MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes.

Li X, Zhan F, Qiu G, Lu P, Shen Z, Qi Y, Wu M, Chu M, Feng J, Wen Z, Yao X, Wang A and 7 more

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Jin W, Zhang X, Liao J, Zhang J, Song M, Wang W, Wang X

Redox biology15 May 2025Cited by 9 (Europe PMC)

PMID40403491PMCIDPMC12150175DOI10.1016/j.redox.2025.103681PepBankPUB-40403491

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Summary

Acute respiratory distress syndrome (ARDS) following cardiopulmonary bypass (CPB) is driven by oxidative stress during lung ischemia-reperfusion injury (LIRI). Mitochondrial-derived peptide MOTS-c has emerged as a regulator of mitochondrial-nuclear communication, yet its role in CPB-induced ARDS remains unclear. Here, we identify MOTS-c as a critical mediator of endothelial protection against LIRI through MYH9-dependent nuclear translocation and transcriptional activation of antioxidant genes. In rat LIRI models, endothelial cells exhibited the most significant MOTS-c upregulation, correlating with barrier preservation and reduced oxidative stress. Mechanistically, hypoxia-reoxygenation (HR) triggered reactive oxygen species (ROS)-dependent phosphorylation of MYH9 at Ser1943 via casein kinase II subunit alpha (CK2A), enabling MOTS-c binding to MYH9-γ-Actin complexes for nuclear transport. RNA sequencing (RNA-seq) combined with chromatin immunoprecipitation sequencing (ChIP-seq) revealed direct MOTS-c interaction with promoters of antioxidant genes (e.g., HMOX1, NQO1), which harbor antioxidant response elements (AREs). Clinically, serum MOTS-c increments within 24 h post-CPB (ΔMOTS-c) outperformed traditional biomarkers in predicting ARDS incidence, with multivariate models incorporating ΔMOTS-c achieving superior discriminative power (AUC = 0.885). Exogenous MOTS-c administration in rats attenuated lung injury by reducing oxidative damage, inflammation, and mortality, recapitulating endogenous protective mechanisms. Our findings establish MOTS-c as a dual-function molecule-acting via ROS-CK2A-MYH9 signaling to activate nuclear antioxidant defenses and serving as a prognostic biomarker for CPB-related complications. This study bridges mitochondrial dynamics, nuclear transcriptional regulation, and clinical outcomes, offering novel preventive avenues for IRI-associated pathologies.

