Disruption Of Mitochondrial Dynamics Research Articles

FNDC5 prevents oxidative stress and neuronal apoptosis after traumatic brain injury through SIRT3-dependent regulation of mitochondrial quality control

Mitochondrial dysfunction and oxidative stress are important mechanisms for secondary injury after traumatic brain injury (TBI), which result in progressive pathophysiological exacerbation. Although the Fibronectin type III domain-containing 5 (FNDC5) was reported to repress oxidative stress by retaining mitochondrial biogenesis and dynamics, its possible role in the secondary injury after TBI remain obscure. In present study, we observed that the level of serum irisin (the cleavage product of FNDC5) significantly correlated with the neurological outcomes of TBI patients. Knockout of FNDC5 increased the lesion volume and exacerbated apoptosis and neurological deficits after TBI in mice, while FNDC5 overexpression yielded a neuroprotective effect. Moreover, FNDC5 deficiency disrupted mitochondrial dynamics and function. Activation of Sirtuin 3 (SIRT3) alleviated FNDC5 deficiency-induced disruption of mitochondrial dynamics and bioenergetics. In neuron-specific SIRT3 knockout mice, FNDC5 failed to attenuate TBI-induced mitochondrial damage and brain injuries. Mechanically, FNDC5 deficiency led to reduced SIRT3 expression via enhanced ubiquitin degradation of transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2), which contributed to the hyperacetylation and inactivation of key regulatory proteins of mitochondrial dynamics and function, including OPA1 and SOD2. Finally, engineered RVG29-conjugated nanoparticles were generated to selectively and efficiently deliver irisin to the brain of mice, which yielded a satisfactory curative effect against TBI. In conclusion, FNDC5/irisin exerts a protective role against acute brain injury by promoting SIRT3-dependent mitochondrial quality control and thus represents a potential target for neuroprotection after TBI.

Role of Flavonoids in Modulation of Mitochondria Dynamics during Oxidative Stress.

Flavonoids are a widespread category of naturally occurring polyphenols distinguished by the flavan nucleus in plant-based foods and beverages, known for their various health benefits. Studies have suggested that consuming 150-500 mg of flavonoids daily is beneficial for health. Recent studies suggest that flavonoids are involved in maintaining mitochondrial activity and preventing impairment of mitochondrial dynamics by oxidative stress. This review emphasized the significance of studying the impact of flavonoids on mitochondrial dynamics, oxidative stress, and inflammatory response. This review analysed and summarised the findings related to the impact of flavonoids on mitochondria from publicly available search engines namely Pubmed, Scopus, and Web of Science. Any disruption in mitochondrial dynamics can contribute to cellular dysfunction and diseases, including cancer, cardiac conditions, and neurodegeneration. Flavonoids have been shown to modulate mitochondrial dynamics by regulating protein expression involved in fission and fusion events. Furthermore, flavonoids exhibit potent antioxidant properties by lowering the production of ROS and boosting the performance of antioxidant enzymes. Persistent inflammation is a characteristic of many different disorders. This is because flavonoids also alter the inflammatory response by controlling the expression of numerous cytokines and chemokines involved in the inflammatory process. Flavonoids exhibit an impressive array of significant health effects, making them an effective therapeutic agent for managing various disorders. Further this review summarised available mechanisms underlying flavonoids' actions on mitochondrial dynamics and oxidative stress to recognize the optimal dose and duration of flavonoid intake for therapeutic purposes. This review may provide a solid foundation for developing targeted therapeutic interventions utilizing flavonoids, ultimately benefiting individuals afflicted with various disorders.

