Abnormal Mitochondrial Dynamics Research Articles

Renal denervation ameliorates atrial remodeling in type 2 diabetic rats by regulating mitochondrial dynamics.

There is no effective treatment for diabetes-related atrial remodeling currently. This study aimed to investigate the effects of renal denervation (RDN) on diabetes-related atrial remodeling and explore the related mechanisms. A type 2 diabetes mellitus model was established by high-fat diet feeding and low-dose streptozotocin injection in Sprague‒Dawley rats. After successful modeling, the diabetic rats were randomly assigned to two groups according to whether they were subjected to RDN or sham RDN surgery. At the end of the experiment, cardiac function and structure were evaluated by echocardiography and histology, respectively. Mitochondrial morphology, function and mitochondrial dynamics were assessed by multiple methods. Mdivi1 was used to verify the mechanism by which RDN improves atrial remodeling. In the 10th week, diabetic rats exhibited obvious atrial remodeling, including atrial enlargement and diastolic dysfunction. Pathological staining showed that diabetic rats had cardiomyocyte hypertrophy and interstitial fibrosis in atrial tissues. In terms of mitochondrial morphology and function, diabetic rats exhibited fragmented mitochondria, reduced adenosine triphosphate production and decreased mitochondrial membrane potential levels. Abnormal mitochondrial dynamics in diabetic rats were characterized by the inhibition of mitochondrial fusion, excessive mitochondrial fission, and the suppression of mitophagy. However, RDN effectively ameliorated diabetes-induced pathological atrial remodeling. In addition, RDN significantly improved mitochondrial morphological and functional abnormalities and corrected the disorders of mitochondrial dynamics. Furthermore, the protective effects of RDN against atrial remodeling were related to the regulation of mitochondrial dynamics. RDN prevented diabetes-induced atrial remodeling. These protective effects might be related to improvements in mitochondrial dynamics.

Astragaloside IV combined with ligustrazine ameliorates abnormal mitochondrial dynamics via Drp1 SUMO/deSUMOylation in cerebral ischemia-reperfusion injury.

Astragaloside IV (AST IV) and ligustrazine (Lig), the main ingredients of Astragali Radix and Chuanxiong Rhizoma respectively, have demonstrated significant benefits in treatment of cerebral ischemia -reperfusion injury (CIRI); however, the mechanisms underlying its benificial effects remain unclear. SUMO-1ylation and deSUMO-2/3ylation of dynamin-related protein 1 (Drp1) results in mitochondrial homeostasis imbalance following CIRI, which subsequently aggravates cell damage. This study investigates the mechanisms by which AST IV combined with Lig protects against CIRI, focusing on the involvement of SUMOylation in mitochondrial dynamics. Rats were administrated AST IV and Lig for 7 days, and middle cerebral artery occlusion was established to mimic CIRI. Neural function, cerebral infarction volume, cerebral blood flow, cognitive function, cortical pathological lesions, and mitochondrial morphology were measured. SH-SY5Y cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury. Mitochondrial membrane potential and lactic dehydrogenase (LDH), reactive oxygen species (ROS), and adenosine triphosphate (ATP) levels were assessed with commercial kits. Moreover, co-immunoprecipitation (Co-IP) was used to detect the binding of SUMO1 and SUMO2/3 to Drp1. The protein expressions of Drp1, Fis1, MFF, OPA1, Mfn1, Mfn2, SUMO1, SUMO2/3, SENP1, SENP2, SENP3, SENP5, and SENP6 were measured using western blot. In rats with CIRI, AST IV and Lig improved neurological and cognitive functions, restored CBF, reduced brain infarct volume, and alleviated cortical neuron and mitochondrial damage. Moreover, in SH-SY5Y cells, the combination of AST IV and Lig enhanced cellular viability, decreased release of LDH and ROS, increased ATP content, and improved mitochondrial membrane potential. Furthermore, AST IV combined with Lig reduced the binding of Drp1 with SUMO1, increased the binding of Drp1 with SUMO2/3, suppressed the expressions of Drp1, Fis1, MFF, and SENP3, and increased the expressions of OPA1, Mfn1, Mfn2, SENP1, SENP2, and SENP5. SUMO1 overexpression promoted mitochondrial fission and inhibited mitochondrial fusion, whereas SUMO2/3 overexpression suppressed mitochondrial fission. AST IV combined with Lig could reverse the effects of SUMO1 overexpression while enhancing those of SUMO2/3 overexpression. This study posits that the combination of AST IV and Lig has the potential to reduce the SUMO-1ylation of Drp1, augment the SUMO-2/3ylation of Drp1, and thereby exert a protective effect against CIRI.

