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Antioxidants & Redox Signaling Jul 2013Mitochondrial function is fundamental to metabolic homeostasis. In addition to converting the nutrient flux into the energy molecule ATP, the mitochondria generate...
Mitochondrial function is fundamental to metabolic homeostasis. In addition to converting the nutrient flux into the energy molecule ATP, the mitochondria generate intermediates for biosynthesis and reactive oxygen species (ROS) that serve as a secondary messenger to mediate signal transduction and metabolism. Alterations of mitochondrial function, dynamics, and biogenesis have been observed in various metabolic disorders, including aging, cancer, diabetes, and obesity. However, the mechanisms responsible for mitochondrial changes and the pathways leading to metabolic disorders remain to be defined. In the last few years, tremendous efforts have been devoted to addressing these complex questions and led to a significant progress. In a timely manner, the Forum on Mitochondria and Metabolic Homeostasis intends to document the latest findings in both the original research article and review articles, with the focus on addressing three major complex issues: (1) mitochondria and mitochondrial oxidants in aging-the oxidant theory (including mitochondrial ROS) being revisited by a hyperfunction hypothesis and a novel role of SMRT in mitochondrion-mediated aging process being discussed; (2) impaired mitochondrial capacity (e.g., fatty acid oxidation and oxidative phosphorylation [OXPHOS] for ATP synthesis) and plasticity (e.g., the response to endocrine and metabolic challenges, and to calorie restriction) in diabetes and obesity; (3) mitochondrial energy adaption in cancer progression-a new view being provided for H(+)-ATP synthase in regulating cell cycle and proliferation by mediating mitochondrial OXPHOS, oxidant production, and cell death signaling. It is anticipated that this timely Forum will advance our understanding of mitochondrial dysfunction in metabolic disorders.
Topics: Energy Metabolism; Homeostasis; Humans; Mitochondria
PubMed: 23432475
DOI: 10.1089/ars.2013.5255 -
Mitochondrion Mar 2017
Topics: Animals; Mitochondria; Protein Processing, Post-Translational; Proteomics
PubMed: 28025171
DOI: 10.1016/j.mito.2016.12.005 -
Journal of Inorganic Biochemistry Jan 2019Copper complexes are hopeful anticancer drugs due to their multifacet biological properties and high biocompatibility. Inflammatory environment plays an important role...
Copper complexes are hopeful anticancer drugs due to their multifacet biological properties and high biocompatibility. Inflammatory environment plays an important role in tumor progression and affects the body response to chemotherapeutic agents. A copper(II) complex CuLA with a phenanthroline derivative N-(1,10-phenanthrolin-5-yl)-nonanamide (L) and two aspirin anions (A) as the ligands was synthesized. CuLA effectively induces mitochondrial dysfunction and promotes early-apoptosis in SKOV-3 cells; moreover, it suppresses the expression of cyclooxygenase-2, a key enzyme involved in inflammatory response, in lipopolysaccharide stimulated RAW 264.7 cells. By contrast, the analogue complex CuL without aspirin ligand shows similar influences on cellular redox homeostasis and cell cycle progression but relatively low cytotoxic activity due to its mild effect on mitochondrial function; more importantly, it lacks inhibition to cyclooxygenase-2. The results demonstrate that CuLA inhibits cancer cells through dual pathways involving DNA damage and mitochondrial dysfunction. The introduction of aspirin not only enhances the antitumour efficacy but also reduces the inflammatory threat. Copper complexes with both antitumor and anti-inflammatory activities may represent a new type of multifunctional metal complexes in hope to be developed into novel metallodrugs.
Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Nucleus; Coordination Complexes; Copper; Cyclooxygenase 2; DNA Damage; Humans; Mitochondria
PubMed: 30352314
DOI: 10.1016/j.jinorgbio.2018.10.003 -
Annals of the New York Academy of... May 2005Recently, the mitochondrion has been considered as a novel pharmacological target for anticancer therapy due to its crucial role involved in arbitrating cell apoptosis....
Recently, the mitochondrion has been considered as a novel pharmacological target for anticancer therapy due to its crucial role involved in arbitrating cell apoptosis. We have previously demonstrated that 488-nm laser irradiation induced a specific mitochondrial reactive oxygen species (mROS) formation and apoptotic death. In this study, we used a second generation of photosensitizers, the benzoporphyrin-derivative monoacid ring A (BPD-MA). We investigated specifically mechanisms at the mitochondrial level for BPD-MA coupled with 690-nm laser irradiation, the photodynamic effect (PDE) of BPD-MA, using conventional and laser scanning imaging microscopy in intact C6 glioma cells. We demonstrated BPD-MA localized mainly in the mitochondrial area. The phototoxicity induced by 1-10 J 690-nm laser irradiation was minor as compared to that induced by 488-nm laser irradiation. Unlike other mitochondrion-targeted photosensitizers, the dark toxicity induced by BPD-MA (0.05-5 mg/mL, effective doses used for the PDE) was relatively low. Nevertheless, the PDE of BPD-MA using 0.5 mg/mL coupled with 5J 690-nm irradiation induced profound and rapid (< 1 min) mitochondrial swelling, mROS formation, and severe plasma membrane blebbing as compared to that induced by 488-nm laser irradiation (< 10 min). Later, the PDE of BPD-MA resulted in positive propidium iodide cell-death stain and positive TUNEL apoptotic nuclear stain and DNA laddering. Finally, the PDT of BPD-MA also instantaneously promoted the mitochondrion to diminish its covalent binding with a mitochondrial marker, MitoTracker Green. We conclude that the PDT of BPD-MA targeted primarily and compellingly the mitochondrion to induce effective mitochondria-mediated apoptosis and thus may serve as a powerful photosensitizer for clinical cancer therapy.
