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

Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects DOI Creative Commons

Qin Ru,

Yusheng Li,

Lin Chen

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Oct. 14, 2024

Iron, an essential mineral in the body, is involved numerous physiological processes, making maintenance of iron homeostasis crucial for overall health. Both overload and deficiency can cause various disorders human diseases. Ferroptosis, a form cell death dependent on iron, characterized by extensive peroxidation lipids. Unlike other kinds classical unprogrammed death, ferroptosis primarily linked to disruptions metabolism, lipid peroxidation, antioxidant system imbalance. Ferroptosis regulated through transcription, translation, post-translational modifications, which affect cellular sensitivity ferroptosis. Over past decade or so, diseases have been as part their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous cardiovascular musculoskeletal Ferroptosis-related proteins become attractive targets many major that are currently incurable, some regulators shown therapeutic effects clinical trials although further validation potential needed. Therefore, in-depth analysis its molecular mechanisms may offer additional strategies prevention treatment. In this review, we discuss significance contribution etiology development along with evidence supporting targeting approach. Importantly, evaluate recent promising interventions, providing guidance future targeted treatment therapies against

Language: Английский

Citations

50
Mitochondrial quality control in human health and disease DOI Creative Commons
Bohao Liu,

Chen-Zhen Xu,

Yi Liu

et al.

Military Medical Research, Journal Year: 2024, Volume and Issue: 11(1)

Published: May 29, 2024

Abstract Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable vital life processes such cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key like biogenesis, dynamics, mitophagy, which have garnered increasing attention from researchers unveil specific molecular mechanisms. this review, we present comprehensive summary of primary mechanisms functions regulators involved major components MQC. Furthermore, critical regulated by MQC its diverse roles progression systemic diseases been described detail. We discuss agonists antagonists targeting MQC, aiming explore potential therapeutic research prospects enhancing stabilize function.

Language: Английский

Citations

29
Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway DOI Creative Commons
Zhangwei Chen, Li Su, Muyin Liu

et al.

Pharmacological Research, Journal Year: 2024, Volume and Issue: 200, P. 107057 - 107057

Published: Jan. 11, 2024

Mitochondria-associated ferroptosis exacerbates cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Nicorandil, an ATP-sensitive K+ channel opener, protects against endothelial dysfunction, mitochondrial and DCM; however, its effects on mitophagy remain unexplored. The present study aimed to assess the beneficial of nicorandil DCM underlying mechanisms. Cardiac perfusion was assessed using a lectin assay, while via mt-Keima transfection transmission electron microscopy. Ferroptosis examined mRNA sequencing, fluorescence staining, western blotting. localization Parkin, ACSL4, AMPK determined immunofluorescence staining. Following long-term diabetes, treatment improved function remodeling by alleviating injuries, as evidenced structural integrity. mRNA-sequencing biochemical analyses showed that occurred Pink1/Parkin-dependent suppressed cells after diabetes. Nicorandil mitochondria-associated promoting mitophagy. Moreover, increased phosphorylation level AMPKα1 promoted translocation, which further inhibited translocation ACSL4 ultimately ferroptosis. Importantly, overexpression mitochondria-localized (mitoAα1) shared similar benefits with mitophagy, cardiovascular protection injury. In conclusion, demonstrated therapeutic revealed AMPK-Parkin-ACSL4 signaling pathway mediates development dysfunction.

Language: Английский

Citations

16
FDX1 downregulation activates mitophagy and the PI3K/AKT signaling pathway to promote hepatocellular carcinoma progression by inducing ROS production DOI Creative Commons
Bo Sun, Peng Ding, Yinghui Song

et al.

Redox Biology, Journal Year: 2024, Volume and Issue: 75, P. 103302 - 103302

Published: Aug. 6, 2024

Mitochondrial dysfunction and metabolic reprogramming can lead to the development progression of hepatocellular carcinoma (HCC). Ferredoxin 1 (FDX1) is a small mitochondrial protein recent studies have shown that FDX1 plays an important role in tumor cuproptosis, but its HCC still elusive. In this study, we aim investigate expression novel functions HCC.

Language: Английский

Citations

16
Ferroptosis - A new target of osteoporosis DOI

Zhonghua Gao,

Zhuoying Chen, Zhifan Xiong

et al.

Experimental Gerontology, Journal Year: 2022, Volume and Issue: 165, P. 111836 - 111836

Published: May 19, 2022

Language: Английский

Citations

60
Ionizing radiation-induced mitophagy promotes ferroptosis by increasing intracellular free fatty acids DOI
Pengfei Yang, Jin Li, Tianyi Zhang

et al.

