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Mitochondrial ROS in Health and Disease

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (31 January 2026) | Viewed by 42842

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Dr. Frank Krause

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Nanolytics Gesellschaft für Kolloidanalytik mbH, 14476 Potsdam, Germany
Interests: proteomics; protein-protein interactions; protein-ligand interactions; oxidative phosphorylation; mitochondria; metabolons; aging research; drug discovery; native electrophoresis; analytical ultracentrifugation
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Dear Colleagues,

Mitochondria are extremely membrane-rich organelles with a central role in metabolism and key functions in cellular signaling and cell survival as well. Therefore, mitochondria are involved in various diseases and the aging process, which has been providing a major impetus for extensive research on mitochondrial structure and function. In recent decades, many essential physiological roles of (mitochondrial) ROS were (re)established, such as in the immune response, cell cycle, and lifespan control.

Though the detrimental role of free radicals and other reactive species on organisms was the prevailing view for a long time, the health- and lifespan-promoting effects of ROS are an emerging topic with some predominantly forgotten roots, e.g., about the medicinal benefits of hydrogen peroxide dating more than a hundred years back. Similarly, many medicinally powerful biomolecules exert oxidative effects either directly or indirectly, including via mitochondrial ROS generation, e.g., paclitaxel and artemisinin.

This Special Issue focuses on the current advances in mitochondrial-derived ROS and their effects on health and disease involving natural-based biomolecules. Both review manuscripts and original research articles are welcome to convey up-to-date insights and avenues of future research.

Dr. Frank Krause
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

aging
apoptosis
respiratory chain
redox signaling
paclitaxel

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Related Special Issue

Mitochondrial ROS in Health and Disease: 2nd Edition in Biomolecules

Published Papers (10 papers)

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Research

Jump to: Review

19 pages, 2139 KB

Open AccessEditor’s ChoiceArticle

Methionine Restriction Differentially Modulates Expression of Genes in the Base Excision Repair Pathway in Rat Brain and Liver

by Ricardo Gredilla, Monica Lopez-Torres and Ines Sanchez-Roman

Biomolecules 2025, 15(7), 969; https://doi.org/10.3390/biom15070969 - 5 Jul 2025

Cited by 1 | Viewed by 1260

Abstract

Methionine restriction (MetR) is a dietary intervention that extends mean and maximum life span in rodents, at least in part, by reducing oxidative stress and promoting DNA stability in different tissues. Regarding DNA stability, DNA repair pathways play a critical role, both in the nuclear and mitochondrial fractions. Base excision repair (BER) is the main one involved in the repair of oxidative damage, as well as the main one in mitochondria. Despite the relevance of DNA repair in DNA maintenance, it is not known whether MetR regulates BER as a mechanism of preserving genomic stability. In this study we analyzed, for the first time, the effect of 40% MetR for 7 weeks on BER in rat brain cortex and liver, focusing on the expression of several key BER genes. In the brain cortex, MetR significantly increased the gene expression of the DNA glycosylase Ogg1 and the DNA endonuclease Ape1 while reducing DNA polymerase γ gene expression. Conversely, MetR led to a general reduction in the expression of BER genes in the liver. Our findings highlight a tissue-specific regulation of the BER gene expression in response to MetR. Different potential mechanisms underlying these changes in BER, such as DNA methylation or activation of signaling pathways, are discussed. Full article

(This article belongs to the Special Issue Mitochondrial ROS in Health and Disease)

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19 pages, 2747 KB

Open AccessArticle

Pathological Defects in a Drosophila Model of Alzheimer’s Disease and Beneficial Effects of the Natural Product Lisosan G

by Silvia Bongiorni, Elisabetta Catalani, Ivan Arisi, Francesca Lazzarini, Simona Del Quondam, Kashi Brunetti, Davide Cervia and Giorgio Prantera

Biomolecules 2024, 14(7), 855; https://doi.org/10.3390/biom14070855 - 15 Jul 2024