Topics: Animals; Apoptosis; Cell Line, Tumor; Mitochondria; Mitochondrial Swelling; Photosensitizing Agents; Porphyrins; Rats; Time Factors; Verteporfin
PubMed: 15965088
DOI: 10.1196/annals.1338.035 -
Mitochondrion Jan 2020The mitochondrion is "jack of many trades and master of one". Despite being a master in energy generation, it plays a significant role in other cellular processes,... (Review)
Review
The mitochondrion is "jack of many trades and master of one". Despite being a master in energy generation, it plays a significant role in other cellular processes, including calcium homeostasis, cell death, and iron metabolism. Since mitochondria employ the majority of cellular iron, it plays a central role in the iron homeostasis. Iron could be a major regulator of mitochondrial dynamics as the excess of iron leads to oxidative stress, which causes a disturbance in mitochondrial dynamics. Remarkably, abnormal iron accumulation has been observed in the brain regions of the neurodegenerative disorders patients. These neurodegenerative disorders are also often associated with the abnormal mitochondrial dynamics. Here in this article, we will mainly discuss the studies focused on unravelling the role of iron in mitochondrial dynamics.
Topics: Animals; Biological Transport; Gene Expression Regulation; Homeostasis; Iron; Mitochondria
PubMed: 31669623
DOI: 10.1016/j.mito.2019.09.007 -
Mitochondrion May 2017There is an extraordinary diversity of reproductive modes in teleost and this variability is related to the phylogenetic relationships and adaption to very different... (Review)
Review
There is an extraordinary diversity of reproductive modes in teleost and this variability is related to the phylogenetic relationships and adaption to very different biotopes. As in all vertebrates, sperm is produced as the end product of the process of spermatogenesis, and regarding teleost the spermatozoa lack an acrosome in almost all species and motility is activated as a response to osmolarity and ion content of the aquatic medium where the sperm is released. In this context, mitochondria possess a fundamental role for fish spermatozoa motility and integrity, hence, fertilizing potential; they are the energy supplier that allows flagellar movement and their dysfunction could play a main role in structural and functional damage to the spermatozoa. The ATP production through oxidative phosphorylation provides not only energy for cell activities, which includes Na/K ATPase pump, endocytosis, protein synthesis and many other cell processes; but also produces reactive oxygen species, that under mitochondrial dysfunction causes oxidative stress. The assessment of mitochondrial function (e.g. through measurement of mitochondrial membrane potential) as well as ATP content (mostly supplied by mitochondrial respiration) can be useful as quality markers of fish spermatozoa. Also quantification of ROS and antioxidant status, strongly influenced by mitochondria, are used as complementary measurements. There is much information about sperm mitochondria and their function but studies of these aspects on fish reproduction are still required for applications in aquaculture. The real role of fish sperm mitochondria under short and long term storage and in vitro manipulation is not fully understood yet. Thus future research should focus on these matters.
Topics: Animals; Cell Movement; Energy Metabolism; Fishes; Male; Mitochondria; Reactive Oxygen Species; Spermatozoa
PubMed: 28065674
DOI: 10.1016/j.mito.2017.01.001 -
Expert Review of Endocrinology &... Mar 2024Type 2 diabetes (T2D) presents significant global health and economic challenges, contributing to complications such as stroke, cardiovascular disease, kidney... (Review)
Review
INTRODUCTION
Type 2 diabetes (T2D) presents significant global health and economic challenges, contributing to complications such as stroke, cardiovascular disease, kidney dysfunction, and cancer. The current review explores the crucial role of mitochondria, essential for fuel metabolism, in diabetes-related processes.
AREAS COVERED
Mitochondrial deficits impact insulin-resistant skeletal muscles, adipose tissue, liver, and pancreatic β-cells, affecting glucose and lipid balance. Exercise emerges as a key factor in enhancing mitochondrial function, thereby reducing insulin resistance. Additionally, the therapeutic potential of mitochondrial uncoupling, which generates heat instead of ATP, is discussed. We explore the intricate link between mitochondrial function and diabetes, investigating genetic interventions to mitigate diabetes-related complications. We also cover the impact of insulin deficiency on mitochondrial function, the role of exercise in addressing mitochondrial defects in insulin resistance, and the potential of mitochondrial uncoupling. Furthermore, a comprehensive analysis of Mitochondrial Replacement Therapies (MRT) techniques is presented.
