bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2024–08–25
eightteen papers selected by
Marc Segarra Mondejar
  1. Inner membrane turns inside out to exit mitochondrial organelles.
  2. Deficiency of thiosulfate sulfurtransferase mediates the dysfunction of renal tubular mitochondrial fatty acid oxidation in diabetic kidney disease.
  3. Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.
  4. MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.
  5. Insulin and leptin acutely modulate the energy metabolism of primary hypothalamic and cortical astrocytes.
  6. Artificial targeting of autophagy components to mitochondria reveals both conventional and unconventional mitophagy pathways.
  7. Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway.
  8. Pulsed electromagnetic fields regulate metabolic reprogramming and mitochondrial fission in endothelial cells for angiogenesis.
  9. BCL2L13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function.
  10. Lysosomes drive the piecemeal removal of mitochondrial inner membrane.
  11. Mitochondrial bioenergetics stimulates autophagy for pathological MAPT/Tau clearance in tauopathy neurons.
  12. Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition.
  13. Biomarker patterns and mechanistic insights into hypothermia from a postmortem metabolomics investigation.
  14. Enhanced metabolic entanglement emerges during the evolution of an interkingdom microbial community.
  15. Development of a Signal-integrating Reporter to Monitor Mitochondria-ER Contacts.
  16. FOXO3 Activates MFN2 Expression to Maintain the Autophagy Response in Cancer Cells Under Amino Acid Deprivation.
  17. AI-recognized mitochondrial phenotype enables identification of drug targets.
  18. Adenosine diphosphate released from stressed cells triggers mitochondrial transfer to achieve tissue homeostasis.
  1. Nature. 2024 Aug;632(8027): 987-988
    Inner membrane turns inside out to exit mitochondrial organelles.
    David Pla-Martín, Andreas S Reichert.
      
    Keywords:  Biochemistry; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-02528-w
  2. Cell Death Differ. 2024 Aug 22.
    Deficiency of thiosulfate sulfurtransferase mediates the dysfunction of renal tubular mitochondrial fatty acid oxidation in diabetic kidney disease.
    Jia Xiu Zhang, Pei Pei Chen, Xue Qi Li, Liang Li, Qin Yi Wu, Gui Hua Wang, Xiong Zhong Ruan, Kun Ling Ma.
      One of the main characteristics of diabetic kidney disease (DKD) is abnormal renal tubular fatty acid metabolism, especially defective fatty acid oxidation (FAO), accelerating tubular injury and tubulointerstitial fibrosis. Thiosulfate sulfurtransferase (TST), a mitochondrial enzyme essential for sulfur transfer, is reduced in metabolic diseases like diabetes and obesity. However, the potential role of TST in regulating fatty acid metabolic abnormalities in DKD remains unclear. Here, our data revealed decreased TST expression in the renal cortex of DKD patients. TST deficiency exacerbated tubular impairment in both diabetic and renal fibrosis mouse models, while sodium thiosulfate treatment or TST overexpression mitigated renal tubular injury with high-glucose exposure. TST downregulation mediated the decrease in S-sulfhydration of very long-chain specific acyl-CoA dehydrogenase, resulting in mitochondrial FAO dysfunction. This sequence of events exacerbates the progression of tubulointerstitial injury in DKD. Together, our findings demonstrate TST as a regulator of renal tubular injury in DKD.
    DOI:  https://doi.org/10.1038/s41418-024-01365-8
  3. Cell Metab. 2024 Aug 13. pii: S1550-4131(24)00287-0. [Epub ahead of print]
    Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.
    Traci E LaMoia, Brandon T Hubbard, Mateus T Guerra, Ali Nasiri, Ikki Sakuma, Mario Kahn, Dongyan Zhang, Russell P Goodman, Michael H Nathanson, Yasemin Sancak, Mark Perelis, Vamsi K Mootha, Gerald I Shulman.
      To examine the roles of mitochondrial calcium Ca2+ ([Ca2+]mt) and cytosolic Ca2+ ([Ca2+]cyt) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium uniporter knockout (MCU KO) mouse model with reduced [Ca2+]mt and increased [Ca2+]cyt content. Despite decreased [Ca2+]mt, deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of [14C16]palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that [Ca2+]cyt activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from [Ca2+]mt and reveal a key role for [Ca2+]cyt in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.
