bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2023–09–03
twenty-one papers selected by
Marc Segarra Mondejar, University of Cologne
  1. Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation.
  2. Cell cycle-linked vacuolar pH dynamics regulate amino acid homeostasis and cell growth.
  3. Mechanical stimulation from the surrounding tissue activates mitochondrial energy metabolism in Drosophila differentiating germ cells.
  4. Mitochondrial phospholipid metabolism in health and disease.
  5. Lysosomal glucose sensing and glycophagy in metabolism.
  6. Inhibition of mitochondrial fusion via SIRT1/PDK2/PARL axis breaks mitochondrial metabolic plasticity and sensitizes cancer cells to glucose restriction therapy.
  7. Unveiling the potential of mitochondrial dynamics as a therapeutic strategy for acute kidney injury.
  8. Pancreatic β-cell mitophagy as an adaptive response to metabolic stress and the underlying mechanism that involves lysosomal Ca2+ release.
  9. AMPK-FOXO-IP3R signaling pathway mediates neurological and developmental defects caused by mitochondrial DNA mutations.
  10. LRRK2 aggravates kidney injury through promoting MFN2 degradation and abnormal mitochondrial integrity.
  11. Mitochondrial Microproteins: Critical Regulators of Protein Import, Energy Production, Stress Response Pathways, and Programmed Cell Death.
  12. Mitophagy-promoting agents and their ability to promote healthy-aging.
  13. Pannexin 1 targets mitophagy to mediate renal ischemia/reperfusion injury.
  14. Mitochondrial vulnerability to oxidation in human brain organoids modelling Alzheimer's disease.
  15. PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development.
  16. In situ and dynamic SERS monitoring of glutathione levels during cellular ferroptosis metabolism.
  17. The spatiotemporal control of ER membrane fragmentation during reticulophagy.
  18. Mitochondrial dysfunction in the pathogenesis of endothelial dysfunction.
  19. Ferroptosis regulation by methylation in cancer.
  20. [Ferroptosis:Mechanism and Role in Malignant Tumors].
  21. Curcumin induces mitophagy by promoting mitochondrial succinate dehydrogenase activity and sensitizes human papillary thyroid carcinoma BCPAP cells to radioiodine treatment.
  1. Biochem Soc Trans. 2023 Aug 29. pii: BST20230012. [Epub ahead of print]
    Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation.
    Sandra H Lee, Hannah E Duron, Dipayan Chaudhuri.
      While mitochondria oxidative phosphorylation is broadly regulated, the impact of mitochondrial Ca2+ on substrate flux under both physiological and pathological conditions is increasingly being recognized. Under physiologic conditions, mitochondrial Ca2+ enters through the mitochondrial Ca2+ uniporter and boosts ATP production. However, maintaining Ca2+ homeostasis is crucial as too little Ca2+ inhibits adaptation to stress and Ca2+ overload can trigger cell death. In this review, we discuss new insights obtained over the past several years expanding the relationship between mitochondrial Ca2+ and oxidative phosphorylation, with most data obtained from heart, liver, or skeletal muscle. Two new themes are emerging. First, beyond boosting ATP synthesis, Ca2+ appears to be a critical determinant of fuel substrate choice between glucose and fatty acids. Second, Ca2+ exerts local effects on the electron transport chain indirectly, not via traditional allosteric mechanisms. These depend critically on the transporters involved, such as the uniporter or the Na+-Ca2+ exchanger. Alteration of these new relationships during disease can be either compensatory or harmful and suggest that targeting mitochondrial Ca2+ may be of therapeutic benefit during diseases featuring impairments in oxidative phosphorylation.
    Keywords:  MCU; NCLX; electron transport chain; mitochondrial dysfunction; mitochondrial permeability transition pores; oxidative phosphorylation
    DOI:  https://doi.org/10.1042/BST20230012
  2. Nat Metab. 2023 Aug 28.
    Cell cycle-linked vacuolar pH dynamics regulate amino acid homeostasis and cell growth.
    Voytek Okreglak, Rachel Ling, Maria Ingaramo, Nathaniel H Thayer, Alfred Millett-Sikking, Daniel E Gottschling.
      Amino acid homeostasis is critical for many cellular processes. It is well established that amino acids are compartmentalized using pH gradients generated between organelles and the cytoplasm; however, the dynamics of this partitioning has not been explored. Here we develop a highly sensitive pH reporter and find that the major amino acid storage compartment in Saccharomyces cerevisiae, the lysosome-like vacuole, alkalinizes before cell division and re-acidifies as cells divide. The vacuolar pH dynamics require the uptake of extracellular amino acids and activity of TORC1, the v-ATPase and the cycling of the vacuolar specific lipid phosphatidylinositol 3,5-bisphosphate, which is regulated by the cyclin-dependent kinase Pho85 (CDK5 in mammals). Vacuolar pH regulation enables amino acid sequestration and mobilization from the organelle, which is important for mitochondrial function, ribosome homeostasis and cell size control. Collectively, our data provide a new paradigm for the use of dynamic pH-dependent amino acid compartmentalization during cell growth/division.