EXPERT OPINION
MRTs hold promise in preventing the transmission of mitochondrial disease. However, addressing ethical, regulatory, and technical considerations is crucial. Integrating mitochondrial-based treatments requires a careful balance between innovation and safety. Ethical dimensions and regulatory aspects of MRT are examined, emphasizing collaborative efforts for the responsible advancement of human health.
Topics: Humans; Diabetes Mellitus, Type 2; Insulin Resistance; Mitochondria; Insulin; Glucose
PubMed: 38347803
DOI: 10.1080/17446651.2024.2307526 -
EMBO Reports Jun 2005Mitochondria are the main sites of biological energy generation in eukaryotes. These organelles are remnants of a bacterial endosymbiont that took up residence inside a... (Review)
Review
Mitochondria are the main sites of biological energy generation in eukaryotes. These organelles are remnants of a bacterial endosymbiont that took up residence inside a host cell over 1,500 million years ago. Comparative genomics studies suggest that the mitochondrion is monophyletic in origin. Thus, the original mitochondrial endosymbiont has evolved independently in anaerobic and aerobic environments that are inhabited by diverse eukaryotic lineages. This process has resulted in a collection of morphologically, genetically and functionally heterogeneous organelle variants that include anaerobic and aerobic mitochondria, hydrogenosomes and mitosomes. Current studies aim to determine whether a central common function drives the retention of mitochondrial organelles in different eukaryotic organisms.
Topics: Biological Evolution; DNA, Mitochondrial; Genetic Variation; Mitochondria
PubMed: 15940286
DOI: 10.1038/sj.embor.7400440 -
Cellular and Molecular Life Sciences :... Nov 2017The skin being a protective barrier between external and internal (body) environments has the sensory and adaptive capacity to maintain local and global body homeostasis... (Review)
Review
The skin being a protective barrier between external and internal (body) environments has the sensory and adaptive capacity to maintain local and global body homeostasis in response to noxious factors. An important part of the skin response to stress is its ability for melatonin synthesis and subsequent metabolism through the indolic and kynuric pathways. Indeed, melatonin and its metabolites have emerged as indispensable for physiological skin functions and for effective protection of a cutaneous homeostasis from hostile environmental factors. Moreover, they attenuate the pathological processes including carcinogenesis and other hyperproliferative/inflammatory conditions. Interestingly, mitochondria appear to be a central hub of melatonin metabolism in the skin cells. Furthermore, substantial evidence has accumulated on the protective role of the melatonin against ultraviolet radiation and the attendant mitochondrial dysfunction. Melatonin and its metabolites appear to have a modulatory impact on mitochondrion redox and bioenergetic homeostasis, as well as the anti-apoptotic effects. Of note, some metabolites exhibit even greater impact than melatonin alone. Herein, we emphasize that melatonin-mitochondria axis would control integumental functions designed to protect local and perhaps global homeostasis. Given the phylogenetic origin and primordial actions of melatonin, we propose that the melatonin-related mitochondrial functions represent an evolutionary conserved mechanism involved in cellular adaptive response to skin injury and repair.
Topics: Animals; Antioxidants; Humans; Melatonin; Mitochondria; Skin; Skin Physiological Phenomena
PubMed: 28803347
DOI: 10.1007/s00018-017-2617-7 -
Seminars in Cancer Biology Dec 2017Mitochondria serves a primary role in energy maintenance but also function to govern levels of mitochondria-derived reactive oxygen species (mROS). ROS have long been... (Review)
Review
Mitochondria serves a primary role in energy maintenance but also function to govern levels of mitochondria-derived reactive oxygen species (mROS). ROS have long been established to play a critical role in tumorigenesis and are now considered to be integral to the regulation of diverse signaling networks that drive proliferation, tumor cell survival and malignant progression. mROS can damage DNA, activate oncogenes, block the function of tumor suppressors and drive migratory signaling. The mitochondrion's oxidant scavenging systems including SOD2, Grx2, GPrx, Trx and TrxR are key of the cellular redox tone. These mitochondrial antioxidant systems serve to tightly control the levels of the primary ROS signaling species, HO. The coordinated control of mROS levels is also coupled to the activity of the primary HO consuming enzymes of the mitochondria which are reliant on the epitranscriptomic control of selenocysteine incorporation. This review highlights the interplay between these many oncogenic signaling networks, mROS and the HO emitting and consuming capacity of the mitochondria.
Topics: Animals; Antioxidants; Cell Transformation, Neoplastic; Disease Progression; Energy Metabolism; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Mitochondria; Molecular Targeted Therapy; Neoplasms; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 28445781
DOI: 10.1016/j.semcancer.2017.04.005