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Insight of the role of mitochondrial calcium homeostasis in hepatic insulin resistance.
Dong, Z, Yao, X
Mitochondrion. 2022;:128-138
Abstract
Due to the rapid rise in the prevalence of chronic metabolic disease, more and more clinicians and basic medical researchers focus their eyesight on insulin resistance (IR), an early and central event of metabolic diseases. The occurrence and development of IR are primarily caused by excessive energy intake and reduced energy consumption. Liver is the central organ that controls glucose homeostasis, playing a considerable role in systemic IR. Decreased capacity of oxidative metabolism and mitochondrial dysfunction are being blamed as the direct reason for the development of IR. Mitochondrial Ca2+ plays a fundamental role in maintaining proper mitochondrial function and redox stability. The maintaining of mitochondrial Ca2+ homeostasis requires the cooperation of ion channels in the inner and outer membrane of mitochondria, such as mitochondrial calcium uniporter complex (MCUC) and voltage-dependent anion channels (VDACs). In addition, the crosstalk between the endoplasmic reticulum (ER), lysosome and plasma membrane with mitochondria is also significant for mitochondrial calcium homeostasis, which is responsible for an efficient network of cellular Ca2+ signaling. Here, we review the recent progression in the research about the regulation factors for mitochondrial Ca2+ and how the dysregulation of mitochondrial Ca2+ homeostasis is involved in the pathogenesis of hepatic IR, providing a new perspective for further exploring the role of ion in the onset and development of IR.
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The Intersection of Purine and Mitochondrial Metabolism in Cancer.
De Vitto, H, Arachchige, DB, Richardson, BC, French, JB
Cells. 2021;(10)
Abstract
Nucleotides are essential to cell growth and survival, providing cells with building blocks for DNA and RNA, energy carriers, and cofactors. Mitochondria have a critical role in the production of intracellular ATP and participate in the generation of intermediates necessary for biosynthesis of macromolecules such as purines and pyrimidines. In this review, we highlight the role of purine and mitochondrial metabolism in cancer and how their intersection influences cancer progression, especially in ovarian cancer. Additionally, we address the importance of metabolic rewiring in cancer and how the evolving landscape of purine synthesis and mitochondria inhibitors can be potentially exploited for cancer treatment.
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Cellular Models for Primary CoQ Deficiency Pathogenesis Study.
Santos-Ocaña, C, Cascajo, MV, Alcázar-Fabra, M, Staiano, C, López-Lluch, G, Brea-Calvo, G, Navas, P
International journal of molecular sciences. 2021;(19)
Abstract
Primary coenzyme Q10 (CoQ) deficiency includes a heterogeneous group of mitochondrial diseases characterized by low mitochondrial levels of CoQ due to decreased endogenous biosynthesis rate. These diseases respond to CoQ treatment mainly at the early stages of the disease. The advances in the next generation sequencing (NGS) as whole-exome sequencing (WES) and whole-genome sequencing (WGS) have increased the discoveries of mutations in either gene already described to participate in CoQ biosynthesis or new genes also involved in this pathway. However, these technologies usually provide many mutations in genes whose pathogenic effect must be validated. To functionally validate the impact of gene variations in the disease's onset and progression, different cell models are commonly used. We review here the use of yeast strains for functional complementation of human genes, dermal skin fibroblasts from patients as an excellent tool to demonstrate the biochemical and genetic mechanisms of these diseases and the development of human-induced pluripotent stem cells (hiPSCs) and iPSC-derived organoids for the study of the pathogenesis and treatment approaches.
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Ferroptosis in Different Pathological Contexts Seen through the Eyes of Mitochondria.
Otasevic, V, Vucetic, M, Grigorov, I, Martinovic, V, Stancic, A
Oxidative medicine and cellular longevity. 2021;:5537330
Abstract
Ferroptosis is a recently described form of regulated cell death characterized by intracellular iron accumulation and severe lipid peroxidation due to an impaired cysteine-glutathione-glutathione peroxidase 4 antioxidant defence axis. One of the hallmarks of ferroptosis is a specific morphological phenotype characterized by extensive ultrastructural changes of mitochondria. Increasing evidence suggests that mitochondria play a significant role in the induction and execution of ferroptosis. The present review summarizes existing knowledge about the mitochondrial impact on ferroptosis in different pathological states, primarily cancer, cardiovascular diseases, and neurodegenerative diseases. Additionally, we highlight pathologies in which the ferroptosis/mitochondria relation remains to be investigated, where the process of ferroptosis has been confirmed (such as liver- and kidney-related pathologies) and those in which ferroptosis has not been studied yet, such as diabetes. We will bring attention to avenues that could be followed in future research, based on the use of mitochondria-targeted approaches as anti- and proferroptotic strategies and directed to the improvement of existing and the development of novel therapeutic strategies.