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

Results from this study8

6 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Efficacy outcome
In rats, exogenous MOTS‑c administration attenuated lung injury.
In plain wordsIn rats, giving MOTS‑c reduced lung injury.
Peptide
MOTS-c
Outcome
DecreaseLung injury after exogenous MOTS-c
Study
ratn: not reported in source
lung ischemia-reperfusion injury
Outcome group
Cardiovascular events · Respiratory
Studied dose
Dose not stated
Source sentences
Summary
Exogenous MOTS-c administration in rats attenuated lung injury by reducing oxidative damage, inflammation, and mortality, recapitulating endogenous protective mechanisms.
Show in the study text Report a problemFND-4040349103
02AnimalAnimal study (in vivo)Efficacy outcome
In rats with lung ischemia-reperfusion injury, exogenous MOTS‑c reduced oxidative damage.
In plain wordsIn rats with lung injury, giving MOTS‑c reduced oxidative damage.
Peptide
MOTS-c
Outcome
DecreaseOxidative damage after exogenous MOTS-c
Study
ratn: not reported in source
lung ischemia-reperfusion injury
Outcome group
Inflammation markers · Respiratory
Studied dose
Dose not stated
Source sentences
Summary
Exogenous MOTS-c administration in rats attenuated lung injury by reducing oxidative damage, inflammation, and mortality, recapitulating endogenous protective mechanisms.
Show in the study text Report a problemFND-4040349104
03AnimalAnimal study (in vivo)Efficacy outcome
In rats with lung ischemia-reperfusion injury, exogenous MOTS‑c reduced inflammation.
In plain wordsIn rats with lung injury, giving MOTS‑c reduced inflammation.
Peptide
MOTS-c
Outcome
DecreaseInflammation after exogenous MOTS-c
Study
ratn: not reported in source
lung ischemia-reperfusion injury
Outcome group
Inflammation markers · Respiratory
Studied dose
Dose not stated
Source sentences
Summary
Exogenous MOTS-c administration in rats attenuated lung injury by reducing oxidative damage, inflammation, and mortality, recapitulating endogenous protective mechanisms.
Show in the study text Report a problemFND-4040349105
04AnimalAnimal study (in vivo)Efficacy outcome
In rats with lung ischemia-reperfusion injury, exogenous MOTS‑c reduced mortality.
In plain wordsIn rats with lung injury, giving MOTS‑c lowered deaths.
Peptide
MOTS-c
Outcome
DecreaseMortality after exogenous MOTS-c
Study
ratn: not reported in source
lung ischemia-reperfusion injury
Outcome group
Mortality · Respiratory
Studied dose
Dose not stated
Source sentences
Summary
Exogenous MOTS-c administration in rats attenuated lung injury by reducing oxidative damage, inflammation, and mortality, recapitulating endogenous protective mechanisms.
Show in the study text Report a problemFND-4040349106
05LabIn vitro (cells)Mechanism
After hypoxia-reoxygenation, ROS-dependent phosphorylation of MYH9 by CK2A enabled MOTS‑c to bind MYH9-γ-Actin complexes for nuclear transport.
In plain wordsIn lab tests, stress from low oxygen then reoxygenation let MOTS‑c bind a protein complex that carries it into the cell nucleus.
Peptide
MOTS-c
Outcome
Not applicableMOTS-c binding to MYH9-γ-Actin complexes after hypoxia-reoxygenation
Study
n: not reported in source
Outcome group
Receptor activity and mechanism · Respiratory
Studied dose
Dose not stated
Source sentences
Summary
Mechanistically, hypoxia-reoxygenation (HR) triggered reactive oxygen species (ROS)-dependent phosphorylation of MYH9 at Ser1943 via casein kinase II subunit alpha (CK2A), enabling MOTS-c binding to MYH9-γ-Actin complexes for nuclear transport.
Show in the study text Report a problemFND-4040349107
06LabIn vitro (cells)Mechanism
RNA-seq and ChIP-seq revealed direct MOTS‑c interaction with promoters of antioxidant genes such as HMOX1 and NQO1.
In plain wordsIn lab tests, MOTS‑c was found to interact directly with the control regions of antioxidant genes.
Peptide
MOTS-c
Outcome
Not applicableMOTS-c interaction with antioxidant gene promoters
Study
n: not reported in source
Outcome group
Receptor activity and mechanism · Respiratory
Studied dose
Dose not stated
Source sentences
Summary
revealed direct MOTS-c interaction with promoters of antioxidant genes (e.g., HMOX1, NQO1), which harbor antioxidant response elements (AREs).
Show in the study text Report a problemFND-4040349108

Natural levels measured2

These results measure the body's own peptide. Nobody was given the peptide. They are not evidence about taking it. They are left out of key results, evidence counts and charts.

07HumanEndogenous levelObservational studyOther
In patients after cardiopulmonary bypass, the 24-hour rise in serum MOTS‑c predicted ARDS better than traditional biomarkers (AUC 0.885 in multivariate models).
In plain wordsIn patients after heart bypass surgery, a rise in the body's own MOTS‑c predicted who got a severe lung condition better than usual markers.
Peptide
MOTS-c
Outcome
Not applicableSerum MOTS-c increment after CPB predicting ARDS
Study
n: not reported in source
Outcome group
Mitochondrial function · Respiratory
Measurements
AUC
0.885 NA
multivariate model with ΔMOTS-c
Source sentences
Summary
Clinically, serum MOTS-c increments within 24 h post-CPB (ΔMOTS-c) outperformed traditional biomarkers in predicting ARDS incidence, with multivariate models incorporating ΔMOTS-c achieving superior discriminative power (AUC = 0.885).
This result measures the body's own MOTS-c. Nobody was given the peptide. It is not evidence about taking it.
Show in the study text Report a problemFND-4040349102
08AnimalEndogenous levelAnimal study (in vivo)Other
In rat lung ischemia-reperfusion injury models, endothelial cells showed the most significant upregulation of the body's own MOTS‑c.
In plain wordsIn rats with lung injury, the body's own MOTS‑c rose most in the cells lining blood vessels.
Peptide
MOTS-c
Outcome
IncreaseEndothelial MOTS-c expression in rat LIRI
Study
ratn: not reported in source
lung ischemia-reperfusion injury
Outcome group
Mitochondrial function · Respiratory
Source sentences
Summary
In rat LIRI models, endothelial cells exhibited the most significant MOTS-c upregulation, correlating with barrier preservation and reduced oxidative stress.
This result measures the body's own MOTS-c. Nobody was given the peptide. It is not evidence about taking it.
Show in the study text Report a problemFND-4040349101

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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