    Keywords:  CAMKII; Q-Flux; calcium; fat oxidation; glucose oxidation; isocitrate dehydrogenase flux; metabolic dysfunction-associated steatotic liver disease; mitochondria; mitochondrial calcium uniporter; succinate dehydrogenase flux; tricarboxylic acid cycle; type 2 diabetes; α-ketoglutarate dehydrogenase flux
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.016
  4. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2402491121
    MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.
    Prottoy Hasan, Elena Berezhnaya, Macarena Rodríguez-Prados, David Weaver, Carmen Bekeova, Benjamin Cartes-Saavedra, Erin Birch, Andreas M Beyer, Janine H Santos, Erin L Seifert, John W Elrod, György Hajnóczky.
      Activating Ca2+-sensitive enzymes of oxidative metabolism while preventing calcium overload that leads to mitochondrial and cellular injury requires dynamic control of mitochondrial Ca2+ uptake. This is ensured by the mitochondrial calcium uptake (MICU)1/2 proteins that gate the pore of the mitochondrial calcium uniporter (mtCU). MICU1 is relatively sparse in the heart, and recent studies claimed the mammalian heart lacks MICU1 gating of mtCU. However, genetic models have not been tested. We find that MICU1 is present in a complex with MCU in nonfailing human hearts. Furthermore, using murine genetic models and pharmacology, we show that MICU1 and MICU2 control cardiac mitochondrial Ca2+ influx, and that MICU1 deletion alters cardiomyocyte mitochondrial calcium signaling and energy metabolism. MICU1 loss causes substantial compensatory changes in the mtCU composition and abundance, increased turnover of essential MCU regulator (EMRE) early on and, later, of MCU, that limit mitochondrial Ca2+ uptake and allow cell survival. Thus, both the primary consequences of MICU1 loss and the ensuing robust compensation highlight MICU1's relevance in the beating heart.
    Keywords:  MICU1; MICU2; calcium; cardiomyocyte; mitochondrial calcium uniporter gating
    DOI:  https://doi.org/10.1073/pnas.2402491121
  5. J Neurochem. 2024 Aug 22.
    Insulin and leptin acutely modulate the energy metabolism of primary hypothalamic and cortical astrocytes.
    Christopher Wolff, Dorit John, Ulrike Winkler, Luise Hochmuth, Johannes Hirrlinger, Susanne Köhler.
      Astrocytes constitute a heterogeneous cell population within the brain, contributing crucially to brain homeostasis and playing an important role in overall brain function. Their function and metabolism are not only regulated by local signals, for example, from nearby neurons, but also by long-range signals such as hormones. Thus, two prominent hormones primarily known for regulating the energy balance of the whole organism, insulin, and leptin, have been reported to also impact astrocytes within the brain. In this study, we investigated the acute regulation of astrocytic metabolism by these hormones in cultured astrocytes prepared from the mouse cortex and hypothalamus, a pivotal region in the context of nutritional regulation. Utilizing genetically encoded, fluorescent nanosensors, the cytosolic concentrations of glucose, lactate, and ATP, along with glycolytic rate and the NADH/NAD+ redox state were measured. Under basal conditions, differences between the two populations of astrocytes were observed for glucose and lactate concentrations as well as the glycolytic rate. Additionally, astrocytic metabolism responded to insulin and leptin in both brain regions, with some unique characteristics for each cell population. Finally, both hormones influenced how cells responded to elevated extracellular levels of potassium ions, a common indicator of neuronal activity. In summary, our study provides evidence that insulin and leptin acutely regulate astrocytic metabolism within minutes. Additionally, while astrocytes from the hypothalamus and cortex share similarities in their metabolism, they also exhibit distinct properties, further underscoring the growing recognition of astrocyte heterogeneity.