    DOI:  https://doi.org/10.1038/s42255-023-00872-1
  3. Dev Cell. 2023 Aug 22. pii: S1534-5807(23)00403-3. [Epub ahead of print]
    Mechanical stimulation from the surrounding tissue activates mitochondrial energy metabolism in Drosophila differentiating germ cells.
    Zong-Heng Wang, Wenjing Zhao, Christian A Combs, Fan Zhang, Jay R Knutson, Mary A Lilly, Hong Xu.
      In multicellular lives, the differentiation of stem cells and progenitor cells is often accompanied by a transition from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). However, the underlying mechanism of this metabolic transition remains largely unknown. In this study, we investigate the role of mechanical stress in activating OXPHOS during differentiation of the female germline cyst in Drosophila. We demonstrate that the surrounding somatic cells flatten the 16-cell differentiating cyst, resulting in an increase of the membrane tension of germ cells inside the cyst. This mechanical stress is necessary to maintain cytosolic Ca2+ concentration in germ cells through a mechanically activated channel, transmembrane channel-like. The sustained cytosolic Ca2+ triggers a CaMKI-Fray-JNK signaling relay, leading to the transcriptional activation of OXPHOS in differentiating cysts. Our findings demonstrate a molecular link between cell mechanics and mitochondrial energy metabolism, with implications for other developmentally orchestrated metabolic transitions in mammals.
    Keywords:  CaMKI; Fray; JNK; Myc; TMC; calcium; mechanotransduction; mitochondria; oogenesis; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.devcel.2023.08.007
  4. J Cell Sci. 2023 Sep 01. pii: jcs260857. [Epub ahead of print]136(17):
    Mitochondrial phospholipid metabolism in health and disease.
    Alaumy Joshi, Travis H Richard, Vishal M Gohil.
      Studies of rare human genetic disorders of mitochondrial phospholipid metabolism have highlighted the crucial role that membrane phospholipids play in mitochondrial bioenergetics and human health. The phospholipid composition of mitochondrial membranes is highly conserved from yeast to humans, with each class of phospholipid performing a specific function in the assembly and activity of various mitochondrial membrane proteins, including the oxidative phosphorylation complexes. Recent studies have uncovered novel roles of cardiolipin and phosphatidylethanolamine, two crucial mitochondrial phospholipids, in organismal physiology. Studies on inter-organellar and intramitochondrial phospholipid transport have significantly advanced our understanding of the mechanisms that maintain mitochondrial phospholipid homeostasis. Here, we discuss these recent advances in the function and transport of mitochondrial phospholipids while describing their biochemical and biophysical properties and biosynthetic pathways. Additionally, we highlight the roles of mitochondrial phospholipids in human health by describing the various genetic diseases caused by disruptions in their biosynthesis and discuss advances in therapeutic strategies for Barth syndrome, the best-studied disorder of mitochondrial phospholipid metabolism.
    Keywords:  Barth syndrome; Cardiolipin; Membranes; Mitochondria; Phosphatidylethanolamine; Phospholipids
    DOI:  https://doi.org/10.1242/jcs.260857
  5. Trends Endocrinol Metab. 2023 Aug 24. pii: S1043-2760(23)00152-2. [Epub ahead of print]
    Lysosomal glucose sensing and glycophagy in metabolism.
    Melina C Mancini, Robert C Noland, J Jason Collier, Susan J Burke, Krisztian Stadler, Timothy D Heden.
      Lysosomes are cellular organelles that function to catabolize both extra- and intracellular cargo, act as a platform for nutrient sensing, and represent a core signaling node integrating bioenergetic cues to changes in cellular metabolism. Although lysosomal amino acid and lipid sensing in metabolism has been well characterized, lysosomal glucose sensing and the role of lysosomes in glucose metabolism is unrefined. This review will highlight the role of the lysosome in glucose metabolism with a focus on lysosomal glucose and glycogen sensing, glycophagy, and lysosomal glucose transport and how these processes impact autophagy and energy metabolism. Additionally, the role of lysosomal glucose metabolism in genetic and metabolic diseases will be briefly discussed.
