Diabetic cardiomyopathy: Role of the cardiac mitochondrial melatonergic pathway

George Anderson; George Anderson

doi:10.3934/molsci.2025022

AIMS Molecular Science

2025, Volume 12, Issue 4: 385-410. doi: 10.3934/molsci.2025022

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Review

Diabetic cardiomyopathy: Role of the cardiac mitochondrial melatonergic pathway

George Anderson ^,

CRC Scotland & London, Eccleston Square, London SW1V 1PG, UK

Received: 27 October 2025 Revised: 20 November 2025 Accepted: 26 November 2025 Published: 05 December 2025

Although cardiovascular diseases, especially diabetic cardiomyopathy (DCM), account for up to 80% of deaths in diabetic patients, the pathophysiological changes driven by diabetes on cardiovascular function are poorly defined and treated. As with many medical conditions, increased levels of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Signal transducer and activator of transcription (STAT)3 are significant aspects of DCM pathophysiology. Research indicates that NF-κB dimer composition and nuclear (canonical) and mitochondrial (noncanonical) STAT3 interact across human cells to regulate the melatonergic pathway. Given the beneficial effects of melatonin across almost all cardiovascular diseases, including DCM, it is amiss that the melatonergic pathway has not been investigated in cardiomyocytes, cardiac fibroblast, or endothelial cells. In this article, we reviewed DCM pathophysiological factors/processes and link these to wider bodies of data on the regulation of the melatonergic pathway, providing a framework that better integrates previous disparate bodies of data on DCM, while indicating clear future research and treatment implications.
- diabetic cardiomyopathy,
- melatonin,
- NF-κB,
- STAT3,
- mitochondria,
- treatment,
- diabetes,
- methylglyoxal,
- RAGE,
- butyrate
Citation: George Anderson. Diabetic cardiomyopathy: Role of the cardiac mitochondrial melatonergic pathway[J]. AIMS Molecular Science, 2025, 12(4): 385-410. doi: 10.3934/molsci.2025022

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Abstract

Although cardiovascular diseases, especially diabetic cardiomyopathy (DCM), account for up to 80% of deaths in diabetic patients, the pathophysiological changes driven by diabetes on cardiovascular function are poorly defined and treated. As with many medical conditions, increased levels of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Signal transducer and activator of transcription (STAT)3 are significant aspects of DCM pathophysiology. Research indicates that NF-κB dimer composition and nuclear (canonical) and mitochondrial (noncanonical) STAT3 interact across human cells to regulate the melatonergic pathway. Given the beneficial effects of melatonin across almost all cardiovascular diseases, including DCM, it is amiss that the melatonergic pathway has not been investigated in cardiomyocytes, cardiac fibroblast, or endothelial cells. In this article, we reviewed DCM pathophysiological factors/processes and link these to wider bodies of data on the regulation of the melatonergic pathway, providing a framework that better integrates previous disparate bodies of data on DCM, while indicating clear future research and treatment implications.

Abbreviations

11β-HSD1

11β-hydroxysteroid dehydrogenase type 1

5-HT

serotonin

5-HTTP

5-hydroxytryptophan

α7nAChR

alpha 7nicotinic acetylcholine receptor

AADC

aromatic-L-amino acid decarboxylase

AANAT

aralkylamine N-acetyltransferase

acetyl-CoA

acetyl-coenzyme A

AhR

aryl hydrocarbon receptor

ASMT

N-acetylserotonin O-methyltransferase

BAG-1

bcl-2 associated athanogene 1

BDNF

brain-derived neurotrophic factor

CAR

cortisol awakening response

CTGR

connective tissue growth factor

CYP

cytochrome P450

DCM

diabetic cardiomyopathy

glucocorticoid receptor

HDAC

histone deacetylase

HPA

hypothalamic-pituitary-adrenal

IDO

indoleamine 2,3-dioxygenase

LETM1

Leucine Zipper EF-hand containing Transmembrane protein 1

LAT-1

large amino acid transporter 1

MAMs

mitochondria-associated membranes

MHC

major histocompatibility complex

NAS

N acetylserotonin

NF-κB

nuclear factor kappa-light-chain-enhancer of activated B cells

NLRP3

NLR family pyrin domain containing 3

OXPHOS

oxidative phosphorylation

PDC

pyruvate dehydrogenase complex

PVN

paraventricular nucleus

RAGE

receptor for advanced glycation end products

SPMs

specialized proresolving mediators

STAT3

signal transducer and activator of transcription 3

T2DM

type 2 diabetes mellitus

TDO

tryptophan 2,3 dioxygenase

TGF-β1

transforming growth factor-beta1

TPH

tryptophan hydroxylase

Conflicts of interest

The author declares that there are no conflicts of interest.

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