bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2023–12–10
sixteen papers selected by
Marc Segarra Mondejar, University of Cologne
  1. Energy metabolic reprogramming regulates programmed cell death of renal tubular epithelial cells and might serve as a new therapeutic target for acute kidney injury.
  2. mTOR takes charge: Relaying uncharged tRNA levels by mTOR ubiquitination.
  3. Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment.
  4. De novo NAD+ synthesis contributes to CD8+ T cell metabolic fitness and antitumor function.
  5. Mitochondrial ATP concentration decreases immediately after glucose administration to glucose-deprived hepatocytes.
  6. Loss of cardiac PFKFB2 drives Metabolic, Functional, and Electrophysiological Remodeling in the Heart.
  7. Mitochondrial dynamics and metabolism across skin cells: implications for skin homeostasis and aging.
  8. Lactate-induced histone lactylation by p300 promotes osteoblast differentiation.
  9. Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity.
  10. Tubular Mitochondrial Pyruvate Carrier Disruption Elicits Redox Adaptations that Protect from Acute Kidney Injury.
  11. Human mitochondrial uncoupling protein 3 functions as a metabolite transporter.
  12. Postsynaptic mitochondria are positioned to support functional diversity of dendritic spines.
  13. Apolipoproteins L1 and L3 control mitochondrial membrane dynamics.
  14. Reactive Oxygen Species Generation by Reverse Electron Transfer at Mitochondrial Complex I Under Simulated Early Reperfusion Conditions.
  15. Predicting pathways for old and new metabolites through clustering.
  16. The mystery of phospho-Drp1 with four adaptors in cell cycle: when mitochondrial fission couples to cell fate decisions.
  1. Front Cell Dev Biol. 2023 ;11 1276217
    Energy metabolic reprogramming regulates programmed cell death of renal tubular epithelial cells and might serve as a new therapeutic target for acute kidney injury.
    Limei Zhao, Yajie Hao, Shuqin Tang, Xiutao Han, Rongshan Li, Xiaoshuang Zhou.
      Acute kidney injury (AKI) induces significant energy metabolic reprogramming in renal tubular epithelial cells (TECs), thereby altering lipid, glucose, and amino acid metabolism. The changes in lipid metabolism encompass not only the downregulation of fatty acid oxidation (FAO) but also changes in cell membrane lipids and triglycerides metabolism. Regarding glucose metabolism, AKI leads to increased glycolysis, activation of the pentose phosphate pathway (PPP), inhibition of gluconeogenesis, and upregulation of the polyol pathway. Research indicates that inhibiting glycolysis, promoting the PPP, and blocking the polyol pathway exhibit a protective effect on AKI-affected kidneys. Additionally, changes in amino acid metabolism, including branched-chain amino acids, glutamine, arginine, and tryptophan, play an important role in AKI progression. These metabolic changes are closely related to the programmed cell death of renal TECs, involving autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis. Notably, abnormal intracellular lipid accumulation can impede autophagic clearance, further exacerbating lipid accumulation and compromising autophagic function, forming a vicious cycle. Recent studies have demonstrated the potential of ameliorating AKI-induced kidney damage through calorie and dietary restriction. Consequently, modifying the energy metabolism of renal TECs and dietary patterns may be an effective strategy for AKI treatment.
    Keywords:  acute kidney injury; energy metabolism; programmed cell death; renal tubular epithelial cells; therapeutic
    DOI:  https://doi.org/10.3389/fcell.2023.1276217
  2. Cell Metab. 2023 Dec 05. pii: S1550-4131(23)00417-5. [Epub ahead of print]35(12): 2097-2099
    mTOR takes charge: Relaying uncharged tRNA levels by mTOR ubiquitination.
    Estela Jacinto.
      Nutrient availability is conveyed to the mechanistic target of rapamycin (mTOR), which couples metabolic processes with cell growth and proliferation. How mTOR itself is modulated by amino acid levels remains poorly understood. Ge and colleagues now demonstrate that broad sensing of uncharged tRNAs by GCN2/FBXO22 inactivates mTOR complex 1 (mTORC1) via mTOR ubiquitination.