    Keywords:  autophagy; carbohydrate sensing; glycogen; nutrient sensing
    DOI:  https://doi.org/10.1016/j.tem.2023.07.008
  6. Biomed Pharmacother. 2023 Aug 24. pii: S0753-3322(23)01133-2. [Epub ahead of print]166 115342
    Inhibition of mitochondrial fusion via SIRT1/PDK2/PARL axis breaks mitochondrial metabolic plasticity and sensitizes cancer cells to glucose restriction therapy.
    Yongjian Guo, Chengju Luo, Yuening Sun, Wenjing Guo, Ruitian Zhang, Xin Zhang, Xue Ke, Libin Wei.
      Mitochondria dynamically change their morphology via fusion and fission, a process called mitochondrial dynamics. Dysregulated mitochondrial dynamics respond rapidly to metabolic cues, and are linked to the initiation and progression of diverse human cancers. Metabolic adaptations significantly contribute to tumor development and escape from tissue homeostatic defenses. In this work, we identified oroxylin A (OA), a dual GLUT1/mitochondrial fusion inhibitor, which restricted glucose catabolism of hepatocellular carcinoma cells and simultaneously inhibited mitochondrial fusion by disturbing SIRT1/PDK2/PARL axis. Based the dual action of OA in metabolic regulation and mitochondrial dynamics, further results revealed that mitochondrial functional status and spare respiratory capacity (SRC) of cancer cells had a close correlation with mitochondrial metabolic plasticity, and played important roles in the susceptibility to cancer therapy aiming at glucose restriction. Cancer cells with healthy mitochondria and high SRC exhibit greater metabolic flexibility and higher resistance to GLUT1 inhibitors. This phenomenon is attributed to the fact that high SRC cells fuse mitochondria in response to glucose restriction, enhancing tolerance to energy deficiency, but undergo less mitochondrial oxidative stress compared to low SRC cells. Thus, inhibiting mitochondrial fusion breaks mitochondrial metabolic plasticity and increases cancer cell susceptibility to glucose restriction therapy. Collectively, these finding indicate that combining a GLUT1 inhibitor with a mitochondrial fusion inhibitor can work synergistically in cancer therapy and, more broadly, suggest that the incorporations of mitochondrial dynamics and metabolic regulation may become the targetable vulnerabilities bypassing the genotypic heterogeneity of multiple malignancies.
    Keywords:  Glucose restriction; Mitochondrial fusion; Mitochondrial metabolic plasticity; Oroxylin A
    DOI:  https://doi.org/10.1016/j.biopha.2023.115342
  7. Front Cell Dev Biol. 2023 ;11 1244313
    Unveiling the potential of mitochondrial dynamics as a therapeutic strategy for acute kidney injury.
    Yajie Hao, Limei Zhao, Jing Yu Zhao, Xiutao Han, Xiaoshuang Zhou.
      Acute Kidney Injury (AKI), a critical clinical syndrome, has been strongly linked to mitochondrial malfunction. Mitochondria, vital cellular organelles, play a key role in regulating cellular energy metabolism and ensuring cell survival. Impaired mitochondrial function in AKI leads to decreased energy generation, elevated oxidative stress, and the initiation of inflammatory cascades, resulting in renal tissue damage and functional impairment. Therefore, mitochondria have gained significant research attention as a potential therapeutic target for AKI. Mitochondrial dynamics, which encompass the adaptive shifts of mitochondria within cellular environments, exert significant influence on mitochondrial function. Modulating these dynamics, such as promoting mitochondrial fusion and inhibiting mitochondrial division, offers opportunities to mitigate renal injury in AKI. Consequently, elucidating the mechanisms underlying mitochondrial dynamics has gained considerable importance, providing valuable insights into mitochondrial regulation and facilitating the development of innovative therapeutic approaches for AKI. This comprehensive review aims to highlight the latest advancements in mitochondrial dynamics research, provide an exhaustive analysis of existing studies investigating the relationship between mitochondrial dynamics and acute injury, and shed light on their implications for AKI. The ultimate goal is to advance the development of more effective therapeutic interventions for managing AKI.
    Keywords:  acute kidney injury; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; therapeutic targets
    DOI:  https://doi.org/10.3389/fcell.2023.1244313
  8. Exp Mol Med. 2023 Sep 01.
    Pancreatic β-cell mitophagy as an adaptive response to metabolic stress and the underlying mechanism that involves lysosomal Ca2+ release.
    Soo-Jin Oh, Kihyoun Park, Seong Keun Sonn, Goo Taeg Oh, Myung-Shik Lee.