The effect of adipose-derived mesenchymal stem cell transplantation on ovarian mitochondrial dysfunction in letrozole-induced polycystic ovary syndrome in rats: the role of PI3K-AKT signaling pathway

ObjectiveThe present study aimed to elucidate how mesenchymal stem cells (MSCs) application could efficiently attenuate pathological changes of letrozole-induced poly cystic ovary syndrome (PCOS) by modulating mitochondrial dynamic via PI3K-AKT pathway.MethodsThirty-two female rats were randomly divided into four experimental groups: Sham, PCOS, PCOS + MSCs, and PCOS + MSCs + LY294002. The Sham group received 0.5% w/v carboxymethyl cellulose (CMC); the PCOS group received letrozole (1 mg/kg, daily) in 0.5% CMC for 21 days. Animals in the PCOS + MSCs group received 1 × 106 MSCs/rat (i.p,) on the 22th day of the study. In the PCOS + MSCs + LY294002 group, rats received LY294002 (PI3K-AKT inhibitor) 40 min before MSC transplantation. Mitochondrial dynamic gene expression, mitochondrial membrane potential (MMP), citrate synthase (CS) activity, oxidative stress, inflammation, ovarian histological parameters, serum hormone levels, homeostatic model assessment for insulin resistance (HOMA-IR), insulin and glucose concentrations, p-PI3K and p-AKT protein levels were evaluated at the end of the experiment.ResultsPCOS rats showed a significant disruption of mitochondrial dynamics and histological changes, lower MMP, CS, ovary super oxide dismutase (SOD) and estrogen level. They also had a notable rise in insulin and glucose concentrations, HOMA-IR, testosterone level, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels, ovarian malondialdehyde (MDA) content as well as a notable decrease in p-PI3K and p-AKT protein levels compared to the Sham group. In the PCOS + MSCs group, the transplantation of MSCs could improve the above parameters. Administration of LY294002 (PI3K-AKT pathway inhibitor) deteriorated mitochondrial dynamic markers, oxidative stress status, inflammation markers, hormonal levels, glucose, and insulin levels and follicular development compared to the PCOS + MSCs group.ConclusionsThis study demonstrated that the protective effects of MSC transplantation in regulating mitochondrial dynamics, promoting mitochondrial biogenesis, competing with redox status and inflammation response were mainly mediated through the PI3K-AKT pathway in the PCOS model.

Novel Relationship between Mitofusin 2-Mediated Mitochondrial Hyperfusion, Metabolic Remodeling, and Glycolysis in Pulmonary Arterial Endothelial Cells.

The disruption of mitochondrial dynamics has been identified in cardiovascular diseases, including pulmonary hypertension (PH), ischemia-reperfusion injury, heart failure, and cardiomyopathy. Mitofusin 2 (Mfn2) is abundantly expressed in heart and pulmonary vasculature cells at the outer mitochondrial membrane to modulate fusion. Previously, we have reported reduced levels of Mfn2 and fragmented mitochondria in pulmonary arterial endothelial cells (PAECs) isolated from a sheep model of PH induced by pulmonary over-circulation and restoring Mfn2 normalized mitochondrial function. In this study, we assessed the effect of increased expression of Mfn2 on mitochondrial metabolism, bioenergetics, reactive oxygen species production, and mitochondrial membrane potential in control PAECs. Using an adenoviral expression system to overexpress Mfn2 in PAECs and utilizing 13C labeled substrates, we assessed the levels of TCA cycle metabolites. We identified increased pyruvate and lactate production in cells, revealing a glycolytic phenotype (Warburg phenotype). Mfn2 overexpression decreased the mitochondrial ATP production rate, increased the rate of glycolytic ATP production, and disrupted mitochondrial bioenergetics. The increase in glycolysis was linked to increased hypoxia-inducible factor 1α (HIF-1α) protein levels, elevated mitochondrial reactive oxygen species (mt-ROS), and decreased mitochondrial membrane potential. Our data suggest that disrupting the mitochondrial fusion/fission balance to favor hyperfusion leads to a metabolic shift that promotes aerobic glycolysis. Thus, therapies designed to increase mitochondrial fusion should be approached with caution.

Hexavalent-Chromium-Induced Disruption of Mitochondrial Dynamics and Apoptosis in the Liver via the AMPK-PGC-1α Pathway in Ducks.