Hydrogen alleviates impaired lung epithelial barrier in acute respiratory distress syndrome via inhibiting Drp1-mediated mitochondrial fission through the Trx1 pathway

Acute respiratory distress syndrome (ARDS) is an acute and severe clinical complication lacking effective therapeutic interventions. The disruption of the lung epithelial barrier plays a crucial role in ARDS pathogenesis. Recent studies have proposed the involvement of abnormal mitochondrial dynamics mediated by dynamin-related protein 1 (Drp1) in the mechanism of impaired epithelial barrier in ARDS. Hydrogen is an anti-oxidative stress molecule that regulates mitochondrial function via multiple signaling pathways. Our previous study confirmed that hydrogen modulated oxidative stress and attenuated acute pulmonary edema in ARDS by upregulating thioredoxin 1 (Trx1) expression, but the exact mechanism remains unclear. This study aimed to investigate the effects of hydrogen on mitochondrial dynamics both in vivo and in vitro. Our study revealed that hydrogen inhibited lipopolysaccharide (LPS)-induced phosphorylation of Drp1 (at Ser616), suppressed Drp1-mediated mitochondrial fission, alleviated epithelial tight junction damage and cell apoptosis, and improved the integrity of the epithelial barrier. This process was associated with the upregulation of Trx1 in lung epithelial tissues of ARDS mice by hydrogen. In addition, hydrogen treatment reduced the production of reactive oxygen species in LPS-induced airway epithelial cells (AECs) and increased the mitochondrial membrane potential, indicating that the mitochondrial dysfunction was restored. Then, the expression of tight junction proteins occludin and zonula occludens 1 was upregulated, and apoptosis in AECs was alleviated. Remarkably, the protective effects of hydrogen on the mitochondrial and epithelial barrier were eliminated after applying the Trx1 inhibitor PX-12. The results showed that hydrogen significantly inhibited the cell apoptosis and the disruption of epithelial tight junctions, maintaining the integrity of the epithelial barrier in mice of ARDS. This might be related to the inhibition of Drp1-mediated mitochondrial fission through the Trx1 pathway. The findings of this study provided a new theoretical basis for the application of hydrogen in the clinical treatment of ARDS.

VPS13D affects epileptic seizures by regulating mitochondrial fission and autophagy in epileptic rats

Abnormal mitochondrial dynamics can lead to seizures, and improved mitochondrial dynamics can alleviate seizures. Vacuolar protein sorting 13D (VPS13D) is closely associated with regulating mitochondrial homeostasis and autophagy. However, further investigation is required to determine whether VPS13D affects seizures by influencing mitochondrial dynamics and autophagy. We aimed to investigate the influence of VPS13D on behavior in a rat model of acute epileptic seizures. Hence, we established an acute epileptic seizure rat model and employed the CRISPR/CAS9 technology to construct a lentivirus to silence the Vps13d gene. Furthermore, we used the HT22 mouse hippocampal neuron cell line to establish a stable strain with suppressed expression of Vps13d in vitro. Then, we performed quantitative proteomic and bioinformatics analyses to confirm the mechanism by which VPS13D influences mitochondrial dynamics and autophagy, both in vitro and in vivo using the experimental acute epileptic seizure model. We found that knockdown of Vps13d resulted in reduced seizure latency and increased seizure frequency in the experimental rats. Immunofluorescence staining and western blot analysis revealed a significant increase in mitochondrial dynamin-related protein 1 expression following Vps13d knockdown. Moreover, we observed a significant reduction in LC3II protein expression levels and the LC3II/LC3I ratio (indicators for autophagy) accompanied by a significant increase in P62 expression (an autophagy adaptor protein). The proteomic analysis confirmed the up-regulation of P62 protein expression. Therefore, we propose that VPS13D plays a role in modulating seizures by influencing mitochondrial dynamics and autophagy.

