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Cell Death & Disease Aug 2023Ferroptosis is a form of regulated cell death induced by iron-dependent lipid peroxidation, and it has been studied extensively since its discovery in 2012. Induced by... (Review)
Review
Ferroptosis is a form of regulated cell death induced by iron-dependent lipid peroxidation, and it has been studied extensively since its discovery in 2012. Induced by iron overload and ROS accumulation, ferroptosis is modulated by various cellular metabolic and signaling pathways. The GSH-GPX4 pathway, the FSP1-CoQ10 pathway, the GCH1-BH4 pathway, the DHODH-CoQH2 system and the sex hormones suppress ferroptosis. Mitochondrial iron metabolism regulates ferroptosis and mitochondria also undergo a morphological change during ferroptosis, these changes include increased membrane density and reduced mitochondrial cristae. Moreover, mitochondrial energy metabolism changes during ferroptosis, the increased oxidative phosphorylation and ATP production rates lead to a decrease in the glycolysis rate. In addition, excessive oxidative stress induces irreversible damage to mitochondria, diminishing organelle integrity. ROS production, mitochondrial membrane potential, mitochondrial fusion and fission, and mitophagy also function in ferroptosis. Notably, some ferroptosis inhibitors target mitochondria. Ferroptosis is a major mechanism for cell death associated with the progression of cancer. Metastasis-prone or metastatic cancer cells are more susceptible to ferroptosis. Inducing ferroptosis in tumor cells shows very promising potential for treating drug-resistant cancers. In this review, we present a brief retrospect of the discovery and the characteristics of ferroptosis, then we discuss the regulation of ferroptosis and highlight the unique role played by mitochondria in the ferroptosis of cancer cells. Furthermore, we explain how ferroptosis functions as a double-edged sword as well as novel therapies aimed at selectively manipulating cell death for cancer eradication.
Topics: Ferroptosis; Reactive Oxygen Species; Mitochondria; Oxidative Stress; Iron; Neoplasms
PubMed: 37580393
DOI: 10.1038/s41419-023-06045-y -
The Journal of Clinical Investigation Jul 2023Hypertrophic cardiomyopathy (HCM) is the most prominent cause of sudden cardiac death in young people. Due to heterogeneity in clinical manifestations, conventional HCM...
Hypertrophic cardiomyopathy (HCM) is the most prominent cause of sudden cardiac death in young people. Due to heterogeneity in clinical manifestations, conventional HCM drugs have limitations for mitochondrial hypertrophic cardiomyopathy. Discovering more effective compounds would be of substantial benefit for further elucidating the pathogenic mechanisms of HCM and treating patients with this condition. We previously reported the MT-RNR2 variant associated with HCM that results in mitochondrial dysfunction. Here, we screened a mitochondria-associated compound library by quantifying the mitochondrial membrane potential of HCM cybrids and the survival rate of HCM-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in galactose media. 1-Deoxynojirimycin (DNJ) was identified to rescue mitochondrial function by targeting optic atrophy protein 1 (OPA1) to promote its oligomerization, leading to reconstruction of the mitochondrial cristae. DNJ treatment further recovered the physiological properties of HCM iPSC-CMs by improving Ca2+ homeostasis and electrophysiological properties. An angiotensin II-induced cardiac hypertrophy mouse model further verified the efficacy of DNJ in promoting cardiac mitochondrial function and alleviating cardiac hypertrophy in vivo. These results demonstrated that DNJ could be a potential mitochondrial rescue agent for mitochondrial hypertrophic cardiomyopathy. Our findings will help elucidate the mechanism of HCM and provide a potential therapeutic strategy.
Topics: Animals; Mice; 1-Deoxynojirimycin; Cardiomyopathy, Hypertrophic; Mitochondria; Myocytes, Cardiac; Cardiomegaly
PubMed: 37200096
DOI: 10.1172/JCI164660 -
Endocrine Reviews Jul 2023Mitochondria sense both biochemical and energetic input in addition to communicating signals regarding the energetic state of the cell. Increasingly, these signaling... (Review)
Review
Mitochondria sense both biochemical and energetic input in addition to communicating signals regarding the energetic state of the cell. Increasingly, these signaling organelles are recognized as key for regulating different cell functions. This review summarizes recent advances in mitochondrial communication in striated muscle, with specific focus on the processes by which mitochondria communicate with each other, other organelles, and across distant organ systems. Intermitochondrial communication in striated muscle is mediated via conduction of the mitochondrial membrane potential to adjacent mitochondria, physical interactions, mitochondrial fusion or fission, and via nanotunnels, allowing for the exchange of proteins, mitochondrial DNA, nucleotides, and peptides. Within striated muscle cells, mitochondria-organelle communication can modulate overall cell function. The various mechanisms by which mitochondria communicate mitochondrial fitness to the rest of the body suggest that extracellular mitochondrial signaling is key during health and disease. Whereas mitochondria-derived vesicles might excrete mitochondria-derived endocrine compounds, stimulation of mitochondrial stress can lead to the release of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) into the circulation to modulate whole-body physiology. Circulating mitochondrial DNA are well-known alarmins that trigger the immune system and may help to explain low-grade inflammation in various chronic diseases. Impaired mitochondrial function and communication are central in common heart and skeletal muscle pathologies, including cardiomyopathies, insulin resistance, and sarcopenia. Lastly, important new advances in research in mitochondrial endocrinology, communication, medical horizons, and translational aspects are discussed.