Hexavalent chromium (Cr(VI)) is a hazardous substance that poses significant risks to environmental ecosystems and animal organisms. However, the specific consequences of Cr(VI) exposure in terms of liver damage remain incompletely understood. This study aims to elucidate the mechanism by which Cr(VI) disrupts mitochondrial dynamics, leading to hepatic injury in ducks. Forty-eight healthy 8-day-old ducks were divided into four groups and subjected to diets containing varying doses of Cr(VI) (0, 9.28, 46.4, and 232 mg/kg) for 49 days. Our results demonstrated that Cr(VI) exposure resulted in disarranged liver lobular vacuolation, along with increasing the serum levels of ALT, AST, and AKP in a dose-dependent manner, which indicated liver damage. Furthermore, Cr(VI) exposure induced oxidative stress by reducing the activities of T-SOD, SOD, GSH-Px, GSH, and CAT, while increasing the contents of MDA and H2O2. Moreover, Cr(VI) exposure downregulated the activities of CS and MDH, resulting in energy disturbance, as evidenced by the reduced AMPK/p-AMPK ratio and PGC-1α protein expression. Additionally, Cr(VI) exposure disrupted mitochondrial dynamics through decreased expression of OPA1, Mfn1, and Mfn2 and increased expression of Drp-1, Fis1, and MFF proteins. This disruption ultimately triggered mitochondria-mediated apoptosis, as evidenced by elevated levels of caspase-3, Cyt C, and Bax, along with decreased expression of Bcl-2 and the Bcl-2/Bax ratio, at both the protein and mRNA levels. In summary, this study highlights that Cr(VI) exposure induces oxidative stress, inhibits the AMPK-PGC-1α pathway, disrupts mitochondrial dynamics, and triggers liver cell apoptosis in ducks.

Mitochondrial hyperfusion induces metabolic remodeling in lung endothelial cells by modifying the activities of electron transport chain complexes I and III

ObjectivePulmonary hypertension (PH) is a progressive disease with vascular remodeling as a critical structural alteration. We have previously shown that metabolic reprogramming is an early initiating mechanism in animal models of PH. This metabolic dysregulation has been linked to remodeling the mitochondrial network to favor fission. However, whether the mitochondrial fission/fusion balance underlies the metabolic reprogramming found early in PH development is unknown. MethodsUtilizing a rat early model of PH, in conjunction with cultured pulmonary endothelial cells (PECs), we utilized metabolic flux assays, Seahorse Bioassays, measurements of electron transport chain (ETC) complex activity, fluorescent microscopy, and molecular approaches to investigate the link between the disruption of mitochondrial dynamics and the early metabolic changes that occur in PH. ResultsWe observed increased fusion mediators, including Mfn1, Mfn2, and Opa1, and unchanged fission mediators, including Drp1 and Fis1, in a two-week monocrotaline-induced PH animal model (early-stage PH). We were able to establish a connection between increases in fusion mediator Mfn1 and metabolic reprogramming. Using an adenoviral expression system to enhance Mfn1 levels in pulmonary endothelial cells and utilizing 13C-glucose labeled substrate, we found increased production of 13C lactate and decreased TCA cycle metabolites, revealing a Warburg phenotype. The use of a 13C5-glutamine substrate showed evidence that hyperfusion also induces oxidative carboxylation. The increase in glycolysis was linked to increased hypoxia-inducible factor 1α (HIF-1α) protein levels secondary to the disruption of cellular bioenergetics and higher levels of mitochondrial reactive oxygen species (mt-ROS). The elevation in mt-ROS correlated with attenuated ETC complexes I and III activities. Utilizing a mitochondrial-targeted antioxidant to suppress mt-ROS, limited HIF-1α protein levels, which reduced cellular glycolysis and reestablished mitochondrial membrane potential. ConclusionsOur data connects mitochondrial fusion-mediated mt-ROS to the Warburg phenotype in early-stage PH development.

Mitochondrial Dynamics and Insulin Secretion.

