bims-celmim 2023-07-23 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2023–07–23
seventeen papers selected by
Marc Segarra Mondejar, University of Cologne

Therapeutic strategies targeting AMPK-dependent autophagy in cancer cells.
Computational modeling of AMPK and mTOR crosstalk in glutamatergic synapse calcium signaling.
Deciphering Rho-associated, coiled-coil-containing protein kinase in diabetic nephropathy: small steps towards a giant leap.
O-GlcNAcylation regulates extracellular signal-regulated kinase (ERK) activation in Alzheimer's disease.
Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P.
P62/SQSTM1 binds with claudin-2 to target for selective autophagy in stressed intestinal epithelium.
A sulfonamide chalcone AMPK activator ameliorates hyperglycemia and diabetic nephropathy in db/db mice.
Understanding sorafenib-induced ferroptosis and resistance mechanisms: Implications for cancer therapy.
Extracellular Vesicle-Serpine-1 Affects Neural Progenitor Cell Mitochondrial Networks and Synaptic Density: Modulation by Amyloid Beta and HIV-1.
Effects of UBE3A on the insulin resistance in polycystic ovary syndrome through the ubiquitination of AMPK.
Fatty acids fuelling astroglia and beyond.
Rutaecarpine Mitigates Cognitive Impairment by Balancing Mitochondrial Function Through Activation of the AMPK/PGC1α Pathway.
A critical evaluation of protein kinase regulation by activation loop autophosphorylation.
PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via Fis1 lactylation.
Targeting the adenosine monophosphate-activated protein kinase signalling pathway by bempedoic acid attenuates Angiotensin II-induced cardiac remodelling in renovascular hypertension in rats.
mTORC1 Signaling and Negative Lens-Induced Axial Elongation.
Aging Differentially Affects Axonal Autophagosome Formation and Maturation.

Biochim Biophys Acta Mol Cell Res. 2023 Jul 16. pii: S0167-4889(23)00109-X. [Epub ahead of print]1870(7): 119537

Therapeutic strategies targeting AMPK-dependent autophagy in cancer cells.

Wenbin Yuan, Wanyi Fang, Rui Zhang, Hao Lyu, Shuai Xiao, Dong Guo, Declan William Ali, Marek Michalak, Xing-Zhen Chen, Cefan Zhou, Jingfeng Tang.

  Macroautophagy is a health-modifying process of engulfing misfolded or aggregated proteins or damaged organelles, coating these proteins or organelles into vesicles, fusion of vesicles with lysosomes to form autophagic lysosomes, and degradation of the encapsulated contents. It is also a self-rescue strategy in response to harsh environments and plays an essential role in cancer cells. AMP-activated protein kinase (AMPK) is the central pathway that regulates autophagy initiation and autophagosome formation by phosphorylating targets such as mTORC1 and unc-51 like activating kinase 1 (ULK1). AMPK is an evolutionarily conserved serine/threonine protein kinase that acts as an energy sensor in cells and regulates various metabolic processes, including those involved in cancer. The regulatory network of AMPK is complicated and can be regulated by multiple upstream factors, such as LKB1, AKT, PPAR, SIRT1, or noncoding RNAs. Currently, AMPK is being investigated as a novel target for anticancer therapies based on its role in macroautophagy regulation. Herein, we review the effects of AMPK-dependent autophagy on tumor cell survival and treatment strategies targeting AMPK.

Keywords:  AMPK; Autophagy; Cancer therapy; Metabolism; Tumor

DOI:  https://doi.org/10.1016/j.bbamcr.2023.119537
NPJ Syst Biol Appl. 2023 07 17. 9(1): 34

Computational modeling of AMPK and mTOR crosstalk in glutamatergic synapse calcium signaling.

A Leung, P Rangamani.

