Fact-checked by Grok 2 weeks ago

Mitochondrial ROS

Mitochondrial reactive oxygen species (ROS) are highly reactive molecules, primarily superoxide (O₂⁻•) and hydrogen peroxide (H₂O₂), generated as byproducts of mitochondrial respiration through the one-electron reduction of molecular oxygen at redox-active sites in the electron transport chain (ETC).^[1] These species arise mainly from complexes I (NADH:ubiquinone oxidoreductase) and III (ubiquinol:cytochrome c oxidoreductase) of the ETC, with production rates influenced by factors such as membrane potential (Δp), substrate availability (e.g., NADH/NAD⁺ ratio), and reverse electron transport.^[1] Mitochondria account for approximately 90% of cellular ROS generation under normal conditions, where superoxide is rapidly converted to H₂O₂ by manganese superoxide dismutase (MnSOD).^[2] In physiological contexts, mitochondrial ROS function as pleiotropic signaling molecules that regulate diverse cellular processes, including cell proliferation, differentiation, autophagy, immune responses, and adaptation to hypoxia via pathways like HIF-1α stabilization.^[2] For instance, transient bursts of ROS, known as "superoxide flashes," modulate mitochondrial permeability transition pores (mPTPs) and influence kinase/phosphatase activity to maintain homeostasis, blood pressure, and synaptic signaling.^[3] They also play roles in immune activation by stimulating inflammasomes (e.g., NLRP3) in phagocytes and in reproductive processes such as sperm capacitation.^[4] However, dysregulated overproduction of mitochondrial ROS leads to oxidative stress, where these species damage biomolecules like mitochondrial DNA (mtDNA), proteins (e.g., aconitase-2), and lipids (e.g., cardiolipin), impairing mitochondrial function and triggering apoptosis.^[3] This imbalance contributes to numerous pathologies, including chronic kidney disease (CKD) progression through podocyte injury and inflammation, cardiovascular diseases like hypertension and atherosclerosis via endothelial dysfunction, neurodegeneration, cancer (e.g., via the Warburg effect), and aging per the mitochondrial free radical theory.^[2]^[4] Cellular antioxidant defenses, such as superoxide dismutases, catalases, and glutathione systems, normally mitigate excess ROS, but their insufficiency amplifies disease states.^[3]

Fundamentals

Definition and Types

Reactive oxygen species (ROS) are a class of highly reactive molecules derived from molecular oxygen (O_2) that play key roles in cellular processes, encompassing free radicals such as the superoxide anion (O_2^{\bullet -}), the hydroxyl radical (\bulletOH), and non-radical species like hydrogen peroxide (H_2O_2).^[5] These species are more reactive than ground-state O_2 due to the presence of unpaired electrons or unstable bonds, enabling them to oxidize biomolecules including proteins, lipids, and DNA.^[6] Mitochondrial ROS (mtROS) specifically refer to ROS generated within the mitochondria, the organelles responsible for cellular energy production, distinguishing them from ROS produced at other cellular sites such as peroxisomes or the plasma membrane.^[7] mtROS primarily arise from the mitochondrial electron transport chain (ETC) but can also form through secondary reactions, and their production is tightly linked to mitochondrial function under both physiological and pathological conditions.^[8] mtROS are classified into primary and secondary types based on their formation. Primary mtROS consist mainly of superoxide (O_2^{\bullet -}), produced directly by electron leakage from the ETC complexes.^[9] Secondary mtROS, such as hydrogen peroxide (H_2O_2), result from the enzymatic dismutation of superoxide by superoxide dismutase (SOD) enzymes located in the mitochondrial matrix (SOD2) or intermembrane space (SOD1).^[8] The hydroxyl radical (\bulletOH) can form secondarily via Fenton chemistry involving H_2O_2 and transition metals like iron, though it is less commonly associated with direct mitochondrial generation compared to O_2^{\bullet -} and H_2O_2.^[5] Unlike non-mitochondrial ROS, which may originate from NADPH oxidases or external sources, mtROS are uniquely tied to oxidative phosphorylation and exhibit site-specific production within the organelle.^[10] The chemical properties of mtROS dictate their biological impact, with reactivity, half-life, and diffusion varying significantly among species. Superoxide (O_2^{\bullet -}) is moderately reactive but has a short half-life (on the order of milliseconds to seconds in aqueous environments, rapidly reduced further in cells by superoxide dismutase) and limited diffusion due to its charged nature and rapid conversion to H_2O_2, restricting its action primarily to the site of production.^[11]^[12] In contrast, H_2O_2 possesses lower reactivity, a longer half-life (milliseconds to seconds), and better membrane permeability, allowing it to diffuse across mitochondrial membranes and even the cytosol via aquaporin channels, thereby enabling broader signaling roles.^[13] The hydroxyl radical (\bulletOH), while highly reactive with a half-life of nanoseconds, reacts indiscriminately with nearby molecules, making its effects highly localized and damaging if formed near critical cellular components.^[14]

Cellular Sources

Mitochondria serve as the primary cellular source of reactive oxygen species (ROS), particularly mitochondrial ROS (mtROS), owing to their high oxygen consumption and the activity of the electron transport chain (ETC) during oxidative phosphorylation. This process involves the transfer of electrons through the ETC, where a small fraction of oxygen is partially reduced to form superoxide anion (O₂⁻•), the precursor to other mtROS species such as hydrogen peroxide (H₂O₂). Under basal conditions, mitochondria are a major source of total cellular ROS, though their contribution varies by cell type and is often estimated at less than 50%, highlighting their important role in cellular redox homeostasis.^[15] In comparison, other cellular compartments contribute lesser amounts of ROS. Peroxisomes primarily produce H₂O₂ through β-oxidation of fatty acids and other enzymatic reactions, accounting for a smaller fraction of overall ROS. NADPH oxidases (NOX enzymes), located in plasma membranes or intracellular compartments, generate superoxide for signaling purposes but represent only about 10% or less of basal cellular ROS production. Endoplasmic reticulum (ER) stress can also lead to ROS generation via protein misfolding and disulfide bond formation, though this is typically stress-induced rather than constitutive.^[2] Within mitochondria, mtROS production occurs across distinct compartments, influencing their downstream effects. The matrix is a key site where superoxide is generated and can be dismutated by superoxide dismutase 2 (SOD2) to H₂O₂, which diffuses freely. The intermembrane space receives superoxide from complex III via semiquinone intermediates, with SOD1 facilitating its conversion to H₂O₂ there. ROS can also form at the inner mitochondrial membrane, primarily through ETC complexes, and to a lesser extent at the outer membrane via cytochrome b5 reductase or other shuttles. These compartmental differences affect ROS localization and reactivity within the organelle. Non-enzymatic sources of mtROS arise from the auto-oxidation of redox-active molecules within mitochondria. Reduced ubiquinone (ubiquinol) can auto-oxidize to form semiquinone radicals that react with oxygen to produce superoxide, particularly under conditions of high reduction potential. Similarly, flavin cofactors in enzymes like complex I undergo auto-oxidation, releasing superoxide directly from their reduced forms. These reactions supplement enzymatic ROS production and contribute to baseline mtROS levels without requiring specific electron donors.^[16]