Mitochondria are involved in the regulation of cellular energy metabolism, calcium homeostasis, and apoptosis. For mitochondrial quality control, dynamic processes, such as mitochondrial fission and fusion, are necessary to maintain shape and function. Disturbances of mitochondrial dynamics lead to dysfunctional mitochondria, which contribute to the development and progression of numerous diseases, including Type 2 Diabetes (T2D). Compelling evidence has been put forward that mitochondrial dynamics play a significant role in the metabolism-secretion coupling of pancreatic β cells. The disruption of mitochondrial dynamics is linked to defects in energy production and increased apoptosis, ultimately impairing insulin secretion and β cell death. This review provides an overview of molecular mechanisms controlling mitochondrial dynamics, their dysfunction in pancreatic β cells, and pharmaceutical agents targeting mitochondrial dynamic proteins, such as mitochondrial division inhibitor-1 (mdivi-1), dynasore, P110, and 15-oxospiramilactone (S3).

Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function.

Clinically, cardiac dysfunction is a key component of sepsis-induced multi-organ failure. Mitochondria are essential for cardiomyocyte homeostasis, as disruption of mitochondrial dynamics enhances mitophagy and apoptosis. However, therapies targeted to improve mitochondrial function in septic patients have not been explored. Transcriptomic data analysis revealed that the peroxisome proliferator-activated receptor (PPAR) signaling pathway in the heart was the most significantly decreased inthe cecal ligation puncture-treated mouse heart model, and PPARα was the most notably decreased among the three PPAR family members. Male Pparafl/fl (wild-type), cardiomyocyte-specific Ppara-deficient (PparaΔCM), and myeloid-specific Ppara-deficient (PparaΔMac) mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxic cardiac dysfunction. PPARα signaling was decreased in LPS-treated wild-type mouse hearts. To determine the cell type in which PPARα signaling was suppressed, the cell type-specific Ppara-null mice were examined. Cardiomyocyte- but not myeloid-specific Ppara deficiency resulted in exacerbated LPS-induced cardiac dysfunction. Ppara disruption in cardiomyocytes augmented mitochondrial dysfunction, as revealed by damaged mitochondria, lowered ATP contents, decreased mitochondrial complex activities, and increased DRP1/MFN1 protein levels. RNA sequencing results further showed that cardiomyocyte Ppara deficiency potentiated the impairment of fatty acid metabolism in LPS-treated heart tissue. Disruption of mitochondrial dynamics resulted in increased mitophagy and mitochondrial-dependent apoptosis in Ppara△CM mice. Moreover, mitochondrial dysfunction caused an increase of reactive oxygen species, leading to increased IL-6/STAT3/NF-κB signaling. 3-Methyladenine (3-MA, an autophagosome formation inhibitor) alleviated cardiomyocyte Ppara disruption-induced mitochondrial dysfunction and cardiomyopathy. Finally, pre-treatment with the PPARα agonist WY14643 lowered mitochondrial dysfunction-induced cardiomyopathy in hearts from LPS-treated mice. Thus, cardiomyocyte but not myeloid PPARα protects against septic cardiomyopathy by improving fatty acid metabolism and mitochondrial dysfunction, thus highlighting that cardiomyocyte PPARα may be a therapeutic target for the treatment of cardiac disease.

The role of circadian clock-controlled mitochondrial dynamics in diabetic cardiomyopathy.

Diabetes mellitus is a metabolic disease with a high prevalence worldwide, and cardiovascular complications are the leading cause of mortality in patients with diabetes. Diabetic cardiomyopathy (DCM), which is prone to heart failure with preserved ejection fraction, is defined as a cardiac dysfunction without conventional cardiac risk factors such as coronary heart disease and hypertension. Mitochondria are the centers of energy metabolism that are very important for maintaining the function of the heart. They are highly dynamic in response to environmental changes through mitochondrial dynamics. The disruption of mitochondrial dynamics is closely related to the occurrence and development of DCM. Mitochondrial dynamics are controlled by circadian clock and show oscillation rhythm. This rhythm enables mitochondria to respond to changing energy demands in different environments, but it is disordered in diabetes. In this review, we summarize the significant role of circadian clock-controlled mitochondrial dynamics in the etiology of DCM and hope to play a certain enlightening role in the treatment of DCM.

Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation

Some forms of mitochondrial dysfunction induce sterile inflammation through mitochondrial DNA recognition by intracellular DNA sensors. However, the involvement of mitochondrial dynamics in mitigating such processes and their impact on muscle fitness remain unaddressed. Here we report that opposite mitochondrial morphologies induce distinct inflammatory signatures, caused by differential activation of DNA sensors TLR9 or cGAS. In the context of mitochondrial fragmentation, we demonstrate that mitochondria-endosome contacts mediated by the endosomal protein Rab5C are required in TLR9 activation in cells. Skeletal muscle mitochondrial fragmentation promotes TLR9-dependent inflammation, muscle atrophy, reduced physical performance and enhanced IL6 response to exercise, which improved upon chronic anti-inflammatory treatment. Taken together, our data demonstrate that mitochondrial dynamics is key in preventing sterile inflammatory responses, which precede the development of muscle atrophy and impaired physical performance. Thus, we propose the targeting of mitochondrial dynamics as an approach to treating disorders characterized by chronic inflammation and mitochondrial dysfunction.

Inhibiting amyloid beta (1-42) peptide-induced mitochondrial dysfunction prevents the degradation of synaptic proteins in the entorhinal cortex.

Increasing evidence suggests that mitochondrial dysfunction and aberrant release of mitochondrial reactive oxygen species (ROS) play crucial roles in early synaptic perturbations and neuropathology that drive memory deficits in Alzheimer’s disease (AD). We recently showed that solubilized human amyloid beta peptide 1–42 (hAβ1–42) causes rapid alterations at glutamatergic synapses in the entorhinal cortex (EC) through the activation of both GluN2A- and GluN2B-containing NMDA receptors. However, whether disruption of mitochondrial dynamics and increased ROS contributes to mechanisms mediating hAβ1–42-induced synaptic perturbations in the EC is unknown. Here we assessed the impact of hAβ1–42 on mitochondrial respiratory functions, and the expression of key mitochondrial and synaptic proteins in the EC. Measurements of mitochondrial respiratory function in wild-type EC slices exposed to 1 μM hAβ1–42 revealed marked reductions in tissue oxygen consumption and energy production efficiency relative to control. hAβ1–42 also markedly reduced the immunoexpression of both mitochondrial superoxide dismutase (SOD2) and mitochondrial-cytochrome c protein but had no significant impact on cytosolic-cytochrome c expression, voltage-dependent anion channel protein (a marker for mitochondrial density/integrity), and the immunoexpression of protein markers for all five mitochondrial complexes. The rapid impairments in mitochondrial functions induced by hAβ1–42 were accompanied by reductions in the presynaptic marker synaptophysin, postsynaptic density protein (PSD95), and the vesicular acetylcholine transporter, with no significant changes in the degradative enzyme acetylcholinesterase. We then assessed whether reducing hAβ1–42-induced increases in ROS could prevent dysregulation of entorhinal synaptic proteins, and found that synaptic impairments induced by hAβ1–42 were prevented by the mitochondria-targeted antioxidant drug mitoquinone mesylate, and by the SOD and catalase mimetic EUK134. These findings indicate that hAβ1–2 can rapidly disrupt mitochondrial functions and increase ROS in the entorhinal, and that this may contribute to synaptic dysfunctions that may promote early AD-related neuropathology.