Neuronal energy consumption is vital for information processing and memory formation in synapses. The brain consists of just 2% of the human body's mass, but consumes almost 20% of the body's energy budget. Most of this energy is attributed to active transport in ion signaling, with calcium being the canonical second messenger of synaptic transmission. Here, we develop a computational model of synaptic signaling resulting in the activation of two protein kinases critical in metabolic regulation and cell fate, AMP-Activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) and investigate the effect of glutamate stimulus frequency on their dynamics. Our model predicts that frequencies of glutamate stimulus over 10 Hz perturb AMPK and mTOR oscillations at higher magnitudes by up to 36% and change the area under curve (AUC) by 5%. This dynamic difference in AMPK and mTOR activation trajectories potentially differentiates high frequency stimulus bursts from basal neuronal signaling leading to a downstream change in synaptic plasticity. Further, we also investigate the crosstalk between insulin receptor and calcium signaling on AMPK and mTOR activation and predict that the pathways demonstrate multistability dependent on strength of insulin signaling and metabolic consumption rate. Our predictions have implications for improving our understanding of neuronal metabolism, synaptic pruning, and synaptic plasticity.

DOI: https://doi.org/10.1038/s41540-023-00295-4
Endocr J. 2023 Jul 20.

Deciphering Rho-associated, coiled-coil-containing protein kinase in diabetic nephropathy: small steps towards a giant leap.

Keiichiro Matoba.

  Diabetic nephropathy is a public health problem worldwide. Our understanding of the molecular machinery, as well as the clinical therapies for diabetic nephropathy, has evolved dramatically in recent years. However, even with this progress, there are residual risks of kidney failure and cardiovascular events in patients with diabetes. Rho-associated, coiled-coil-containing protein kinase (ROCK) is activated in response to various pathologic stimuli in the context of diabetes. The contribution of ROCK has been investigated in vivo using gene deletion rodent models and specific inhibitors, which are providing key insights into the pathologic function of ROCK in diabetic nephropathy. ROCK has two isoforms, ROCK1 and ROCK2. Both isoforms are expressed in the kidney, including mesangial cells, podocytes, and endothelial cells. ROCK1 blunts AMP-activated protein kinase (AMPK), while ROCK2 negatively regulates peroxisome proliferator-activated receptor α (PPARα) to inhibit fatty acid oxidation, both of which lead to structural and functional impairment of glomeruli in diabetes. Of note, ROCK signaling is activated in the kidney of animal models and patients with diabetes. In addition, an observational study has shown that fasudil hydrochloride, an ATP-competitive selective ROCK inhibitor, significantly attenuated proteinuria among patients with diabetes. These findings highlight the promising prospects for the development of a ROCK-centered approach against the progression of diabetic nephropathy.

Keywords:  Chronic kidney disease; Diabetes; Diabetic nephropathy; Rho-associated, coiled-coil-containing protein kinase (ROCK)

DOI:  https://doi.org/10.1507/endocrj.EJ23-0282
Front Aging Neurosci. 2023 ;15 1155630

O-GlcNAcylation regulates extracellular signal-regulated kinase (ERK) activation in Alzheimer's disease.

Sophiya John Ephrame, Gentry K Cork, Victoria Marshall, Margaret A Johnston, Jenna Shawa, Ibtihal Alghusen, Amy Qiang, Aspin R Denson, Marisa S Carman, Halyna Fedosyuk, Russell H Swerdlow, Chad Slawson.