      Mitophagy is an excellent example of selective autophagy that eliminates damaged or dysfunctional mitochondria, and it is crucial for the maintenance of mitochondrial integrity and function. The critical roles of autophagy in pancreatic β-cell structure and function have been clearly shown. Furthermore, morphological abnormalities and decreased function of mitochondria have been observed in autophagy-deficient β-cells, suggesting the importance of β-cell mitophagy. However, the role of authentic mitophagy in β-cell function has not been clearly demonstrated, as mice with pancreatic β-cell-specific disruption of Parkin, one of the most important players in mitophagy, did not exhibit apparent abnormalities in β-cell function or glucose homeostasis. Instead, the role of mitophagy in pancreatic β-cells has been investigated using β-cell-specific Tfeb-knockout mice (TfebΔβ-cell mice); Tfeb is a master regulator of lysosomal biogenesis or autophagy gene expression and participates in mitophagy. TfebΔβ-cell mice were unable to adaptively increase mitophagy or mitochondrial complex activity in response to high-fat diet (HFD)-induced metabolic stress. Consequently, TfebΔβ-cell mice exhibited impaired β-cell responses and further exacerbated metabolic deterioration after HFD feeding. TFEB was activated by mitochondrial or metabolic stress-induced lysosomal Ca2+ release, which led to calcineurin activation and mitophagy. After lysosomal Ca2+ release, depleted lysosomal Ca2+ stores were replenished by ER Ca2+ through ER→lysosomal Ca2+ refilling, which supplemented the low lysosomal Ca2+ capacity. The importance of mitophagy in β-cell function was also demonstrated in mice that developed β-cell dysfunction and glucose intolerance after treatment with a calcineurin inhibitor that hampered TFEB activation and mitophagy.
    DOI:  https://doi.org/10.1038/s12276-023-01055-4
  9. Proc Natl Acad Sci U S A. 2023 Sep 05. 120(36): e2302490120
    AMPK-FOXO-IP3R signaling pathway mediates neurological and developmental defects caused by mitochondrial DNA mutations.
    Hu Zhang, Yunan Zhu, Yuji Suehiro, Shohei Mitani, Ding Xue.
      Pathological mutations in human mitochondrial genomes (mtDNA) can cause a series of neurological, behavioral, and developmental defects, but the underlying molecular mechanisms are poorly understood. We show here that the energy-sensing adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway plays a key role in mediating similar defects caused by different mtDNA mutations in Caenorhabditis elegans, including loss or reduction of osmotic, chemical and olfactory sensing, locomotion, and associative learning and memory, as well as increased embryonic lethality. mtDNA mutations cause reduced ATP (adenosine triphosphate) levels, activation of C. elegans AMPK AAK-2, and nuclear translocation of the FOXO transcription factor DAF-16. Activated DAF-16 up-regulates the expression of inositol triphosphate receptor ITR-1, an endoplasmic reticulum calcium channel, leading to increased basal cytosolic Ca2+ levels, decreased neuronal responsiveness, compromised synapses, and increased embryonic death. Treatment of mtDNA mutants with vitamin MK-4 restores cellular ATP and cytosolic Ca2+ levels, improves synaptic development, and suppresses sensory and behavioral defects and embryonic death. Our study provides crucial mechanistic insights into neuronal and developmental defects caused by mtDNA mutations and will improve understanding and treatment of related mitochondrial diseases.
    Keywords:  AMP-activated protein kinase; Caenorhabditis elegans; calcium homeostasis; mitochondrial genome mutations; neurological and developmental defects
    DOI:  https://doi.org/10.1073/pnas.2302490120
  10. Redox Biol. 2023 Aug 22. pii: S2213-2317(23)00261-6. [Epub ahead of print]66 102860
    LRRK2 aggravates kidney injury through promoting MFN2 degradation and abnormal mitochondrial integrity.
    Shun Zhang, Subo Qian, Hailong Liu, Ding Xu, Weimin Xia, Huangqi Duan, Chen Wang, Shenggen Yu, Yingying Chen, Ping Ji, Shujun Wang, Xingang Cui, Ying Wang, Haibo Shen.
      Mitochondrial dysfunction is one of the key features of acute kidney injury (AKI) and associated fibrosis. Leucine-rich repeat kinase 2 (LRRK2) is highly expressed in kidneys and regulates mitochondrial homeostasis. How it functions in AKI is unclear. Herein we reported that LRRK2 was dramatically downregulated in AKI kidneys. Lrrk2-/- mice exhibited less severity of AKI when compared to wild-type counterparts with less mitochondrial fragmentation and decreased reactive oxygen species (ROS) production in proximal renal tubular cells (PTCs) due to mitofusin 2 (MFN2) accumulation. Overexpression of LRRK2 in human PTC cell lines promoted LRRK2-MKK4/JNK-dependent phosphorylation of MFN2Ser27 and subsequently ubiquitination-mediated MFN2 degradation, which in turn exaggerated mitochondrial damage upon ischemia/reperfusion (I/R) mimicry treatment. Lrrk2 deficiency also alleviated AKI-to-chronic kidney disease (CKD) transition with less fibrosis. In vivo pretreatment of LRRK2 inhibitors attenuated the severity of AKI as well as CKD, potentiating LRRK2 as a novel target to alleviate AKI and fibrosis.