    Keywords:  astrocyte; energy metabolism; heterogeneity; insulin; leptin; metabolic nanosensors
    DOI:  https://doi.org/10.1111/jnc.16211
  6. Autophagy. 2024 Aug 23.
    Artificial targeting of autophagy components to mitochondria reveals both conventional and unconventional mitophagy pathways.
    Katharina C Lorentzen, Alan R Prescott, Ian G Ganley.
      Macroautophagy/autophagy enables lysosomal degradation of a diverse array of intracellular material. This process is essential for normal cellular function and its dysregulation is implicated in many diseases. Given this, there is much interest in understanding autophagic mechanisms of action in order to determine how it can be best targeted therapeutically. In mitophagy, the selective degradation of mitochondria via autophagy, mitochondria first need to be primed with signals that allow the recruitment of the core autophagy machinery to drive the local formation of an autophagosome around the target mitochondrion. To determine how the recruitment of different core autophagy components can drive mitophagy, we took advantage of the mito-QC mitophagy assay (an outer mitochondrial membrane-localized tandem mCherry-GFP tag). By tagging autophagy proteins with an anti-mCherry (or anti-GFP) nanobody, we could recruit them to mitochondria and simultaneously monitor levels of mitophagy. We found that targeting ULK1, ATG16L1 and the different Atg8-family proteins was sufficient to induce mitophagy. Mitochondrial recruitment of ULK1 and the Atg8-family proteins induced a conventional mitophagy pathway, requiring RB1CC1/FIP200, PIK3C3/VPS34 activity and ATG5. Surprisingly, the mitophagy pathway upon recruitment of ATG16L1 proceeded independently of ATG5, although it still required RB1CC1 and PIK3C3/VPS34 activity. In this latter pathway, mitochondria were alternatively delivered to lysosomes via uptake into early endosomes.
    Keywords:  ATG16L1; Atg8; ULK1; nanobody; targeted organelle degradation
    DOI:  https://doi.org/10.1080/15548627.2024.2395149
  7. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2322755121
    Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway.
    Max L Valenstein, Pranav V Lalgudi, Xin Gu, Jibril F Kedir, Martin S Taylor, Raghu R Chivukula, David M Sabatini.
      The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth and metabolism in response to many environmental cues, including nutrients. Amino acids signal to mTORC1 by modulating the guanine nucleotide loading states of the heterodimeric Rag GTPases, which bind and recruit mTORC1 to the lysosomal surface, its site of activation. The Rag GTPases are tethered to the lysosome by the Ragulator complex and regulated by the GATOR1, GATOR2, and KICSTOR multiprotein complexes that localize to the lysosomal surface through an unknown mechanism(s). Here, we show that mTORC1 is completely insensitive to amino acids in cells lacking the Rag GTPases or the Ragulator component p18. Moreover, not only are the Rag GTPases and Ragulator required for amino acids to regulate mTORC1, they are also essential for the lysosomal recruitment of the GATOR1, GATOR2, and KICSTOR complexes, which stably associate and traffic to the lysosome as the "GATOR" supercomplex. The nucleotide state of RagA/B controls the lysosomal association of GATOR, in a fashion competitively antagonized by the N terminus of the amino acid transporter SLC38A9. Targeting of Ragulator to the surface of mitochondria is sufficient to relocalize the Rags and GATOR to this organelle, but not to enable the nutrient-regulated recruitment of mTORC1 to mitochondria. Thus, our results reveal that the Rag-Ragulator complex is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway and underscore that mTORC1 activation requires signal transduction on the lysosomal surface.
    Keywords:  biochemistry; mTOR signaling; nutrient sensing
    DOI:  https://doi.org/10.1073/pnas.2322755121
  8. Sci Rep. 2024 08 16. 14(1): 19027
    Pulsed electromagnetic fields regulate metabolic reprogramming and mitochondrial fission in endothelial cells for angiogenesis.
    Chengyi Yang, Li Xu, Feng Liao, Chunmei Liao, Yunying Zhao, Yijie Chen, Qian Yu, Bo Peng, Huifang Liu.