Acetylated tau exacerbates apoptosis by disturbing mitochondrial dynamics in HEK293 cells.

An increase in tau acetylation at K274 and K281 and abnormal mitochondrial dynamics have been observed in the brains of Alzheimer's disease (AD) patients. Here, we constructed three types of tau plasmids, TauKQ (acetylated tau mutant, by mutating its K274/K281 into glutamine to mimic disease-associated lysine acetylation), TauKR (non-acetylated tau mutant, by mutating its K274/K281 into arginine), and TauWT (wild-type human full-length tau). By transfecting these tau plasmids in HEK293 cells, we found that TauWT and TauKR induced mitochondrial fusion by increasing the level of mitochondrial fusion proteins. Conversely, TauKQ induced mitochondrial fission by reducing mitochondrial fusion proteins, exacerbating mitochondrial dysfunction and apoptosis. BGP-15 ameliorated TauKQ-induced mitochondrial dysfunction and apoptosis by improving mitochondrial dynamics. Our findings suggest that acetylation of K274/281 represents an important post-translational modification site regulating mitochondrial dynamics, and that BGP-15 holds potential as a therapeutic agent for mitochondria-associated diseases such as AD.

Decreased ATF5 level contributes to improved mitochondrial function in oocytes exposed to vitrification stress.

Mitochondrial unfolded protein response (mtUPR) plays an essential role in the response of mitochondria to stress-induced damage. Activating of transcription factor 5 (ATF5) can help to sustain mitochondrial function and regulate organelle recovery under mitochondrial stress. Vitrification is a stressor that disrupts mitochondrial activity and cell homeostasis. However, little is known about the function of ATF5 in response to the extreme biophysical and chemical stresses during oocyte vitrification. The expression of ATF5 and mtUPR biomarkers were measured in fresh and vitrified oocytes. Subsequently, oocytes with ATF5 deficiency were constructed by siRNA microinjection, and the function of ATF5 in mitochondrial function and oocyte development were analyzed in vitrified oocytes. Furthermore, transcriptome analysis was performed to uncover the molecular network regulated by ATF5 in response to oocyte vitrification. In the present study, the mitochondrial membrane potential and ATP levels were decreased in ATF5 knockdown oocytes, in line with the phenotypes observed in vitrified oocytes. In addition, ATF5 knockdown resulted in decreased mitochondrial temperature, reduced unfolded protein levels, abnormal mitochondrial dynamics (fusion and fission), and increased autophagy. Subsequent experiments indicated that mtUPR was suppressed in oocytes with ATF5 knockdown. Interestingly, ATF5 was aberrantly upregulated in oocytes exposed to vitrification stress. Reduced ATF5 expression to a homeostatic level in vitrified oocytes led to accumulated unfolded protein levels and increased mitochondrial membrane potential. Moreover, increased mitochondrial dynamics and an increased germinal vesicle breakdown (GVBD) rate were detected after in vitro maturation. Transcriptome analysis revealed that ATF5 is involved in the vitrification stress response, and ATF5 regulated the in vitro maturation potential in vitrified oocytes through the cAMP-PKA and PI3K/AKT pathways. Our findings indicate that mtUPR was initiated in response to vitrification stimuli, and downregulated ATF5 level to a homeostatic state contributes to improved mitochondrial function in oocytes exposed to vitrification stress. Our results highlight the crucial role of ATF5 in the regulation of mitochondrial function in vitrified oocytes through mediating mtUPR.