Cited by 5 | Viewed by 2599

Abstract

Alzheimer’s disease (AD) brains are histologically marked by the presence of intracellular and extracellular amyloid deposits, which characterize the onset of the disease pathogenesis. Increasing evidence suggests that certain nutrients exert a direct or indirect effect on amyloid β (Aβ)-peptide production and accumulation and, consequently, on AD pathogenesis. We exploited the fruit fly Drosophila melanogaster model of AD to evaluate in vivo the beneficial properties of Lisosan G, a fermented powder obtained from organic whole grains, on the intracellular Aβ-42 peptide accumulation and related pathological phenotypes of AD. Our data showed that the Lisosan G-enriched diet attenuates the production of neurotoxic Aβ peptides in fly brains and reduces neuronal apoptosis. Notably, Lisosan G exerted anti-oxidant effects, lowering brain levels of reactive oxygen species and enhancing mitochondrial activity. These aspects paralleled the increase in autophagy turnover and the inhibition of nucleolar stress. Our results give support to the use of the Drosophila model not only to investigate the molecular genetic bases of neurodegenerative disease but also to rapidly and reliably test the efficiency of potential therapeutic agents and diet regimens. Full article

(This article belongs to the Special Issue Mitochondrial ROS in Health and Disease)

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14 pages, 2237 KB

Open AccessArticle

Exogenous Iron Induces Mitochondrial Lipid Peroxidation, Lipofuscin Accumulation, and Ferroptosis in H9c2 Cardiomyocytes

by Konstantin G. Lyamzaev, He Huan, Alisa A. Panteleeva, Ruben A. Simonyan, Armine V. Avetisyan and Boris V. Chernyak

Biomolecules 2024, 14(6), 730; https://doi.org/10.3390/biom14060730 - 19 Jun 2024

Cited by 19 | Viewed by 3771

Abstract

Lipid peroxidation plays an important role in various pathologies and aging, at least partially mediated by ferroptosis. The role of mitochondrial lipid peroxidation during ferroptosis remains poorly understood. We show that supplementation of exogenous iron in the form of ferric ammonium citrate at submillimolar doses induces production of reactive oxygen species (ROS) and lipid peroxidation in mitochondria that precede ferroptosis in H9c2 cardiomyocytes. The mitochondria-targeted antioxidant SkQ1 and the redox mediator methylene blue, which inhibits the production of ROS in complex I of the mitochondrial electron transport chain, prevent both mitochondrial lipid peroxidation and ferroptosis. SkQ1 and methylene blue also prevented accumulation of lipofuscin observed after 24 h incubation of cardiomyocytes with ferric ammonium citrate. Using isolated cardiac mitochondria as an in vitro ferroptosis model, it was shown that rotenone (complex I inhibitor) in the presence of ferrous iron stimulates lipid peroxidation and lipofuscin accumulation. Our data indicate that ROS generated in complex I stimulate mitochondrial lipid peroxidation, lipofuscin accumulation, and ferroptosis induced by exogenous iron. Full article

(This article belongs to the Special Issue Mitochondrial ROS in Health and Disease)

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Review

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39 pages, 2798 KB

Open AccessReview

Mitochondrial ROS in Retinal Neurodegeneration: Thresholds, Quality Control Failure, and Precision Therapeutic Windows

by Snježana Kaštelan, Antonela Gverović Antunica, Suzana Konjevoda, Zora Tomić, Ana Sarić, Marjan Kulaš, Lorena Kulaš, Emina Kujundžić Begović, Samir Čanović, Petra Kovačević and Mira Ivanković

Biomolecules 2026, 16(3), 445; https://doi.org/10.3390/biom16030445 - 16 Mar 2026

Viewed by 621

Abstract

Mitochondrial reactive oxygen species (mtROS) play a dual role in retinal physiology, acting as essential redox signalling mediators under homeostatic conditions but driving oxidative damage and neurodegeneration once regulatory thresholds are exceeded. Owing to the exceptionally high energetic demands of retinal neurons and supporting cells, even subtle perturbations in mitochondrial redox balance can precipitate progressive retinal dysfunction. Increasing evidence indicates that retinal neurodegenerative diseases, including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), and inherited optic neuropathies, are characterised not by uniform oxidative stress, but by disease- and stage-specific mtROS signatures shaped by mitochondrial quality control capacity. This review synthesises current insights into the sources, regulation, and signalling functions of mtROS in the retina, with particular emphasis on threshold-dependent redox transitions, reverse electron transport, and the progressive failure of mitochondrial quality control mechanisms, including mitophagy, mitochondrial dynamics, and redox-responsive transcriptional networks. The limitations of non-selective antioxidant strategies are critically examined, highlighting why indiscriminate ROS suppression has yielded limited clinical benefit. In contrast, emerging therapeutic approaches aimed at recalibrating mitochondrial redox homeostasis, rather than abolishing physiological signalling, are discussed in the context of disease stage, metabolic state, and mitochondrial competence. By integrating redox biology with mitochondrial quality control and precision medicine concepts, this review proposes a unifying framework in which retinal neurodegeneration is governed by regulated mtROS signalling and the progressive exhaustion of mitochondrial resilience. This model defines critical therapeutic windows for mitochondria-targeted intervention and provides a framework for biomarker-guided patient stratification. Full article