      Pulsed electromagnetic field (PEMF) therapy has been extensively investigated in clinical studies for the treatment of angiogenesis-related diseases. However, there is a lack of research on the impact of PEMFs on energy metabolism and mitochondrial dynamics during angiogenesis. The present study included tube formation and CCK-8 assays. A Seahorse assay was conducted to analyze energy metabolism, and mitochondrial membrane potential assays, mitochondrial imaging, and reactive oxygen species assays were used to measure changes in mitochondrial structure and function in human umbilical vein endothelial cells (HUVECs) exposed to PEMFs. Real-time polymerase chain reaction was used to analyze the mRNA expression levels of antioxidants, glycolytic pathway-related genes, and genes associated with mitochondrial fission and fusion. The tube formation assay demonstrated a significantly greater tube network in the PEMF group compared to the control group. The glycolysis and mitochondrial stress tests revealed that PEMFs promoted a shift in the energy metabolism pattern of HUVECs from oxidative phosphorylation to aerobic glycolysis. Mitochondrial imaging revealed a wire-like mitochondrial morphology in the control group, and treatment with PEMFs led to shorter and more granular mitochondria. Our major findings indicate that exposure to PEMFs accelerates angiogenesis in HUVECs, likely by inducing energy metabolism reprogramming and mitochondrial fission.
    Keywords:  Angiogenesis; Energy metabolism; Mitochondria; Pulsed electromagnetic field
    DOI:  https://doi.org/10.1038/s41598-024-69862-x
  9. iScience. 2024 Aug 16. 27(8): 110510
    BCL2L13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function.
    Dogan Grepper, Cassandra Tabasso, Nadège Zanou, Axel K F Aguettaz, Mauricio Castro-Sepulveda, Dorian V Ziegler, Sylviane Lagarrigue, Yoan Arribat, Adrien Martinotti, Ammar Ebrahimi, Jean Daraspe, Lluis Fajas, Francesca Amati.
      The physical connection between mitochondria and endoplasmic reticulum (ER) is an essential signaling hub to ensure organelle and cellular functions. In skeletal muscle, ER-mitochondria calcium (Ca2+) signaling is crucial to maintain cellular homeostasis during physical activity. High expression of BCL2L13, a member of the BCL-2 family, was suggested as an adaptive response in endurance-trained human subjects. In adult zebrafish, we found that the loss of Bcl2l13 impairs skeletal muscle structure and function. Ca2+ signaling is altered in Bcl2l13 knockout animals and mitochondrial complexes activity is decreased. Organelle fractioning in mammalian cells shows BCL2L13 at mitochondria, ER, and mitochondria-associated membranes. ER-mitochondria contact sites number is not modified by BCL2L13 modulation, but knockdown of BCL2L13 in C2C12 cells changes cytosolic Ca2+ release and mitochondrial Ca2+ uptake. This suggests that BCL2L13 interaction with mitochondria and ER, and its role in Ca2+ signaling, contributes to proper skeletal muscle function.
    Keywords:  cell biology; pharmacology
    DOI:  https://doi.org/10.1016/j.isci.2024.110510
  10. Nature. 2024 Aug 21.
    Lysosomes drive the piecemeal removal of mitochondrial inner membrane.
    Akriti Prashar, Claudio Bussi, Antony Fearns, Mariana I Capurro, Xiaodong Gao, Hiromi Sesaki, Maximiliano G Gutierrez, Nicola L Jones.
      Mitochondrial membranes define distinct structural and functional compartments. Cristae of the inner mitochondrial membrane (IMM) function as independent bioenergetic units that undergo rapid and transient remodelling, but the significance of this compartmentalized organization is unknown1. Using super-resolution microscopy, here we show that cytosolic IMM vesicles, devoid of outer mitochondrial membrane or mitochondrial matrix, are formed during resting state. These vesicles derived from the IMM (VDIMs) are formed by IMM herniation through pores formed by voltage-dependent anion channel 1 in the outer mitochondrial membrane. Live-cell imaging showed that lysosomes in proximity to mitochondria engulfed the herniating IMM and, aided by the endosomal sorting complex required for transport machinery, led to the formation of VDIMs in a microautophagy-like process, sparing the remainder of the organelle. VDIM formation was enhanced in mitochondria undergoing oxidative stress, suggesting their potential role in maintenance of mitochondrial function. Furthermore, the formation of VDIMs required calcium release by the reactive oxygen species-activated, lysosomal calcium channel, transient receptor potential mucolipin 1, showing an interorganelle communication pathway for maintenance of mitochondrial homeostasis. Thus, IMM compartmentalization could allow for the selective removal of damaged IMM sections via VDIMs, which should protect mitochondria from localized injury. Our findings show a new pathway of intramitochondrial quality control.