Cell Death and Differentiation, Journal Year: 2023, Volume and Issue: 30(11), P. 2432 - 2445

Published: Oct. 12, 2023

Language: Английский

Citations

37
Mitochondrial disorder and treatment of ischemic cardiomyopathy: Potential and advantages of Chinese herbal medicine DOI Open Access
Xing Chang, Jinfeng Liu, Yanli Wang

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 159, P. 114171 - 114171

Published: Jan. 13, 2023

Mitochondrial dysfunction is the main cause of damage to pathological mechanism ischemic cardiomyopathy. In addition, mitochondrial can also affect homeostasis cardiomyocytes or endothelial cell dysfunction, leading a vicious cycle oxidative stress. And an important basis for cardiomyopathy and reperfusion injury after myocardial infarction end-stage coronary heart disease. Therefore, mitochondria be used as therapeutic targets against ischemia injury, regulation morphology, function structure key way targeting quality control mechanisms. includes mechanisms such mitophagy, dynamics (mitochondrial fusion/fission), biosynthesis, unfolded protein responses. Among them, increase fragmentation caused by fission initial factor. The protective fusion strengthen interaction synthesis paired promote biosynthesis. hypoxia, formation fragments, fragmented lead damaged DNA production, which biosynthesis insufficient ATP ROS. Burst growth loss membrane potential. This eventually leads accumulation mitochondria. Then, under leadership complete degradation process through transport morphologically structurally lysosomes degradation. But once increases, may activate pathway cardiomyocyte death. Although laboratory studies have found that variety mitochondrial-targeted drugs reduce protect cardiomyocytes, there are still few successfully passed clinical trials. this review, we describe role MQS in ischemia/hypoxia-induced physiopathology elucidate relevant further explained advantages natural products improving protecting cells from perspective pharmacological mechanism, its related Potential targeted therapies improve ischemia/hypoxia discussed, aiming accelerate development cardioprotective dysfunction.

Language: Английский

Citations

28
Mitochondria as intracellular signalling organelles. An update DOI Creative Commons
Lucia‐Doina Popov

Cellular Signalling, Journal Year: 2023, Volume and Issue: 109, P. 110794 - 110794

Published: July 6, 2023

Traditionally, mitochondria are known as "the powerhouse of the cell," responsible for energy (ATP) generation (by electron transport chain, oxidative phosphorylation, tricarboxylic acid cycle, and fatty ß-oxidation), regulation several metabolic processes, including redox homeostasis, calcium signalling, cellular apoptosis. The extensive studies conducted in last decades portray multifaceted signalling organelles that ultimately command cells' survival or death. Based on current knowledge, we'll outline mitochondrial to other intracellular compartments homeostasis pathology-related stress conditions here. following topics discussed: (i) mtROS mitohormesis, (ii) Ca2+ signalling; (iii) anterograde (nucleus-to-mitochondria) retrograde (mitochondria-to-nucleus) signal transduction, (iv) mtDNA role immunity inflammation, (v) induction mitophagy- apoptosis - cascades, (vi) dysfunctions (mitochondriopathies) cardiovascular, neurodegenerative, malignant diseases. novel insights into molecular mechanisms mitochondria-mediated can explain adaptation environmental stresses achieve cell survival.

Language: Английский

Citations

28
GPR176 Promotes Cancer Progression by Interacting with G Protein GNAS to Restrain Cell Mitophagy in Colorectal Cancer DOI Creative Commons
Junwei Tang, Wen Peng,

Jiangzhou Ji

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 10(12)

Published: March 11, 2023

Abstract GPR176 belongs to the G protein‐coupled receptor superfamily, which responds external stimuli and regulates cancer progression, but its role in colorectal (CRC) remains unclear. In present study, expression analyses of are performed patients with cancer. Genetic mouse models CRC coupled Gpr176‐deficiency investigated, vivo vitro treatments conducted. A positive correlation between upregulation proliferation poor overall survival is demonstrated. confirmed activate cAMP/PKA signaling pathway modulate mitophagy, promoting oncogenesis development. Mechanistically, protein GNAS recruited intracellularly transduce amplify extracellular signals from GPR176. homolog model tool that recruits via transmembrane helix 3‐intracellular loop 2 domain. The GPR176/GNAS complex inhibits mitophagy cAMP/PKA/BNIP3L axis, thereby tumorigenesis progression CRC.

Language: Английский

Citations

26
The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions DOI Creative Commons
Jonathan M. Borkum

Advanced Biology, Journal Year: 2023, Volume and Issue: 7(7)

Published: May 2, 2023

Abstract Certain metabolic interventions such as caloric restriction, fasting, exercise, and a ketogenic diet extend lifespan and/or health span. However, their benefits are limited connections to the underlying mechanisms of aging not fully clear. Here, these explored in terms tricarboxylic acid (TCA) cycle (Krebs cycle, citric cycle) suggest reasons for loss effectiveness ways overcoming it. Specifically, deplete acetate likely reduce conversion oxaloacetate aspartate, thereby inhibiting mammalian target rapamycin (mTOR) upregulating autophagy. Synthesis glutathione may provide high‐capacity sink amine groups, facilitating autophagy, prevent buildup alpha‐ketoglutarate, supporting stem cell maintenance. Metabolic also accumulation succinate, slowing DNA hypermethylation, repair double‐strand breaks, reducing inflammatory hypoxic signaling, lowering reliance on glycolysis. In part through mechanisms, decelerate aging, extending lifespan. Conversely, with overnutrition or oxidative stress, processes function reverse, accelerating impairing longevity. Progressive damage aconitase, inhibition succinate dehydrogenase, downregulation hypoxia‐inducible factor‐1 α , phosphoenolpyruvate carboxykinase (PEPCK) emerge potentially modifiable interventions.

Language: Английский

Citations

23