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.006
  3. Nat Cell Biol. 2023 Dec 04.
    Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment.
    Jenna M Giafaglione, Preston D Crowell, Amelie M L Delcourt, Takao Hashimoto, Sung Min Ha, Aishwarya Atmakuri, Nicholas M Nunley, Rachel M A Dang, Mao Tian, Johnny A Diaz, Elisavet Tika, Marie C Payne, Deborah L Burkhart, Dapei Li, Nora M Navone, Eva Corey, Peter S Nelson, Neil Y C Lin, Cedric Blanpain, Leigh Ellis, Paul C Boutros, Andrew S Goldstein.
      Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity.
    DOI:  https://doi.org/10.1038/s41556-023-01274-x
  4. Cell Rep. 2023 Dec 01. pii: S2211-1247(23)01530-9. [Epub ahead of print]42(12): 113518
    De novo NAD+ synthesis contributes to CD8+ T cell metabolic fitness and antitumor function.
    Jie Wan, Cheng Cheng, Jiajia Hu, Haiyan Huang, Qiaoqiao Han, Zuliang Jie, Qiang Zou, Jian-Hong Shi, Xiaoyan Yu.
      The dysfunction and clonal constriction of tumor-infiltrating CD8+ T cells are accompanied by alterations in cellular metabolism; however, how the cell-intrinsic metabolic pathway specifies intratumoral CD8+ T cell features remains elusive. Here, we show that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD+) via the kynurenine pathway (KP) contributes to the maintenance of intratumoral CD8+ T cell metabolic and functional fitness. De novo NAD+ synthesis is involved in CD8+ T cell metabolism and antitumor function. KP-derived NAD+ promotes PTEN deacetylation, thereby facilitating PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, impaired cell-autonomous NAD+ synthesis limits CD8+ T cell responses in human colorectal cancer samples. Our results reveal that KP-derived NAD+ regulates the CD8+ T cell metabolic and functional state by restricting PTEN activity and suggest that modulation of de novo NAD+ synthesis could restore CD8+ T cell metabolic fitness and antitumor function.
    Keywords:  CP: Cancer; CP: Metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2023.113518
  5. FEBS Open Bio. 2023 Dec 04.
    Mitochondrial ATP concentration decreases immediately after glucose administration to glucose-deprived hepatocytes.
    Saki Tsuno, Kazuki Harada, Mina Horikoshi, Marie Mita, Tetsuya Kitaguchi, Masami Yokota Hirai, Mitsuharu Matsumoto, Takashi Tsuboi.
      Hepatocytes can switch their metabolic processes in response to nutrient availability. However, the dynamics of metabolites (such as lactate, pyruvate, and ATP) in hepatocytes during the metabolic switch remain unknown. In this study, we visualized metabolite dynamics in primary cultured hepatocytes during recovery from glucose-deprivation. We observed a decrease in the mitochondrial ATP concentration when glucose was administered to hepatocytes under glucose-deprivation conditions. In contrast, there was slight change in the cytoplasmic ATP concentration. A decrease in mitochondrial ATP concentration was associated with increased protein synthesis rather than glycogen synthesis, activation of urea cycle, and production of reactive oxygen species. These results suggest that mitochondrial ATP is important in switching metabolic processes in the hepatocytes.
    Keywords:  ATP; glucose-deprivation; hepatocyte; live-cell imaging; mitochondria
    DOI:  https://doi.org/10.1002/2211-5463.13744
  6. bioRxiv. 2023 Nov 23. pii: 2023.11.22.568379. [Epub ahead of print]
    Loss of cardiac PFKFB2 drives Metabolic, Functional, and Electrophysiological Remodeling in the Heart.
    Kylene M Harold, Satoshi Matsuzaki, Atul Pranay, Brooke L Loveland, Albert Batushansky, Maria F Mendez Garcia, Craig Eyster, Stavros Stavrakis, Ying Ann Chiao, Michael Kinter, Kenneth M Humphries.