    DOI:  https://doi.org/10.1038/s41586-024-07835-w
  11. Autophagy. 2024 Aug 22.
    Mitochondrial bioenergetics stimulates autophagy for pathological MAPT/Tau clearance in tauopathy neurons.
    Nuo Jia, Dhasarathan Ganesan, Hongyuan Guan, Yu Young Jeong, Sinsuk Han, Gavesh Rajapaksha, Marialaina Nissenbaum, Alexander W Kusnecov, Qian Cai.
      Hyperphosphorylation and aggregation of MAPT (microtubule-associated protein tau) is a pathogenic hallmark of tauopathies and a defining feature of Alzheimer disease (AD). Pathological MAPT/tau is targeted by macroautophagy/autophagy for clearance after being sequestered within autophagosomes, but autophagy dysfunction is indicated in tauopathy. While mitochondrial bioenergetic deficits have been shown to precede MAPT/tau pathology in tauopathy brains, it is unclear whether energy metabolism deficiency is involved in the pathogenesis of autophagy defects. Here, we reveal that stimulation of anaplerotic metabolism restores defective oxidative phosphorylation (OXPHOS) in tauopathy neurons which, strikingly, leads to pronounced MAPT/tau clearance by boosting autophagy functionality through enhancements of mitochondrial biosynthesis and supply of phosphatidylethanolamine for autophagosome biogenesis. Furthermore, early anaplerotic stimulation of OXPHOS elevates autophagy activity and attenuates MAPT/tau pathology, thereby counteracting memory impairment in tauopathy mice. Taken together, our study sheds light on a pivotal role of mitochondrial bioenergetic deficiency in tauopathy-related autophagy defects and suggests a new therapeutic strategy to prevent the buildup of pathological MAPT/tau in AD and other tauopathy diseases.
    Keywords:  Alzheimer; anaplerotic metabolism; autophagy; phospholipid biosynthesis; phosphorylated MAPT/tau; tauopathy
    DOI:  https://doi.org/10.1080/15548627.2024.2392408
  12. Cell Rep. 2024 Aug 18. pii: S2211-1247(24)00982-3. [Epub ahead of print]43(8): 114632
    Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition.
    Patrick M Gubser, Sharanya Wijesinghe, Leonie Heyden, Sarah S Gabriel, David P de Souza, Christoph Hess, Malcolm M McConville, Daniel T Utzschneider, Axel Kallies.
      Tumor cells undergo uncontrolled proliferation driven by enhanced anabolic metabolism including glycolysis and glutaminolysis. Targeting these pathways to inhibit cancer growth is a strategy for cancer treatment. Critically, however, tumor-responsive T cells share metabolic features with cancer cells, making them susceptible to these treatments as well. Here, we assess the impact on anti-tumor T cell immunity and T cell exhaustion by genetic ablation of lactate dehydrogenase A (LDHA) and glutaminase1 (GLS1), key enzymes in aerobic glycolysis and glutaminolysis. Loss of LDHA severely impairs expansion of T cells in response to tumors and chronic infection. In contrast, T cells lacking GLS1 can compensate for impaired glutaminolysis by engaging alternative pathways, including upregulation of asparagine synthetase, and thus efficiently respond to tumor challenge and chronic infection as well as immune checkpoint blockade. Targeting GLS1-dependent glutaminolysis, but not aerobic glycolysis, may therefore be a successful strategy in cancer treatment, particularly in combination with immunotherapy.
