Cell-permeable, mitochondrial-targeted, peptide antioxidants
Open accessAbstract
Cellular oxidative injury has been implicated in aging and a wide array of clinical disorders including ischemia-reperfusion injury; neurodegenerative diseases; diabetes; inflammatory diseases such as atherosclerosis, arthritis, and hepatitis; and drug-induced toxicity. However, available antioxidants have not proven to be particularly effective against many of these disorders. A possibility is that some of the antioxidants do not reach the relevant sites of free radical generation, especially if mitochondria are the primary source of reactive oxygen species (ROS). The SS (Szeto-Schiller) peptide antioxidants represent a novel approach with targeted delivery of antioxidants to the inner mitochondrial membrane. The structural motif of these SS peptides centers on alternating aromatic residues and basic amino acids (aromatic-cationic peptides). These SS peptides can scavenge hydrogen peroxide and peroxynitrite and inhibit lipid peroxidation. Their antioxidant action can be attributed to the tyrosine or dimethyltyrosine residue. By reducing mitochondrial ROS, these peptides inhibit mitochondrial permeability transition and cytochrome c release, thus preventing oxidant-induced cell death. Because these peptides concentrate >1000-fold in the inner mitochondrial membrane, they prevent oxidative cell death with EC50 in the nM range. Preclinical studies support their potential use for ischemia-reperfusion injury and neurodegenerative disorders. Although peptides have often been considered to be poor drug candidates, these small peptides have excellent "druggable" properties, making them promising agents for many diseases with unmet needs.
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Activation of AMP kinase can lead to mitochondrial biogenesis and increased mitochondrial number, and this pathway can also be stimulated by mitochondrial hydrogen peroxide-dependent activation of Akt.
“Although activation of AMP kinase can lead to mitochondrial biogenesis and increased mitochondrial number, this pathway can also directly be stimulated by mitochondrial hydrogen peroxide-dependent activation of the MAP kinase Akt (911, 919).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [919]
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- Authors
- Szeto, H. H.
- Affiliations
- Cornell University (US)
- Corresponding author
- Szeto, Hazel H.
- ORCID
- Szeto, Hazel H.
- Venue
- The AAPS Journal
- Published
- 2006-06
- Volume
- 8
- Issue
- 2
- Pages
- E277-E283
- ISSN
- 1550-7416 (ISSN-L)
- PMC
- PMC3231562
- OpenAlex
- W1997308718
- Cited by
- 316
- References
- 33
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 10 · 2023: 16 · 2022: 18 · 2021: 31 · 2020: 20 · 2019: 12 · 2018: 23 · 2017: 13 · 2016: 18 · 2015: 20 · 2014: 21 · 2013: 19 · 2012: 11
- FWCI
- 0.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- The AAPS Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (DA08924, P01 DA 08924, P01DA008924)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Physical Sciences › Chemistry › Organic Chemistry › Free Radicals and Antioxidants
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- mitochondria-targeted antioxidants, reactive oxygen species, oxidative cell death, mitochondrial permeability transition, cytochrome c release, hydrogen peroxide scavenging, peroxynitrite scavenging, lipid peroxidation inhibition, ischemia-reperfusion injury, neurodegenerative diseases, aging, drug toxicity
- MeSH terms
- Animals, Antioxidants, Cell Membrane Permeability, Humans, Mitochondria, Models, Biological, Peptides, Reperfusion Injury, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Reactive Nitrogen Species
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