Reduction of Elevated Proton Leak Rejuvenates Mitochondria in the Aged Cardiomyocyte

Zhang H, Alder N, Wang W, Szeto H, Marcinek D, Rabinovitch P

Innovation in aging1 Jan 2020

PMCIDPMC7743695PepBankPUB-94238354

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Summary

Abstract Rational: Aging-associated diseases, including cardiac dysfunction, are increasingly common in the population. However, the mechanisms of physiologic aging in general, and cardiac aging in particular, remain poorly understood. While effective medical interventions are available for some kinds of heart failure, one age-related impairment, diastolic dysfunction in Heart Failure with Preserved Ejection Fraction (HFpEF) is lacking a clinically effective treatment. Methods and Results: Using the pH indicator cpYFP in the model of naturally aging mice and rats, we show direct evidence of increased mitochondrial proton leak in aged heart mitochondria following a pH gradient stress. Furthermore, we identified Adenine Nucleotide Translocator 1 (ANT1) as mediating the increased proton permeability of old cardiomyocytes. Most importantly, acute (2 hours) in vitro treatment with the tetra-peptide drug SS-31 (elamipretide) reverses age-related excess proton entry, decreases the mitochondrial flash activity and mitochondrial permeability transition pore (mPTP) opening and rejuvenates mitochondrial function. Moreover, we show that SS-31 benefits the old mitochondria by direct association with ANT1 and stabilization of the mitochondrial ATP synthasome, leading to substantial reversal of diastolic dysfunction. Conclusion: Our results uncover excessive mitochondrial proton leak as a novel mechanism of age-related cardiac dysfunction and elucidate how SS-31 is able to reverse this clinically important complication of cardiac aging.

