Mechanistic Insights into Metabolic Function of Dynamin-Related Protein 1 (DRP1) DOI Creative Commons
Xin Li,

Katherine Pham,

Jazmin Ysaguirre

et al.

Journal of Lipid Research, Journal Year: 2024, Volume and Issue: 65(9), P. 100633 - 100633

Published: Aug. 25, 2024

Dynamin-related protein 1 (DRP1) plays crucial roles in mitochondrial and peroxisome fission. However, the mechanisms underlying functional regulation of DRP1 adipose tissue during obesity remain unclear. To elucidate metabolic pathological significance diminished obese tissue, we utilized tissue-specific KO mice challenged with a high-fat diet. We observed significant dysregulations mice. Mechanistically, exerts multifaceted functions dynamics endoplasmic reticulum (ER)-lipid droplet crosstalk normal Loss function resulted abnormally giant shapes, distorted membrane structure, disrupted cristae architecture. Meanwhile, deficiency induced retention nascent lipid droplets ER, leading to perturbed overall Collectively, dysregulation mitochondria, contributes whole-body disorders, as evidenced by perturbations energy metabolites. Our findings demonstrate that diverse critical regulating metabolism within progression obesity.

Language: Английский

Mitophagy for cardioprotection DOI Creative Commons
Allen Sam Titus, Eun‐Ah Sung,

Daniela Zablocki

et al.

Basic Research in Cardiology, Journal Year: 2023, Volume and Issue: 118(1)

Published: Oct. 5, 2023

Abstract Mitochondrial function is maintained by several strictly coordinated mechanisms, collectively termed mitochondrial quality control including fusion and fission, degradation, biogenesis. As the primary source of energy in cardiomyocytes, mitochondria are central organelle for maintaining cardiac function. Since adult cardiomyocytes humans rarely divide, number dysfunctional cannot easily be diluted through cell division. Thus, efficient degradation crucial to cellular Mitophagy, a specific form autophagy, major mechanism which damaged or unnecessary targeted eliminated. Mitophagy active at baseline response stress, plays an essential role cardiomyocytes. mediated multiple mechanisms heart, each these can partially compensate loss another mechanism. However, insufficient levels mitophagy eventually lead dysfunction development heart failure. In this review, we discuss molecular pathophysiology, with focus on recent findings field.

Language: Английский

Citations

49
mtDNA-cGAS-STING axis-dependent NLRP3 inflammasome activation contributes to postoperative cognitive dysfunction induced by sevoflurane in mice DOI Creative Commons

Nan‐Shi‐Yu Yang,

Wenjing Zhong,

Han-Xi Sha

et al.

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(5), P. 1927 - 1946

Published: Jan. 1, 2024

The activation of NLRP3 inflammasome in microglia is critical for neuroinflammation during postoperative cognitive dysfunction (POCD) induced by sevoflurane.However, the molecular mechanism which sevoflurane activates remains unclear.The cGAS-STING pathway an evolutionarily conserved inflammatory defense mechanism.The role sevoflurane-induced inflammasome-dependent and underlying mechanisms require further investigation.We found that prolonged anesthesia with triggered characterized vivo.Interestingly, was activated hippocampus mice receiving sevoflurane.While blockade cGAS RU.521 attenuated mice.In vitro, we treatment significantly microglia, while pre-treatment robustly inhibited activation.Mechanistically, mitochondrial fission released DNA (mtDNA) into cytoplasm, could be abolished Mdivi-1.Blocking mtDNA release via mPTP-VDAC channel inhibitor cytosolic escape reduced finally inhibiting activation.Therefore, regulating targeting may provide a novel therapeutic target POCD.

Language: Английский

Citations

21
Redefining Diabetic Cardiomyopathy: Perturbations in Substrate Metabolism at the Heart of its Pathology DOI
Lisa C. Heather, Keshav Gopal, Nikola Srnic

et al.