SIRT1, a target of miR-708-3p, alleviates fluoride-induced neuronal damage via remodeling mitochondrial network dynamics

IntroductionNeurological dysfunction induced by fluoride contamination is still one of major concern worldwide. Recently, neuroprotective roles of silent information regulator 1 (SIRT1) focusing on mitochondrial function have been highlighted. However, what roles SIRT1 exerts and the underlying regulative mechanisms, remain largely uncharacterized in such neurotoxic process of fluoride. ObjectivesWe aimed at evaluating the regulatory roles of SIRT1 in human neuroblastoma SH-SY5Y cells and Sprague-Dawley rats with fluoride treatment, and to further identify potential miRNA directly targeting SIRT1. MethodsPharmacological suppression of SIRT1 by nicotinamide (NIC) and promotion of SIRT1 by adenovirus (Ad-SIRT1) or resveratrol (RSV) were employed to assess the effects of SIRT1 in mitochondrial dysfunction induced by fluoride. Also, miRNAs profiling and bioinformatic prediction were used to screen the miRNAs which can regulate SIRT1 directly. Further, chemical mimic or inhibitor of chosen miRNA was applied to validate the modulation of chosen miRNA. ResultsNIC exacerbated defects in mitochondrial network dynamics and cytochrome c (Cyto C) release-driven apoptosis, contributing to fluoride-induced neuronal death. In contrast, the ameliorative effects were observed when overexpressing SIRT1 by Ad-SIRT1 in vitro or RSV in vivo. More importantly, miR-708-3p targeting SIRT1 directly was identified. And interestingly, moreover, treatment with chemically modified miR-708-3p mimic aggravated, while miR-708-3p inhibitor suppressed fluoride-caused neuronal death. Further confirmedly, overexpressing SIRT1 effectively neutralized miR-708-3p mimic-worsened fluoride neuronal death via correcting mitochondrial network dynamics. On contrary, inhibiting SIRT1 counteracted the promotive effects of miR-708-3p inhibitor against neurotoxic response by fluoride through aggravating abnormal mitochondrial network dynamics. ConclusionThese data underscore the functional importance of SIRT1 to mitochondrial network dynamics in neurotoxic process of fluoride and further screen a novel unreported neuronal function of miR-708-3p as an upstream regulator of targeting SIRT1, which has important theoretical implications for a potential therapeutic and preventative target for treatment of neurotoxic progression by fluoride.

Enterovirus 71 leads to abnormal mitochondrial dynamics in human neuroblastoma SK-N-SH cells

EV71, a significant pathogen causing hand-foot-mouth disease, is associated with severe neurological complications such as brain stem encephalitis, aseptic meningitis, and acute flaccid paralysis. While the role of mitochondrial dynamics in regulating the replication of numerous viruses is recognized, its specific involvement in EV71 remains unclear. This study aimed to elucidate the role of mitochondrial dynamics in human neuroblastoma SK-N-SH cells during EV71 infection. Utilizing laser confocal microscopy and transmission electron microscopy, we observed that EV71 infection induced mitochondrial elongation and damage to cristae structures, concurrently accelerating mitochondrial movement. Furthermore, we identified the reduction in the expression of dynamin-related protein 1 (Drp1) and optic atrophy protein 1 (Opa1) and the increased expression of Mitofusion 2 (Mfn2) upon EV71 infection. Notably, EV71 directly stimulated the generation of mitochondrial reactive oxygen species (ROS), leading to a decline in mitochondrial membrane potential and ATP levels. Remarkably, the application of melatonin, a potent mitochondrial protector, inhibited EV71 replication by restoring Drp1 expression. These findings collectively indicate that EV71 induces alterations in mitochondrial morphology and dynamics within SK-N-SH cells, potentially impairing mitochondrial function and contributing to nervous system dysfunction. The restoration of proper mitochondrial dynamics may hold promise as a prospective approach to counteract EV71 infection.