Production Mechanisms

Electron Transport Chain Role

The mitochondrial electron transport chain (ETC) consists of four multi-subunit protein complexes (I–IV) embedded in the inner mitochondrial membrane, along with the mobile electron carriers ubiquinone (coenzyme Q) and cytochrome c. Electrons from the reducing equivalents NADH and FADH₂, generated by the tricarboxylic acid cycle, are sequentially transferred through Complexes I (or II), III, and IV to molecular oxygen, the terminal electron acceptor, which is reduced to water at Complex IV. This electron flow is tightly coupled to the vectorial translocation of protons from the matrix to the intermembrane space by Complexes I, III, and IV, thereby establishing an electrochemical proton gradient (Δp) across the inner membrane that powers ATP synthesis through the F₁F₀-ATP synthase (Complex V).^[17]^[18] Reactive oxygen species (ROS) in mitochondria are primarily generated as superoxide anion (O₂•⁻) via partial, one-electron reduction of O₂ by electrons that leak from the ETC rather than following the main pathway. The principal sites of this leakage are within Complex I and Complex III. In Complex I, superoxide production occurs at two distinct locations: the flavin mononucleotide (FMN) site (denoted as site I_F), where electrons from NADH can directly reduce O₂, and the ubiquinone reduction site (site I_Q), involving the semiquinone intermediate at the Q-binding pocket. In Complex III, ROS formation is localized to the outer ubiquinol oxidation site (Qo site) of the cytochrome bc₁ complex, where the transiently formed ubisemiquinone radical (QH•) donates an electron to O₂ during the Q-cycle. The core mechanism of superoxide generation at these sites is the diversion of high-energy electrons to O₂, as depicted in the following reaction:

\ce{O2 + e^- -> O2^{\bullet-}}

This process accounts for the majority of mitochondrial superoxide, which primarily references the superoxide type of ROS.^[17]^[18]^[19] A prominent pathway amplifying ROS production at Complex I involves reverse electron transport (RET), wherein electrons from succinate (via Complex II) reduce ubiquinone to ubiquinol, which then transfers electrons backward through Complex I to reduce NAD⁺ to NADH, driven by a highly negative membrane potential (Δψ_m). RET-mediated superoxide generation is markedly enhanced under conditions of high Δψ_m (typically >150 mV) or elevated concentrations of reduced substrates like succinate or NADH, which thermodynamically favor electron backflow and increase the probability of leakage to O₂. Seminal investigations, such as those by Turrens and colleagues on Complex III semiquinone reactivity and by Murphy and colleagues on Complex I flavin sites, have established these mechanisms through isotopic labeling and inhibitor studies.^[18]00658-1)

Influencing Factors

Several physiological and environmental factors modulate the rate of mitochondrial reactive oxygen species (mtROS) production, primarily by altering electron flow through the electron transport chain (ETC). Substrate availability plays a critical role, as a high NADH/NAD⁺ ratio in the mitochondrial matrix promotes reverse electron transport (RET) at Complex I, driving superoxide generation from the flavin mononucleotide site.^[20] This occurs when NADH accumulation exceeds the capacity for forward electron transfer, such as during high rates of substrate oxidation like succinate, leading to elevated mtROS levels that can signal cellular stress.^[21] Oxygen availability also influences mtROS production in a biphasic manner. Under hypoxic conditions, reduced oxygen as the terminal electron acceptor slows ETC activity at Complex IV, but paradoxically, Complex I can generate increased superoxide due to altered redox poise and partial reduction of electron carriers.^[20] Upon reoxygenation, a burst of mtROS often ensues, particularly via RET at Complex I, as restored oxygen enables rapid oxidation of accumulated reducing equivalents like succinate, exacerbating oxidative stress in post-hypoxic tissues.^[22] Changes in pH and temperature further affect ETC efficiency and mtROS output. Acidic intracellular pH, as seen in ischemia or metabolic acidosis, enhances RET-mediated ROS at Complex I by inhibiting Complex II activity and favoring electron backflow, thereby increasing superoxide emission.^[23] Elevated temperatures, such as during hyperthermia, accelerate ETC enzyme kinetics but also heighten the ROS/O₂ consumption ratio during phosphorylating respiration, promoting greater electron leakage and H₂O₂ release from mitochondrial sites.^[24] Pathological states like ischemia-reperfusion (I/R) injury trigger pronounced mtROS bursts. During ischemia, succinate accumulates via reversal of succinate dehydrogenase, creating a highly reduced ubiquinone pool; upon reperfusion, rapid succinate oxidation fuels RET at Complex I, resulting in a surge of superoxide that damages mitochondrial components and propagates tissue injury.^[25] Pharmacological agents can similarly elevate mtROS by disrupting ETC function. Antimycin A, a classic inhibitor, blocks the Qi site of Complex III, stabilizing the semiquinone radical at the Qo site and markedly increasing superoxide production from this site during forward electron transport from Complex I or II substrates.^[26] This tool has been instrumental in elucidating Complex III as a key ROS source under inhibited conditions.^[27]

Regulation and Control

Antioxidant Systems

Mitochondrial antioxidant systems comprise a network of enzymatic and non-enzymatic components that neutralize reactive oxygen species (ROS), particularly superoxide (O₂•⁻) and hydrogen peroxide (H₂O₂), to prevent oxidative damage while maintaining redox homeostasis.^[14] These systems are essential in the mitochondrial matrix and inner membrane, where ROS production is highest, ensuring that physiological ROS levels support cellular signaling without causing harm.^[14] The primary enzymatic antioxidant is superoxide dismutase 2 (SOD2), a manganese-dependent enzyme localized in the mitochondrial matrix that catalyzes the dismutation of superoxide radicals to hydrogen peroxide and oxygen.^[14] This reaction proceeds as follows:

$2O_2^{\bullet-} + 2H^+ \rightarrow H_2O_2 + O_2

SOD2 operates with a high rate constant of approximately 1–2 × 10⁹ M⁻¹·s⁻¹, efficiently reducing superoxide levels, though it generates H₂O₂ as a byproduct that requires further detoxification.^[14] Downstream, H₂O₂ is scavenged by multiple enzymes: catalase, which decomposes H₂O₂ into water and oxygen with high capacity at elevated substrate concentrations and is present in certain mitochondrial populations like those in heart and liver; glutathione peroxidase (GPx), particularly isoforms GPx1 and GPx4 in mitochondria, which reduce H₂O₂ using reduced glutathione (GSH) as a cofactor; and peroxiredoxins (Prx3 and Prx5), thioredoxin-dependent enzymes that account for about 90% of mitochondrial H₂O₂ metabolism.^[14] The GPx reaction is:

$2GSH + H_2O_2 \rightarrow GSSG + 2H_2O

where GSSG is oxidized glutathione, recycled back to GSH via glutathione reductase using NADPH.^[28] The thioredoxin system, including thioredoxin 2 (Trx2) and thioredoxin reductase 2 (TrxR2), regenerates Prx3 and Prx5 through thiol-disulfide exchange, providing a NADPH-dependent pathway for peroxide reduction and protein thiol protection.^[14] Non-enzymatic antioxidants complement these enzymes by directly scavenging ROS or regenerating other defenders. Reduced glutathione (GSH) maintains a high mitochondrial concentration of about 10 mM, serving as a substrate for GPx and directly neutralizing peroxides via nucleophilic attack.^[14] Coenzyme Q10 (CoQ10), embedded in the inner mitochondrial membrane, acts as a lipid-soluble chain-breaking antioxidant that intercepts lipid peroxyl radicals and regenerates vitamins E and C.^[14] Vitamins E (α-tocopherol) and C (ascorbate) also contribute: vitamin E traps lipid radicals in membranes, while vitamin C, transported into mitochondria, donates electrons to reduce various ROS and recycle vitamin E.^[14] These systems are dynamically regulated through feedback loops involving the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), which responds to mild mtROS elevations by dissociating from Keap1, translocating to the nucleus, and binding antioxidant response elements (AREs) to upregulate genes encoding SOD2, GPx, Prx3/5, and TrxR2.^[29] This Nrf2-mediated induction enhances mitochondrial antioxidant capacity, forming a protective feedback mechanism that mitigates oxidative stress while promoting mitohormesis—adaptive responses to low-level ROS.^[29] In severe stress, however, alternative pathways like Klf9 can repress these genes, fine-tuning the response.^[29]

Mitochondrial Dynamics

Mitochondrial dynamics, which include the processes of fission, fusion, and mitophagy, are essential for mitochondrial quality control and directly influence mitochondrial reactive oxygen species (mtROS) levels by maintaining organelle integrity and function. These dynamic events allow cells to adapt to stress, distribute mtDNA and proteins evenly, and eliminate damaged components that could otherwise amplify ROS production through electron leakage in the electron transport chain. Disruptions in this balance often result in elevated mtROS, contributing to cellular dysfunction across various physiological contexts. Mitochondrial fission, predominantly mediated by dynamin-related protein 1 (Drp1), fragments the mitochondrial network into smaller units, facilitating distribution during cell division and enabling the isolation of damaged segments for degradation. However, excessive Drp1 activity promotes the formation of fragmented, dysfunctional mitochondria that exhibit increased mtROS generation due to impaired respiratory chain efficiency and heightened vulnerability to oxidative stress. For example, Drp1 phosphorylation at serine 616 enhances fission and correlates with elevated ROS in stress conditions, underscoring fission's role in amplifying mtROS when dysregulated.^[30] Mitochondrial fusion counteracts fission by merging organelles, primarily through mitofusins 1 and 2 (MFN1/2) on the outer membrane and optic atrophy 1 (OPA1) on the inner membrane, which facilitates the exchange of mtDNA, lipids, and proteins to dilute localized damage. This process enhances overall respiratory capacity and reduces mtROS production by restoring cristae structure and minimizing electron leakage. OPA1, in particular, maintains inner membrane integrity, and its deficiency leads to fragmented mitochondria with elevated ROS, while fusion promotion preserves membrane potential and limits oxidative burden.^[31] Mitophagy serves as a selective degradation mechanism to remove high-mtROS-producing mitochondria, primarily via the PINK1/Parkin pathway, where damaged organelles accumulate PINK1 on their surface, recruiting Parkin E3 ligase to ubiquitinate outer membrane proteins for autophagosome targeting. This clearance prevents the persistence of ROS-generating mitochondria, preserving cellular redox homeostasis, and its impairment results in mtROS buildup and bioenergetic failure.^[32] The interplay among fission, fusion, and mitophagy ensures mitochondrial network homeostasis; imbalances, such as fission dominance, hinder fusion and mitophagy efficiency, leading to dysfunctional mitochondria accumulation and sustained mtROS elevation. In aging, for instance, age-related shifts toward excessive Drp1-mediated fission impair fusion, fostering oxidative stress through persistent damaged organelles.^[33]^[34] Recent findings from 2020 onward emphasize mitochondrial dynamics' role in ischemia-reperfusion injury, where reperfusion triggers excessive Drp1-dependent fission, exacerbating mtROS bursts and cellular damage, while pharmacological inhibition of fission preserves function and reduces ROS-mediated injury. These insights highlight dynamics as a therapeutic target for mitigating oxidative stress in acute conditions.^[35]^[36]

Physiological Roles

Redox Signaling

Mitochondrial reactive oxygen species (mtROS) serve as second messengers in redox signaling, facilitating cellular homeostasis by modulating the oxidation of protein thiols at physiological levels. These species, primarily superoxide and hydrogen peroxide, reversibly oxidize cysteine residues in target proteins, thereby altering their conformation, activity, or interactions without causing widespread damage. This thiol-based signaling enables mtROS to propagate signals from mitochondria to other cellular compartments, influencing processes such as adaptation to stress and maintenance of redox balance.^[37] A prominent example involves the Keap1-Nrf2 pathway, where low levels of mtROS oxidize specific cysteine residues in Kelch-like ECH-associated protein 1 (Keap1), disrupting its interaction with nuclear factor erythroid 2-related factor 2 (Nrf2). This modification prevents Nrf2 ubiquitination and proteasomal degradation, allowing Nrf2 translocation to the nucleus to activate antioxidant response element (ARE)-driven genes, including those encoding glutathione peroxidase and superoxide dismutase, which bolster cellular defense against oxidative perturbations. Similarly, mtROS oxidize the active-site cysteine (Cys124) in phosphatase and tensin homolog (PTEN), inactivating its lipid phosphatase activity and thereby enhancing phosphoinositide 3-kinase (PI3K)/Akt signaling to promote cell survival and proliferation under mild stress.^[38]^[39] In oxygen sensing, mtROS contribute to the stabilization of hypoxia-inducible factor (HIF)-1α by inhibiting prolyl hydroxylase domain enzymes (PHDs), which require molecular oxygen as a cofactor. During hypoxia, increased mtROS production from complex III of the electron transport chain oxidizes and inactivates PHDs, preventing hydroxylation of HIF-1α proline residues and subsequent recognition by the von Hippel-Lindau ubiquitin ligase complex, thus allowing HIF-1α accumulation and transcriptional activation of genes involved in angiogenesis and glycolysis. This mechanism ensures adaptive responses to low oxygen without relying solely on oxygen availability.^[40] mtROS also regulate calcium handling by influencing the mitochondrial calcium uniporter (MCU), a channel complex that facilitates Ca²⁺ influx into the mitochondrial matrix. Oxidation of redox-sensitive residues in MCU components, such as Cys97 in MCU, alters channel gating via S-glutathionylation, modulating Ca²⁺ uptake and thereby linking mitochondrial bioenergetics to cytosolic signaling; for instance, moderate mtROS levels enhance MCU activity to support Ca²⁺-dependent dehydrogenases in the Krebs cycle, optimizing ATP production during physiological demands.^[41] In metabolic regulation, mtROS promote AMP-activated protein kinase (AMPK) activation, a central sensor of energy status that restores homeostasis by stimulating catabolic pathways. mtROS generated under metabolic stress, such as nutrient deprivation, activate AMPK by altering the ATP/ADP ratio or through direct S-glutathionylation, leading to phosphorylation at Thr172 and subsequent inhibition of anabolic processes while enhancing mitochondrial biogenesis via PGC-1α. This mtROS-AMPK axis maintains energy balance during fasting or hypoxia.^[42] Physiologically, mtROS signaling modulates vascular tone by influencing endothelial nitric oxide synthase (eNOS) activity in endothelial cells, contributing to NO production and vasodilation through redox-sensitive signaling pathways.^[43] In skeletal muscle, exercise-induced mtROS act as signals for adaptation, activating pathways like PGC-1α and AMPK to increase mitochondrial content and oxidative capacity, enhancing endurance and fatigue resistance without pathological overload.^[44]^[45]