(This article belongs to the Special Issue Mitochondrial ROS in Health and Disease)

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23 pages, 1378 KB

Open AccessReview

Mitochondrial Dysfunction: The Cellular Bridge from Emotional Stress to Disease Onset: A Narrative Review

by Sakthipriyan Venkatesan, Cristoforo Comi, Fabiola De Marchi, Teresa Esposito, Carla Gramaglia, Carlo Smirne, Mohammad Mostafa Ola Pour, Mario Pirisi, Rosanna Vaschetto, Patrizia Zeppegno and Elena Grossini

Biomolecules 2026, 16(1), 117; https://doi.org/10.3390/biom16010117 - 8 Jan 2026

Viewed by 1874

Abstract

Severe emotional stress constitutes a significant public-health concern associated with negative health outcomes. Although the clinical effects are well acknowledged, the specific biological mechanisms that translate emotional suffering into systemic disease remain incompletely understood. Psychological stress activates the sympathetic nervous system and hypothalamic–pituitary–adrenal axis, which directly target mitochondria and alter their bioenergetic and redox capacity. For this reason, this narrative review proposes that mitochondria serve as the primary subcellular link in the mind–body connection, as they play a pivotal role in converting neuroendocrine signals into cellular dysfunction. In particular, we focus on the concept of mitochondrial allostatic load (MALT), a framework explaining how the progressive decline in mitochondrial functions, from their initial adaptive roles in energy production, reactive oxygen species signaling, and calcium regulation, to being sources of inflammation and systemic damage, occurs when stress exceeds regulatory limits. We also, discuss how this transition turns mitochondria from adaptive responders into drivers of multi-organ disease. In subsequent sections, we examine diagnostic potentials related to MALT, including the use of biomarkers, such as growth differentiation factor 15, cell-free mitochondrial desoxyribonucleic acid, and functional respirometry. Furthermore, we evaluate mitochondria-targeted therapeutic strategies, encompassing pharmacological compounds, such as mitoquinone mesylate, Skulachev ions, and elamipretide, alongside lifestyle and psychological interventions. Here, we aim to translate MALT biology into clinical applications, positioning mitochondrial health as a target for preventing and treating stress-related disorders. We propose that MALT may serve as a quantifiable bridge between emotional stress and somatic disease, enabling future precision medicine strategies integrating mitochondrial care. Full article

(This article belongs to the Special Issue Mitochondrial ROS in Health and Disease)

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29 pages, 1962 KB

Open AccessReview

Mitochondrial Reactive Oxygen Species: A Unifying Mechanism in Long COVID and Spike Protein-Associated Injury: A Narrative Review

by Eunseuk Lee, Adaobi Amelia Ozigbo, Joseph Varon, Mathew Halma, Madison Laezzo, Song Peng Ang and Jose Iglesias

Biomolecules 2025, 15(9), 1339; https://doi.org/10.3390/biom15091339 - 18 Sep 2025

Cited by 6 | Viewed by 7471

Abstract

Post-acute sequelae of SARS-CoV-2 infection (long COVID) present with persistent fatigue, cognitive impairment, and autonomic and multisystem dysfunctions that often go unnoticed by standard diagnostic tests. Increasing evidence suggests that mitochondrial dysfunction and oxidative stress are central drivers of these post-viral sequelae. Viral infections, particularly SARS-CoV-2, disrupt mitochondrial bioenergetics by altering membrane integrity, increasing mitochondrial reactive oxygen species (mtROS), and impairing mitophagy, leading to sustained immune activation and metabolic imbalance. This review synthesizes an understanding of how mitochondrial redox signaling and impaired clearance of damaged mitochondria contribute to chronic inflammation and multisystem organ symptoms in both long COVID and post-vaccine injury. We discuss translational biomarkers and non-invasive techniques, exploring therapeutic strategies that include pharmacological, non-pharmacological, and nutritional approaches, as well as imaging modalities aimed at assessing and restoring mitochondrial health. Recognizing long COVID as a mitochondrial disorder that stems from redox imbalance will open new options for personalized treatment and management guided by biomarkers. Future clinical trials are essential to validate these approaches and translate mitochondrial resuscitation into effective care for patients suffering from long COVID and related post-viral syndromes. Full article