    Keywords:  CP: Cancer; CP: Metabolism; GLS1; LDHA; Tpex
    DOI:  https://doi.org/10.1016/j.celrep.2024.114632
  13. Sci Rep. 2024 08 16. 14(1): 18972
    Biomarker patterns and mechanistic insights into hypothermia from a postmortem metabolomics investigation.
    Albert Elmsjö, Liam J Ward, Kie Horioka, Shimpei Watanabe, Fredrik C Kugelberg, Henrik Druid, Henrik Green.
      Postmortem metabolomics holds promise for identifying crucial biological markers relevant to death investigations and clinical scenarios. We aimed to assess its applicability in diagnosing hypothermia, a condition lacking definitive biomarkers. Our retrospective analysis involved 1095 postmortem femoral blood samples, including 150 hypothermia cases, 278 matched controls, and 667 randomly selected test cases, analyzed using UHPLC-QTOF mass spectrometry. The model demonstrated robustness with an R2 and Q2 value of 0.73 and 0.68, achieving 94% classification accuracy, 92% sensitivity, and 96% specificity. Discriminative metabolite patterns, including acylcarnitines, stress hormones, and NAD metabolites, along with identified pathways, suggest that metabolomics analysis can be helpful to diagnose fatal hypothermia. Exposure to cold seems to trigger a stress response in the body, increasing cortisol production to maintain core temperature, possibly explaining the observed upregulation of cortisol levels and alterations in metabolic markers related to renal function. In addition, thermogenesis seems to increase metabolism in brown adipose tissue, contributing to changes in nicotinamide metabolism and elevated levels of ketone bodies and acylcarnitines, these findings highlight the effectiveness of UHPLC-QTOF mass spectrometry, multivariate analysis, and pathway identification of postmortem samples in identifying metabolite markers with forensic and clinical significance. The discovered patterns may offer valuable clinical insights and diagnostic markers, emphasizing the broader potential of postmortem metabolomics in understanding critical states or diseases.
    Keywords:  Biomarkers; Hypothermia; Metabolomics; Nicotinamide metabolism; Postmortem
    DOI:  https://doi.org/10.1038/s41598-024-68973-9
  14. Nat Commun. 2024 Aug 22. 15(1): 7238
    Enhanced metabolic entanglement emerges during the evolution of an interkingdom microbial community.
    Giovanni Scarinci, Jan-Luca Ariens, Georgia Angelidou, Sebastian Schmidt, Timo Glatter, Nicole Paczia, Victor Sourjik.
      While different stages of mutualism can be observed in natural communities, the dynamics and mechanisms underlying the gradual erosion of independence of the initially autonomous organisms are not yet fully understood. In this study, by conducting the laboratory evolution on an engineered microbial community, we reproduce and molecularly track the stepwise progression towards enhanced partner entanglement. We observe that the evolution of the community both strengthens the existing metabolic interactions and leads to the emergence of de novo interdependence between partners for nitrogen metabolism, which is a common feature of natural symbiotic interactions. Selection for enhanced metabolic entanglement during the community evolution repeatedly occurred indirectly, via pleiotropies and trade-offs within cellular regulatory networks, and with no evidence of group selection. The indirect positive selection of metabolic dependencies between microbial community members, which results from the direct selection of other coupled traits in the same regulatory network, may therefore be a common but underappreciated driving force guiding the evolution of natural mutualistic communities.
    DOI:  https://doi.org/10.1038/s41467-024-51702-1
  15. ACS Synth Biol. 2024 Aug 20.
    Development of a Signal-integrating Reporter to Monitor Mitochondria-ER Contacts.
    Zheng Yang, David C Chan.