Topics: Humans; Mitochondria; Muscle, Skeletal
PubMed: 36725366
DOI: 10.1210/endrev/bnad004 -
Nature Aug 2023Distinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate. The mechanochemical...
Distinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate. The mechanochemical GTPase optic atrophy 1 (OPA1) influences the architecture of cristae and catalyses the fusion of the mitochondrial inner membrane. Despite its fundamental importance, the molecular mechanisms by which OPA1 modulates mitochondrial morphology are unclear. Here, using a combination of cellular and structural analyses, we illuminate the molecular mechanisms that are key to OPA1-dependent membrane remodelling and fusion. Human OPA1 embeds itself into cardiolipin-containing membranes through a lipid-binding paddle domain. A conserved loop within the paddle domain inserts deeply into the bilayer, further stabilizing the interactions with cardiolipin-enriched membranes. OPA1 dimerization through the paddle domain promotes the helical assembly of a flexible OPA1 lattice on the membrane, which drives mitochondrial fusion in cells. Moreover, the membrane-bending OPA1 oligomer undergoes conformational changes that pull the membrane-inserting loop out of the outer leaflet and contribute to the mechanics of membrane remodelling. Our findings provide a structural framework for understanding how human OPA1 shapes mitochondrial morphology and show us how human disease mutations compromise OPA1 functions.
Topics: Humans; Biocatalysis; Cardiolipins; GTP Phosphohydrolases; Membrane Fusion; Mitochondria; Mitochondrial Membranes; Mutation; Protein Domains; Protein Multimerization; Mitochondrial Dynamics
PubMed: 37612504
DOI: 10.1038/s41586-023-06441-6 -
Nature Communications Jan 2024Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and...
Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.
Topics: Mice; Animals; Lipid Metabolism; Non-alcoholic Fatty Liver Disease; Endoplasmic Reticulum Stress; Liver; Mitochondria; Liver Cirrhosis; Endoplasmic Reticulum
PubMed: 38168065
DOI: 10.1038/s41467-023-44057-6 -
Science Advances Oct 2023Spinal cord injury (SCI) often leads to physical limitations, persistent pain, and major lifestyle shifts, enhancing the likelihood of prolonged psychological stress and...
Spinal cord injury (SCI) often leads to physical limitations, persistent pain, and major lifestyle shifts, enhancing the likelihood of prolonged psychological stress and associated disorders such as anxiety and depression. The mechanisms linking stress with regeneration remain elusive, despite understanding the detrimental impact of chronic stress on SCI recovery. In this study, we investigated the effect of chronic stress on primary sensory axon regeneration using a preconditioning lesions mouse model. Our data revealed that chronic stress-induced mitochondrial cristae loss and a decrease in oxidative phosphorylation (OXPHOS) within primary sensory neurons, impeding central axon regrowth. Corticosterone, a stress hormone, emerged as a pivotal player in this process, affecting satellite glial cells by reducing Kir4.1 expression. This led to increased neuronal hyperactivity and reactive oxygen species levels, which, in turn, deformed mitochondrial cristae and impaired OXPHOS, crucial for axonal regeneration. Our study underscores the need to manage psychological stress in patients with SCI for effective sensory-motor rehabilitation.
Topics: Humans; Mice; Animals; Axons; Nerve Regeneration; Oxidative Phosphorylation; Neurons; Spinal Cord Injuries
PubMed: 37801508
DOI: 10.1126/sciadv.adh0183 -
Nature Metabolism Nov 2023Reversible acetylation of mitochondrial proteins is a regulatory mechanism central to adaptive metabolic responses. Yet, how such functionally relevant protein...
Reversible acetylation of mitochondrial proteins is a regulatory mechanism central to adaptive metabolic responses. Yet, how such functionally relevant protein acetylation is achieved remains unexplored. Here we reveal an unprecedented role of the MYST family lysine acetyltransferase MOF in energy metabolism via mitochondrial protein acetylation. Loss of MOF-KANSL complex members leads to mitochondrial defects including fragmentation, reduced cristae density and impaired mitochondrial electron transport chain complex IV integrity in primary mouse embryonic fibroblasts. We demonstrate COX17, a complex IV assembly factor, as a bona fide acetylation target of MOF. Loss of COX17 or expression of its non-acetylatable mutant phenocopies the mitochondrial defects observed upon MOF depletion. The acetylation-mimetic COX17 rescues these defects and maintains complex IV activity even in the absence of MOF, suggesting an activatory role of mitochondrial electron transport chain protein acetylation. Fibroblasts from patients with MOF syndrome who have intellectual disability also revealed respiratory defects that could be restored by alternative oxidase, acetylation-mimetic COX17 or mitochondrially targeted MOF. Overall, our findings highlight the critical role of MOF-KANSL complex in mitochondrial physiology and provide new insights into MOF syndrome.