(This article belongs to the Special Issue Mitochondrial ROS in Health and Disease)

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18 pages, 2642 KB

Open AccessReview

Postbiotics as Mitochondrial Modulators in Inflammatory Bowel Disease: Mechanistic Insights and Therapeutic Potential

by Santosh Kumar Prajapati, Dhananjay Yadav, Shweta Katiyar, Shalini Jain and Hariom Yadav

Biomolecules 2025, 15(7), 954; https://doi.org/10.3390/biom15070954 - 1 Jul 2025

Cited by 14 | Viewed by 3128

Abstract

Postbiotics, which are non-viable microbial derivatives including short-chain fatty acids (SCFAs), microbial peptides, and cell wall components, are emerging as novel therapeutic agents for Inflammatory Bowel Disease (IBD). Unlike probiotics, postbiotics offer a safer, more stable alternative while retaining potent bioactivity. IBD, encompassing Crohn’s disease and ulcerative colitis, is characterized by chronic gastrointestinal inflammation, epithelial barrier dysfunction, and immune dysregulation. Recent evidence links mitochondrial dysfunction marked by impaired energy metabolism, oxidative stress, and apoptosis with the pathogenesis and persistence of IBD. Postbiotics have shown the ability to modulate mitochondrial health through multiple mechanisms. SCFAs such as butyrate serve as primary energy substrates for colonocytes, enhancing mitochondrial respiration and promoting biogenesis. They improve mitochondrial function and boost ATP production. Moreover, postbiotics reduce oxidative damage by regulating antioxidant defenses. These antioxidant actions limit epithelial apoptosis and preserve cellular integrity. In addition, postbiotics regulate mitophagy and help maintain mitochondrial quality and reduce inflammation. Structural components such as lipoteichoic acid and peptidoglycan have been shown to interact with mitochondrial pathways and modulate inflammatory responses. Collectively, this review explores the interplay between mitochondrial dysfunction, IBD, and preventive approach using postbiotics. Understanding the connections with postbiotics could open up new avenues for therapeutic interventions aimed at mitigating IBD severity in people with IBD. Full article

(This article belongs to the Special Issue Mitochondrial ROS in Health and Disease)

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20 pages, 746 KB

Open AccessReview

The Association Among Bipolar Disorder, Mitochondrial Dysfunction, and Reactive Oxygen Species

by Yuki Kageyama, Shohei Okura, Ayaka Sukigara, Ayaka Matsunaga, Kunio Maekubo, Takafumi Oue, Koki Ishihara, Yasuhiko Deguchi and Koki Inoue

Biomolecules 2025, 15(3), 383; https://doi.org/10.3390/biom15030383 - 6 Mar 2025

Cited by 14 | Viewed by 5263

Abstract

Mitochondria, often known as the cell’s powerhouses, are primarily responsible for generating energy through aerobic oxidative phosphorylation. However, their functions extend far beyond just energy production. Mitochondria play crucial roles in maintaining calcium balance, regulating apoptosis (programmed cell death), supporting cellular signaling, influencing cell metabolism, and synthesizing reactive oxygen species (ROS). Recent research has highlighted a strong link between bipolar disorder (BD) and mitochondrial dysfunction. Mitochondrial dysfunction contributes to oxidative stress, particularly through the generation of ROS, which are implicated in the pathophysiology of BD. Oxidative stress arises when there is an imbalance between the production of ROS and the cell’s ability to neutralize them. In neurons, excessive ROS can damage various cellular components, including proteins in neuronal membranes and intracellular enzymes. Such damage may interfere with neurotransmitter reuptake and the function of critical enzymes, potentially affecting brain regions involved in mood regulation and emotional control, which are key aspects of BD. In this review, we will explore how various types of mitochondrial dysfunction contribute to the production of ROS. These include disruptions in energy metabolism, impaired ROS management, and defects in mitochondrial quality control mechanisms such as mitophagy (the process by which damaged mitochondria are selectively degraded). We will also examine how abnormalities in calcium signaling, which is crucial for synaptic plasticity, can lead to mitochondrial dysfunction. Additionally, we will discuss the specific mitochondrial dysfunctions observed in BD, highlighting how these defects may contribute to the disorder’s pathophysiology. Finally, we will identify potential therapeutic targets to improve mitochondrial function, which could pave the way for new treatments to manage or mitigate symptoms of BD. Full article

