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Central Role of Mitochondrial Oxidative Stress in the Pathophysiology of...
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Central Role of Mitochondrial Oxidative Stress in the Pathophysiology of Disorders (2nd Edition)

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: 31 July 2026 | Viewed by 5245

Special Issue Editors

Dr. Guilhian Leipnitz

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Guest Editor
Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre CEP 90035-903, Brazil
Interests: oxidative stress
Special Issues, Collections and Topics in MDPI journals
Dr. André Quincozes-Santos

E-Mail Website
Guest Editor
Departamento de Bioquímica, Universidade Federal do Rio, Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Bairro Santa Cecília, Porto Alegre 90035-003, RS, Brazil
Interests: oxidative stress; glial cells; neuroprotection

Special Issue Information

Dear Colleagues,

Mitochondria are the main sites of cellular oxidation and energy conversion, and most cellular ATP is produced by oxidative phosphorylation. During oxidative phosphorylation, reactive oxygen species (ROS) are produced as byproducts in mitochondria, primarily by the respiratory chain complexes I and III, and are sequestered by antioxidant defenses. Mitochondrial functionality is also maintained by the so-called mitochondrial quality control, which includes processes such as mitochondrial biogenesis, dynamics, and mitophagy. Since mitochondria are considered the main source of reactive oxygen species (ROS) production in cells, impairments in bioenergetics or any mitochondrial quality control process are often accompanied by elevated ROS and oxidative damage. Therefore, mitochondrial dysfunction and ROS production are involved in the pathophysiology of primary mitochondrial diseases, neurodegenerative disorders, cardiac insufficiency, diabetes mellitus, and aging, among others. Antioxidants and modulators of mitochondrial function can reduce mitochondrial oxidative damage and are considered promising therapeutic strategies for these pathologies. In this Special Issue, we aim to contribute to a better understanding of the pathophysiology of different pathologies characterized by mitochondrial dysfunction and reveal novel therapeutic approaches for these disorders. We look forward to your contributions to this Special Issue.

Dr. Guilhian Leipnitz
Dr. André Quincozes-Santos
Guest Editors

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Keywords

  • mitochondrial dysfunction
  • reactive oxygen species
  • bioenergetics
  • mitochondrial quality control
  • pathologies
  • protective agents

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Published Papers (3 papers)