    Keywords:  Acute kidney injury (AKI); Chronic kidney disease (CKD); Leucine-rich repeat kinase 2 (LRRK2); Mitochondrial damages; Mitofusin 2 (MFN2); Proximal tubular cell (PTC)
    DOI:  https://doi.org/10.1016/j.redox.2023.102860
  11. Am J Physiol Cell Physiol. 2023 Aug 29.
    Mitochondrial Microproteins: Critical Regulators of Protein Import, Energy Production, Stress Response Pathways, and Programmed Cell Death.
    Michael L Kamradt, Catherine A Makarewich.
      Mitochondria rely upon the coordination of protein import, protein translation, and proper functioning of oxidative phosphorylation (OXPHOS) complexes I-V to sustain the activities of life for an organism. Each process is dependent upon the function of profoundly large protein complexes found in the mitochondria (TOMM complex, TIMM complex, OXPHOS complexes, mitoribosomes). These massive protein complexes, in some instances more than one megadalton, are built up from numerous protein subunits of varying sizes, including many proteins that are ≤100-150 amino acids. However, these small proteins, termed microproteins, not only act as cogs in large molecular machines; they also have important steps in inhibiting or promoting the intrinsic pathway of apoptosis, coordinate responses to cellular stress and even act as hormones. This review focuses on microproteins that occupy the mitochondria and are critical for its function. Although the microprotein field is relatively new, researchers have long recognized the existence of these mitochondrial proteins as critical components of virtually all aspects of mitochondrial biology. Thus, recent studies estimating that hundreds of new microproteins of unknown function exist and are missing from current genome annotations suggests that the mitochondrial "microproteome" is a rich area for future biological investigation.
    Keywords:  cell stress; microproteins; mitochondria; mitochondrial protein import; oxidative phosphorylation
    DOI:  https://doi.org/10.1152/ajpcell.00189.2023
  12. Biochem Soc Trans. 2023 Aug 31. pii: BST20221363. [Epub ahead of print]
    Mitophagy-promoting agents and their ability to promote healthy-aging.
    Vijigisha Srivastava, Einav Gross.
      The removal of damaged mitochondrial components through a process called mitochondrial autophagy (mitophagy) is essential for the proper function of the mitochondrial network. Hence, mitophagy is vital for the health of all aerobic animals, including humans. Unfortunately, mitophagy declines with age. Many age-associated diseases, including Alzheimer's and Parkinson's, are characterized by the accumulation of damaged mitochondria and oxidative damage. Therefore, activating the mitophagy process with small molecules is an emerging strategy for treating multiple aging diseases. Recent studies have identified natural and synthetic compounds that promote mitophagy and lifespan. This article aims to summarize the existing knowledge about these substances. For readers' convenience, the knowledge is presented in a table that indicates the chemical data of each substance and its effect on lifespan. The impact on healthspan and the molecular mechanism is reported if known. The article explores the potential of utilizing a combination of mitophagy-inducing drugs within a therapeutic framework and addresses the associated challenges of this strategy. Finally, we discuss the process that balances mitophagy, i.e. mitochondrial biogenesis. In this process, new mitochondrial components are generated to replace the ones cleared by mitophagy. Furthermore, some mitophagy-inducing substances activate biogenesis (e.g. resveratrol and metformin). Finally, we discuss the possibility of combining mitophagy and biogenesis enhancers for future treatment. In conclusion, this article provides an up-to-date source of information about natural and synthetic substances that activate mitophagy and, hopefully, stimulates new hypotheses and studies that promote healthy human aging worldwide.
    Keywords:  aging; lifespan; mitochondria; mitochondrial autophagy; mitochondrial biogenesis; mitophagy
    DOI:  https://doi.org/10.1042/BST20221363
  13. Commun Biol. 2023 08 29. 6(1): 889
    Pannexin 1 targets mitophagy to mediate renal ischemia/reperfusion injury.
    Lianjiu Su, Jiahao Zhang, Jing Wang, Xiaozhan Wang, Edward Cao, Chen Yang, Qihao Sun, Ramadoss Sivakumar, Zhiyong Peng.