   Introduction: Aberrant activation of Extracellular Signal-Regulated Kinase (ERK) signaling is associated with Alzheimer's disease (AD) pathogenesis. For example, enhanced ERK signal activation mediated by Apolipoprotein E4 (APOE4), which is a critical genetic risk factor for AD, increases the transcription of amyloid precursor protein (APP). We hypothesize that O-linked N-acetylglucosamine (O-GlcNAc) regulates the phosphorylation and activation of ERK. O-GlcNAc is a single sugar post-translational modification that dynamically cycles on and off proteins in response to nutrient changes by the action of the enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. However, O-GlcNAc quickly returns to a baseline level after stimulus removal (called O-GlcNAc homeostasis).
Methods: We did a serum reactivation time-course followed by western blot in SH-SY5Y neuroblastoma cells after long-term O-GlcNAcase (OGA) inhibition by Thiamet-G (TMG) treatment, O-GlcNAc transferase (OGT) knock-down (KD) and OGA KD. Brain tissues of C57BL6/J mice and 5XFAD Alzheimer's disease mice intra-peritoneally injected with TMG for 1 month and C57BL6/J mice intra-peritoneally injected with TMG for 6 months were also used for western blot.
Results: We found that ERK1/2 phosphorylation at Thr 202/Tyr204 and Thr183/Tyr185 (p-ERK) are amplified and hence ERK1/2 are activated after long-term OGA inhibition in SH-SY5Y cells. In addition to pharmacological treatment, genetic disruption of O-GlcNAc by OGT KD and OGA KD also increased p-ERK in SH-SY5Y cells suggesting O-GlcNAc homeostasis controls ERK signaling. To determine how O-GlcNAc regulates p-ERK, we probed the expression of phosphorylated mitogen-activated protein kinase-kinase (p-MEK) which phosphorylates and activates ERK and Dual specificity phosphatase-4 (DUSP4) which dephosphorylates and inactivates ERK in SH-SY5Y cells. p-MEK increases in TMG treated and OGT KD cells whereas total DUSP4 decreases in OGT KD and OGA KD cells with serum reactivation time course. Next, we probed the role of OGA inhibition in regulating ERK activation using mice brain-tissue samples. Interestingly, 6-month intra-peritoneal TMG injection in C57BL/6J mice showed an increase in amplitude of p-ERK and APP protein levels, indicating long-term OGA inhibition potentially contributes to AD progression. Furthermore, 1-month TMG injection was sufficient to increase the amplitude of p-ERK in 5XFAD AD mice brains suggesting AD phenotype contributes to the acceleration of ERK activation mediated by OGA inhibition.
Conclusion: Together, these results indicate that disruptions to O-GlcNAc homeostasis amplify ERK signal activation in AD.

Keywords:  APP; Alzheimer’s disease; ERK; O-GlcNAc; OGA; OGT; Thiamet-G

DOI:  https://doi.org/10.3389/fnagi.2023.1155630
Cell Res. 2023 Jul 17.

Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P.

Yuan-Li Ai, Wei-Jia Wang, Fan-Jian Liu, Wei Fang, Hang-Zi Chen, Liu-Zheng Wu, Xuehui Hong, Yuekun Zhu, Ci-Xiong Zhang, Long-Yu Liu, Wen-Bin Hong, Bo Zhou, Qi-Tao Chen, Qiao Wu.

Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N-acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDMET6E or GSDMET6A knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.

DOI: https://doi.org/10.1038/s41422-023-00848-6
Commun Biol. 2023 07 17. 6(1): 740

P62/SQSTM1 binds with claudin-2 to target for selective autophagy in stressed intestinal epithelium.

Rizwan Ahmad, Balawant Kumar, Raju Lama Tamang, Geoffrey A Talmon, Punita Dhawan, Amar B Singh.

Impaired autophagy promotes Inflammatory Bowel Disease (IBD). Claudin-2 is upregulated in IBD however its role in the pathobiology remains uncertain due to its complex regulation, including by autophagy. Irrespective, claudin-2 expression protects mice from DSS colitis. This study was undertaken to examine if an interplay between autophagy and claudin-2 protects from colitis and associated epithelial injury. Crypt culture and intestinal epithelial cells (IECs) are subjected to stress, including starvation or DSS, the chemical that induces colitis in-vivo. Autophagy flux, cell survival, co-immunoprecipitation, proximity ligation assay, and gene mutational studies are performed. These studies reveal that under colitis/stress conditions, claudin-2 undergoes polyubiquitination and P62/SQSTM1-assisted degradation through autophagy. Inhibiting autophagy-mediated claudin-2 degradation promotes cell death and thus suggest that claudin-2 degradation promotes autophagy flux to promote cell survival. Overall, these data inform for the previously undescribed role for claudin-2 in facilitating IECs survival under stress conditions, which can be harnessed for therapeutic advantages.