Secondary brain injury after polystyrene microplastic-induced intracerebral hemorrhage is associated with inflammation and pyroptosis

Unlike regular environmental pollutants, microplastics cannot dissolve in liquids. Physical contact of microplastic (MPs) with tissue can damage tissue structure, and it is unclear how this physical secondary injury affects brain tissue. Through CTD database analysis, it was determined that cerebral ischemia may be one of the main ways of brain tissue damage caused by MPs, and inflammatory response may play a key role in it. In the present study, PS-MPs (L-PS group:1 mg/L, M − PS group:10 mg/L, H-PS group: 100 mg/L in water) were assessed to brain tissue damage in chicken after six weeks of continuous exposure. Exposure to PS-MPs caused cerebral hemorrhage as well as generation of microthrombi and loss of Purkinje cells. Intracerebral hemorrhage caused a strong infiltration of inflammatory cells and activated the ASC-NLRP3-GSDMD signaling pathway to induce pyroptosis. Disruption of mitochondrial dynamics by PS-MPs exposure disrupts mitochondrial function and activates AMPK signaling. In conclusion, this study explored the mechanism regulation of subsequent brain injury from the perspective of physical injury (cerebral hemorrhage) of PS-MPs. To provide a reference for elucidating the neurotoxicity induced by microplastic exposure.

Icariin attenuates excessive alcohol consumption-induced susceptibility to atrial fibrillation through SIRT3 signaling

Excessive alcohol consumption has long been identified as a risk factor for adverse atrial remodeling and atrial fibrillation (AF). Icariin is a principal active component from traditional Chinese medicine Herba Epimedii and has been demonstrated to exert potential antiarrhythmic effect. The present study was designed to evaluate the effect of icariin against alcohol-induced atrial remodeling and disruption of mitochondrial dynamics and furthermore, to elucidate the underlying mechanisms. Excessive alcohol-treated C57BL/6 J mice were infected with serotype 9 adeno-associated virus (AAV9) carrying mouse SIRT3 gene or negative control virus. Meanwhile, icariin (50 mg/kg/d) was administered to the animals in the presence or absence of AAV9 carrying SIRT3 shRNA. We noted that 8 weeks of icariin treatment effectively attenuated alcohol consumption-induced atrial structural and electrical remodeling as evidenced by reduced AF inducibility and reversed atrial electrical conduction pattern as well as atrial enlargement. Furthermore, icariin-treated group exhibited significantly enhanced atrial SIRT3-AMPK signaling, decreased atrial mitoSOX fluorescence and mitochondrial fission markers, elevated mitochondrial fusion markers (MFN1, MFN2) as well as NRF-1-Tfam-mediated mitochondrial biogenesis. Importantly, these beneficial effects were mimicked by SIRT3 overexpression while abolished by SIRT3 knockdown. These data revealed that targeting atrial SIRT3-AMPK signaling and preserving mitochondrial dynamics might serve as the novel therapeutic strategy against alcohol-induced AF genesis. Additionally, icariin ameliorated atrial remodeling and mitochondrial dysfunction by activating SIRT3-AMPK signaling, highlighting the use of icariin as a promising antiarrhythmic agent in this circumstance.

Role of Impaired Mitochondrial Dynamics Processes in the Pathogenesis of Alzheimer's Disease.

Mitochondrial dysfunction is now recognized as a contributing factor to neurodegenerative diseases, including Alzheimer’s disease (AD). Mitochondria are signaling organelles with a variety of functions ranging from energy production to the regulation of cellular metabolism, energy homeostasis, and response to stress. The successful functioning of these complex processes is critically dependent on the accuracy of mitochondrial dynamics, which includes the ability of mitochondria to change shape and position in the cell, which is necessary to maintain proper function and quality control, especially in polarized cells such as neurons. There has been much evidence to suggest that the disruption of mitochondrial dynamics may play a critical role in the pathogenesis of AD. This review highlights aspects of altered mitochondrial dynamics in AD that may contribute to the etiology of this debilitating condition. We also discuss therapeutic strategies to improve mitochondrial dynamics and function that may provide an alternative treatment approach.