Topics: Humans; Animals; Mice; Acetylation; Fibroblasts; Mitochondria; Energy Metabolism; Electron Transport Complex IV; Copper Transport Proteins
PubMed: 37813994
DOI: 10.1038/s42255-023-00904-w -
Scientific Reports Apr 2024Mitochondria, the powerhouse and the vital signaling hub of the cell, participate in a variety of biological processes, such as apoptosis, redox responses, cell...
Mitochondria, the powerhouse and the vital signaling hub of the cell, participate in a variety of biological processes, such as apoptosis, redox responses, cell senescence, autophagy, and iron homeostasis. Mitochondria form a mostly tubular network, made up of an outer and a cristeae-forming inner membrane. The network undergoes dynamic fusion and fission that change its morphological structure according to the functional needs. Approximately 1500 mitochondrial proteins encoded by nuclear genome plus over 10 proteins encoded by mitochondrial DNA are folded and assembled in the mitochondria under a high-fidelity control system. These proteins are involved in oxidative phosphorylation, metabolism, network and cristae dynamics, mitophagy, import machinery, ion channels, and mitochondrial DNA maintenance. This Collection gathers original research that advances our understanding of the monitoring techniques and pathophysiological significance of mitochondrial dynamics in health and disease.
Topics: Mitochondrial Dynamics; Humans; Mitochondria; Animals
PubMed: 38688939
DOI: 10.1038/s41598-024-59998-1 -
Biomedicine & Pharmacotherapy =... Aug 2023Diabetic nephropathy (DN) is characterized by tubulointerstitial fibrosis caused by epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells. Although...
Diabetic nephropathy (DN) is characterized by tubulointerstitial fibrosis caused by epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells. Although ferroptosis promotes DN development, the specific pathological process that is affected by ferroptosis in DN remains unclear. Herein, EMT-related changes, including increased α-smooth muscle actin (α-SMA) and Vimentin expression and decreased E-cadherin expression, were observed in the renal tissues of streptozotocin-induced DN mice and high glucose-cultured human renal proximal tubular (HK-2) cells. Treatment with ferrostatin-1 (Fer-1) ameliorated these changes and rescued renal pathological injury in diabetic mice. Interestingly, endoplasmic reticulum stress (ERS) was activated during EMT progression in DN. Inhibiting ERS improved the expression of EMT-associated indicators and further rescued the characteristic changes in ferroptosis caused by high glucose, including reactive oxygen species (ROS) accumulation, iron overload, increased lipid peroxidation product generation, and reduced mitochondrial cristae. Moreover, overexpression of XBP1 increased Hrd1 expression and inhibited NFE2-related factor 2 (Nrf2) expression, which could enhance cell susceptibility to ferroptosis. Co-immunoprecipitation (Co-IP) and ubiquitylation assays indicated that Hrd1 interacted with and ubiquitinated Nrf2 under high-glucose conditions. Collectively, our results demonstrated that ERS triggers ferroptosis-related EMT progression through the XBP1-Hrd1-Nrf2 pathway, which provides new insights into potential mechanisms for delaying EMT progression in DN.
Topics: Animals; Humans; Mice; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endoplasmic Reticulum Stress; Epithelial-Mesenchymal Transition; Ferroptosis; Glucose; NF-E2-Related Factor 2; X-Box Binding Protein 1
PubMed: 37224754
DOI: 10.1016/j.biopha.2023.114897 -
Nature Methods Apr 2024Although StayGold is a bright and highly photostable fluorescent protein, its propensity for obligate dimer formation may hinder applications in molecular fusion and...
Although StayGold is a bright and highly photostable fluorescent protein, its propensity for obligate dimer formation may hinder applications in molecular fusion and membrane targeting. To attain monovalent as well as bright and photostable labeling, we engineered tandem dimers of StayGold to promote dispersibility. On the basis of the crystal structure of this fluorescent protein, we disrupted the dimerization to generate a monomeric variant that offers improved photostability and brightness compared to StayGold. We applied the new monovalent StayGold tools to live-cell imaging experiments using spinning-disk laser-scanning confocal microscopy or structured illumination microscopy. We achieved cell-wide, high-spatiotemporal resolution and sustained imaging of dynamic subcellular events, including the targeting of endogenous condensin I to mitotic chromosomes, the movement of the Golgi apparatus and its membranous derivatives along microtubule networks, the distribution of cortical filamentous actin and the remolding of cristae membranes within mobile mitochondria.
Topics: Mitochondria; Golgi Apparatus; Microtubules; Microscopy, Confocal
PubMed: 38036853
DOI: 10.1038/s41592-023-02085-6