DOI: https://doi.org/10.1038/s42003-023-05116-2
Biomed Pharmacother. 2023 Jul 18. pii: S0753-3322(23)00949-6. [Epub ahead of print]165 115158

A sulfonamide chalcone AMPK activator ameliorates hyperglycemia and diabetic nephropathy in db/db mice.

Suchada Kaewin, Wanangkan Poolsri, Gül Gizem Korkut, Jaakko Patrakka, Thitinan Aiebchun, Thanyada Rungrotmongkol, Titiwat Sungkaworn, I Butu Sukanadi, Warinthorn Chavasiri, Chatchai Muanprasat.

  Diabetic nephropathy (DN) is a serious complication of diabetes mellitus (DM), which currently lacks effective treatments. AMP-activated protein kinase (AMPK) stimulation by chalcones, a class of polyphenols abundantly found in plants, is proposed as a promising therapeutic approach for DM. This study aimed to identify novel chalcone derivatives with improved AMPK-stimulating activity in human podocytes and evaluate their mechanisms of action as well as in vivo efficacy in a mouse model of DN. Among 133 chalcone derivatives tested, the sulfonamide chalcone derivative IP-004 was identified as the most potent AMPK activator in human podocytes. Western blot analyses, intracellular calcium measurements and molecular docking simulation indicated that IP-004 activated AMPK by mechanisms involving direct binding at allosteric site of calcium-dependent protein kinase kinase β (CaMKKβ) without affecting intracellular calcium levels. Interestingly, eight weeks of intraperitoneal administration of IP-004 (20 mg/kg/day) significantly decreased fasting blood glucose level, activated AMPK in the livers, muscles and glomeruli, and ameliorated albuminuria in db/db type II diabetic mice. Collectively, this study identifies a novel chalcone derivative capable of activating AMPK in vitro and in vivo and exhibiting efficacy against hyperglycemia and DN in mice. Further development of AMPK activators based on chalcone derivatives may provide an effective treatment of DN.

Keywords:  AMPK activator; Albuminuria; Chalcone derivatives; Diabetic nephropathy; db/db mice

DOI:  https://doi.org/10.1016/j.biopha.2023.115158
Eur J Pharmacol. 2023 Jul 17. pii: S0014-2999(23)00425-9. [Epub ahead of print]955 175913

Understanding sorafenib-induced ferroptosis and resistance mechanisms: Implications for cancer therapy.

Qiuhong Li, Kexin Chen, Tianyi Zhang, Donghui Jiang, Ligang Chen, Jun Jiang, Chunxiang Zhang, Shengbiao Li.

  Sorafenib is an important first-line treatment option for liver cancer due to its well-characterized safety profile. While novel first-line drugs may have better efficacy than Sorafenib, they also have limitations such as worse safety and cost-effectiveness. In addition to inducing apoptosis, Sorafenib can also trigger ferroptosis, which has recently been recognized as an immunogenic cell death, unleashing new possibilities for cancer treatment. However, resistance to Sorafenib-induced ferroptosis remains a major challenge. To overcome this resistance and augment the efficacy of Sorafenib, a wide range of nanomedicines has been developed to amplify its pro-ferroptotic effects. This review highlights the mechanisms underlying Sorafenib-triggered ferroptosis and its resistance, and outlines innovative strategies, particularly nanomedicines, to overcome ferroptosis resistance. Moreover, we summarize molecular biomarkers that signify resistance to Sorafenib-mediated ferroptosis, which can assist in predicting therapeutic outcomes.

Keywords:  Biomarker; Ferroptosis resistance; Molecular mechanism; Nanomedicine; Sorafenib

DOI:  https://doi.org/10.1016/j.ejphar.2023.175913
Mol Neurobiol. 2023 Jul 17.

Extracellular Vesicle-Serpine-1 Affects Neural Progenitor Cell Mitochondrial Networks and Synaptic Density: Modulation by Amyloid Beta and HIV-1.

Ibolya E András, Nelson Serrano, Irina Djuraskovic, Nikolai Fattakhov, Enze Sun, Michal Toborek.