Silver nanoparticle-induced alteration of mitochondrial and ER homeostasis affects human breast cancer cell fate

Breast cancer is one of the most frequent forms of cancer. Although different treatment modalities are available, none has proved to be a game-changer. In this context, nanomedicine is one of the hot research areas, with different nano-formulations being explored as a therapeutic strategy against breast cancer. Herein, silver nanoparticles (AgNPs) have shown prospects with their anti-tumor properties and are currently being explored aggressively; however, the underlying molecular mechanisms of AgNP action remain to be unearthed. As part of this study, human breast cancer cells- MCF7 were exposed to AgNPs (∼9 nm), and the effect of the same was explored on mitochondrial and endoplasmic reticulum (ER) dynamicity. We observed that the AgNPs co-localize with mitochondria and cause mitochondrial membrane depolarization, ROS generation, and destabilized mitochondrial homeostasis. Also, the NPs were found to enhance ER stress. We further found that increased ER stress is linked to the disruption of mitochondrial dynamics. Overall, our study shows that the AgNPs can effectively cause apoptosis of MCF-7 cells by regulating the mitochondrial-ER dynamicity. The results provide an insight into the mechanisms via which AgNPs act and can be used in developing a potential chemotherapeutic agent.

MiR-125b Disrupts Mitochondrial Dynamics via Targeting Mitofusin 1 in Cisplatin-Induced Acute Kidney Injury

Background: Mitochondria are dynamic organelles whose structure are maintained by continuous fusion and fission. During acute kidney injury (AKI) progression, mitochondrial fission in renal tubular cells was elevated, characterized by mitochondrial fragmentation. It is tightly associated with mitochondrial dysfunction, which has been proven as a critical mechanism responsible for AKI. However, the initiating factor for the disruption of mitochondrial dynamics in AKI was not well understood. Objectives: To explore the molecular mechanisms of mitochondrial disorders and kidney damage. Methods: We established cisplatin-induced AKI model in C57BL/6 mice and proximal tubular cells, and detected the expression of miR-125b by qPCR. Then we delivered miR-125b antagomir after cisplatin treatment in mice via hydrodynamic-based gene transfer technique. Subsequently, we performed luciferase reporter and immunoblotting ­assays to prove miR-125b could directly modulate mitofusin1 (MFN1) expression. We also tested the role of miR-125b in mitochondrial and renal injury through immunofluorescent staining, qPCR, and immunoblotting assays. Results: miR-125b levels were induced in cisplatin-challenged mice and cultured tubular cells. Anti-miR-125b could effectively alleviate cisplatin-induced mitochondrial fragmentation and kidney injury both in vitro and in vivo. Furthermore, miR-125b could directly regulate MFN1, which is a key regulator of mitochondrial fusion. Our study indicated that miR-125b is upregulated during cisplatin-induced AKI. Inhibition of miR-125b may suppress mitochondrial and renal damage through upregulating MFN1. This study suggests that miR-125b could be a potential therapeutic target in AKI.

Early triggers of moderately high-fat diet-induced kidney damage.

Most of the obesity murine models inducing renal injury use calorie‐enriched foods, where fat represents 60% of the total caloric supply, however, this strategy doubles the standard proportion of fat ingestion in obese patients. Therefore, it is crucial to study the impact of a high‐fat intake on kidney physiology that resembles common obesity in humans to understand the trigger mechanisms of the long‐term consequences of overweight and obesity. In this study, we analyzed whether chronic feeding with a moderately high fat diet (MHFD) representing 45% of total calories, may induce kidney function and structural injury compared to C57BL/6 mice fed a control diet. After 14 weeks, MHFD induced significant mice obesity. At the functional level, obese mice showed signs of kidney injury characterized by increased albuminuria/creatinine ratio and higher excretion of urinary biomarkers of kidney damage. While, at the structural level, glomerular hypertrophy was observed. Although, we did not detect renal fibrosis, the obese mice exhibited a significant elevation of Tgfb1 mRNA levels. Kidney damage caused by the exposure to MHFD was associated with greater oxidative stress, renal inflammation, higher endoplasmic reticulum (ER)‐stress, and disruption of mitochondrial dynamics. In summary, our data demonstrate that obesity induced by a milder fat content diet is enough to establish renal injury, where oxidative stress, inflammation, ER‐stress, and mitochondrial damage take relevance, pointing out the importance of opportune interventions to avoid the long‐term consequences associated with obesity and metabolic syndrome.

Mitochondrial fusion and fission: The fine-tune balance for cellular homeostasis.