Deficiency of aldehyde dehydrogenase 2 aggravates ethanol-induced cytotoxicity in N2a cells via CaMKII/Drp1-mediated mitophagy

Chronic alcohol abuse causes brain damage and has been associated with an increased risk of Alzheimer's disease. The toxic metabolite of alcohol, acetaldehyde, which is converted to acetate by aldehyde dehydrogenase 2 (ALDH2), has been shown to induce excessive mitochondrial fragmentation and dysfunction leading to neurotoxicity. However, it is still unclear how alcohol affects mitochondrial function in ALDH2-deficient cells. The present study investigated the association between abnormal mitochondrial dynamics, mitophagy and cytotoxicity in ALDH2-deficient N2a cells treated with ethanol. It was found that ethanol induced dynamin-related protein 1 (Drp1)-mediated mitochondrial fragmentation and impaired mitochondrial function, causing excessive mitophagy and cytotoxicity in ALDH2-deficient N2a cells while inducing Ca2+ influx and activating Ca2+/calmodulin-dependent protein kinase II (CaMKII). Inhibition of Ca2+ overload or CaMKII activation prevented Drp1 phosphorylation and ameliorated ethanol-induced mitophagy and cytotoxicity, indicating that Ca2+-dependent CaMKII activation was critical for mediating Drp1-dependent excessive mitochondrial fission and mitophagy in ALDH2-deficient N2a cells. The results of the present study suggested that prevention of intracellular Ca2+ overload might be beneficial for preventing neurotoxicity associated with alcohol abuse in individuals with defective ALDH2.

Roles of mitochondrial dynamics and mitophagy in diabetic myocardial microvascular injury.

Myocardial microvessels are composed of a monolayer of endothelial cells, which play a crucial role in maintaining vascular barrier function, luminal latency, vascular tone, and myocardial perfusion. Endothelial dysfunction is a key factor in the development of cardiac microvascular injury and diabetic cardiomyopathy. In addition to their role in glucose oxidation and energy metabolism, mitochondria also participate in non-metabolic processes such as apoptosis, intracellular ion handling, and redox balancing. Mitochondrial dynamics and mitophagy are responsible for regulating the quality and quantity of mitochondria in response to hyperglycemia. However, these endogenous homeostatic mechanisms can both preserve and/or disrupt non-metabolic mitochondrial functions during diabetic endothelial damage and cardiac microvascular injury. This review provides an overview of the molecular features and regulatory mechanisms of mitochondrial dynamics and mitophagy. Furthermore, we summarize findings from various investigations that suggest abnormal mitochondrial dynamics and defective mitophagy contribute to the development of diabetic endothelial dysfunction and myocardial microvascular injury. Finally, we discuss different therapeutic strategies aimed at improving endothelial homeostasis and cardiac microvascular function through the enhancement of mitochondrial dynamics and mitophagy.

The Chinese herbal medicine Fufang Zhenzhu Tiaozhi ameliorates diabetic cardiomyopathy by regulating cardiac abnormal lipid metabolism and mitochondrial dynamics in diabetic mice

Diabetic cardiomyopathy (DCM) is an important complication leading to the death of patients with diabetes, but there is no effective strategy for clinical treatments. Fufang Zhenzhu Tiaozhi (FTZ) is a patent medicine that is a traditional Chinese medicine compound preparation with comprehensive effects for the prevention and treatment of glycolipid metabolic diseases under the guidance of “modulating liver, starting pivot and cleaning turbidity”. FTZ was proposed by Professor Guo Jiao and is used for the clinical treatment of hyperlipidemia. This study was designed to explore the regulatory mechanisms of FTZ on heart lipid metabolism dysfunction and mitochondrial dynamics disorder in mice with DCM, and it provides a theoretical basis for the myocardial protective effect of FTZ in diabetes. In this study, we demonstrated that FTZ protected heart function in DCM mice and downregulated the overexpression of free fatty acids (FFAs) uptake-related proteins cluster of differentiation 36 (CD36), fatty acid binding protein 3 (FABP3) and carnitine palmitoyl transferase 1 (CPT1). Moreover, FTZ treatment showed a regulatory effect on mitochondrial dynamics by inhibiting mitochondrial fission and promoting mitochondrial fusion. We also identified in vitro that FTZ could restore lipid metabolism-related proteins, mitochondrial dynamics-related proteins and mitochondrial energy metabolism in PA-treated cardiomyocytes. Our study indicated that FTZ improves the cardiac function of diabetic mice by attenuating the increase in fasting blood glucose levels, inhibiting the decrease in body weight, alleviating disordered lipid metabolism, and restoring mitochondrial dynamics and myocardial apoptosis in diabetic mouse hearts.

Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice.

Alzheimer's disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with the small molecule CP2 induces an adaptive stress response, activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, Aβ and pTau accumulation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication, reducing ER and unfolded protein response (UPR) stress in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that in the hippocampus of APP/PS1 mice, dendritic mitochondria primarily exist as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS have extensive interaction with the ER membranes, forming multiple mitochondria-ER contact sites (MERCS) known to facilitate abnormal lipid and calcium homeostasis, accumulation of Aβ and pTau, abnormal mitochondrial dynamics, and apoptosis. CP2 treatment reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reductions in MERCS, ER/UPR stress, and improved lipid homeostasis. These data provide novel information on the MOAS-ER interaction in AD and additional support for the further development of partial MCI inhibitors as a disease-modifying strategy for AD.

The role of mitochondrial dynamics imbalance in hexavalent chromium-induced apoptosis and autophagy in rat testis

Hexavalent chromium (Cr(VI)) is a ubiquitous environmental pollutant that can cause reproductive toxicity. However, the exact mechanism of Cr(VI)-induced testis toxicity remains largely elusive. This study aims to explore the possible molecular mechanism of Cr(VI)-provoked testicular toxicity. Male Wistar rats were intraperitoneally injected with 0, 2, 4, or 6 mg/kg body weight/day of potassium dichromate (K2Cr2O7), respectively, for 5 weeks. The results revealed that Cr(VI)-treated rat testis presented varying degrees of damage in a dose-dependent manner. Concretely, Cr(VI) administration suppressed Sirtuin 1/Peroxisome proliferator-activated receptor-γ coactivator-1α pathway and led to mitochondrial dynamics disorder, along with the elevation of mitochondrial division and the repression of mitochondrial fusion. Meanwhile, the downstream effector of Sirt1, nuclear factor-erythroid-2-related factor 2 (Nrf2), was downregulated, and correspondingly exacerbated oxidative stress. Mitochondrial dynamics disorder and Nrf2 inhibition collectively contribute to abnormal mitochondrial dynamics in testis, which further promotes apoptosis and autophagy, evidenced by dose-dependently increasing the protein levels and gene expressions of apoptosis-related (including Bcl-2-associated X protein, cytochrome c, and cleaved-caspase 3) and autophagy-related (Beclin-1, ATG4B, and ATG5). Collectively, our results demonstrate that Cr(VI) exposure induced testis apoptosis and autophagy by disrupting the balance of mitochondrial dynamics and the oxidation-reduction process in rats.

Acquired disorders of mitochondrial metabolism and dynamics in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is an orphan disease of the cardiopulmonary unit that reflects an obstructive pulmonary vasculopathy and presents with hypertrophy, inflammation, fibrosis, and ultimately failure of the right ventricle (RVF). Despite treatment using pulmonary hypertension (PH)-targeted therapies, persistent functional impairment reduces the quality of life for people with PAH and death from RVF occurs in approximately 40% of patients within 5 years of diagnosis. PH-targeted therapeutics are primarily vasodilators and none, alone or in combination, are curative. This highlights a need to therapeutically explore molecular targets in other pathways that are involved in the pathogenesis of PAH. Several candidate pathways in PAH involve acquired mitochondrial dysfunction. These mitochondrial disorders include: 1) a shift in metabolism related to increased expression of pyruvate dehydrogenase kinase and pyruvate kinase, which together increase uncoupled glycolysis (Warburg metabolism); 2) disruption of oxygen-sensing related to increased expression of hypoxia-inducible factor 1α, resulting in a state of pseudohypoxia; 3) altered mitochondrial calcium homeostasis related to impaired function of the mitochondrial calcium uniporter complex, which elevates cytosolic calcium and reduces intramitochondrial calcium; and 4) abnormal mitochondrial dynamics related to increased expression of dynamin-related protein 1 and its binding partners, such as mitochondrial dynamics proteins of 49kDa and 51kDa, and depressed expression of mitofusin 2, resulting in increased mitotic fission. These acquired mitochondrial abnormalities increase proliferation and impair apoptosis in most pulmonary vascular cells (including endothelial cells, smooth muscle cells and fibroblasts). In the RV, Warburg metabolism and induction of glutaminolysis impairs bioenergetics and promotes hypokinesis, hypertrophy, and fibrosis. This review will explore our current knowledge of the causes and consequences of disordered mitochondrial function in PAH.