  Brain endothelial extracellular vesicles carrying amyloid beta (EV-Aβ) can be transferred to neural progenitor cells (NPCs) leading to NPC dysfunction. However, the events involved in this EV-mediated Aβ pathology are unclear. EV-proteomics studies identified Serpine-1 (plasminogen activator inhibitor 1, PAI-1) as a major connecting "hub" on several protein-protein interaction maps. Serpine-1 was described as a key player in Aβ pathology and was linked to HIV-1 infection as well. Therefore, the aim of this work was to address the hypothesis that Serpine-1 can be transferred via EVs from brain endothelial cells (HBMEC) to NPCs and contribute to NPC dysfunction. HBMEC concentrated and released Serpine-1 via EVs, the effect that was potentiated by HIV-1 and Aβ. EVs loaded with Serpine-1 were readily taken up by NPCs, and HIV-1 enhanced this event. Interestingly, a highly specific Serpine-1 inhibitor PAI039 increased EV-Aβ transfer to NPCs in the presence of HIV-1. PAI039 also partially blocked mitochondrial network morphology alterations in the recipient NPCs, which developed mainly after HIV + Aβ-EV transfer. PAI039 partly attenuated HIV-EV-mediated decreased synaptic protein levels in NPCs, while increased synaptic protein levels in NPC projections. These findings contribute to a better understanding of the complex mechanisms underlying EV-Serpine-1 related Aβ pathology in the context of HIV infection. They are relevant to HIV-1 associated neurocognitive disorders (HAND) in an effort to elucidate the mechanisms of neuropathology in HIV infection.

Keywords:  Amyloid beta; Blood–brain barrier; Extracellular vesicles; HIV-1; Neural progenitor cells; Serpine-1

DOI:  https://doi.org/10.1007/s12035-023-03456-y
BMC Endocr Disord. 2023 Jul 17. 23(1): 152

Effects of UBE3A on the insulin resistance in polycystic ovary syndrome through the ubiquitination of AMPK.

Ning Ma, Jing Zhou, Zhi Zhou, Bangbei Wan, Weiying Lu.

   BACKGROUND: Polycystic ovary syndrome (PCOS) is a reproductive hormonal abnormality and a metabolic disorder, which is frequently associated with insulin resistance (IR). We aim to investigate the potential therapeutic effects of Ubiquitin-protein ligase E3A (UBE3A) on IR in the PCOS rats via Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation.
METHODS: The PCOS and IR rats model was established by dehydroepiandrosterone (DHEA) and high fat diet (HFD) treatment, and the fat rate, glucose tolerance and insulin tolerance were measured. The IR rats numbers were calculated. Besides, the mRNA levels of glucose transporter 4 (GLUT4) and UBE3A were detected by RT-qPCR. Furthermore, the relationship between was demonstrated by co-IP assay. The phosphorylation and ubiquitination of AMPK were analyzed by western blot.
RESULTS: UBE3A was up-regulated in the PCOS rats. UBE3A knockdown significantly decreased the fat rate, glucose tolerance and insulin tolerance in the PCOS and IR rats. Additionally, the GLUT4 levels were significantly increased in PCOS + IR rats. Besides, after UBE3A knockdown, the IR rats were decreased, the p-IRS1 and p-AKT levels were significantly up-regulated. Furthermore, UBE3A knockdown enhanced phosphorylation of AMPK through decreasing the ubiquitination of AMPK. AMPK knockdown reversed the role of UBE3A knockdown in the PCOS + IR rats.
CONCLUSIONS: UBE3A knockdown inhibited the IR in PCOS rats through targeting AMPK. Our study indicated that UBE3A might become a potential biological target for the clinical treatment of PCOS.

Keywords:  Denosine 5‘-monophosphate (AMP)-activated protein kinase; Insulin resistance; Polycystic ovary syndrome; Ubiquitin-protein ligase E3A

DOI:  https://doi.org/10.1186/s12902-023-01400-8
Nat Metab. 2023 Jul 17.

Fatty acids fuelling astroglia and beyond.

Manuel Guzmán.

DOI: https://doi.org/10.1038/s42255-023-00845-4
Mol Neurobiol. 2023 Jul 19.