Diabetes, Journal Year: 2024, Volume and Issue: 73(5), P. 659 - 670

Published: Feb. 22, 2024

Cardiovascular disease represents the leading cause of death in people with diabetes, most notably from macrovascular diseases such as myocardial infarction or heart failure. Diabetes also increases risk a specific form cardiomyopathy, referred to diabetic cardiomyopathy (DbCM), originally defined ventricular dysfunction absence underlying coronary artery and/or hypertension. Herein, we provide an overview on key mediators DbCM, emphasis role for perturbations cardiac substrate metabolism. We discuss mechanisms regulating metabolic additional focus metabolites signaling molecules within heart. Furthermore, preclinical approaches target these alleviate DbCM. With several advancements our understanding, propose following new definition for, approach classify, DbCM: “diastolic presence altered metabolism person diabetes but other known causes hypertension.” However, recognize that no can fully explain complexity why some individuals DbCM exhibit diastolic dysfunction, whereas others develop systolic dysfunction. Due sharing pathological features failure preserved ejection fraction (HFpEF), latter which is more prevalent population it imperative determine whether effective management decreases HFpEF prevalence. Article Highlights

Language: Английский

Citations

20
Hyperglycemia triggers RyR2-dependent alterations of mitochondrial calcium homeostasis in response to cardiac ischemia-reperfusion: Key role of DRP1 activation DOI Creative Commons

Mathilde Dubois,

Doria Boulghobra,

Gilles Rochebloine

et al.

Redox Biology, Journal Year: 2024, Volume and Issue: 70, P. 103044 - 103044

Published: Jan. 19, 2024

Hyperglycemia increases the heart sensitivity to ischemia-reperfusion (IR), but underlying cellular mechanisms remain unclear. Mitochondrial dynamics (the processes that govern mitochondrial morphology and their interactions with other organelles, such as reticulum), has emerged a key factor in vulnerability IR. However, it is unknown whether contributes hyperglycemia deleterious effect during We hypothesized (i) higher IR hyperglycemic conditions could be explained by on complex interplay between dynamics, Ca

Language: Английский

Citations

12
Targeting selective autophagy and beyond: From underlying mechanisms to potential therapies DOI Creative Commons
Wei Ma, Yingying Lü, Xin Jin

et al.

Journal of Advanced Research, Journal Year: 2024, Volume and Issue: 65, P. 297 - 327

Published: May 14, 2024

Autophagy is an evolutionarily conserved turnover process for intracellular substances in eukaryotes, relying on lysosomal (in animals) or vacuolar yeast and plants) mechanisms. In the past two decades, emerging evidence suggests that, under specific conditions, autophagy can target particular macromolecules organelles degradation, a termed selective autophagy. Recently, accumulating studies have demonstrated that abnormality of closely associated with occurrence progression many human diseases, including neurodegenerative cancers, metabolic cardiovascular diseases. This review aims at systematically comprehensively introducing its role various while unravelling molecular mechanisms By providing theoretical basis development related small-molecule drugs as well treating this seeks to contribute understanding therapeutic potential. review, we introduce dissect major categories been discovered. We also focus recent advances underlying both classical non-classical Moreover, current situation targeting different types further summarized, valuable insights into discovery more candidate future. On other hand, reveal clinically relevant implementations are potentially autophagy, such predictive approaches treatments tailored individual patients.

Language: Английский

Citations

12
Autophagy in High-Fat Diet and Streptozotocin-Induced Metabolic Cardiomyopathy: Mechanisms and Therapeutic Implications DOI Open Access
Rong Zhou, Zhaoming Zhang, Xinjie Li