Research Progress of Mitochondrial Dynamics in Leukemia --Review

Mitochondria is one of the most important organelles of eukaryotic cells, which is closely related to cell proliferation, apoptosis, autophagy and other life processes. Mitochondrias in biological cells are actually in a highly dynamic state. The fusion and division of mitochondria and their secondary effects play an important role in the regulation of cell life. As a malignant disease of hematopoietic system, leukemia is characterized by excessive proliferation, limited apoptosis, abnormal autophagy and other abnormal cell regulation. Therefore, abnormal mitochondrial dynamics regulation may play a key role in the pathogenesis of leukemia, refractory and drug resistance of leukemia. The article reviews the role of mitochondrial dynamics and abnormal regulation in the pathogenesis and development of leukemia, and provides a theoretical basis for the research on the regulation of mitochondrial dynamics in leukemia.

Osthole: A potential AMPK agonist that inhibits NLRP3 inflammasome activation by regulating mitochondrial homeostasis for combating rheumatoid arthritis

BackgroundOsthole (OST), a characteristic coumarin compound in Angelicae pubescentis radix (APR), has shown potent efficacy in the treatment of rheumatoid arthritis (RA), but its specific targets and potential mechanism are limited. PurposeThis study aimed to explore the potential targets and molecular mechanisms of OST against RA using computer-assisted techniques in combination with RA fibroblast-like synoviocytes (FLS) inflammation model and CIA rat model. MethodsNetwork pharmacology and molecular docking were applied to initially predict the potential targets of OST for the treatment of RA. Thereafter, TNFα was used to stimulate FLS to build an in vitro model of inflammation, combined with RNA-seq technology and molecular biology such as qPCR to investigate the anti-inflammatory effects and related mechanisms of OST. Finally, the anti-RA effect of OST was demonstrated by establishing a CIA rat model. ResultsThe network model results showed that the anti-RA effect of OST was mainly related to its anti-inflammatory effect, and AMPK was identified as a potential target for the potency of OST. In the TNFα-induced FLS cells, OST inhibited the secretion of FLS inflammatory factors, which was attributed to the ability of OST to activate AMPK to inhibit the activation of the NLRP3 inflammasome. Further, it was observed that the activation of AMPK by OST facilitated mitochondrial biogenesis, and corrected abnormal mitochondrial dynamics in FLS, which was favoured to the restoration of mitochondrial homeostasis, and further promoted the occurrence of apoptosis and the decrease of ROS in FLS. Consistent with in vivo studies, administration of OST significantly improved joint deformity and toe erythema, reduced arthritis index scores and inhibited synovial inflammation in CIA rats. ConclusionOur study proposed for the first time that AMPK, served as a potential target of OST, positively participated in the anti-RA therapeutic effect of OST. By regulating mitochondrial homeostasis and function, OST can effectively inhibit the activation of inflammasome and the secretion of inflammatory factors in vitro and in vivo, and finally achieve beneficial effects in the treatment of RA, which provides support and greater possibility to make further efforts on pharmacological research and clinical application of OST.

Pearson syndrome-like anemia induced by accumulation of mutant mtDNA and anemia with imbalanced white blood cell lineages induced by Drp1 deletion in a murine model

Regulation of mitochondrial respiration and morphology is important for maintaining steady-state hematopoiesis, yet few studies have comparatively evaluated the effects of abnormal mitochondrial respiration and dynamics on blood-cell differentiation in isolation or combination. This study sought to explore these effects in mouse models with one or both of the following deficits: a large-scale deletion of mitochondrial DNA (ΔmtDNA), accumulated to varying extents, or knockout of the mitochondrial fission factor Drp1. Each deficit was found to independently provoke anemia but with clearly different manifestations. The former showed signs of aberrant respiration, analogous to Pearson syndrome, while the latter showed signs of abnormal mitochondrial dynamics and was associated with changes in the relative proportions of leukocyte lineages. Combining these deficits acted to amplify abnormal iron metabolism in erythropoiesis, exacerbating anemia in an additive manner. Our results indicate that mitochondrial respiration and dynamics play distinct roles in different sets of processes and cell lineages in hematopoietic differentiation.