Rutaecarpine Mitigates Cognitive Impairment by Balancing Mitochondrial Function Through Activation of the AMPK/PGC1α Pathway.

Min Gong, Jianping Jia.

  Mitochondrial dysfunction plays a fundamental role in the pathogenesis of cognitive deficit. Rutaecarpine (Rut) is a natural alkaloid with anti-inflammatory and antioxidant properties. This study explored whether Rut treatment could enhance cognitive function by improving mitochondrial function and examined the potential mechanisms underlying this ameliorative effect. We used the Morris water maze and Y-maze tests to evaluate the behavioral effects of Rut in a mouse model of cognitive impairment induced by subcutaneous injection of D-galactose (D-gal). Furthermore, we assessed the effects of Rut on mitochondrial function using cell viability assays, flow cytometry, western blotting, biochemical analysis, and immunochemical techniques in vivo and in vitro. The results indicated Rut treatment attenuated cognitive deficits and mitochondrial dysfunction in the mouse model. Similarly, it maintained the balance of mitochondrial dynamics in neurocytes and reduced oxidative stress and mitochondrial apoptosis in the HT22 cell model. Moreover, we found that these protective effects were dependent on the activation of the AMP-activated protein kinase/proliferator-activated receptor gamma coactivator 1-alpha (AMPK/PGC1α) signaling pathway. Our data indicate that Rut treatment are sensitive to reversal cognitive deficits and mitochondrial dysfunction induced by D-gal; this suggests that Rut is a promising mitochondria-targeted therapeutic agent for treating cognitive impairment.

Keywords:  Cognitive deficit; D-galactose; Mitochondrial dysfunction; Mouse model; Rutaecarpine

DOI:  https://doi.org/10.1007/s12035-023-03505-6
Elife. 2023 07 20. pii: e88210. [Epub ahead of print]12

A critical evaluation of protein kinase regulation by activation loop autophosphorylation.

Ronja Reinhardt, Thomas A Leonard.

  Phosphorylation of proteins is a ubiquitous mechanism of regulating their function, localization, or activity. Protein kinases, enzymes that use ATP to phosphorylate protein substrates are, therefore, powerful signal transducers in eukaryotic cells. The mechanism of phosphoryl-transfer is universally conserved among protein kinases, which necessitates the tight regulation of kinase activity for the orchestration of cellular processes with high spatial and temporal fidelity. In response to a stimulus, many kinases enhance their own activity by autophosphorylating a conserved amino acid in their activation loop, but precisely how this reaction is performed is controversial. Classically, kinases that autophosphorylate their activation loop are thought to perform the reaction in trans, mediated by transient dimerization of their kinase domains. However, motivated by the recently discovered regulation mechanism of activation loop cis-autophosphorylation by a kinase that is autoinhibited in trans, we here review the various mechanisms of autoregulation that have been proposed. We provide a framework for critically evaluating biochemical, kinetic, and structural evidence for protein kinase dimerization and autophosphorylation, and share some thoughts on the implications of these mechanisms within physiological signaling networks.

Keywords:  activation; allostery; biochemistry; chemical biology; dimerization; inhibition; kinase; molecular biophysics; phosphorylation; structural biology

DOI:  https://doi.org/10.7554/eLife.88210
Cell Death Dis. 2023 Jul 21. 14(7): 457

PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via Fis1 lactylation.

Sheng An, Yi Yao, Hongbin Hu, Junjie Wu, Jiaxin Li, Lulan Li, Jie Wu, Maomao Sun, Zhiya Deng, Yaoyuan Zhang, Shenhai Gong, Qiaobing Huang, Zhongqing Chen, Zhenhua Zeng.