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1668 - 1668

Published: Feb. 15, 2025

Metabolic cardiomyopathy, encompassing diabetic and obese is an escalating global health concern, driven by the rising prevalence of metabolic disorders such as insulin resistance, type 1 2 diabetes, obesity. These conditions induce structural functional alterations in heart, including left ventricular dysfunction, fibrosis, ultimately heart failure, particularly presence coronary artery disease or hypertension. Autophagy, a critical cellular process for maintaining cardiac homeostasis, frequently disrupted cardiomyopathy. This review explores role autophagy pathogenesis high-fat diet (HFD) streptozotocin (STZ)-induced focusing on non-selective selective pathways, mitophagy, ER-phagy, ferritinophagy. Key proteins genes PINK1, Parkin, ULK1, AMPK, mTOR, ATG7, ATG5, Beclin-1, miR-34a are central to regulation Dysregulated autophagic flux impairs mitochondrial function, promotes oxidative stress, drives fibrosis heart. Additionally, processes lipophagy, regulated PNPLA8, ferritinophagy, modulated NCOA4, play pivotal roles lipid metabolism iron homeostasis. Emerging therapeutic strategies targeting autophagy, plant extracts (e.g., curcumin, dihydromyricetin), endogenous compounds sirtuin 3, LC3), lipid/glucose-lowering drugs, offer promising avenues mitigating effects Despite recent advances, precise mechanisms underlying this context remain poorly understood. A deeper understanding autophagy's regulatory networks, involving these proteins, may lead novel approaches treating

Language: Английский

Citations

1
Targeting autophagy drug discovery: Targets, indications and development trends DOI

Mengjia Jiang,

Wayne Wu,

Zijie Xiong

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 267, P. 116117 - 116117

Published: Jan. 23, 2024

Language: Английский

Citations

8
Baicalein ameliorated obesity-induced cardiac dysfunction by regulating the mitochondrial unfolded protein response through NRF2 signaling DOI Creative Commons
Lulu Guo,

Junle Yang,

Wenting Yuan

et al.

Phytomedicine, Journal Year: 2024, Volume and Issue: 126, P. 155441 - 155441

Published: Feb. 10, 2024

The mitochondrial unfolded protein response (UPRmt) is the first line of defense against dysfunction in several diseases. Baicalein, which an extract Scutellaria baicalensis Georgi roots, exerts mitoprotective effects on metabolic disorders and cardiovascular However, it remains unclear whether baicalein alleviates obesity-induced cardiac damage through UPRmt. present research designed to clarify role lipotoxicity-induced myocardial apoptosis investigated UPRmt-related mechanism. In vitro experiment, palmitic acid (PA)-treated AC16 cardiomyocytes were established mimic injury. After pretreatment cells with baicalein, levels cell vitality, apoptosis, membrane potential, oxidative stress, proteins determined. Additionally, treated ML385 or siRNA explore regulation UPRmt by NRF2 signaling. vivo male db/db mice administered for 8 weeks used validate induced obesity, UPRmt, NRF2-related pathway. cardiomyocytes, PA dose-dependently increased expression markers (HSP60, LONP1, ATF4, ATF5). This increase was accompanied enhanced production ROS, reduced elevated cytochrome c, cleaved caspase-3, Bax/Bcl2, eventually leading apoptosis. Baicalein treatment reversed activation impeded mitochondrial-mediated Moreover, downregulation its inhibitor diminished baicalein-mediated signaling inhibition triggered dysfunction. deficiency more intensely activated resulting stress PA-induced thus indicating that plays a vital homeostasis regulation. study mice, inhibited antioxidant capacity, attenuated NRF2-activated To our best knowledge, these results provide insight inhibits induce protective effect cardiomyocyte via activating suggest new

Language: Английский

Citations

8
Mitophagy modulation for the treatment of cardiovascular diseases DOI Creative Commons
Maurizio Forte, Luca D’Ambrosio, Gabriele G. Schiattarella

et al.

European Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 54(8)

Published: March 26, 2024

Defects of mitophagy, the selective form autophagy for mitochondria, are commonly observed in several cardiovascular diseases and represent main cause mitochondrial dysfunction. For this reason, mitophagy has emerged as a novel potential therapeutic target.

Language: Английский

Citations

6
Rhein alleviates myocardial ischemic injury by inhibiting mitochondrial division, activating mitochondrial autophagy and suppressing myocardial cell apoptosis through the Drp1/Pink1/Parkin pathway DOI
Hanqing Li, Yan Jia,

Daomin Yao

et al.

Molecular Biology Reports, Journal Year: 2024, Volume and Issue: 51(1)

Published: Feb. 1, 2024

Language: Английский

Citations

5