A Role for PGC-1a in the Control of Abnormal Mitochondrial Dynamics in Alzheimer's Disease.

Emerging evidence suggests that the proper control of mitochondrial dynamics provides a window for therapeutic intervention for Alzheimer’s disease (AD) progression. The transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator 1 (PGC-1a) has been shown to regulate mitochondrial biogenesis in neurons. Thus far, the roles of PGC-1a in Alzheimer’s disease and its potential value for restoring mitochondrial dysfunction remain largely unknown. In the present study, we explored the impacts of PGC-1a on AD pathology and neurobehavioral dysfunction and its potential mechanisms with a particular focus on mitochondrial dynamics. Paralleling AD-related pathological deposits, neuronal apoptosis, abnormal mitochondrial dynamics and lowered membrane potential, a remarkable reduction in the expression of PGC-1a was shown in the cortex of APP/PS1 mice at 6 months of age. By infusing AAV-Ppargc1α into the lateral parietal association (LPtA) cortex of the APP/PS1 brain, we found that PGC-1a ameliorated AD-like behavioral abnormalities, such as deficits in spatial reference memory, working memory and sensorimotor gating. Notably, overexpressed PGC-1a in LPtA rescued mitochondrial swelling and damage in neurons, likely through correcting the altered balance in mitochondrial fission–fusion and its abnormal distribution. Our findings support the notion that abnormal mitochondrial dynamics is likely an important mechanism that leading to mitochondrial dysfunction and AD-related pathological and cognitive impairments, and they indicate the potential value of PGC-1a for restoring mitochondrial dynamics as an innovative therapeutic target for AD.

Mitochondrial fission mediated by Drp1-Fis1 pathway and neurodegenerative diseases.

In recent years, the role of mitochondrial dynamics in neurodegenerative diseases has becoming increasingly important. More and more evidences have shown that in pathological conditions, abnormal mitochondrial divisions, especially Drp1-Fis1-mediated divisions, play an important role in the occurrence and development of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, glaucoma, and other neurodegenerative diseases. This review highlights several new mechanisms of physiological fission of mitochondria and the difference/connection of physiological/pathological mitochondrial fission. In addition, we described the relationship between abnormal mitochondrial dynamics and neurodegenerative diseases in detail and emphatically summarized its detection indicators in basic experiments, trying to provide references for further mechanism exploration and therapeutic targets.

Inhibitors of Mitochondrial Dynamics Mediated by Dynamin-Related Protein 1 in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a chronic, lethal pulmonary disease characterized by pulmonary vascular remodeling. It leads to malignant results, such as rupture of pulmonary arterial dissection, dyspnea, right heart failure, and even death. Previous studies have confirmed that one of the main pathological changes of this disease is abnormal mitochondrial dynamics, which include mitochondrial fission, fusion, and autophagy that keep a dynamic balance under certain physiological state. Dynamin-related protein 1 (Drp1), the key molecule in mitochondrial fission, mediates mitochondrial fission while also affecting mitochondrial fusion and autophagy through numerous pathways. There are various abnormalities of Drp1 in PAH pathophysiology, including Drp1 overexpression and activation as well as an upregulation of its outer mitochondrial membrane ligands. These aberrant alterations will eventually induce the development of PAH. With the process of recent studies, the structure and function of Drp1 have been gradually revealed. Meanwhile, inhibitors targeting this pathway have also been discovered. This review aims to shed more light on the mechanism of Drp1 and its inhibitors in the abnormal mitochondrial dynamics of PAH. Furthermore, it seeks to provide more novel insights to clinical therapy.