      Renal ischemia/reperfusion (I/R) injury contributes to the development of acute kidney injury (AKI). Kidney is the second organ rich in mitochondrial content next to the heart. Mitochondrial damage substantially contributes for AKI development. Mitophagy eliminates damaged mitochondria from the cells to maintain a healthy mitochondrial population, which plays an important role in AKI. Pannexin 1 (PANX1) channel transmembrane proteins are known to drive inflammation and release of adenosine triphosphate (ATP) during I/R injury. However, the specific role of PANX1 on mitophagy regulation in renal I/R injury remains elusive. In this study, we find that serum level of PANX1 is elevated in patients who developed AKI after cardiac surgery, and the level of PANX1 is positively correlated with serum creatinine and urea nitrogen levels. Using the mouse model of renal I/R injury in vivo and cell-based hypoxia/reoxygenation (H/R) model in vitro, we prove that genetic deletion of PANX1 mitigate the kidney tubular cell death, oxidative stress and mitochondrial damage after I/R injury through enhanced mitophagy. Mechanistically, PANX1 disrupts mitophagy by influencing ATP-P2Y-mTOR signal pathway. These observations provide evidence that PANX1 could be a potential biomarker for AKI and a therapeutic target to alleviate AKI caused by I/R injury.
    DOI:  https://doi.org/10.1038/s42003-023-05226-x
  14. Free Radic Biol Med. 2023 Aug 30. pii: S0891-5849(23)00608-1. [Epub ahead of print]
    Mitochondrial vulnerability to oxidation in human brain organoids modelling Alzheimer's disease.
    Mariana I Holubiec, Matias Alloatti, Bianchelli Julieta, Greloni Francisco, Arnaiz Cayetana, Gonzalez Prinz Melina, Fernandez Bessone Ivan, Pozo Devoto Victorio, Tomas L Falzone.
      Reactive Oxygen Species (ROS) and mitochondrial dysfunction are implicated in the pathogenesis of Alzheimer's disease (AD), a common neurodegenerative disorder characterized by abnormal metabolism of the amyloid precursor protein (APP) in brain tissue. However, the exact mechanism by which abnormal APP leads to oxidative distress remains unclear. Damage to mitochondrial membrane and inhibition of mitochondrial respiration are thought to contribute to the progression of the disease. However, the lack of suitable human models that replicate pathological features, together with impaired cellular pathways, constitutes a major challenge in AD studies. In this work, we induced pluripotency in patient-derived skin fibroblasts carrying the Swedish mutation in App (APPswe), to generate human brain organoids that model AD, and studied redox regulation and mitochondrial homeostasis. We found time-dependent increases in AD-related pathological hallmarks in APPswe brain organoids, including elevated Aβ levels, increased extracellular amyloid deposits, and enhanced tau phosphorylation. Interestingly, using live-imaging spinning-disk confocal microscopy, we found an increase in mitochondrial fragmentation and a significant loss of mitochondrial membrane potential in APPswe brain organoids when subjected to oxidative conditions. Moreover, ratiometric dyes in a live imaging setting revealed a selective increase in mitochondrial superoxide anion and hydrogen peroxide levels in APPswe brain organoids that were coupled to impairments in cytosolic and mitochondrial redoxin expression. Our results suggest a selective increase in mitochondrial vulnerability to oxidative conditions in APPswe organoids, indicating that the abnormal metabolism of APP leads to specific changes in mitochondrial homeostasis that enhance the vulnerability to oxidation in AD.
    Keywords:  Alzheimer's disease; Amyloid precursor protein; Human brain organoids; Mitochondrial homeostasis; Oxidative distress; Swedish mutation; Thioredoxins
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.08.028
  15. Cell. 2023 Aug 21. pii: S0092-8674(23)00862-0. [Epub ahead of print]
    PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development.
    Ruoxi Wang, Tina M Fortier, Fei Chai, Guangyan Miao, James L Shen, Lucas J Restrepo, Jeromy J DiGiacomo, Panagiotis D Velentzas, Eric H Baehrecke.
      Selective clearance of organelles, including endoplasmic reticulum (ER) and mitochondria, by autophagy plays an important role in cell health. Here, we describe a developmentally programmed selective ER clearance by autophagy. We show that Parkinson's disease-associated PINK1, as well as Atl, Rtnl1, and Trp1 receptors, regulate ER clearance by autophagy. The E3 ubiquitin ligase Parkin functions downstream of PINK1 and is required for mitochondrial clearance while having the opposite function in ER clearance. By contrast, Keap1 and the E3 ubiquitin ligase Cullin3 function downstream of PINK1 to regulate ER clearance by influencing Rtnl1 and Atl. PINK1 regulates a change in Keap1 localization and Keap1-dependent ubiquitylation of the ER-phagy receptor Rtnl1 to facilitate ER clearance. Thus, PINK1 regulates the selective clearance of ER and mitochondria by influencing the balance of Keap1- and Parkin-dependent ubiquitylation of substrates that determine which organelle is removed by autophagy.