      Mitochondria-endoplasmic reticulum contact sites (MERCS) serve as hotspots for important cellular processes, including calcium homeostasis, phospholipid homeostasis, mitochondria dynamics, and mitochondrial quality control. MERCS reporters based on complementation of green fluorescent proteins (GFP) fragments have been designed to visualize MERCS in real-time, but we find that they do not accurately respond to changes in MERCS content. Here, we utilize split LacZ complementing fragments to develop the first MERCS reporter system (termed SpLacZ-MERCS) that continuously integrates the MERCS information within a cell and generates a fluorescent output. Our system exhibits good organelle targeting, no artifactual tethering, and effective, dynamic tracking of the MERCS level in single cells. The SpLacZ-MERCS reporter was validated by drug treatments and genetic perturbations known to affect mitochondria-ER contacts. The signal-integrating nature of SpLacZ-MERCS may enable systematic identification of genes and drugs that regulate mitochondria-ER interactions. Our successful application of the split LacZ complementation strategy to study MERCS may be extended to study other forms of interorganellar crosstalk.
    Keywords:  contact sites; endoplasmic reticulum; mitochondria; organelle interactions
    DOI:  https://doi.org/10.1021/acssynbio.4c00098
  16. J Cell Biochem. 2024 Aug 22. e30641
    FOXO3 Activates MFN2 Expression to Maintain the Autophagy Response in Cancer Cells Under Amino Acid Deprivation.
    Xu Jiang, Jing Wang, Fang Ma, Yuyun Li.
      The lack of amino acids triggers the autophagic response. Some studies have shown such starvation conditions also induce mitochondrial fusion, revealing a close correlation between the two processes. Although Mitofusin-2 (MFN2) has been demonstrated to play a role in fusion regulation, its role in the autophagic response and the variables that activate MFN2 under stress remain unknown. In this investigation, we screened and confirmed that forkhead box protein O3 (FOXO3) participates in MFN2's expression during short periods of starvation. Luciferase reporter test proved that FOXO3 facilitates MFN2's transcription by binding to its promoter region, and FOXO3 downregulation directly depresses MFN2's expression. Consequently, inhibiting the FOXO3-MFN2 axis results in the loss of mitochondrial fusion, disrupting the normal morphology of mitochondria, impairing the degradation of substrates, and reducing autophagosome accumulation, ultimately leading to the blockage of the autophagy. In conclusion, our work demonstrates that the FOXO3-MFN2 pathway is essential for adaptive changes in mitochondrial morphology and cellular autophagy response under nutritional constraints.
    Keywords:  FOXO3; MFN2; autophagy; mitochondrial fusion; starvation stress
    DOI:  https://doi.org/10.1002/jcb.30641
  17. Nat Comput Sci. 2024 Aug 22.
    AI-recognized mitochondrial phenotype enables identification of drug targets.
      
    DOI:  https://doi.org/10.1038/s43588-024-00682-9
  18. PLoS Biol. 2024 Aug;22(8): e3002753
    Adenosine diphosphate released from stressed cells triggers mitochondrial transfer to achieve tissue homeostasis.
    Hao Li, Hongping Yu, Delin Liu, Peng Liao, Chuan Gao, Jian Zhou, Jialun Mei, Yao Zong, Peng Ding, Meng Yao, Bingqi Wang, Yafei Lu, Yigang Huang, Youshui Gao, Changqing Zhang, Minghao Zheng, Junjie Gao.
      Cell-to-cell mitochondrial transfer has recently been shown to play a role in maintaining physiological functions of cell. We previously illustrated that mitochondrial transfer within osteocyte dendritic network regulates bone tissue homeostasis. However, the mechanism of triggering this process has not been explored. Here, we showed that stressed osteocytes in mice release adenosine diphosphate (ADP), resulting in triggering mitochondrial transfer from healthy osteocytes to restore the oxygen consumption rate (OCR) and to alleviate reactive oxygen species accumulation. Furthermore, we identified that P2Y2 and P2Y6 transduced the ADP signal to regulate osteocyte mitochondrial transfer. We showed that mitochondrial metabolism is impaired in aged osteocytes, and there were more extracellular nucleotides release into the matrix in aged cortical bone due to compromised membrane integrity. Conditioned medium from aged osteocytes triggered mitochondrial transfer between osteocytes to enhance the energy metabolism. Together, using osteocyte as an example, this study showed new insights into how extracellular ADP triggers healthy cells to rescue energy metabolism crisis in stressed cells via mitochondrial transfer in tissue homeostasis.
    DOI:  https://doi.org/10.1371/journal.pbio.3002753
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