(This article belongs to the Special Issue Mitochondrial ROS in Health and Disease)

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24 pages, 1618 KB

Open AccessReview

Antioxidative Function of Zinc and Its Protection Against the Onset and Progression of Kidney Disease Due to Cadmium

by Soisungwan Satarug

Biomolecules 2025, 15(2), 183; https://doi.org/10.3390/biom15020183 - 27 Jan 2025

Cited by 5 | Viewed by 3414

Abstract

Chronic kidney disease (CKD) is now the world’s top seventh cause of death from a non-communicable disease, and its incidence is projected to increase further as its major risk factors, including obesity, diabetes, hypertension, and non-alcoholic fatty liver disease (NAFLD), continue to rise. Current evidence has linked the increased prevalence of CKD, diabetes, hypertension, and NAFLD to chronic exposure to the metal pollutant cadmium (Cd). Exposure to Cd is widespread because diet is the main exposure route for most people. Notably, however, the health risk of dietary Cd exposure is underappreciated, and the existing tolerable exposure guidelines for Cd do not afford health protection. New health-protective exposure guidelines are needed. From one’s diet, Cd is absorbed by the intestinal epithelium from where it passes through the liver and accumulates within the kidney tubular epithelial cells. Here, it is bound to metallothionine (MT), and as it is gradually released, it induces tubular damage, tubulointerstitial inflammation and fibrosis, and nephron destruction. The present review provides an update on our knowledge of the exposure levels of Cd that are found to be associated with CKD, NAFLD, and mortality from cardiovascular disease. It discusses the co-existence of hypertension and CKD in people environmentally exposed to Cd. It highlights nuclear and mitochondrial targeting and zinc deficiency as the universal cytotoxic mechanisms of Cd. Special emphasis is placed on the novel antioxidative function of zinc involving de novo heme biosynthesis and the induced expression of heme oxygenase-1 (HO-1). Other exogenous biomolecules with promising anti-Cd toxicity are highlighted. Full article

(This article belongs to the Special Issue Mitochondrial ROS in Health and Disease)

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32 pages, 1987 KB

Open AccessReview

Mitochondrial Reactive Oxygen Species in Infection and Immunity

by Arunima Mukherjee, Krishna Kanta Ghosh, Sabyasachi Chakrabortty, Balázs Gulyás, Parasuraman Padmanabhan and Writoban Basu Ball

Biomolecules 2024, 14(6), 670; https://doi.org/10.3390/biom14060670 - 8 Jun 2024

Cited by 58 | Viewed by 11298

Abstract

Reactive oxygen species (ROS) contain at least one oxygen atom and one or more unpaired electrons and include singlet oxygen, superoxide anion radical, hydroxyl radical, hydroperoxyl radical, and free nitrogen radicals. Intracellular ROS can be formed as a consequence of several factors, including ultra-violet (UV) radiation, electron leakage during aerobic respiration, inflammatory responses mediated by macrophages, and other external stimuli or stress. The enhanced production of ROS is termed oxidative stress and this leads to cellular damage, such as protein carbonylation, lipid peroxidation, deoxyribonucleic acid (DNA) damage, and base modifications. This damage may manifest in various pathological states, including ageing, cancer, neurological diseases, and metabolic disorders like diabetes. On the other hand, the optimum levels of ROS have been implicated in the regulation of many important physiological processes. For example, the ROS generated in the mitochondria (mitochondrial ROS or mt-ROS), as a byproduct of the electron transport chain (ETC), participate in a plethora of physiological functions, which include ageing, cell growth, cell proliferation, and immune response and regulation. In this current review, we will focus on the mechanisms by which mt-ROS regulate different pathways of host immune responses in the context of infection by bacteria, protozoan parasites, viruses, and fungi. We will also discuss how these pathogens, in turn, modulate mt-ROS to evade host immunity. We will conclude by briefly giving an overview of the potential therapeutic approaches involving mt-ROS in infectious diseases. Full article

(This article belongs to the Special Issue Mitochondrial ROS in Health and Disease)

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