    Keywords:  Drosophila; ER-phagy; Keap1; PINK1; Parkin; Rtnl1
    DOI:  https://doi.org/10.1016/j.cell.2023.08.008
  16. Anal Bioanal Chem. 2023 Aug 30.
    In situ and dynamic SERS monitoring of glutathione levels during cellular ferroptosis metabolism.
    Lixing Xu, Xing Du, Tianqing Liu, Dan Sun.
      Ferroptosis is a non-apoptotic cell death regulated by iron-dependent lipid peroxidation. Glutathione (GSH), a key antioxidant against oxidative damage, is involved in one of the most important metabolic pathways of ferroptosis. Herein, an excellent plasmonic nanoprobe was developed for highly sensitive, in situ, dynamic real-time monitoring of intracellular GSH levels during ferroptosis. A nanoprobe was prepared by functionalizing gold nanoparticles (AuNPs) with the probe molecule crystal violet (CV). The fluctuation in the SERS signal intensity of CV via the competitive displacement reaction can be used to detect GSH. The advantages of the plasmonic nanoprobe including low-cost production techniques, outstanding stability and biocompatibility, high specificity and sensitivity towards GSH with a detection limit of 0.05 μM. It enables real-time dynamic monitoring of GSH levels in living cells during erastin-induced ferroptosis. This approach is expected to provide important theoretical support for elucidating the GSH-related ferroptosis metabolic mechanism and advancing our understanding of ferroptosis-based cancer therapy. Overview of the workflow of sensing principle for highly sensitive, in situ and dynamic tracking of intracellular GSH levels during drug-triggered ferroptosis process.
    Keywords:  Ferroptosis; Glutathione; Nanoprobe; Surface-enhanced Raman scattering
    DOI:  https://doi.org/10.1007/s00216-023-04909-y
  17. Autophagy. 2023 Aug 31. 1-2
    The spatiotemporal control of ER membrane fragmentation during reticulophagy.
    Xinyi Wang, Boran Li, Qiming Sun.
      Reticulophagy is an evolutionarily conserved mechanism essential to maintain the endoplasmic reticulum (ER) homeostasis. A series of studies identified a panel of reticulophagy receptors. However, it remains unclear how these receptors sense upstream signals for spatiotemporal control of reticulophagy and how ER is fragmented into small pieces for sequestration into phagophores. Recently, we and others showed that the oligomerization of RETREG1/FAM134B (reticulophagy regulator 1), an reticulophagy receptor, triggers the scission of ER membrane to facilitate reticulophagy. Furthermore, we demonstrated that upstream signals are transduced by sequential phosphorylation and acetylation of RETREG1, which stimulate its oligomerization, ER fragmentation and reticulophagy. Our work provides further mechanistic insights into how reticulophagy receptor conveys cellular signals to fine-tune of ER homeostasis.Abbreviations: ER, endoplasmic reticulum; MAP1LC3, microtubule-associated protein light chain 3; RETREG1, reticulophagy regulator 1; RHD, reticulon-homology domain.
    Keywords:  RETREG1; acetylation; membrane fragmentation; phosphorylation; reticulophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2252723
  18. Mol Cell Biochem. 2023 Aug 29.
    Mitochondrial dysfunction in the pathogenesis of endothelial dysfunction.
    Suresh Kumar Prajapat, Krushna Ch Maharana, Sanjiv Singh.
      Cardiovascular diseases (CVDs) are a matter of concern worldwide, and mitochondrial dysfunction is one of the major contributing factors. Vascular endothelial dysfunction has a major role in the development of atherosclerosis because of the abnormal chemokine secretion, inflammatory mediators, enhancement of LDL oxidation, cytokine elevation, and smooth muscle cell proliferation. Endothelial cells transfer oxygen from the pulmonary circulatory system to the tissue surrounding the blood vessels, and a majority of oxygen is transferred to the myocardium by endothelial cells, which utilise a small amount of oxygen to generate ATP. Free radicals of oxide are produced by mitochondria, which are responsible for cellular oxygen uptake. Increased mitochondrial ROS generation and reduction in agonist-stimulated eNOS activation and nitric oxide bioavailability were directly linked to the observed change in mitochondrial dynamics, resulting in various CVDs and endothelial dysfunction. Presently, the manuscript mainly focuses on endothelial dysfunction, providing a deep understanding of the various features of mitochondrial mechanisms that are used to modulate endothelial dysfunction. We talk about recent findings and approaches that may make it possible to detect mitochondrial dysfunction as a potential biomarker for risk assessment and diagnosis of endothelial dysfunction. In the end, we cover several targets that may reduce mitochondrial dysfunction through both direct and indirect processes and assess the impact of several different classes of drugs in the context of endothelial dysfunction.
