Plant-derived mitochondria-targeting cysteine-rich peptide modulates cellular bioenergetics
Mitochondria are attractive therapeutic targets for developing agents to delay age-related frailty and diseases. However, few promising leads have been identified from natural products. Previously, we identified roseltide rT1, a hyperstable 27-residue cysteine-rich peptide from Hibiscus sabdarif...
| Main Authors: | , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2019
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/89096 http://hdl.handle.net/10220/48850 |
| Summary: | Mitochondria are attractive therapeutic targets for developing
agents to delay age-related frailty and diseases. However, few
promising leads have been identified from natural products.
Previously, we identified roseltide rT1, a hyperstable 27-residue
cysteine-rich peptide from Hibiscus sabdariffa, as a knottintype
neutrophil elastase inhibitor. Here, we show that roseltide
rT1 is also a cell-penetrating, mitochondria-targeting peptide
that increases ATP production. Results from flow cytometry,
live-cell imaging, pulldown assays, and genetically-modified cell
lines supported that roseltide rT1 enters cells via glycosaminoglycan-
dependent endocytosis, and enters the mitochondria
through TOM20, a mitochondrial protein import receptor. We
further showed that roseltide rT1 increases cellular ATP production
via mitochondrial membrane hyperpolarization. Using
biotinylated roseltide rT1 for target identification and proteomic
analysis, we showed that human mitochondrial membrane
ATP synthase subunit O is an intramitochondrial target.
Collectively, these data support our discovery that roseltide rT1
is a first-in-class mitochondria-targeting, cysteine-rich peptide
with potentials to be developed into tools to further our understanding
of mitochrondria-related diseases. |
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