LAT1-mediated delivery of engineered R13A-MOTS-c attenuates radiation-induced lung injury via Nrf2 activation and mitochondrial protection.

Zhang YL, Huang G, Li SP, Zhang WL, Chen D, Jin LG, Pang QF, Wu YX, Huang JF

Redox biology9 May 2026

PMID42142418PMCIDPMC13199819DOI10.1016/j.redox.2026.104204PepBankPUB-42142418

Summary

MOTS-c exhibits substantial antioxidant and anti-inflammatory properties, yet its therapeutic potential is constrained by poor membrane permeability due to its high polarity. To overcome this limitation, we engineered R13A-MOTS-c by substituting the polar arginine at position 13 with alanine in the wild-type peptide (Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg). This modification increased the peptide's hydrophobicity index from -0.938 to -0.544, measurably improving its cellular uptake. Functional uptake assays, including competition with canonical LAT1 substrates (leucine, BCH) and LAT1 knockdown experiments, further confirmed that R13A-MOTS-c enters cells via LAT1-mediated transport. In vitro experiments revealed that R13A-MOTS-c suppressed inflammatory responses, oxidative damage, and mitochondrial impairment in MLE-12 cells. In vivo studies demonstrated that daily intraperitoneal administration of R13A-MOTS-c (5 mg/kg for 2 weeks) effectively mitigated radiation-induced pulmonary inflammation, oxidative stress, and mitochondrial dysfunction in C57BL/6 mice exposed to 20 Gy thoracic irradiation. Mechanistically, R13A-MOTS-c activated the Nrf2 signaling pathway, as evidenced by increased nuclear translocation of Nrf2 and upregulation of its downstream targets gene. These effects were abolished upon LAT1 inhibition, Nrf2 inhibition, or in Nrf2-knockout conditions. Collectively, these findings indicate that LAT1-mediated uptake of R13A-MOTS-c alleviates radiation-induced lung injury through Nrf2 pathway activation and mitochondrial function restoration, offering a promising therapeutic strategy for clinical applications.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study11

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone11

In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking MOTS-c.

