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Mitochondria-targeted peptide prevents mitochondrial depolarization and apoptosis induced by tert-butyl hydroperoxide in neuronal cell lines
Abstract
Oxidative stress and mitochondrial oxidative damage have been implicated in aging and many common diseases. Mitochondria are a primary source of reactive oxygen species (ROS) in the cell, and are particularly susceptible to oxidative damage. Oxidative damage to mitochondria results in mitochondrial permeability transition (MPT), mitochondrial depolarization, further ROS production, swelling, and release of cytochrome c (cyt c). Cytosolic cyt c triggers apoptosis by activating the caspase cascade. In the present work, we examined the ability of a novel cell-penetrating, mitochondria-targeted peptide antioxidant in protecting against oxidant-induced mitochondrial dysfunction and apoptosis in two neuronal cell lines. Treatment with tert-butyl hydroperoxide (tBHP) for 24 h resulted in lipid peroxidation and significant cell death via apoptosis in both N2A and SH-SY5Y cells, with phosphatidylserine translocation, nuclear condensation and increased caspase activity. Cells treated with tBHP showed significant increase in intracellular ROS, mitochondrial depolarization and reduced mitochondrial viability. Concurrent treatment with <1 nM SS-31 (D-Arg-Dmt-Lys-Phe-NH2; Dmt = 2',6'-dimethyltyrosine) significantly decreased intracellular ROS, increased mitochondrial potential, and prevented tBHP-induced apoptosis. The remarkable potency of SS-31 can be explained by its extensive cellular uptake and selective partitioning into mitochondria. Intracellular concentrations of [3H]SS-31 were 6-fold higher than extracellular concentrations. Studies using isolated mitochondria revealed that [3H]SS-31 was concentrated approximately 5000-fold in the mitochondrial pellet. By concentrating in the inner mitochondrial membrane, SS-31 is localized to the site of ROS production, and can therefore protect against mitochondrial oxidative damage and further ROS production. SS-31 represents a novel platform of mitochondria-targeted antioxidants with broad therapeutic potential.
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“SS-31 protects neuronal cells against tert-butyl-hydroperoxide (tBHP) induced mitochondrial depolarization and apoptotic cell death by reducing intracellular ROS, decreasing markers of apoptotic cell death and caspase activity177.”
From Mitochondrial Approaches for Neuroprotection (2008) · cites this paper as [177]
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Metadata
- Authors
- Zhao, K., Luo, G., Giannelli, S., & Szeto, H. H.
- Affiliations
- Cornell University (US)
- Corresponding author
- Szeto, Hazel H.
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2005-12
- Volume
- 70
- Issue
- 12
- Pages
- 1796-1806
- ISSN
- 0006-2952 (ISSN-L)
- OpenAlex
- W2032478715
- Cited by
- 251
- References
- 49
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 16 · 2023: 19 · 2022: 13 · 2021: 15 · 2020: 9 · 2019: 13 · 2018: 11 · 2017: 9 · 2016: 12 · 2015: 14 · 2014: 16 · 2013: 19 · 2012: 7
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (DA08924, P01DA008924)
- National Institute of Neurological Disorders and Stroke (R21NS048295, NS-48295)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- mitochondria-targeted peptide, SS-31, tert-butyl hydroperoxide, oxidative stress, mitochondrial depolarization, apoptosis, reactive oxygen species, mitochondrial permeability transition, cytochrome c release, lipid peroxidation, neuronal cell lines, N2a cells, SH-SY5Y cells, caspase activation, mitochondrial membrane potential
- MeSH terms
- Mitochondrial Permeability Transition Pore, Antioxidants, Cell Line, Humans, Ion Channels, Mitochondria, Neurons, Oligopeptides, Lipid Peroxidation, Apoptosis, Reactive Oxygen Species, tert-Butylhydroperoxide, Caspases, Mitochondrial Membrane Transport Proteins, Caspase 9
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