       Background: Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) is a critical glycolytic regulator responsible for upregulation of glycolysis in response to insulin and adrenergic signaling. PFKFB2, the cardiac isoform of PFK-2, is degraded in the heart in the absence of insulin signaling, contributing to diabetes-induced cardiac metabolic inflexibility. However, previous studies have not examined how the loss of PFKFB2 affects global cardiac metabolism and function.
    Methods: To address this, we have generated a mouse model with a cardiomyocyte-specific knockout of PFKFB2 (cKO). Using 9-month-old cKO and control (CON) mice, we characterized impacts of PFKFB2 on cardiac metabolism, function, and electrophysiology.
    Results: cKO mice have a shortened lifespan of 9 months. Metabolically, cKO mice are characterized by increased glycolytic enzyme abundance and pyruvate dehydrogenase (PDH) activity, as well as decreased mitochondrial abundance and beta oxidation, suggesting a shift toward glucose metabolism. This was supported by a decrease in the ratio of palmitoyl carnitine to pyruvate-dependent mitochondrial respiration in cKO relative to CON animals. Metabolomic, proteomic, and western blot data support the activation of ancillary glucose metabolism, including pentose phosphate and hexosamine biosynthesis pathways. Physiologically, cKO animals exhibited impaired systolic function and left ventricular (LV) dilation, represented by reduced fractional shortening and increased LV internal diameter, respectively. This was accompanied by electrophysiological alterations including increased QT interval and other metrics of delayed ventricular conduction.
    Conclusions: Loss of PFKFB2 results in metabolic remodeling marked by cardiac ancillary pathway activation. This could delineate an underpinning of pathologic changes to mechanical and electrical function in the heart.
    Clinical Perspective: What is New?: We have generated a novel cardiomyocyte-specific knockout model of PFKFB2, the cardiac isoform of the primary glycolytic regulator Phosphofructokinase-2 (cKO).The cKO model demonstrates that loss of cardiac PFKFB2 drives metabolic reprogramming and shunting of glucose metabolites to ancillary metabolic pathways.The loss of cardiac PFKFB2 promotes electrophysiological and functional remodeling in the cKO heart.What are the Clinical Implications?: PFKFB2 is degraded in the absence of insulin signaling, making its loss particularly relevant to diabetes and the pathophysiology of diabetic cardiomyopathy.Changes which we observe in the cKO model are consistent with those often observed in diabetes and heart failure of other etiologies.Defining PFKFB2 loss as a driver of cardiac pathogenesis identifies it as a target for future investigation and potential therapeutic intervention.
    DOI:  https://doi.org/10.1101/2023.11.22.568379
  7. Front Physiol. 2023 ;14 1284410
    Mitochondrial dynamics and metabolism across skin cells: implications for skin homeostasis and aging.
    Ines Martic, Federica Papaccio, Barbara Bellei, Maria Cavinato.
      Aging of human skin is a complex process leading to a decline in homeostasis and regenerative potential of this tissue. Mitochondria are important cell organelles that have a crucial role in several cellular mechanisms such as energy production and free radical maintenance. However, mitochondrial metabolism as well as processes of mitochondrial dynamics, biogenesis, and degradation varies considerably among the different types of cells that populate the skin. Disturbed mitochondrial function is known to promote aging and inflammation of the skin, leading to impairment of physiological skin function and the onset of skin pathologies. In this review, we discuss the essential role of mitochondria in different skin cell types and how impairment of mitochondrial morphology, physiology, and metabolism in each of these cellular compartments of the skin contributes to the process of skin aging.
    Keywords:  aging; mitochondria; skin; skin cells; skin homeostasis
    DOI:  https://doi.org/10.3389/fphys.2023.1284410
  8. PLoS One. 2023 ;18(12): e0293676
    Lactate-induced histone lactylation by p300 promotes osteoblast differentiation.
    Erika Minami, Kiyohito Sasa, Atsushi Yamada, Ryota Kawai, Hiroshi Yoshida, Haruhisa Nakano, Koutaro Maki, Ryutaro Kamijo.