    Keywords:  Endothelial dysfunction; Mitochondrial deficiency; Oxidative excess; UCP1; Uncoupling protein; eNOS
    DOI:  https://doi.org/10.1007/s11010-023-04835-8
  19. Biochim Biophys Acta Rev Cancer. 2023 Aug 25. pii: S0304-419X(23)00121-X. [Epub ahead of print] 188972
    Ferroptosis regulation by methylation in cancer.
    Mengqiu Hao, Yixin Jiang, Yang Zhang, Xuyang Yang, Junhong Han.
      Epigenetic regulation plays a critical role in cancer development and progression. Methylation is an important epigenetic modification that influences gene expression by adding a methyl group to nucleic acids and proteins. Ferroptosis is a new form of regulated cell death triggered by the accumulation of iron and lipid peroxidation. Emerging evidence have shown that methylation regulation plays a significant role in the regulation of ferroptosis in cancer. This review aims to explore the methylation regulation of ferroptosis in cancer, including reactive oxygen species and iron bio-logical activity, amino acid and lipid metabolism, and drugs interaction. The findings of this review may provide new insights and strategies for the prevention and treatment of cancer.
    Keywords:  Cancer; Drugs; Epigenetic; Ferroptosis; Methylation
    DOI:  https://doi.org/10.1016/j.bbcan.2023.188972
  20. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2023 Aug;45(4): 647-654
    [Ferroptosis:Mechanism and Role in Malignant Tumors].
    Xin-Feng Wang, Yu-Xin Yao, Pan Wang.
      Ferroptosis is a new type of programmed cell death different from other cell death pathways such as apoptosis,autophagy,necrosis,and pyroptosis in terms of initiation,mechanisms,and molecular characteristics.As the accumulation of phospholipid hydroperoxides is the hallmark of ferroptosis,the balance between oxidative damage and antioxidant defense is critical to the regulatory mechanism of ferroptosis.In cancer,the upregulation of antioxidant defense pathways can inhibit ferroptosis,thereby promoting cancer cells to survive the oxidative stress and develop drug resistance.This review systematically introduces the main features and regulatory mechanisms of ferroptosis.In addition,we summarize the role of ferroptosis in the progression and drug resistance of malignant tumors,providing novel implications for further research on the pathogenesis of malignant tumors and discovery of new targets for anti-cancer therapy.
    Keywords:  antioxidant mechanism; ferroptosis; iron accumulation; lipid peroxidation; malignant tumor
    DOI:  https://doi.org/10.3881/j.issn.1000-503X.15379
  21. Toxicol In Vitro. 2023 Aug 25. pii: S0887-2333(23)00118-2. [Epub ahead of print]93 105669
    Curcumin induces mitophagy by promoting mitochondrial succinate dehydrogenase activity and sensitizes human papillary thyroid carcinoma BCPAP cells to radioiodine treatment.
    Li Zhang, Ling Qiu, Shichen Xu, Xian Cheng, Jing Wu, Yunping Wang, Wenjing Gao, Jiandong Bao, Huixin Yu.
      Thyroid cancer is one of the most common endocrine malignancies. Differentiated thyroid cancer (DTC) treatment is based on the ability of thyroid follicular cells to accumulate radioactive iodide (RAI). DTC generally has a good prognosis. However, tumor dedifferentiation or defect in certain cell death mechanism occurs in a subset of DTC patients, leading to RAI resistance. Therefore, developing novel therapeutic approaches that enhance RAI sensitivity are still warranted. We found that curcumin, an active ingredient in turmeric with anti-cancer properties, rapidly accumulated in the mitochondria of thyroid cancer cells but not normal epithelial cells. Curcumin treatment triggered mitochondrial membrane depolarization, engulfment of mitochondria within autophagosomes and a robust decrease in mitochondrial mass and proteins, indicating that curcumin selectively induced mitophagy in thyroid cancer cells. In addition, curcumin-induced mitophagic cell death and its synergistic cytotoxic effect with radioiodine could be attenuated by autophagy inhibitor, 3-methyladenine (3-MA). Interestingly, the mechanism of mitophagy-inducing potential of curcumin was its unique mitochondria-targeting property, which induced a burst of SDH activity and excessive ROS production. Our data suggest that curcumin induces mitochondrial dysfunction and triggers lethal mitophagy, which synergizes with radioiodine to kill thyroid cancer cells.
    Keywords:  Curcumin; Differentiated thyroid cancer; Mitophagy; Radioactive iodide therapy; Succinate dehydrogenase
    DOI:  https://doi.org/10.1016/j.tiv.2023.105669
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