01AnimalNot a test of MOTS-c aloneAnimal study (in vivo)Efficacy outcome
In mice with thoracic irradiation, R13A-MOTS‑c (5 mg/kg intraperitoneally for 2 weeks) mitigated pulmonary inflammation.
In plain wordsIn irradiated mice, the engineered peptide reduced lung inflammation.
Peptide
MOTS-c
Outcome
DecreaseRadiation-induced pulmonary inflammation
Study
mousen: not reported in source
20 Gy thoracic irradiation, C57BL/6 mice
Outcome group
Inflammation markers · Respiratory
Source sentences
Summary
In vivo studies demonstrated that daily intraperitoneal administration of R13A-MOTS-c (5 mg/kg for 2 weeks) effectively mitigated radiation-induced pulmonary inflammation, oxidative stress, and mitochondrial dysfunction in C57BL/6 mice exposed to 20 Gy thoracic irradiation.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4214241807
02AnimalNot a test of MOTS-c aloneAnimal study (in vivo)Efficacy outcome
In mice with thoracic irradiation, R13A-MOTS‑c (5 mg/kg intraperitoneally for 2 weeks) mitigated oxidative stress.
In plain wordsIn irradiated mice, the engineered peptide reduced oxidative stress in the lungs.
Peptide
MOTS-c
Outcome
DecreaseRadiation-induced pulmonary oxidative stress
Study
mousen: not reported in source
20 Gy thoracic irradiation, C57BL/6 mice
Outcome group
Oxidative stress · Respiratory
Source sentences
Summary
In vivo studies demonstrated that daily intraperitoneal administration of R13A-MOTS-c (5 mg/kg for 2 weeks) effectively mitigated radiation-induced pulmonary inflammation, oxidative stress, and mitochondrial dysfunction in C57BL/6 mice exposed to 20 Gy thoracic irradiation.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4214241808
03AnimalNot a test of MOTS-c aloneAnimal study (in vivo)Efficacy outcome
In mice with thoracic irradiation, R13A-MOTS‑c (5 mg/kg intraperitoneally for 2 weeks) mitigated mitochondrial dysfunction.
In plain wordsIn irradiated mice, the engineered peptide reduced mitochondrial damage in the lungs.
Peptide
MOTS-c
Outcome
DecreaseRadiation-induced mitochondrial dysfunction
Study
mousen: not reported in source
20 Gy thoracic irradiation, C57BL/6 mice
Outcome group
Mitochondrial function · Respiratory
Source sentences
Summary
In vivo studies demonstrated that daily intraperitoneal administration of R13A-MOTS-c (5 mg/kg for 2 weeks) effectively mitigated radiation-induced pulmonary inflammation, oxidative stress, and mitochondrial dysfunction in C57BL/6 mice exposed to 20 Gy thoracic irradiation.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4214241809
04LabNot a test of MOTS-c aloneIn vitro (cells)Pharmacokinetics
The R13A modification measurably improved cellular uptake of the peptide.
In plain wordsIn lab tests, the engineered peptide entered cells better than the original.
Peptide
MOTS-c
Outcome
IncreaseCellular uptake of R13A-MOTS-c
Study
n: not reported in source
Outcome group
Pharmacokinetics · Pharmacology
Source sentences
Summary
This modification increased the peptide's hydrophobicity index from -0.938 to -0.544, measurably improving its cellular uptake.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4214241802
05LabNot a test of MOTS-c aloneIn vitro (cells)Mechanism
Competition with LAT1 substrates and LAT1 knockdown confirmed that R13A-MOTS‑c enters cells via LAT1-mediated transport.
In plain wordsIn lab cells, the engineered peptide entered through a transporter called LAT1.
Peptide
MOTS-c
Outcome
Not applicableLAT1-mediated uptake of R13A-MOTS-c
Study
n: not reported in source
Outcome group
Pharmacokinetics · Pharmacology
Source sentences
Summary
Functional uptake assays, including competition with canonical LAT1 substrates (leucine, BCH) and LAT1 knockdown experiments, further confirmed that R13A-MOTS-c enters cells via LAT1-mediated transport.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4214241803
06LabNot a test of MOTS-c aloneIn vitro (cells)Efficacy outcome
R13A-MOTS‑c suppressed inflammatory responses in MLE-12 cells.
In plain wordsIn lung cells in the lab, the engineered peptide reduced inflammation.
Peptide
MOTS-c
Outcome
DecreaseInflammatory responses in MLE-12 cells
Study
n: not reported in source
MLE-12 cells
Outcome group
Inflammation markers · Respiratory
Source sentences
Summary
R13A-MOTS-c suppressed inflammatory responses
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4214241804
07LabNot a test of MOTS-c aloneIn vitro (cells)Efficacy outcome
R13A-MOTS‑c suppressed oxidative damage in MLE-12 cells.
In plain wordsIn lung cells in the lab, the engineered peptide reduced oxidative damage.
Peptide
MOTS-c
Outcome
DecreaseOxidative damage in MLE-12 cells
Study
n: not reported in source
MLE-12 cells
Outcome group
Oxidative stress · Respiratory
Source sentences
Summary
R13A-MOTS-c suppressed inflammatory responses, oxidative damage, and mitochondrial impairment in MLE-12 cells
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4214241805
08LabNot a test of MOTS-c aloneIn vitro (cells)Efficacy outcome
R13A-MOTS‑c suppressed mitochondrial impairment in MLE-12 cells.
In plain wordsIn lung cells in the lab, the engineered peptide reduced damage to mitochondria.
Peptide
MOTS-c
Outcome
DecreaseMitochondrial impairment in MLE-12 cells
Study
n: not reported in source
MLE-12 cells
Outcome group
Mitochondrial function · Respiratory
Source sentences
Summary
R13A-MOTS-c suppressed inflammatory responses, oxidative damage, and mitochondrial impairment in MLE-12 cells
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4214241806
09LabNot a test of MOTS-c aloneIn vitro (cells)Mechanism
R13A-MOTS‑c activated the Nrf2 pathway, with increased Nrf2 nuclear translocation and upregulated downstream target genes.
In plain wordsIn lab tests, the engineered peptide switched on the Nrf2 protective pathway.
Peptide
MOTS-c
Outcome
IncreaseNrf2 pathway activation
Study
n: not reported in source
Outcome group
Receptor activity and mechanism · Respiratory
Source sentences
Summary
Mechanistically, R13A-MOTS-c activated the Nrf2 signaling pathway, as evidenced by increased nuclear translocation of Nrf2 and upregulation of its downstream targets gene.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4214241810
10LabNot a test of MOTS-c aloneIn vitro (cells)Mechanism
The effects of R13A-MOTS‑c were abolished by LAT1 inhibition, Nrf2 inhibition, or Nrf2 knockout.
In plain wordsIn lab tests, blocking LAT1 or Nrf2 cancelled the effects of the engineered peptide.
Peptide
MOTS-c
Outcome
Not applicableDependence of R13A-MOTS-c effects on LAT1 and Nrf2
Study
n: not reported in source
Outcome group
Receptor activity and mechanism · Respiratory
Source sentences
Summary
These effects were abolished upon LAT1 inhibition, Nrf2 inhibition, or in Nrf2-knockout conditions.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4214241811
11Computer modelNot a test of MOTS-c aloneIn silicoOther
The R13A substitution raised the hydrophobicity index of MOTS‑c from -0.938 to -0.544.
In plain wordsA one-amino-acid change made the MOTS‑c peptide less water-loving, which was linked to better uptake into cells.
Peptide
MOTS-c
Outcome
IncreaseHydrophobicity index of R13A-MOTS-c
Study
n: not reported in source
Outcome group
Receptor activity and mechanism · Pharmacology
Measurements
Hydrophobicity index
−0.938
wild-type MOTS-c
Hydrophobicity index
−0.544
R13A-MOTS-c
Source sentences
Summary
This modification increased the peptide's hydrophobicity index from -0.938 to -0.544, measurably improving its cellular uptake.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4214241801

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
10 Oct 2026, 08:19 UTC
Study results updated
Version 1
9 Oct 2026, 02:47 UTC
First added · source update from Europe PMC

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Terms as the source lists them.

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