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Research

24 pages, 3968 KB  
Article
Restoration of Interaction Between Fatty Acid Oxidation and Electron Transport Chain Proteins In Vitro by Addition of Recombinant VLCAD
by Yudong Wang, Gregory Varga, Meicheng Wang, Johan Palmfeldt, Shakuntala Basu, Erik Koppes, Andrew Jeffrey, Robert James Hannan, Grant Sykuta and Jerry Vockley
Biomedicines 2026, 14(1), 222; https://doi.org/10.3390/biomedicines14010222 - 20 Jan 2026
Viewed by 849
Abstract
Background/Objectives: We have previously demonstrated that fatty acid oxidation (FAO) enzymes physically and functionally interact with electron transfer chain supercomplexes (ETC-SC) at two contact points. The FAO trifunctional protein (TFP) and electron transfer flavoprotein dehydrogenase (ETFDH) interact with the NADH+-binding domain [...] Read more.
Background/Objectives: We have previously demonstrated that fatty acid oxidation (FAO) enzymes physically and functionally interact with electron transfer chain supercomplexes (ETC-SC) at two contact points. The FAO trifunctional protein (TFP) and electron transfer flavoprotein dehydrogenase (ETFDH) interact with the NADH+-binding domain of ETC complex I (com I) and the core 2 subunit of complex III (com III), respectively. In addition, the FAO enzyme very-long-chain acyl-CoA dehydrogenase (VLCAD) interacts with TFP. These interactions define a functional FAO-ETC macromolecular complex (FAO-ETC MEC) in which FAO-generated NADH+ and FADH2 can safely transfer electron equivalents to ETC in order to generate ATP. Methods: In this study, we use multiple mitochondrial functional studies to demonstrate the effect of added VLCAD protein on mutant mitochondria. Results: We demonstrate that heart mitochondria from a VLCAD knockout (KO) mouse exhibit disrupted supercomplexes, with significantly reduced levels of TFPα and TFPβ subunits, electron transfer flavoprotein a-subunit (ETFα), and NDUFV2 subunit of com I in the FAO-ETC MEC. In addition, the activities of individual oxidative phosphorylation (OXPHOS) enzymes are decreased, as is the transfer of reducing equivalents from palmitoyl-CoA to ETC (FAO-ETC flux). However, the total amount of these proteins did not decrease in VLCAD KO animals. These results suggest that loss of VLCAD affects the interactions of FAO and ETC proteins in the FAO-ETC MEC. Reconstitution of VLCAD-deficient heart mitochondria with recombinant VLCAD improved the levels of FAO-ETC MEC proteins and enzyme activities, as well as restoring FAO-ETC flux. It also reduced mitochondrial ROS levels, previously demonstrated to be elevated in VLCAD-deficient mitochondria. In contrast, incubation of VLCAD KO mitochondria with two VLCADs with mutations in the C-terminal domain of the enzyme (A450P and L462P) did not restore FAO-ETC MECs. Conclusions: These results suggest that VLCAD is a necessary component of the FAO-ETC MEC and plays a major role in assembly of the macro-supercomplex. These studies provide evidence that both the level of enzyme and its structural confirmation are necessary to stabilize the FAO-ETC MEC. Full article
(This article belongs to the Special Issue Central Role of Mitochondrial Oxidative Stress in the Pathophysiology of Disorders (2nd Edition))
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19 pages, 5092 KB  
Article
Melatonin Modulates Astrocyte Inflammatory Response and Nrf2/SIRT1 Signaling Pathways in Adult Rat Cortical Cultures
by Ester Rezena, Matheus Sinhorelli Cioccari, Aline Daniel Moreira de Moraes, Giancarlo Tomazzoni de Oliveira, Vanessa-Fernanda Da Silva, Izaviany Schmitz, Guilhian Leipnitz, Carlos-Alberto Gonçalves, Carmem Gottfried, Larissa Daniele Bobermin and André Quincozes-Santos
Biomedicines 2025, 13(12), 2967; https://doi.org/10.3390/biomedicines13122967 - 2 Dec 2025
Cited by 1 | Viewed by 1433
Abstract
Background/Objectives: The cerebral cortex is critical for neurological functions that are strongly affected by the aging process. Astrocytes play a central role in maintaining neurotransmitter balance and regulating antioxidant and anti-inflammatory responses, but these physiological functions may also decline with age. This study [...] Read more.