The increase of lactate is an independent risk factor for patients with sepsis-induced acute kidney injury (SAKI). However, whether elevated lactate directly promotes SAKI and its mechanism remain unclear. Here we revealed that downregulation of the deacetylase Sirtuin 3 (SIRT3) mediated the hyperacetylation and inactivation of pyruvate dehydrogenase E1 component subunit alpha (PDHA1), resulting in lactate overproduction in renal tubular epithelial cells. We then found that the incidence of SAKI and renal replacement therapy (RRT) in septic patients with blood lactate ≥ 4 mmol/L was increased significantly, compared with those in septic patients with blood lactate < 2 mmol/L. Further in vitro and in vivo experiments showed that additional lactate administration could directly promote SAKI. Mechanistically, lactate mediated the lactylation of mitochondrial fission 1 protein (Fis1) lysine 20 (Fis1 K20la). The increase in Fis1 K20la promoted excessive mitochondrial fission and subsequently induced ATP depletion, mitochondrial reactive oxygen species (mtROS) overproduction, and mitochondrial apoptosis. In contrast, PDHA1 activation with sodium dichloroacetate (DCA) or SIRT3 overexpression decreased lactate levels and Fis1 K20la, thereby alleviating SAKI. In conclusion, our results show that PDHA1 hyperacetylation and inactivation enhance lactate overproduction, which mediates Fis1 lactylation and exacerbates SAKI. Reducing lactate levels and Fis1 lactylation attenuate SAKI.

DOI: https://doi.org/10.1038/s41419-023-05952-4
Life Sci. 2023 Jul 18. pii: S0024-3205(23)00598-2. [Epub ahead of print] 121963

Targeting the adenosine monophosphate-activated protein kinase signalling pathway by bempedoic acid attenuates Angiotensin II-induced cardiac remodelling in renovascular hypertension in rats.

Asmaa A Ahmed, Shimaa K Mohamed, Shahira Nofal, Engy M El Morsy, Amany A E Ahmed.

  The crosstalk between the renin-angiotensin system and Adenosine monophosphate-activated protein kinase (AMPK) gained significant interest due to their involvement in the pathogenesis of several cardiovascular diseases. Angiotensin II (Ang II) plays a crucial role in developing cardiac remodelling by inducing energy imbalance, inflammation, oxidative and endoplasmic reticulum stress, and transforming growth factor-β (TGF-β)-induced fibrosis. Ang II directly or through extracellular signal-regulated kinase (ERK) activation impairs AMPK signalling with well-known antioxidant, anti-inflammatory, and anti-fibrotic effects.
AIM: This study aimed to investigate the role of bempedoic acid, a novel antihyperlipidemic drug, in attenuating hypertension-induced cardiac remodelling in rats by modulating Ang II-induced damage and activating the AMPK signalling pathway.
METHOD: Sixty adult male Sprague Dawley rats were randomly allocated into the Sham control group, Hypertensive group, Captopril group (30 mg/kg), and Bempedoic acid group (30 mg/kg). Hypertension was induced by left renal artery ligation in all groups except the Sham control group. Treatment with captopril and bempedoic acid started 14 days post-surgy and lasted two weeks. Finally, Hemodynamic measurements and electrocardiographic examination were done followed by heart tissue samples collection for biochemical, histopathological, and immunohistochemical examinations.
KEY FINDINGS: Bempedoic acid preserved the cardiac function and electrocardiogram patterns. It inhibited endoplasmic reticulum stress, exhibited antioxidant activity, and increased endothelial nitric oxide synthase activity. Bempedoic acid interfered with ERK signalling pathways, including nuclear factor-κB and TGF-β, exerting anti-inflammatory and anti-fibrotic effects.
SIGNIFICANCE: These findings indicate the cardioprotective and antihypertrophic activity of bempedoic acid, which are suggested to result from energy-independent AMPK downstream signalling activation.

Keywords:  AMPK; Angiotensin II; Bempedoic acid; Cardiac remodelling; Rats; Renovascular hypertension model

DOI:  https://doi.org/10.1016/j.lfs.2023.121963
Invest Ophthalmol Vis Sci. 2023 07 03. 64(10): 24

mTORC1 Signaling and Negative Lens-Induced Axial Elongation.

Ruiheng Zhang, Li Dong, Haotian Wu, Xuhan Shi, Wenda Zhou, Heyan Li, Yitong Li, Chuyao Yu, Yifan Li, Yao Nie, Lei Shao, Chuan Zhang, Yueming Liu, Jost B Jonas, Wenbin Wei, Qiong Yang.