Mitochondria are highly dynamic, maternally inherited cytoplasmic organelles, which fulfill cellular energy demand through the oxidative phosphorylation system. Besides, they play an active role in calcium and damage-associated molecular patterns signaling, amino acid, and lipid metabolism, and apoptosis. Thus, the maintenance of mitochondrial integrity and homeostasis is extremely critical, which is achieved through continual fusion and fission. Mitochondrial fusion allows the transfer of gene products between mitochondria for optimal functioning, especially under metabolic and environmental stress. On the other hand, fission is crucial for mitochondrial division and quality control. The imbalance between these two processes is associated with various ailments such as cancer, neurodegenerative and cardiovascular diseases. This review discusses the molecular mechanisms that control mitochondrial fusion and fission and how the disruption of mitochondrial dynamics manifests into various disease conditions.

Genome-wide RNAi screen for regulators of UPRmt in Caenorhabditis elegans mutants with defects in mitochondrial fusion.

Mitochondrial dynamics plays an important role in mitochondrial quality control and the adaptation of metabolic activity in response to environmental changes. The disruption of mitochondrial dynamics has detrimental consequences for mitochondrial and cellular homeostasis and leads to the activation of the mitochondrial unfolded protein response (UPRmt), a quality control mechanism that adjusts cellular metabolism and restores homeostasis. To identify genes involved in the induction of UPRmt in response to a block in mitochondrial fusion, we performed a genome-wide RNAi screen in Caenorhabditis elegans mutants lacking the gene fzo-1, which encodes the ortholog of mammalian Mitofusin, and identified 299 suppressors and 86 enhancers. Approximately 90% of these 385 genes are conserved in humans, and one-third of the conserved genes have been implicated in human disease. Furthermore, many have roles in developmental processes, which suggests that mitochondrial function and their response to stress are defined during development and maintained throughout life. Our dataset primarily contains mitochondrial enhancers and non-mitochondrial suppressors of UPRmt, indicating that the maintenance of mitochondrial homeostasis has evolved as a critical cellular function, which, when disrupted, can be compensated for by many different cellular processes. Analysis of the subsets “non-mitochondrial enhancers” and “mitochondrial suppressors” suggests that organellar contact sites, especially between the ER and mitochondria, are of importance for mitochondrial homeostasis. In addition, we identified several genes involved in IP3 signaling that modulate UPRmt in fzo-1 mutants and found a potential link between pre-mRNA splicing and UPRmt activation.

Mst1 Knockout Alleviates Mitochondrial Fission and Mitigates Left Ventricular Remodeling in the Development of Diabetic Cardiomyopathy.

The disruption of mitochondrial dynamics is responsible for the development of diabetic cardiomyopathy (DCM). However, the mechanisms that regulate the balance of mitochondrial fission and fusion are not well-understood. Wild-type, Mst1 transgenic and Mst1 knockout mice were induced with experimental diabetes by streptozotocin injection. In addition, primary neonatal cardiomyocytes were isolated and cultured to simulate diabetes to explore the mechanisms. Echocardiograms and hemodynamic measurements revealed that Mst1 knockout alleviated left ventricular remodeling and cardiac dysfunction in diabetic mice. Mst1 knockdown significantly decreased the number of TUNEL-positive cardiomyocytes subjected to high-glucose (HG) medium culture. Immunofluorescence study indicated that Mst1 overexpression enhanced, while Mst1 knockdown mitigated mitochondrial fission in DCM. Mst1 participated in the regulation of mitochondrial fission by upregulating the expression of Drp1, activating Drp1S616 phosphorylation and Drp1S637 dephosphorylation, as well as promoting Drp1 recruitment to the mitochondria. Furthermore, Drp1 knockdown abolished the effects of Mst1 on mitochondrial fission, mitochondrial membrane potential and mitochondrial dysfunction in cardiomyocytes subjected to HG treatment. These results indicated that Mst1 knockout inhibits mitochondrial fission and alleviates left ventricular remodeling thus prevents the development of DCM.