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Amendatory Effect of Flavonoids in Alzheimer's Disease Against Mitochondrial Dysfunction.
Gulcan, HO, Orhan, IE
Current drug targets. 2021;(14):1618-1628
Abstract
Flavonoids are chromene analogues abundantly found in plants. It has always been of interest to discover natural flavonoid structures, since living things, including humans, are routinely exposed to these compounds through many dietaries. So far, numerous studies have been conducted on flavonoids with diverse biological actions. The activity results obtained, particularly regarding the effects of flavonoids on various validated and non-validated targets of Alzheimer's Disease (AD), make these compounds promising agents either to be directly employed in clinical trials or to be utilized as important scaffolds for flavonoid-based drug design studies. Although there are many review articles on the treatment and protective effects of flavonoids on AD, within this review, the effects of flavonoids on mitochondrial dysfunction developing throughout AD have been presented concomitant to their structural organization.
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Mitochondrion-driven nephroprotective mechanisms of novel glucose lowering medications.
Afsar, B, Hornum, M, Afsar, RE, Ertuglu, LA, Ortiz, A, Covic, A, van Raalte, DH, Cherney, DZI, Kanbay, M
Mitochondrion. 2021;:72-82
Abstract
Therapy for diabetic kidney disease (DKD) is undergoing a revolution with the realization that some glucose-lowering drugs have nephroprotective actions that may be intrinsic to the drugs and not dependent on the impact on diabetes control, as demonstrated with the sodium glucose co-transporter-2 (SGLT-2) inhibitors. Mitochondria are a critical factor required for the maintenance of kidney function, given its high energy demanding profile, with extensive use of adenosine triphosphate (ATP). Consequently, deficiency of the master regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor gamma coactivator 1α predisposes to kidney disease. Perhaps as a result of key role of mitochondria in fundamental cellular functions, mitochondrial dysfunction may play a role in the pathogenesis of common conditions such as DKD. Finding pharmacological agents to influence this pathway could therefore lead to early implementation of therapy. Importantly, glucose-lowering drugs such as glucagon-like peptide-1 receptor activators and SGLT2 inhibitors have kidney and/or cardioprotective actions in patients with diabetes. Accumulating evidence from preclinical studies has suggested a protective effect of these drugs that is in part mediated by normalizing mitochondrial function. We now critically review this evidence and discuss studies needed to confirm mitochondrial protective benefits across a range of clinical studies.
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[The Molecular Mechanisms of Mitochondrial Calcium Uptake by Calcium Uniporter].
Yamamoto, T
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2021;(4):491-499
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Abstract
Mitochondria play a role as intracellular calcium stores as well as energy conversion functions. Excessive calcium accumulation in mitochondria induces cell death and induces diseases such as ischemia-reperfusion injury. Mitochondrial calcium uptake is considered to be mediated by calcium uniporters, which have attracted much attention as potential drug targets. Although calcium uniporter was shown to function as an ion channel, the molecular mechanisms have long been unclear. In this decade, the molecular composition of the calcium uniporter complex was discovered; the calcium uniporter consists of the 7 subunits. Each subunit has no structural similarity to other Ca ion channels; thus, the novel molecular mechanism of the Ca2+ uptake by calcium uniporter is of interest. Although calcium uniporter is conserved in human to warm, yeast lack mitochondrial calcium uptake activity. In the previous study, various subunits of mammalian calcium uniporter were expressed in the yeast mitochondria. As a result, although the expression of each subunit alone did not affect on the mitochondrial calcium uptake activity, the co-expression of mitochondrial calcium uniporter (MCU) and essential MCU regulator (EMRE) enabled to reconstitute calcium uptake activity in yeast mitochondria. This indicated that MCU and EMRE are key factors of the calcium uptake activity in mitochondria. This yeast reconstitution technique has also enabled us to perform detailed structure-function analysis of the MCU and EMRE. In this paper, we will discuss the molecular mechanism of Ca2+ uptake and the prospects for drug discovery.
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8.
Organelle-specific regulation of ferroptosis.
