The phosphorylation of AMPKβ1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids DOI Creative Commons
Eric M. Desjardins, Brennan K. Smith, Emily A. Day

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(48)

Published: Nov. 21, 2022

Fatty acids are vital for the survival of eukaryotes, but when present in excess can have deleterious consequences. The AMP-activated protein kinase (AMPK) is an important regulator multiple branches metabolism. Studies purified enzyme preparations and cultured cells shown that AMPK allosterically activated by small molecules as well fatty acyl-CoAs through a mechanism involving Ser108 within regulatory β1 isoform. However, vivo physiological significance this residue has not been evaluated. In current study, we generated mice with targeted germline knock-in (KI) mutation AMPKβ1 to Ala (S108A-KI), which renders site phospho-deficient. S108A-KI had reduced activity (50 75%) liver skeletal muscle. On chow diet, impairments exogenous lipid-induced acid oxidation. fed high-fat diet found tendency greater glucose intolerance elevated triglycerides. Consistent increased triglycerides, livers reductions mitochondrial content respiration were accompanied enlarged mitochondria, suggestive mitophagy. Subsequent studies primary hepatocytes palmitate- stimulated Cpt1a Ppargc1a mRNA, ULK1 phosphorylation autophagic/mitophagic flux. These data demonstrate role promoting oxidation, biogenesis autophagy under conditions high lipid availability. As both ketogenic diets intermittent fasting increase circulating free levels, activity, biogenesis, mitophagy, these suggest potential unifying may be mediating effects.

Language: Английский

Exploring the mystery of tumor metabolism: Warburg effect and mitochondrial metabolism fighting side by side DOI
Yongxin Yu,

Yulang Jiang,

Christian Glandorff

et al.

Cellular Signalling, Journal Year: 2024, Volume and Issue: 120, P. 111239 - 111239

Published: May 28, 2024

Language: Английский

Citations

13
Mitochondrial Dysfunction in Systemic Lupus Erythematosus with a Focus on Lupus Nephritis DOI Open Access
Matthieu Halfon, Aurel T. Tankeu, Camillo Ribi

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(11), P. 6162 - 6162

Published: June 3, 2024

Systemic lupus erythematosus (SLE) is an autoimmune disease affecting mostly women of child-bearing age. Immune dysfunction in SLE results from disrupted apoptosis which lead to unregulated interferon (IFN) stimulation and the production autoantibodies, leading immune complex formation, complement activation, organ damage. Lupus nephritis (LN) a common severe complication SLE, impacting approximately 30% 40% patients. Recent studies have demonstrated alteration mitochondrial homeostasis Mitochondrial contributes significantly pathogenesis by enhancing type 1 IFN through various pathways involving neutrophils, platelets, T cells. Defective mitophagy, process clearing damaged mitochondria, exacerbates this cycle, increased dysregulation. In review, we aim detail physiopathological link between activity SLE. Additionally, will explore potential role mitochondria as biomarkers therapeutic targets with specific focus on LN. LN, abnormalities are observed renal cells, correlating progression fibrosis. Studies exploring cell-free DNA biomarker LN shown promising but preliminary results, necessitating further validation standardization. Therapeutically targeting using drugs like metformin or mTOR inhibitors, shows modulating responses improving clinical outcomes. The interplay dysregulation, involvement underscores need for comprehensive research innovative strategies. Understanding dynamics their impact offers avenues developing personalized treatments non-invasive biomarkers, ultimately outcomes

Language: Английский

Citations

11
Soy isoflavones induces mitophagy to inhibit the progression of osteosarcoma by blocking the AKT/mTOR signaling pathway DOI Creative Commons

Ziang Zheng,

Xinghan Zhao,

Bo Yuan

et al.

Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(1)

Published: Jan. 8, 2024

Abstract Background Soy isoflavones (SI) is a natural bioactive substance exhibiting beneficial effects on human health. This study aims to elucidate the therapeutic potential of SI in treatment osteosarcoma (OS) and investigate underlying mechanisms, particularly focusing mitophagy. Methods The proliferation, apoptosis, migration, invasion U2OS cells were analyzed. Mitophagy was assessed through multiple parameters: mitochondrial autophagosomes, membrane potential, autophagy-related proteins, reactive oxygen species (ROS), consumption rate (OCR). Protein levels related autophagy, AKT/mTOR pathway analyzed using western blot. efficacy further identified mouse tumor xenograft model. Cell apoptosis proliferation xenografts detected by TUNEL staining immunohistochemistry (IHC), respectively. Results dose-dependently suppressed viability, colony formation, cells, enhanced apoptosis. also induced mitophagy OS evidenced an increase autophagosomes ROS levels, decrease OCR, concomitant changes proteins. Mdivi-1, inhibitor mitophagy, reversed anti-tumor cells. In addition, blocked SC-79, AKT agonist, effect inducing Moreover, promoted cell vivo . Conclusions induces blocking pathway, contributing inhibition OS.

Language: Английский

Citations

10
Kynurenines, Neuronal Excitotoxicity, and Mitochondrial Oxidative Stress: Role of the Intestinal Flora DOI Open Access
Gábor Nagy-Grócz, Eleonóra Spekker, László Vécsei

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(3), P. 1698 - 1698

Published: Jan. 30, 2024

The intestinal flora has been the focus of numerous investigations recently, with inquiries not just into gastrointestinal aspects but also pathomechanism other diseases such as nervous system disorders and mitochondrial diseases. Mitochondrial are most common type inheritable metabolic illness caused by mutations nuclear DNA. Despite intensive research, its diagnosis is usually difficult, unfortunately, treating it challenges physicians. Metabolites kynurenine pathway linked to many disorders, depression, schizophrenia, migraine, associated impaired function. includes substances, for instance kynurenic acid quinolinic acid. In this review, we would like show a possible link between metabolites stress in context flora. Furthermore, summarize markers future therapeutic options excitotoxicity oxidative stress.

Language: Английский

Citations

10
Mitophagy in relation to chronic inflammation/ROS in aging DOI
Liang Kong, Shuhao Li, Yu Fu

et al.

Molecular and Cellular Biochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: June 4, 2024

Language: Английский

Citations

9
Ferroptosis and musculoskeletal diseases: “Iron Maiden” cell death may be a promising therapeutic target DOI Creative Commons
Yili Zhang, Xinyi Huang,

Baoyu Qi

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Oct. 11, 2022

Ferroptosis is a novel form of cell death precisely regulated by iron metabolism, antioxidant processes, and lipid metabolism that plays an irreplaceable role in the development many diseases. Musculoskeletal disorders (MSKs), including osteoporosis, osteoarthritis, rheumatoid arthritis, intervertebral disc degeneration, sarcopenia, rhabdomyolysis, have become one most common causes disability major burden on public health social care systems. The mechanism ferroptosis MSKs has recently been elucidated. In this review, we briefly introduce illustrate pathological roles with focus how can be exploited as promising treatment strategy. Notably, because toxicity compounds inhibit or induce other organs largely unknown, appears to double-edged sword. We point out more research needed future verify therapeutic effects based MSKs.

Language: Английский

Citations

30
L‐carnitine alleviates cardiac microvascular dysfunction in diabetic cardiomyopathy by enhancing PINK1‐Parkin‐dependent mitophagy through the CPT1a‐PHB2‐PARL pathways DOI Creative Commons
Li Su, Muyin Liu, Jinxiang Chen

et al.

Acta Physiologica, Journal Year: 2023, Volume and Issue: 238(3)

Published: April 12, 2023

Abstract Aim To explore the beneficial effects of L‐carnitine on cardiac microvascular dysfunction in diabetic cardiomyopathy from perspectives mitophagy and mitochondrial integrity. Methods Male db/db db/m mice were randomly assigned to groups treated with or a solvent for 24 weeks. Endothelium‐specific PARL overexpression was attained via adeno‐associated virus serotype 9 (AAV9) transfection. Adenovirus (ADV) vectors overexpressing wild‐type CPT1a, mutant transfected into endothelial cells exposed high glucose free fatty acid (HG/FFA) injury. Cardiac function, mitophagy, function analyzed by immunofluorescence transmission electron microscopy. Protein expression interactions assessed western blotting immunoprecipitation. Results treatment enhanced perfusion, reinforced barrier repressed inflammatory response, maintained structure mice. Further results demonstrated that PINK1‐Parkin‐dependent suppressed suffering injury, these largely alleviated through inhibition detachment PHB2. Moreover, CPT1a modulated PHB2‐PARL interaction directly binding The increase activity induced amino mutation (M593S) interaction, thereby improving function. In contrast, inhibited abolished all integrity Conclusion maintaining reversing injury cardiomyopathy.