Immune Modulation

Mitochondrial reactive oxygen species (mtROS) play a pivotal role in innate immunity by facilitating the activation of the NLRP3 inflammasome in macrophages and neutrophils. During pathogen recognition, mtROS production from the electron transport chain serves as a key signal for NLRP3 assembly, leading to the processing and secretion of pro-inflammatory cytokines such as interleukin-1β (IL-1β). This process is particularly evident in response to microbial stimuli, where mtROS oxidize and release mitochondrial DNA, which acts as a damage-associated molecular pattern (DAMP) to prime the inflammasome.^[46]^[47] Studies have shown that inhibiting mtROS generation, such as through mitochondrial-targeted antioxidants, significantly impairs NLRP3-dependent responses in these immune cells, underscoring their essential function in antimicrobial defense.^[48] In adaptive immunity, mtROS exhibit a dose-dependent regulation of T-cell activation and fate. Low levels of mtROS, generated during early T-cell receptor signaling, promote proliferation by enhancing IL-2 production and sustaining metabolic reprogramming toward glycolysis, thereby supporting effector functions.^[49] Conversely, elevated mtROS levels trigger apoptosis in activated T cells, preventing excessive expansion and maintaining immune homeostasis through activation of caspase pathways.^[50] This biphasic effect ensures balanced T-cell responses, with chronic high mtROS linked to T-cell exhaustion in prolonged immune challenges.^[51] mtROS also contribute to antiviral immunity by driving interferon production in infected cells. In plasmacytoid dendritic cells and epithelial cells, mtROS signaling activates pathways like MAVS (mitochondrial antiviral-signaling protein), culminating in type I interferon (IFN-α/β) and type III interferon (IFN-λ) expression to establish an antiviral state.^[52]^[53] For instance, during influenza A virus infection, mtROS from complex I and III of the respiratory chain amplify RIG-I-mediated interferon responses, enhancing viral clearance.^[54]

Pathophysiological Effects

Oxidative Damage Mechanisms

Mitochondrial reactive oxygen species (mtROS) induce oxidative damage by reacting with key biomolecules, leading to structural and functional impairments in mitochondria and surrounding cellular components. This damage primarily targets lipids, proteins, and DNA within the organelle, disrupting energy production and cellular homeostasis. Excess mtROS overwhelm antioxidant defenses, initiating irreversible modifications that propagate further stress.^[55] Lipid peroxidation represents a primary mechanism of mtROS-induced damage, occurring in the polyunsaturated fatty acids of mitochondrial inner and outer membranes. Superoxide and hydrogen peroxide initiate the process by abstracting hydrogen atoms from lipids, forming lipid radicals that react with oxygen to create peroxyl radicals; this self-propagating chain reaction amplifies damage and compromises membrane integrity. Key products include 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), reactive aldehydes that form covalent adducts with proteins and DNA, inhibiting enzymes and signaling pathways. For instance, 4-HNE modifies sulfhydryl groups on the adenine nucleotide translocase (ANT), reducing its activity and promoting mitochondrial permeability transition. MDA, meanwhile, cross-links proteins and DNA, serving as a biomarker of oxidative stress in mitochondrial contexts. These alterations disrupt electron transport and ion homeostasis, exacerbating cellular dysfunction.^[55]^[56] Protein oxidation by mtROS targets critical residues in mitochondrial enzymes, leading to functional loss and structural instability. Carbonylation, a stable oxidative modification, occurs when mtROS or secondary lipid peroxidation products oxidize amino acids like lysine, arginine, and proline, forming carbonyl groups that alter protein conformation and activity. In the electron transport chain (ETC), carbonylation affects complexes I, III, and IV, damaging iron-sulfur clusters and heme groups, which reduces electron flow and ATP synthesis efficiency. Sulfenylation, involving the reversible oxidation of cysteine thiols to sulfenic acids, disrupts thiol-dependent proteins such as ANT and creatine kinase; for example, oxidation of specific cysteines (e.g., Cys160, Cys257 in ANT) facilitates mitochondrial permeability transition pore opening. These modifications collectively impair ETC performance, with oxidized complexes showing reduced activity in stressed conditions.^[55]^[55] mtROS also cause significant DNA damage, particularly to mitochondrial DNA (mtDNA) due to its proximity to ROS production sites in the ETC. This results in base modifications, such as 8-oxoguanine, single- and double-strand breaks, and deletions, often without protective histones to shield the genome. mtDNA mutation rates are 10-20 times higher than those of nuclear DNA, attributed to the lack of efficient repair mechanisms and constant exposure to mtROS; for example, more than 150 pathogenic mtDNA mutations have been identified, with oxidative stress contributing to their accumulation and impairing replication and transcription.^[55] While mtDNA damage predominates, mtROS can diffuse to the cytosol, inducing strand breaks and mutations in nuclear DNA, though at lower rates due to better protective systems. Repair enzymes like OGG1 and MYH mitigate some mtDNA lesions, but chronic exposure leads to persistent genomic instability.^[57] The oxidative damage creates a vicious cycle wherein impaired mitochondria generate even more ROS. Damaged ETC complexes leak electrons prematurely, elevating superoxide production, while lipid peroxidation products and carbonylated proteins further inhibit respiratory function, amplifying mtROS output. This feedback loop sustains oxidative stress, contributing to progressive cellular decline.^[55]