      Lactate, which is synthesized as an end product by lactate dehydrogenase A (LDHA) from pyruvate during anaerobic glycolysis, has attracted attention for its energy metabolism and oxidant effects. A novel histone modification-mediated gene regulation mechanism termed lactylation by lactate was recently discovered. The present study examined the involvement of histone lactylation in undifferentiated cells that underwent differentiation into osteoblasts. C2C12 cells cultured in medium with a high glucose content (4500 mg/L) showed increases in marker genes (Runx2, Sp7, Tnap) indicating BMP-2-induced osteoblast differentiation and ALP staining activity, as well as histone lactylation as compared to those cultured in medium with a low glucose content (900 mg/L). Furthermore, C2C12 cells stimulated with the LDH inhibitor oxamate had reduced levels of BMP-2-induced osteoblast differentiation and histone lactylation, while addition of lactate to C2C12 cells cultured in low glucose medium resulted in partial restoration of osteoblast differentiation and histone lactylation. These results indicate that lactate synthesized by LDHA during glucose metabolism is important for osteoblast differentiation of C2C12 cells induced by BMP-2. Additionally, silencing of p300, a possible modifier of histone lactylation, also inhibited osteoblast differentiation and reduced histone lactylation. Together, these findings suggest a role of histone lactylation in promotion of undifferentiated cells to undergo differentiation into osteoblasts.
    DOI:  https://doi.org/10.1371/journal.pone.0293676
  9. Sci Adv. 2023 Dec 08. 9(49): eadf9522
    Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity.
    Chao Chen, Hong Zheng, Edwin M Horwitz, Satomi Ando, Koichi Araki, Peng Zhao, Zhiguo Li, Mandy L Ford, Rafi Ahmed, Cheng-Kui Qu.
      Mitochondria use different substrates for energy production and intermediatory metabolism according to the availability of nutrients and oxygen levels. The role of mitochondrial metabolic flexibility for CD8+ T cell immune response is poorly understood. Here, we report that the deletion or pharmacological inhibition of protein tyrosine phosphatase, mitochondrial 1 (PTPMT1) significantly decreased CD8+ effector T cell development and clonal expansion. In addition, PTPMT1 deletion impaired stem-like CD8+ T cell maintenance and accelerated CD8+ T cell exhaustion/dysfunction, leading to aggravated tumor growth. Mechanistically, the loss of PTPMT1 critically altered mitochondrial fuel selection-the utilization of pyruvate, a major mitochondrial substrate derived from glucose-was inhibited, whereas fatty acid utilization was enhanced. Persistent mitochondrial substrate shift and metabolic inflexibility induced oxidative stress, DNA damage, and apoptosis in PTPMT1 knockout cells. Collectively, this study reveals an important role of PTPMT1 in facilitating mitochondrial utilization of carbohydrates and that mitochondrial flexibility in energy source selection is critical for CD8+ T cell antitumor immunity.
    DOI:  https://doi.org/10.1126/sciadv.adf9522
  10. Mol Metab. 2023 Dec 04. pii: S2212-8778(23)00183-7. [Epub ahead of print] 101849
    Tubular Mitochondrial Pyruvate Carrier Disruption Elicits Redox Adaptations that Protect from Acute Kidney Injury.
    Adam J Rauckhorst, Gabriela Vasquez Martinez, Gabriel Mayoral Andrade, Hsiang Wen, Ji Young Kim, Aaron Simoni, Claudia Robles-Planells, Kranti A Mapuskar, Prerna Rastogi, Emily J Steinbach, Michael L McCormick, Bryan G Allen, Navjot S Pabla, Ashley R Jackson, Mitchell C Coleman, Douglas R Spitz, Eric B Taylor, Diana Zepeda-Orozco.
       OBJECTIVE: Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Although tubular metabolism changes markedly following acute kidney injury (AKI), it remains unclear which metabolic alterations are beneficial or detrimental. By analyzing large-scale, publicly available datasets, we observed that AKI consistently leads to downregulation of the mitochondrial pyruvate carrier (MPC). This investigation aimed to understand the contribution of the tubular MPC to kidney function, metabolism, and acute injury severity.
    METHODS: We generated tubular epithelial cell-specific Mpc1 knockout (MPC TubKO) mice and employed renal function tests, in vivo renal 13C-glucose tracing, mechanistic enzyme activity assays, and tests of injury and survival in an established rhabdomyolysis model of AKI.