Background/Objectives: The cerebral cortex is critical for neurological functions that are strongly affected by the aging process. Astrocytes play a central role in maintaining neurotransmitter balance and regulating antioxidant and anti-inflammatory responses, but these physiological functions may also decline with age. This study aimed to investigate the effects of melatonin, a molecule with known antioxidant, anti-inflammatory and neuroprotective properties, on astrocytes of mature cortical tissue obtained from adult Wistar rats. Methods: Primary cortical astrocyte cultures were obtained from neonatal and 90-day-old Wistar rats and treated with melatonin (300 µM for 24 h). We assessed cell viability and metabolism (MTT and extracellular lactate levels), glutamine synthetase (GS) activity, glutathione (GSH) content, release of cytokines, and the expression of genes and proteins associated with oxidative stress and inflammation by RT-qPCR and Western blotting. Results: Melatonin did not affect cell viability or lactate production. Moreover, there were no changes in GS activity, a key enzyme in glutamate metabolism, or in GSH levels, an antioxidant defense molecule synthesized by astrocytes. However, melatonin significantly reduced the expression of the nuclear factor NFκB, cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS), while increasing interleukin 6 and 10 levels. Melatonin also upregulated the gene expression of the transcriptional factors Nrf2 and sirtuin 1 (SIRT1) and downregulated AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), while PGC-1α protein levels remained unchanged. A complementary analysis of astrocytes obtained from neonatal rats showed that melatonin did not change metabolic or redox parameters under basal conditions. Conclusions: Melatonin exerted anti-inflammatory effects on adult astrocyte cultures, likely through modulation of protective signaling pathways, such as Nrf2/SIRT1. These findings highlight the potential role of melatonin in preserving astrocytic function and mitigating age-related neuroinflammatory processes. Full article
(This article belongs to the Special Issue Central Role of Mitochondrial Oxidative Stress in the Pathophysiology of Disorders (2nd Edition))
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36 pages, 19130 KB  
Article
The Transgenerational Impact of High-Fat Diet and Diabetic Pregnancy on Embryonic Transcriptomics and Mitochondrial Health
by Abigail K. Klein, Benjamin P. Derenge, Malini Mukherjee, Srikrishna P. Reddy, Tricia D. Larsen, Prathapan Ayyappan, Tyler C. T. Gandy, Kyle M. Siemers, Michael S. Kareta and Michelle L. Baack
Biomedicines 2025, 13(8), 2019; https://doi.org/10.3390/biomedicines13082019 - 19 Aug 2025
Cited by 1 | Viewed by 2379
Abstract
Background/Objectives: Overnutrition increases comorbidities such as gestational diabetes during pregnancy that can have detrimental consequences for both parent and progeny. We previously reported that high-fat (HF) diet and late-gestation diabetes (DM) incite mitochondrial dysfunction, oxidative stress, and cardiometabolic disease in first generation (F1) [...] Read more.
Background/Objectives: Overnutrition increases comorbidities such as gestational diabetes during pregnancy that can have detrimental consequences for both parent and progeny. We previously reported that high-fat (HF) diet and late-gestation diabetes (DM) incite mitochondrial dysfunction, oxidative stress, and cardiometabolic disease in first generation (F1) rat offspring, partially through epigenomic and transcriptomic programming. Primordial germ cells, which become the second generation (F2), are also exposed, which could incite generational risk. This study aimed to determine whether the F2 transcriptome already has genomic variation at the preimplantation embryo stage, and whether variations normalize, persist or compound in the third generation (F3). Methods: F0 female rats were fed a control or HF diet, then DM was induced in HF-fed dams on gestational day (GD)14, exposing F1 offspring and F2 primordial germ cells to hyperlipidemia, hyperglycemia and fetal hyperinsulinemia during the last third of pregnancy. F1 pups were reared by healthy dams and bred to produce F2 embryos (F2e) and F2 pups. F2 offspring were bred to produce F3 embryos (F3e). Embryos were assessed by a novel grading method, live cell imaging, and single-cell RNA sequencing. Results: Embryo grades were not different, but HF+DM F2e had more cells while F3e had fewer cells and overall fewer embryos. HF+DM F2e had similar mitochondria quantity but a downregulation of genes involved in lipid metabolism and more oxidative stress, consistent with mitochondrial dysfunction. They also had an upregulation of chromatin-remodeling genes. The predicted developmental effect is accelerated embryo aging and epigenetic drift. In contrast, HF+DM F3e had an adaptive stress response leading to increased mitochondria quantity and an upregulation of genes involved in mitochondrial respiration, metabolism, and genomic repair that led to a predicted developmental effect of delayed embryo maturation. Conclusions: Although pathways vary, both generations have metabolically linked differentially expressed genes that influence cell fate and developmental pathways. In conclusion, HF+DM pregnancy can program the early embryonic transcriptome for three generations, despite an intergenerational healthy diet. Full article
(This article belongs to the Special Issue Central Role of Mitochondrial Oxidative Stress in the Pathophysiology of Disorders (2nd Edition))
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