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

Results from this study7

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

01AnimalAnimal study (in vivo)Mechanism
In aged mice and rats, SS‑31 led to substantial reversal of diastolic dysfunction.
In plain wordsIn aged mice and rats, SS‑31 substantially reversed diastolic dysfunction of the heart.
Peptide
Elamipretide (SS-31)
Outcome
DecreaseDiastolic dysfunction
Study
mouse and ratn: not reported in source
Aged heart mitochondria and cardiomyocytes
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
leading to substantial reversal of diastolic dysfunction.
1 context sentence(design, population, supporting numbers)
Summary · context
Methods and Results: Using the pH indicator cpYFP in the model of naturally aging mice and rats, we show direct evidence of increased mitochondrial proton leak in aged heart mitochondria following a pH gradient stress.
Show in the study text Report a problemFND-9423835407
02LabEx vivo tissueMechanism
In aged mouse and rat cardiomyocytes, acute in vitro SS‑31 treatment reversed the age-related excess proton entry into mitochondria.
In plain wordsIn aged heart cells from mice and rats, SS‑31 reversed the excess leak of protons in mitochondria.
Peptide
Elamipretide (SS-31)
Outcome
DecreaseAge-related excess mitochondrial proton entry
Study
mouse and ratn: not reported in source
Aged heart mitochondria and cardiomyocytes
Outcome group
Mitochondrial function · Cardiovascular
Studied dose
Dose not stated · in vitro treatment · 2 hoursAs given in this study (mouse and rat).
Source sentences
Summary
acute (2 hours) in vitro treatment with the tetra-peptide drug SS-31 (elamipretide) reverses age-related excess proton entry
1 context sentence(design, population, supporting numbers)
Summary · context
Methods and Results: Using the pH indicator cpYFP in the model of naturally aging mice and rats, we show direct evidence of increased mitochondrial proton leak in aged heart mitochondria following a pH gradient stress.
Show in the study text Report a problemFND-9423835401
03LabEx vivo tissueMechanism
In aged mouse and rat cardiomyocytes, SS‑31 decreased mitochondrial flash activity.
In plain wordsIn aged heart cells from mice and rats, SS‑31 lowered mitochondrial flash activity.
Peptide
Elamipretide (SS-31)
Outcome
DecreaseMitochondrial flash activity
Study
mouse and ratn: not reported in source
Aged heart mitochondria and cardiomyocytes
Outcome group
Mitochondrial function · Cardiovascular
Studied dose
Dose not stated · in vitro treatment · 2 hoursAs given in this study (mouse and rat).
Source sentences
Summary
acute (2 hours) in vitro treatment with the tetra-peptide drug SS-31 (elamipretide) reverses age-related excess proton entry, decreases the mitochondrial flash activity
1 context sentence(design, population, supporting numbers)
Summary · context
Methods and Results: Using the pH indicator cpYFP in the model of naturally aging mice and rats, we show direct evidence of increased mitochondrial proton leak in aged heart mitochondria following a pH gradient stress.
Show in the study text Report a problemFND-9423835402
04LabEx vivo tissueMechanism
In aged mouse and rat cardiomyocytes, SS‑31 decreased opening of the mitochondrial permeability transition pore.
In plain wordsIn aged heart cells from mice and rats, SS‑31 reduced opening of a pore that can damage mitochondria.
Peptide
Elamipretide (SS-31)
Outcome
DecreasemPTP opening
Study
mouse and ratn: not reported in source
Aged heart mitochondria and cardiomyocytes
Outcome group
Mitochondrial function · Cardiovascular
Studied dose
Dose not stated · in vitro treatment · 2 hoursAs given in this study (mouse and rat).
Source sentences
Summary
acute (2 hours) in vitro treatment with the tetra-peptide drug SS-31 (elamipretide) reverses age-related excess proton entry, decreases the mitochondrial flash activity and mitochondrial permeability transition pore (mPTP) opening
1 context sentence(design, population, supporting numbers)
Summary · context
Methods and Results: Using the pH indicator cpYFP in the model of naturally aging mice and rats, we show direct evidence of increased mitochondrial proton leak in aged heart mitochondria following a pH gradient stress.
Show in the study text Report a problemFND-9423835403
05LabEx vivo tissueMechanism
In aged mouse and rat cardiomyocytes, SS‑31 rejuvenated mitochondrial function.
In plain wordsIn aged heart cells from mice and rats, SS‑31 improved mitochondrial function.
Peptide
Elamipretide (SS-31)
Outcome
IncreaseMitochondrial function in aged cardiomyocytes
Study
mouse and ratn: not reported in source
Aged heart mitochondria and cardiomyocytes
Outcome group
Mitochondrial function · Cardiovascular
Studied dose
Dose not stated · in vitro treatment · 2 hoursAs given in this study (mouse and rat).
Source sentences
Summary
acute (2 hours) in vitro treatment with the tetra-peptide drug SS-31 (elamipretide) reverses age-related excess proton entry, decreases the mitochondrial flash activity and mitochondrial permeability transition pore (mPTP) opening and rejuvenates mitochondrial function.
1 context sentence(design, population, supporting numbers)
Summary · context
Methods and Results: Using the pH indicator cpYFP in the model of naturally aging mice and rats, we show direct evidence of increased mitochondrial proton leak in aged heart mitochondria following a pH gradient stress.
Show in the study text Report a problemFND-9423835404
06LabEx vivo tissueMechanism
In aged mouse and rat heart mitochondria, SS‑31 associated directly with ANT1.
In plain wordsIn lab tests on aged mouse and rat heart mitochondria, SS‑31 bound directly to the protein ANT1.
Peptide
Elamipretide (SS-31)
Outcome
Not applicableSS-31 association with ANT1
Study
mouse and ratn: not reported in source
Aged heart mitochondria and cardiomyocytes
Outcome group
Receptor activity and mechanism · Cardiovascular
Studied dose
Dose not stated · in vitro treatment · 2 hoursAs given in this study (mouse and rat).
Source sentences
Summary
we show that SS-31 benefits the old mitochondria by direct association with ANT1
1 context sentence(design, population, supporting numbers)
Summary · context
Methods and Results: Using the pH indicator cpYFP in the model of naturally aging mice and rats, we show direct evidence of increased mitochondrial proton leak in aged heart mitochondria following a pH gradient stress.
Show in the study text Report a problemFND-9423835405
07LabEx vivo tissueMechanism
In aged mouse and rat heart mitochondria, SS‑31 stabilized the mitochondrial ATP synthasome.
In plain wordsIn lab tests on aged mouse and rat heart mitochondria, SS‑31 stabilized the mitochondrial ATP-making complex.
Peptide
Elamipretide (SS-31)
Outcome
IncreaseATP synthasome stability
Study
mouse and ratn: not reported in source
Aged heart mitochondria and cardiomyocytes
Outcome group
Mitochondrial function · Cardiovascular
Studied dose
Dose not stated · in vitro treatment · 2 hoursAs given in this study (mouse and rat).
Source sentences
Summary
we show that SS-31 benefits the old mitochondria by direct association with ANT1 and stabilization of the mitochondrial ATP synthasome
1 context sentence(design, population, supporting numbers)
Summary · context
Methods and Results: Using the pH indicator cpYFP in the model of naturally aging mice and rats, we show direct evidence of increased mitochondrial proton leak in aged heart mitochondria following a pH gradient stress.
Show in the study text Report a problemFND-9423835406

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

Subjects

Terms as the source lists them.

Publication types

Abstract

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