Mitochondrial physiology and beyond: Mechanistic insights into kaempferol actions

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Marcos Roberto de Oliveira
{"title":"Mitochondrial physiology and beyond: Mechanistic insights into kaempferol actions","authors":"Marcos Roberto de Oliveira","doi":"10.1016/j.cbi.2025.111743","DOIUrl":null,"url":null,"abstract":"<div><div>Kaempferol (KAE), a dietary flavonoid, has emerged as a potent modulator of mitochondrial physiology, exerting multifaceted actions on bioenergetics, redox balance, mitochondrial dynamics, biogenesis, and quality control. Thus, the aim of this review is to discuss the effects promoted by KAE on mitochondrial physiology from a mechanistic view. Data from diverse <em>in vitro</em> and <em>in vivo</em> models indicate that KAE enhances mitochondrial function by stimulating ATP production, preserving membrane potential, promoting calcium uptake, and increasing the activity or expression of oxidative phosphorylation (OXPHOS) complexes. KAE also activates key signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt, adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1-α (AMPK/PGC-1α), and nuclear factor erythroid 2-related factor 2 (Nrf2), contributing to mitochondrial biogenesis, antioxidant defense, and cellular survival. In parallel, KAE modulates mitochondrial dynamics by inhibiting fission and promoting fusion, while also inducing mitophagy, particularly under neurotoxic or ischemic conditions. However, at elevated concentrations, KAE may disrupt mitochondrial homeostasis by inhibiting Complex V activity, inducing oxidative stress, and depolarizing mitochondria, suggesting a concentration- and context-dependent duality. Furthermore, nanotechnology-based delivery systems targeting KAE to mitochondria have demonstrated enhanced therapeutic potential in preclinical disease models, reinforcing its translational relevance. Collectively, these findings support KAE as a promising candidate for mitochondrial-targeted interventions in diseases characterized by mitochondrial dysfunction. Nonetheless, mechanistic gaps remain regarding its impact on mitochondrial protein acetylation, quality control signaling, and the long-term effects of chronic exposure. Future research should focus on dissecting these pathways and validating the therapeutic window of KAE in clinical settings.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111743"},"PeriodicalIF":5.4000,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemico-Biological Interactions","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0009279725003734","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Kaempferol (KAE), a dietary flavonoid, has emerged as a potent modulator of mitochondrial physiology, exerting multifaceted actions on bioenergetics, redox balance, mitochondrial dynamics, biogenesis, and quality control. Thus, the aim of this review is to discuss the effects promoted by KAE on mitochondrial physiology from a mechanistic view. Data from diverse in vitro and in vivo models indicate that KAE enhances mitochondrial function by stimulating ATP production, preserving membrane potential, promoting calcium uptake, and increasing the activity or expression of oxidative phosphorylation (OXPHOS) complexes. KAE also activates key signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt, adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1-α (AMPK/PGC-1α), and nuclear factor erythroid 2-related factor 2 (Nrf2), contributing to mitochondrial biogenesis, antioxidant defense, and cellular survival. In parallel, KAE modulates mitochondrial dynamics by inhibiting fission and promoting fusion, while also inducing mitophagy, particularly under neurotoxic or ischemic conditions. However, at elevated concentrations, KAE may disrupt mitochondrial homeostasis by inhibiting Complex V activity, inducing oxidative stress, and depolarizing mitochondria, suggesting a concentration- and context-dependent duality. Furthermore, nanotechnology-based delivery systems targeting KAE to mitochondria have demonstrated enhanced therapeutic potential in preclinical disease models, reinforcing its translational relevance. Collectively, these findings support KAE as a promising candidate for mitochondrial-targeted interventions in diseases characterized by mitochondrial dysfunction. Nonetheless, mechanistic gaps remain regarding its impact on mitochondrial protein acetylation, quality control signaling, and the long-term effects of chronic exposure. Future research should focus on dissecting these pathways and validating the therapeutic window of KAE in clinical settings.

Abstract Image

线粒体生理学和超越:山奈酚作用的机械见解
山奈酚(KAE)是一种膳食类黄酮,作为线粒体生理的有效调节剂,在生物能量学、氧化还原平衡、线粒体动力学、生物发生和质量控制等方面发挥着多方面的作用。因此,这篇综述的目的是从机制的角度来讨论KAE对线粒体生理的影响。来自各种体外和体内模型的数据表明,KAE通过刺激ATP产生、保持膜电位、促进钙摄取和增加氧化磷酸化(OXPHOS)复合物的活性或表达来增强线粒体功能。KAE还激活关键的信号通路,包括磷脂酰肌醇3-激酶(PI3K)/Akt、单磷酸腺苷活化蛋白激酶/过氧化物酶体增殖体活化受体γ辅助激活因子1-α (AMPK/PGC-1α)和核因子红系2相关因子2 (Nrf2),参与线粒体的生物发生、抗氧化防御和细胞存活。同时,KAE通过抑制裂变和促进融合来调节线粒体动力学,同时也诱导线粒体自噬,特别是在神经毒性或缺血情况下。然而,在浓度升高时,KAE可能会通过抑制Complex V活性、诱导氧化应激和线粒体去极化来破坏线粒体稳态,这表明KAE具有浓度依赖性和环境依赖性的双重特性。此外,以纳米技术为基础的靶向KAE到线粒体的递送系统在临床前疾病模型中显示出增强的治疗潜力,加强了其翻译相关性。总的来说,这些发现支持KAE作为线粒体靶向干预以线粒体功能障碍为特征的疾病的有希望的候选者。尽管如此,关于其对线粒体蛋白乙酰化、质量控制信号传导和慢性暴露的长期影响的影响,机制上的差距仍然存在。未来的研究应侧重于解剖这些途径,并在临床环境中验证KAE的治疗窗口。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
7.70
自引率
3.90%
发文量
410
审稿时长
36 days
期刊介绍: Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信