Contribution to Aging

The free radical theory of aging, originally proposed by Denham Harman in 1956, posits that endogenous free radicals, particularly reactive oxygen species (ROS) generated by mitochondria, accumulate over time and cause progressive damage to cellular components, leading to aging and associated degenerative diseases. Although once influential, the mitochondrial free radical theory of aging has been largely refuted by studies as of 2025 showing that lowering ROS levels—through genetic or pharmacological means—does not consistently extend lifespan, shifting emphasis to broader mitochondrial dysfunction as a driver of aging.^[58]^[59] This theory has evolved to emphasize mitochondrial ROS (mtROS) as key contributors, where chronic low-level production during oxidative phosphorylation results in oxidative modifications to biomolecules, impairing cellular function and homeostasis, though its causal role remains debated.^[60] A central mechanism in this process involves mtROS-induced mutations in mitochondrial DNA (mtDNA), which lacks robust protective histones and repair mechanisms compared to nuclear DNA, leading to their accumulation with age. These somatic mtDNA mutations disrupt electron transport chain complexes, further elevating mtROS production in a vicious cycle that exacerbates age-related mitochondrial dysfunction across tissues.^[61] In aging models, such as rodents, mtDNA mutation loads increase progressively, correlating with declined respiratory capacity and bioenergetic failure.^[62] mtROS-mediated oxidative stress also accelerates telomere shortening, a hallmark of replicative senescence, by promoting DNA strand breaks and inhibiting telomerase activity, thereby limiting cell proliferation and contributing to tissue regeneration deficits.^[63] This oxidative burden further drives stem cell exhaustion, where elevated ROS levels in hematopoietic and mesenchymal stem cells impair self-renewal and differentiation, reducing the regenerative reserve essential for maintaining tissue integrity during aging.^[64] In skeletal muscle, mtROS contribute to sarcopenia by suppressing mitochondrial biogenesis through downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a master regulator that coordinates mitochondrial turnover and antioxidant defenses, resulting in fiber atrophy and reduced physical function.^[65] Similarly, in the brain, chronic mtROS exposure impairs PGC-1α signaling, leading to bioenergetic deficits and neuronal vulnerability that underpin neurodegeneration, as seen in models of age-related cognitive decline.^[66] Recent 2025 research highlights imbalances in mitochondrial dynamics—fission and fusion processes—as a driver of cellular senescence, where mtROS-induced fragmentation accumulates dysfunctional mitochondria, amplifying oxidative stress and inflammatory signaling in senescent cells.^[61] Interventions targeting NAD+ precursors, such as nicotinamide mononucleotide (NMN), have shown promise in restoring NAD+ levels to enhance sirtuin activity, thereby reducing mtROS production and mitigating senescence in aging models.^[67]^[68] Supporting evidence comes from caloric restriction (CR) studies, which consistently lower mtROS generation at complex I of the electron transport chain, preserving mitochondrial efficiency and extending lifespan by 30-50% in rodent models without malnutrition.^[69] In these paradigms, CR upregulates antioxidant pathways and PGC-1α, delaying mtDNA damage accumulation and age-related functional decline.^[70]

Disease Associations

Infectious Diseases Including COVID-19

Mitochondrial reactive oxygen species (mtROS) play a dual role in viral infections, acting as key mediators of antiviral innate immune signaling while also contributing to pathological inflammation. During viral invasion, mtROS generated from the electron transport chain activate pathways such as the NLRP3 inflammasome and RIG-I-like receptors, promoting type I interferon production and restricting viral replication in infected cells.^[71] However, excessive mtROS can exacerbate cytokine storms by amplifying proinflammatory responses, leading to tissue damage and systemic inflammation that favors viral persistence.^[72] In SARS-CoV-2 infection, the virus disrupts mitochondrial function through its proteins, including ORF9b and the spike protein, which localize to mitochondria and impair bioenergetics, resulting in elevated mtROS production.^[73] This mtROS surge contributes to endothelial dysfunction, ferroptosis in lung epithelial cells, and acute respiratory distress syndrome by promoting lipid peroxidation and inflammasome activation.^[74] Studies, including from 2023, highlight how SARS-CoV-2 suppresses mitochondrial gene expression, further amplifying mtROS and linking it to severe COVID-19 outcomes like multi-organ involvement.^[75] Post-acute sequelae of SARS-CoV-2 infection, or long COVID, involve persistent mtROS-mediated oxidative stress, with 2025 research demonstrating elevated ROS levels and mitochondrial structural abnormalities in affected patients, correlating with fatigue, cognitive impairment, and chronic inflammation.^[76] These findings indicate that unresolved mtROS imbalance sustains low-grade inflammation, distinguishing long COVID from resolved acute infection.^[77] In bacterial infections, mtROS are essential for phagocytic killing by macrophages and neutrophils, where they facilitate bacterial clearance through oxidative burst and direct antimicrobial effects within phagosomes.^[78] For instance, mtROS production enhances the efficacy of NADPH oxidase-independent pathways in engulfing pathogens like Streptococcus pneumoniae, supporting host defense without excessive tissue harm.^[72] During sepsis, dysregulated mtROS contribute to multi-organ failure by overwhelming antioxidant defenses, leading to mitochondrial swelling, reduced ATP synthesis, and apoptosis in vital tissues such as the heart, kidneys, and lungs.^[79] This excessive mtROS arises from bacterial toxins and inflammatory cytokines, perpetuating a vicious cycle of oxidative damage and hemodynamic instability.^[80] Therapeutic strategies targeting mtROS in infectious diseases include mitochondria-permeable antioxidants like MitoQ, which mitigate ROS-induced inflammation in experimental models of viral pneumonia and sepsis, improving survival and organ function.^[81] Clinical trials exploring such agents, alongside N-acetylcysteine, show promise in reducing cytokine storms during severe infections, though optimal dosing remains under investigation.^[82]

Chronic Diseases

Mitochondrial reactive oxygen species (mtROS) contribute significantly to the pathogenesis of various chronic diseases by inducing oxidative stress, disrupting cellular homeostasis, and amplifying inflammatory responses. In non-communicable conditions, excessive mtROS production from the electron transport chain impairs mitochondrial function, leading to energy deficits and downstream tissue damage. This section examines the roles of mtROS in neurodegenerative, cardiovascular, oncological, and metabolic disorders, highlighting specific mechanisms and recent insights. In neurodegenerative diseases, mtROS drive protein aggregation and neuronal loss. In Parkinson's disease, mitochondrial oxidant stress promotes α-synuclein aggregation through reactive oxygen species (ROS) that damage mitochondrial proteins like NDUFB8 and NDUFS3, exacerbating pathology in models with GBA1 mutations such as L444P, where ROS levels increase by 30-50% and aggregation by fivefold.^[83] Overexpression of superoxide dismutase 2 mitigates this by reducing ROS burden and halting α-synuclein spreading.^[83] Similarly, in Alzheimer's disease, mitochondrion-derived ROS trigger amyloid-β (Aβ) production by enhancing β-site APP cleaving enzyme (BACE1) activity; for instance, complex I inhibition with rotenone elevates Aβ1-40 levels by 75% in cell models, establishing a vicious cycle where Aβ further impairs mitochondria and boosts ROS.^[84] Antioxidants like vitamin C partially reverse this elevation by about 20%.^[84] Cardiovascular chronic conditions involve mtROS-mediated vascular injury and myocardial damage. In atherosclerosis, excessive mtROS from complexes I and III reduce nitric oxide bioavailability via peroxynitrite formation, uncouple endothelial nitric oxide synthase (eNOS), and promote endothelial inflammation and pyroptosis, accelerating plaque formation in models like ApoE-deficient mice exposed to trimethylamine N-oxide. Risk factors such as hyperglycemia and hypertension amplify mtROS through mitochondrial fission via Drp1 activation, impairing endothelial barrier function. During ischemia-reperfusion injury in the heart, mtROS bursts induce mitochondrial permeability transition and damage intramitochondrial structures, contributing to acute injury and chronic remodeling toward heart failure by regulating pro-apoptotic and inflammatory signaling. Cancer exhibits a dual role for mtROS, acting as both promoters and therapeutic targets. In tumor initiation and progression, mtROS facilitate oncogenic signaling, such as activation of proto-oncogenes and inactivation of tumor suppressors, while sustaining proliferation within a sub-toxic range; however, therapeutic strategies exploit this by inducing excessive mtROS to trigger apoptosis. In malignant melanoma, ROS-mediated mitochondrial dysfunction disrupts energy metabolism and activates apoptotic pathways, yet also enhances proliferation via HGF/c-Met signaling; recent 2025 studies show tumor-associated macrophages in the tumor microenvironment mediate ROS to boost immunotherapy efficacy through glycerophospholipid metabolism alterations. Agents like salidroside (2024 findings) induce ferroptosis by elevating mitochondrial ROS, inhibiting melanoma growth.^[85] Metabolic disorders highlight mtROS-induced cellular dysfunction in endocrine and hepatic tissues. In type 2 diabetes, mitochondrial ROS activate uncoupling protein 2 (UCP2), causing proton leak and reducing ATP/ADP ratios by up to 60% in β-cells, impairing glucose-stimulated insulin secretion and promoting apoptosis via cardiolipin oxidation and cytochrome c release, which diminishes β-cell mass by 63% in obese patients. In liver diseases such as alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH), mitochondrial ROS from cytochrome P450 2E1 (in ASH) or fatty acid overload (in NASH) activate the NLRP3 inflammasome by releasing oxidized mtDNA and depleting glutathione, leading to IL-1β/IL-18 secretion, pyroptosis, and fibrosis progression in 10-35% of ASH cases and 5-20% of NASH.^[86] Emerging 2025 research underscores mtROS risks in space radiation exposure for astronauts, where cosmic rays induce mitochondrial electron leakage and significantly elevated ROS production compared to Earth levels, exacerbating chronic conditions like cancer, cardiovascular disease, and neurodegeneration through DNA damage and gut dysbiosis during long-duration missions.^[87] Microgravity further disrupts mitochondrial homeostasis, amplifying oxidative stress and posing sustained health threats beyond terrestrial chronic diseases.