Purpose: The mechanism underlying axial elongation during myopia progression remains unknown. Epidermal growth factor receptor (EGFR) signaling is associated with axial elongation. We explored whether mammalian target of rapamycin complex 1 (mTORC1) signaling acts as the downstream pathway of EGFR and participates in negative lens-induced axial elongation (NLIAE).
Methods: Three-week-old male pigmented guinea pigs underwent binocular NLIAE. (1) To investigate whether EGFR is the upstream regulator of mTORC1, an EGFR inhibitor (20 µg erlotinib) was intravitreally injected once a week for three weeks. (2) To assess the effect of mTORC1 inhibition on NLIAE, an mTORC1 inhibitor (2 µg, 10 µg, and 20 µg everolimus) was intravitreally injected once a week for three weeks. (3) To explore the long-term effect of mTORC1 overactivation on axial elongation, an mTORC1 agonist (4 µg MHY1485) was intravitreally injected once a week for three months. Biometric measurements included axial length and choroidal thickness were performed.
Results: Compared with the guinea pigs without NLIAE, NLIAE was associated with activation of mTORC1 signaling, which was suppressed by intravitreal erlotinib injection. Intravitreally injected everolimus suppressed NLIAE-induced axial elongation, mTORC1 activation, choroidal thinning, and hypoxia-inducible factor-1α expression in the sclera. Immunofluorescence revealed that the retinal pigment epithelium was the primary location of mTORC1 activation during NLIAE. Combining NLIAE and MHY1485 intravitreal injections significantly promoted axial elongation, choroidal thinning, and peripapillary choroidal atrophy.
Conclusions: The mTORC1 signaling is associated with increased axial elongation, as in NLIAE, raising the possibility of inhibiting mTORC1 as a novel treatment for slowing myopia progression.

DOI: https://doi.org/10.1167/iovs.64.10.24
Autophagy. 2023 Jul 18. 1-17

Aging Differentially Affects Axonal Autophagosome Formation and Maturation.

Heather Tsong, Erika Lf Holzbaur, Andrea Kh Stavoe.

  Misregulation of neuronal macroautophagy/autophagy has been implicated in age-related neurodegenerative diseases. We compared autophagosome formation and maturation in primary murine neurons during development and through aging to elucidate how aging affects neuronal autophagy. We observed an age-related decrease in the rate of autophagosome formation leading to a significant decrease in the density of autophagosomes along the axon. Next, we identified a surprising increase in the maturation of autophagic vesicles in neurons from aged mice. While we did not detect notable changes in endolysosomal content in the distal axon during early aging, we did observe a significant loss of acidified vesicles in the distal axon during late aging. Interestingly, we found that autophagic vesicles were transported more efficiently in neurons from adult mice than in neurons from young mice. This efficient transport of autophagic vesicles in both the distal and proximal axon is maintained in neurons during early aging, but is lost during late aging. Our data indicate that early aging does not negatively impact autophagic vesicle transport nor the later stages of autophagy. However, alterations in autophagic vesicle transport efficiency during late aging reveal that aging differentially impacts distinct aspects of neuronal autophagy.Abbreviations: ACAP3: ArfGAP with coiled-coil, ankyrin repeat and PH domains 3; ARF6: ADP-ribosylation factor 6; ATG: autophagy related; AVs: autophagic vesicles; DCTN1/p150Glued: dynactin 1; DRG: dorsal root ganglia; GAP: GTPase activating protein; GEF: guanine nucleotide exchange factor; LAMP2: lysosomal-associated protein 2; LysoT: LysoTracker; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAPK8IP1/JIP1: mitogen-activated protein kinase 8 interacting protein 1; MAPK8IP3/JIP3: mitogen-activated protein kinase 8 interacting protein 3; mCh: mCherry; PE: phosphatidylethanolamine.

Keywords:  Autophagy; axonal transport; lysosome; microtubule transport; neuron

DOI:  https://doi.org/10.1080/15548627.2023.2236485