These oxidation events open the mitochondrial permeability transition pore (PTP) leading to neuronal death. Thus, a meeting point between α-synuclein aggregation and neuronal mitochondrial dysfunction in PD is represented by the mitochondrial PTP. The authors have used an array of methods including biophysical techniques, super-resolution microscopy, electro-
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© XXXX American Chemical Society
Received: August 7, 2018 Accepted: August 7, 2018
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DOI: 10.1021/acschemneuro.8b00407 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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Figure 1. Schematic representation of oligomeric α-synuclein effects on mitochondria. Monomeric α-synuclein interacts with ATP synthase and helps in improving the efficiency of ATP synthesis. Oligomeric α-synuclein also interacts with ATP synthase but in contrast impairs respiration and depolarizes the mitochondria. ROS production is induced by oligomers, which leads to lipid peroxidation and oxidation of important mitochondrial proteins. Simultaneously, these oligomer-induced events led to the opening of the mitochondrial PTP. IMM, Inner mitochondrial membrane; Δψm, mitochondrial membrane potential; PTP, Permeability transition pore.
The authors hypothesize that the monomeric α-synuclein interacts with the ATP synthase and enhances its efficiency under normal disease-free conditions. As the disease progresses, the monomeric α-synuclein aggregates, and this process generates oligomers with high β-sheet structures. These oligomers are in close proximity to the proteins of the inner mitochondrial membrane, and bind to the α-subunit of ATP synthase, thereby inhibiting the function of complex I. In addition, oxidative stress induced by the oligomers cause oxidative modifications of interacting proteins, and lipids. Under this oxidative condition, the α-synuclein aggregates generate a collection of bioenergetically compromised mitochondria, eventually leading to opening of the mitochondrial PTP (Figure 1). Since it has long been debated whether the aggregation is a cause of the oxidative stress in PD or if it is merely a byproduct of the latter. Further momentum was added to this controversy by the recent failures of several clinical trials of aggregation inhibiting molecules. Although these studies provide supports that α-synuclein aggregation is a crucial event in the pathogenesis of PD, the exact nature of the toxic aggregate remains unclear. The determination of high resolution structure of α-synuclein oligomers would provide understanding of their binding to ATP synthase, which may be essential to answer why the α-synuclein oligomer specifically opens the PTP, whereas the monomer cannot.
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Funding
T.T. and K.C. are supported by a joint Twinning Project Grant from the Department of Biotechnology, Government of India, India [Grant No. MED/2017/50]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to Parismita Kalita (NEHU) for generating the figure. REFERENCES
(1) Bonini, N. M., and Giasson, B. I. (2005) Snaring the function of alpha-synuclein. Cell 123 (3), 359−61. (2) Guardia-Laguarta, C., Area-Gomez, E., Rub, C., Liu, Y., Magrane, J., Becker, D., Voos, W., Schon, E. A., and Przedborski, S. (2014) alpha-Synuclein is localized to mitochondria-associated ER membranes. J. Neurosci. 34 (1), 249−59. (3) Robotta, M., Gerding, H. R., Vogel, A., Hauser, K., Schildknecht, S., Karreman, C., Leist, M., Subramaniam, V., and Drescher, M. (2014) Alpha-synuclein binds to the inner membrane of mitochondria in an alpha-helical conformation. ChemBioChem 15 (17), 2499−502. (4) Ludtmann, M. H., Angelova, P. R., Ninkina, N. N., Gandhi, S., Buchman, V. L., and Abramov, A. Y. (2016) Monomeric AlphaSynuclein Exerts a Physiological Role on Brain ATP Synthase. J. Neurosci. 36 (41), 10510−10521. (5) Ludtmann, M. H. R., Angelova, P. R., Horrocks, M. H., Choi, M. L., Rodrigues, M., Baev, A. Y., Berezhnov, A. V., Yao, Z., Little, D., Banushi, B., Al-Menhali, A. S., Ranasinghe, R. T., Whiten, D. R., Yapom, R., Dolt, K. S., Devine, M. J., Gissen, P., Kunath, T., Jaganjac, M., Pavlov, E. V., Klenerman, D., Abramov, A. Y., and Gandhi, S. (2018) alpha-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease. Nat. Commun. 9 (1), 2293.
AUTHOR INFORMATION
ORCID
Timir Tripathi: 0000-0001-5559-289X Krishnananda Chattopadhyay: 0000-0002-1449-8909 B
DOI: 10.1021/acschemneuro.8b00407 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