References

[1]
How mitochondria produce reactive oxygen species - PubMed Central
The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies.
[2]
Mitochondrial Reactive Oxygen Species and Their Contribution in ...
This article aims to review the contribution of mtROS and OS to CKD progression and kidney function deterioration.
[3]
Mitochondria and Reactive Oxygen Species | Hypertension
This review is focused on one component of the noxious mitochondrial pathway: reactive oxygen species (ROS) from a mitochondrial perspective.Mitochondrial Ros And... · Mitochondrial Ros Generation · Mitochondrial Oxidative...
[4]
Reactive Oxygen Species: the Dual Role in Physiological and ...
Reactive oxygen species (ROS) are well-known for playing a dual role as destructive and constructive species. Indeed, ROS are engaged in many redox-governing ...
[5]
Mitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ...
The term ROS encompasses oxygen free radicals, such as superoxide anion radical (O2·−) and hydroxyl radical (·OH), and nonradical oxidants, such as hydrogen ...
[6]
Guidelines for measuring reactive oxygen species and oxidative ...
Jun 27, 2022 · Reactive oxygen species (ROS) is a collective term for species derived from O2 that are more reactive than O2 itself. The term includes not only ...
[7]
Mitochondrial ROS - an overview | ScienceDirect Topics
Mitochondrial ROS (mtROS) is a crucial component of host defense and immunity and a driving factor of inflammatory responses.
[8]
Review Mitochondrial ROS Signaling in Organismal Homeostasis
Oct 22, 2015 · Superoxide can be converted to hydrogen peroxide (H2O2) by superoxide dismutase enzymes (SOD1 in the IMS or SOD2 in the matrix). The resulting ...
[9]
Production of superoxide and hydrogen peroxide from specific ...
Mitochondrial production of superoxide and hydrogen peroxide is potentially important in cell signaling and disease. Eleven distinct mitochondrial sites ...<|control11|><|separator|>
[10]
Detection and manipulation of mitochondrial reactive oxygen ...
Both CI- and α-KGDH generate ROS in the form of superoxide (O2•−), which can be subsequently converted into other ROS including hydrogen peroxide (H2O2).2.1. Types Of Ros · 2.2. 2. Complex Iii · 4.1. 1. Chemical Ros...
[11]
Review: Using isolated mitochondria to investigate mitochondrial ...
While much of the initial ROS formed by mitochondria is superoxide, this is rapidly converted to hydrogen peroxide (H2O2) which more readily crosses membranes ...
[12]
Interactions between mitochondrial reactive oxygen species and ...
Hydrogen peroxide is believed to be a main player in ROS signaling due to its physicochemical properties, which include a relatively low reactivity, long half- ...
[13]
Mitochondrial Management of Reactive Oxygen Species - PMC
ROS include species that are highly reactive, such as the hydroxyl radical (•OH), and species with a low reactivity, such as the superoxide (O2•−) and hydrogen ...
[14]
How mitochondria produce reactive oxygen species - Portland Press
The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies.The Control Of O Production... · O Production Within Isolated... · Sites Of O Production Within...Missing: enzymatic | Show results with:enzymatic<|control11|><|separator|>
[15]
Mitochondrial electron transport chain, ROS generation and ...
Mitochondria are a main source of cellular ROS. Under physiological conditions, 0.2-2% of the electrons in the ETC do not follow the normal transfer order but ...
[16]
Cardiac Mitochondria and Reactive Oxygen Species Generation | Circulation Research
### Summary of Mitochondrial Electron Transport Chain and ROS Production
[17]
Mitochondrial electron transport chain: Oxidative phosphorylation ...
In this graphical review we provide an overview of oxidative phosphorylation and its inter-relationship with ROS production by the electron transport chain. We ...
[18]
Mitochondrial complex I ROS production and redox signaling in ...
Thus, increase in cellular NADH/NAD+ ratio favors RET by complex I (Fig. 2C) [94]. Mitochondria maintain a pool of NAD that is distinct from the rest of the ...3. Complex I Ros · 3.2. Sites And Modes Of Ros... · 4. Complex I Ros Signaling
[19]
Regulation of Reactive Oxygen Species Generation in Cell Signaling
Higher mitochondrial superoxide generation is observed when the matrix NADH/NAD+ ratio is high or during reverse electron transport from succinate to NAD+ in ...Minireview · Intracellular Ros Increase... · Regulation Of Nadph Oxidase<|separator|>
[20]
Relationship between oxidative stress and HIF-1α mRNA during ...
Concomitantly, hypoxic cells increase paradoxically their mitochondrial production of reactive oxygen species (ROS) leading to oxidative stress. The primary ...<|separator|>
[21]
Acid enhancement of ROS generation by complex-I reverse electron ...
ROS from complex I (Cx-I) reverse electron transport (RET) is enhanced at acidic pH. Mitochondrial complex II (Cx-II) activity is inhibited at acidic pH.Short Communication · 1. Introduction · 2. ResultsMissing: NAD+ | Show results with:NAD+
[22]
Effects of hyperthermia and acidosis on mitochondrial production of ...
Dec 1, 2023 · Hyperthermia increased the ratio of ROS production to O2 consumption during phosphorylating respiration, suggesting that high-temperature ...Missing: transport chain
[23]
Ischaemic accumulation of succinate controls reperfusion injury ...
Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we ...Missing: burst | Show results with:burst
[24]
Production of Reactive Oxygen Species by Mitochondria
Inhibition of complex III with antimycin A increased the production of ROS during the oxidation of complex I substrates in both mitochondria and ...Missing: elevates | Show results with:elevates
[25]
Reactive Oxygen Species Generated at Mitochondrial Complex III ...
ROS generation at Complex III increases when antimycin A inhibits electron flux at its downstream end while succinate is used to supply electrons into it ...Missing: elevates | Show results with:elevates
[26]
Research progress of glutathione peroxidase family (GPX) in ... - NIH
GPX4 converts reduced glutathione (GSH) to oxidized glutathione (GSSG) and reduces toxic lipid peroxides (R-OOH) to corresponding alcohols (R-OH) or free ...2.2 Gpx2 · 2.4 Gpx4 · 2.7 Gpx7Missing: equation 2GSH + → 2H2O<|separator|>
[27]
Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species ... - NIH
Intriguingly, the expression levels of the mitochondrial antioxidants peroxiredoxin-3, Txnrd2 and SOD2 are increased, and mtROS are decreased by exercise in ...
[28]
ROS-Drp1-mediated mitochondria fission contributes to ... - PubMed
May 9, 2023 · Our results showed that acute exposure to AgNPs at low doses (2-8 μg/mL) increased ROS generation, decreased mitochondrial membrane potential ( ...
[29]
Mfn2-mediated mitochondrial fusion promotes autophagy and ...
Oct 29, 2022 · Mfn2-mediated mitochondrial fusion promotes autophagy and suppresses ovarian cancer progression by reducing ROS through AMPK/mTOR/ERK signaling.
[30]
Full-coverage regulations of autophagy by ROS - PubMed
Oct 18, 2021 · Autophagy is unique, because it removes not only oxidized/damaged proteins but also bulky ROS-generating organelles (such as mitochondria and ...<|separator|>
[31]
Crosstalk between mitochondrial dysfunction, oxidative stress, and ...
Feb 1, 2019 · Aging is associated with the generation and accumulation of reactive oxygen species (ROS) that are the major contributors to oxidative stress.
[32]
Mitochondrial dysfunction in aging - PubMed
A growing body of evidence points out that reactive oxygen species (ROS) stimulates mitochondrial dynamic changes and accelerates the accumulation of oxidized ...
[33]
Modulating mitochondrial dynamics attenuates cardiac ischemia ...
Generally, caspases also play a critical role in cardiac cell death in I/R injury [59]. Prolonged periods of myocardial ischemia are related to an increase in ...<|separator|>
[34]
ROS Function in Redox Signaling and Oxidative Stress - PMC
In this review we discuss the two faces of ROS, redox signaling and oxidative stress, and their contribution to both physiological and pathological conditions.Missing: seminal | Show results with:seminal
[35]
Keap1/Nrf2/ARE signaling unfolds therapeutic targets for redox ...
These ROS, at the basal level, serves as intracellular second messengers that trigger redox-sensitive signaling transduction cascade while in pathological ...Review · 4. Keap1/nrf2/are Signaling... · 5.2. Nrf2 Phosphorylation...<|separator|>
[36]
Mitochondrial H2O2 Regulates the Angiogenic Phenotype via PTEN ...
This study describes the use of redox-engineered cell lines to identify PTEN as sensitive to oxidative inactivation by mitochondrial H2O2. Increases in the ...<|separator|>
[37]
Mitochondrial complex III is required for hypoxia-induced ROS ...
We find that functionality of complex III of the mitochondrial electron transport chain (ETC) is required for the hypoxic stabilization of HIF-1α and HIF-2α.Missing: paper | Show results with:paper
[38]
Mitochondria-derived ROS activate AMP-activated protein kinase ...
Mitochondrial reactive oxygen species (ROS) production is a tightly regulated redox signal that transmits information from the organelle to the cell.Missing: seminal | Show results with:seminal
[39]
Regulation of signal transduction by reactive oxygen species in the ...
Here we review the current literature regarding ROS signaling in the cardiovascular system, focusing on the role of ROS in normal physiology and how ...Missing: mtROS | Show results with:mtROS
[40]
Oxidative Stress, Mitochondrial Function and Adaptation to Exercise
Nov 22, 2021 · Through endurance, exercise improves the mitochondrial OxPho by means of better ROS elimination and diminishes hypoxia-induced UPC-3 ...2. Oxidative Stress In... · 3.2. Mitohormesis And... · 5.2. Mitochondria As Targets...Missing: tone | Show results with:tone
[41]
The NLRP3 Inflammasome Pathway: A Review of Mechanisms and ...
Jun 10, 2022 · Mitochondrial reactive oxygen species (mtROS) is one of the first discovered activators of the NLRP3 inflammasome and is produced during ...
[42]
Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome ...
We report that in the presence of signal 1 (NF-κB), the NLRP3 inflammasome was activated by mitochondrial apoptotic signaling that licensed production of ...
[43]
Loop Between NLRP3 Inflammasome and Reactive Oxygen Species
Recent Advances: Reactive oxygen species (ROS), especially derived from the mitochondria, are one of the critical mediators of NLRP3 inflammasome activation.
[44]
Reactive Oxygen Species Regulate T Cell Immune Response in the ...
Mitochondrial ROS are indispensable for T cell activation by regulating IL-2 and IL-4 secretion. Chronic exposure to ROS may inhibit NF-κB phosphorylation and ...
[45]
The Role of Reactive Oxygen Species in Regulating T Cell ...
Feb 22, 2018 · ROS signaling mediates T cell apoptosis following activation. Although moderate levels of ROS can support T cell proliferation and ...
[46]
Mitochondrial respiration is necessary for CD8+ T cell proliferation ...
Jul 16, 2025 · Elevated ROS levels are associated with CD8+ T cell exhaustion after chronic stimulation. Here we tested whether mitochondrial complex III- ...
[47]
Regulation of type I interferon responses by mitochondria-derived ...
Jul 29, 2017 · In this study we have investigated the regulation of antiviral signaling by increased mtROS production in plasmacytoid dendritic cells (pDCs).
[48]
Reactive Oxygen Species Induce Antiviral Innate Immune Response ...
Mitochondria induce ROS-regulated IFN-λ expression after IAV infection in NHNE cells. Furthermore, inhibition of the mitochondrial respiratory chain reaction ...
[49]
Mitochondrial Reactive Oxygen Species in Infection and Immunity
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.4. Mitochondrial Ros In... · 5. Mitochondrial Ros In... · 6. Mitochondrial Ros In...<|control11|><|separator|>
[50]
Mitochondria reactive oxygen species signaling in immune responses
Aug 12, 2025 · For decades, mitochondrial ROS (mtROS) were predominantly considered damaging metabolic byproducts, contributing to oxidative stress, cellular ...
[51]
The Pathophysiological Role of Mitochondrial Oxidative Stress in ...
Sep 1, 2025 · Mitochondria play a crucial role in reactive oxygen species (ROS)-dependent rheumatic diseases, including ankylosing spondylitis, osteoarthritis ...
[52]
Mitochondria: a breakthrough in combating rheumatoid arthritis
This review summarises the role and mechanisms of mitochondrial dysfunction in RA and discusses the potential and challenges of mitochondria as a novel ...
[53]
Mitochondria as a Disease-Relevant Organelle in Rheumatoid Arthritis