Chen, X, Kang, R, Kroemer, G, Tang, D
Cell death and differentiation. 2021;(10):2843-2856
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Abstract
Ferroptosis, a cell death modality characterized by iron-dependent lipid peroxidation, is involved in the development of multiple pathological conditions, including ischemic tissue damage, infection, neurodegeneration, and cancer. The cellular machinery responsible for the execution of ferroptosis integrates multiple pro-survival or pro-death signals from subcellular organelles and then 'decides' whether to engage the lethal process or not. Here, we outline the evidence implicating different organelles (including mitochondria, lysosomes, endoplasmic reticulum, lipid droplets, peroxisomes, Golgi apparatus, and nucleus) in the ignition or avoidance of ferroptosis, while emphasizing their potential relevance for human disease and their targetability for pharmacological interventions.
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Molecular machinery regulating mitochondrial calcium levels: The nuts and bolts of mitochondrial calcium dynamics.
Tanwar, J, Singh, JB, Motiani, RK
Mitochondrion. 2021;:9-22
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Abstract
Mitochondria play vital role in regulating the cellular energetics and metabolism. Further, it is a signaling hub for cell survival and apoptotic pathways. One of the key determinants that calibrate both cellular energetics and survival functions is mitochondrial calcium (Ca2+) dynamics. Mitochondrial Ca2+ regulates three Ca2+-sensitive dehydrogenase enzymes involved in tricarboxylic acid cycle (TCA) cycle thereby directly controlling ATP synthesis. On the other hand, excessive Ca2+ concentration within the mitochondrial matrix elevates mitochondrial reactive oxygen species (mROS) levels and causes mitochondrial membrane depolarization. This leads to opening of the mitochondrial permeability transition pore (mPTP) and release of cytochrome c into cytosol eventually triggering apoptosis. Therefore, it is critical for cell to maintain mitochondrial Ca2+ concentration. Since cells can neither synthesize nor metabolize Ca2+, it is the dynamic interplay of Ca2+ handling proteins involved in mitochondrial Ca2+ influx and efflux that take the center stage. In this review we would discuss the key molecular machinery regulating mitochondrial Ca2+ concentration. We would focus on the channel complex involved in bringing Ca2+ into mitochondrial matrix i.e. Mitochondrial Ca2+ Uniporter (MCU) and its key regulators Mitochondrial Ca2+ Uptake proteins (MICU1, 2 and 3), MCU regulatory subunit b (MCUb), Essential MCU Regulator (EMRE) and Mitochondrial Ca2+ Uniporter Regulator 1 (MCUR1). Further, we would deliberate on major mitochondrial Ca2+ efflux proteins i.e. Mitochondrial Na+/Ca2+/Li+ exchanger (NCLX) and Leucine zipper EF hand-containing transmembrane1 (Letm1). Moreover, we would highlight the physiological functions of these proteins and discuss their relevance in human pathophysiology. Finally, we would highlight key outstanding questions in the field.
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Ultrastructure of mitochondria of human oocytes in different clinical conditions during assisted reproduction.
Belli, M, Palmerini, MG, Bianchi, S, Bernardi, S, Khalili, MA, Nottola, SA, Macchiarelli, G
Archives of biochemistry and biophysics. 2021;:108854
Abstract
Infertility affects around 8% of couples with a slight change in percentage in the last years. Despite the significant efforts made in Assisted Reproductive Technologies (ARTs) in handling this disorder, oocyte quality remains a crucial factor for a positive outcome. A better understanding of the dynamics underlying oocyte maturation, fertilization, and embryo development remains one of the main areas for progress in the ARTs field. Mitochondria are believed to play an essential role in these processes. Mitochondria have a crucial part in producing energy for oocyte maturation and embryo development throughout precise cellular functions comprising Ca2+ homeostasis regulation, glycolysis, amino acid and fatty acid metabolism, and regulation of apoptosis. Recent studies suggest that mitochondrial structure, content, and function may be related to oocyte competence, embryo viability, and implantation success during ARTs. Their defects could lead to low fertilization rates and embryonic development failure. This review aimed to provide an overview of the available literature data surrounding the correlation between changes at ultrastructural level of mitochondria or correlated-mitochondrial aggregates and oocyte quality and ARTs treatments. Our reported data demonstrated that oocyte mitochondrial ultrastructural alterations could be partial or complete recovery during the early embryo stages. However, these changes could persist as quiescent during the pre-implantation embryo development, causing abnormalities that become evident only during fetal and postnatal life. These factors led to consider the mitochondria as a crucial marker of oocyte and embryo quality, as well as a strategic target for further prospective therapeutical approaches.