Language: Английский

Citations

21
Alamandine/MrgD axis prevents TGF-β1-mediated fibroblast activation via regulation of aerobic glycolysis and mitophagy DOI Creative Commons
Wei Wang, Yue Zhang, Wenhui Huang

et al.

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Jan. 13, 2023

Abstract Background Idiopathic pulmonary fibrosis is a chronic progressive, lethal disease in which ectopic lung fibroblast (LF) activation plays vital part. We have previously shown that alamandine (ALA) exerts anti-fibrosis effects via the MAS-related G-protein coupled receptor D (MrgD). Here, we further investigate how it moderates transforming growth factor β1 (TGF-β1)-induced LF by regulating glucose metabolism and mitochondria autophagy (mitophagy). Methods In vitro, examined glycolysis-related protein hexokinase 2 (HK2), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), lactic acid cells treated with TGF-β1. The oxygen consumption rate extracellular acidification were detected using Seahorse assays. Then, mitophagy was evaluated transmission electron microscopy, mt-Keima, co-localization of Parkin COX IV LC3 LAMP1, respectively. autophagic degradation HK2 PFKFB3 3MA bafilomycin A1 assessed their ALA on markers collagen I α-SMA detected. metabolism, mitophagy, also investigated vivo. Results found ALA/MrgD axis improved TGF-β1-mediated repressing glycolysis downregulating expression. Lactic sustained positive feedback between maintaining expression PFKFB3. showed enhancement resulted from blocking while upregulated mRNA levels TGF-β1, all those adding. Importantly, determined moderation Parkin/LC3-mediated TGF-β1 promotes but reversed ALA. Furthermore, proved counteracts bleomycin HK2, PFKFB3, LC3, Parkin, Conclusion this study, show prevents regulation aerobic mitophagy.

Language: Английский

Citations

18
Mitochondrial Modulators: The Defender DOI Creative Commons
Emmanuel Ayobami Makinde, Linlin Ma, George D. Mellick

et al.

Biomolecules, Journal Year: 2023, Volume and Issue: 13(2), P. 226 - 226

Published: Jan. 24, 2023

Mitochondria are widely considered the "power hub" of cell because their pivotal roles in energy metabolism and oxidative phosphorylation. However, beyond production ATP, which is major source chemical supply eukaryotes, mitochondria also central to calcium homeostasis, reactive oxygen species (ROS) balance, apoptosis. The perform crucial multifaceted biosynthetic pathways, serving as an important building blocks for biosynthesis fatty acid, cholesterol, amino glucose, heme. Since play multiple vital cell, it not surprising that disruption mitochondrial function has been linked a myriad diseases, including neurodegenerative cancer, metabolic disorders. In this review, we discuss key physiological pathological functions present bioactive compounds with protective effects on mechanisms action. We highlight promising existing difficulties limiting therapeutic use these potential solutions. provide insights perspectives into future research windows modulators.

Language: Английский

Citations

17
Advances in mitophagy and mitochondrial apoptosis pathway-related drugs in glioblastoma treatment DOI Creative Commons
Weiping Li, Xia Xu

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: June 30, 2023

Glioblastoma (GBM) is the most common malignant tumor of central nervous system (CNS). It a leading cause death among patients with intracranial tumors. GBM exhibits intra- and inter-tumor heterogeneity, to drug resistance eventual recurrence. Conventional treatments for include maximum surgical resection glioma tissue, temozolomide administration, radiotherapy, but these methods do not effectively halt cancer progression. Therefore, development novel treatment identification new therapeutic targets are urgently required. In recent years, studies have shown that drugs related mitophagy mitochondrial apoptosis pathways can promote glioblastoma cells by inducing damage, impairing adenosine triphosphate (ATP) synthesis, depleting large amounts ATP. Some also modern nano-drug delivery technology targeting mitochondria achieve better release deeper tissue penetration, suggesting could be target intervention therapy. The combination autophagy nanotechnology promising approach treating GBM.This article reviews current status therapy GBM, pathways, potential as treatment, latest developments pertaining directions future research.

Language: Английский

Citations

16