Mitochondria play a crucial role in the physiopathology of RA, contributing to chronic inflammation, cartilage and bone injury and chronic autoimmune response.
[54]
Mitochondria-Ros Crosstalk in the Control of Cell Death and Aging
Reactive oxygen species (ROS) are highly reactive molecules, mainly generated inside mitochondria that can oxidize DNA, proteins, and lipids.2. Mitochondrial Ros... · 3.3. Peroxidation Of... · 4. Mitochondrial Ros...<|control11|><|separator|>
[55]
Lipid Peroxidation-Derived Aldehydes, 4-Hydroxynonenal and ... - NIH
Jul 30, 2018 · In particular, ROS cause the oxidation of polyunsaturated fatty acids in membrane lipid bilayers, leading eventually to the formation of ...
[56]
Human Mitochondrial DNA: Particularities and Diseases - PMC
Oct 1, 2021 · High Mutation Rate. The mitochondrial genome is fragile and has an average mutation rate 10–20 times higher than that of the nuclear genome.
[57]
Aging: A Theory Based on Free Radical and Radiation Chemistry
Denham Harman, M.D., Ph.D.; Aging: A Theory Based on Free Radical and Radiation Chemistry, Journal of Gerontology, Volume 11, Issue 3, 1 July 1956, Pages 2.
[58]
The Free Radical Theory of Aging Revisited: The Cell Signaling ...
In his seminal paper, Harman stated that “aging and the degenerative diseases associated with it are attributed basically to the deleterious side attacks of ...
[59]
Mitochondria in oxidative stress, inflammation and aging - Nature
Jun 11, 2025 · This review hypothesizes that mitochondria serve as central hubs regulating oxidative stress, inflammation, and aging, and their dysfunction contributes to ...
[60]
Updating the Free Radical Theory of Aging - Frontiers
The free radical theory of aging hypothesizes that oxidative damage to the mtDNA induces random de novo mtDNA mutations which gradually accumulate over time, ...Missing: seminal | Show results with:seminal
[61]
Telomerase does not counteract telomere shortening but protects ...
Apr 1, 2008 · Our data now show that chronic oxidative stress interferes with telomere maintenance at two levels: it increases the basal rate of telomere ...Results · Tert Protects Mitochondria · Telomere Length And...
[62]
Oxidative Stress in Stem Cell Aging - PMC - NIH
Here we explore the key features of stem cell aging biology, with an emphasis on the roles of oxidative stress in the aging process at the molecular level.Missing: mtROS exhaustion
[63]
Muscle-specific PGC-1α modulates mitochondrial oxidative stress in ...
Our study demonstrated that PGC-1α modulated mitochondrial oxidative stress in aged sarcopenia through regulating Nrf2.Missing: mtROS biogenesis neurodegeneration
[64]
Study insights in the role of PGC-1α in neurological diseases
The activation or overexpression of PGC-1α after ICH injury promoted mitochondrial biogenesis and mitochondrial-related ROS metabolism, reduced mitochondrial ...Missing: mtROS sarcopenia
[65]
The role of NAD+ metabolism and its modulation of mitochondria in ...
Jun 18, 2025 · NMN supplementation in mice also improved mitochondrial morphology through DRP1, and reduced ROS through antioxidant response expression.
[66]
Caloric restriction decreases mitochondrial free radical generation at ...
May 9, 2001 · Long-term caloric restriction decreased mitochondrial H2O2 generation by 45% and lowered mtDNA oxidative damage by 30% in rat hearts.
[67]
Calorie restriction induces mitochondrial biogenesis and ... - PNAS
We propose that CR improves energy production through a balanced respiration maintaining lower oxygen consumption associated with low ROS production. To ...
[68]
Mitochondria-mediated oxidative stress during viral infection - PubMed
Jan 19, 2022 · Here, we review the key molecular mechanisms employed by viruses to interact with mitochondria and induce oxidative stress.
[69]
Mitochondrial Reactive Oxygen Species: Double-Edged Weapon in ...
Aug 14, 2020 · Here, we discuss the beneficial and detrimental roles of mtROS in the innate immune system during bacterial, viral, and fungal infections.
[70]
Mechanisms of Mitochondrial Impairment by SARS-CoV-2 Proteins
Oct 11, 2025 · Notably, mitochondrial dysfunction caused by the Spike protein significantly contributes to the hyperinflammation seen in severe COVID-19 cases.
[71]
Ferroptosis and mitochondrial ROS are central to SARS-CoV-2 ...
Aug 10, 2025 · SARS-CoV-2 disrupts mitochondrial homeostasis and lipid metabolism in hepatocytes, promoting ferroptosis as a major contributor to virus-induced cytopathology.
[72]
Core mitochondrial genes down during SARS-CoV-2 infection
Aug 9, 2023 · The virus is able to block expression of both nuclear-encoded and mitochondrial-encoded mitochondrial genes, resulting in impaired host mitochondrial function.
[73]
Oxidative stress is a shared characteristic of ME/CFS and Long COVID
2025 Jul 15;122(28):e2426564122. ... While ME/CFS females exhibit higher total ROS and mitochondrial calcium levels, males have normal ROS levels, with pronounced ...
[74]
Full article: Mitochondrial function is impaired in long COVID patients
Previous studies have observed reductions in mitochondrial DNA gene expression in CD8+ lymphocytes (including memory T cells) of cases with acute SARS–CoV-2 ...
[75]
Mitochondrial reactive oxygen species as major effectors of ... - NIH
May 28, 2020 · This review focuses on the underappreciated but important roles of mitochondrial ROS (mitoROS) in antimicrobial immune defenses.
[76]
The role of mitochondrial dysfunction in sepsis-induced multi-organ ...
The mitochondrion has intrinsic defense mechanisms to protect against damage induced by ROS through its large array of antioxidants (e.g., superoxide dismutase, ...
[77]
Oxidative stress and mitochondrial dysfunction in sepsis
Sepsis-induced organ failure is associated with oxidative stress and mitochondrial damage. · Reactive oxygen species are produced as a normal consequence of ...
[78]
Protective effect of mitochondria-targeted antioxidants in an ... - PNAS
Our data demonstrate that mitochondrial ROS are an important contributor to inflammation-induced tissue damage and that targeting mitochondrial ROS can improve ...
[79]
Mitochondrion-Permeable Antioxidants to Treat ROS-Burst ...
Therefore, antioxidant is an important medicine to ROS-related diseases. For example, ascorbic acid (vitamin C, VC) was suggested as the candidate antioxidant ...