    RESULTS: MPC TubKO mice retained normal kidney function, displayed unchanged markers of kidney injury, but exhibited coordinately increased enzyme activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, compared to WT control mice, MPC TubKO mice showed increased glycolysis, decreased kidney injury and oxidative stress markers, and strikingly increased survival.
    CONCLUSIONS: Our findings suggest that decreased renal tubular mitochondrial pyruvate uptake hormetically upregulates oxidant defense systems before AKI and is a beneficial adaptive response after rhabdomyolysis-induced AKI. This raises the possibility of therapeutically modulating the MPC to attenuate AKI severity.
    Keywords:  acute kidney injury; hormesis; metabolomics; mitochondrial metabolism; oxidative stress
    DOI:  https://doi.org/10.1016/j.molmet.2023.101849
  11. FEBS Lett. 2023 Dec 06.
    Human mitochondrial uncoupling protein 3 functions as a metabolite transporter.
    Francesco De Leonardis, Amer Ahmed, Angelo Vozza, Loredana Capobianco, Christopher L Riley, Simona Nicole Barile, Daria Di Molfetta, Stefano Tiziani, John DiGiovanni, Luigi Palmieri, Vincenza Dolce, Giuseppe Fiermonte.
      Since its discovery, a major debate about mitochondrial uncoupling protein 3 (UCP3) has been whether its metabolic actions result primarily from mitochondrial inner membrane proton transport, a process that decreases respiratory efficiency and ATP synthesis. However, UCP3 expression and activity are induced by conditions that would seem at odds with inefficient "uncoupled" respiration, including fasting and exercise. Here we demonstrate that the bacterially expressed human UCP3, reconstituted into liposomes, catalyses a strict exchange of aspartate, malate, oxaloacetate, and phosphate. The R282Q mutation abolishes the transport activity of the protein. Although the substrate specificity and inhibitor sensitivity of UCP3 display similarity with that of its close homolog UCP2, the two proteins significantly differ in their transport mode and kinetic constants.
    Keywords:  amino acid transport; anion transport; bioenergetics; mitochondrial metabolism; mitochondrial transport; uncoupling protein
    DOI:  https://doi.org/10.1002/1873-3468.14784
  12. Elife. 2023 Dec 07. pii: RP89682. [Epub ahead of print]12
    Postsynaptic mitochondria are positioned to support functional diversity of dendritic spines.
    Connon I Thomas, Melissa A Ryan, Naomi Kamasawa, Benjamin Scholl.
      Postsynaptic mitochondria are critical for the development, plasticity, and maintenance of synaptic inputs. However, their relationship to synaptic structure and functional activity is unknown. We examined a correlative dataset from ferret visual cortex with in vivo two-photon calcium imaging of dendritic spines during visual stimulation and electron microscopy reconstructions of spine ultrastructure, investigating mitochondrial abundance near functionally and structurally characterized spines. Surprisingly, we found no correlation to structural measures of synaptic strength. Instead, we found that mitochondria are positioned near spines with orientation preferences that are dissimilar to the somatic preference. Additionally, we found that mitochondria are positioned near groups of spines with heterogeneous orientation preferences. For a subset of spines with a mitochondrion in the head or neck, synapses were larger and exhibited greater selectivity to visual stimuli than those without a mitochondrion. Our data suggest mitochondria are not necessarily positioned to support the energy needs of strong spines, but rather support the structurally and functionally diverse inputs innervating the basal dendrites of cortical neurons.
    Keywords:  Mustela furo; dendrite spine; electron microscopy; mitochondria; neuroscience; two-photon calcium imaging
    DOI:  https://doi.org/10.7554/eLife.89682
  13. Cell Rep. 2023 Dec 01. pii: S2211-1247(23)01540-1. [Epub ahead of print]42(12): 113528
    Apolipoproteins L1 and L3 control mitochondrial membrane dynamics.
    Laurence Lecordier, Paul Heo, Jonas H Graversen, Dorle Hennig, Maria Kløjgaard Skytthe, Alexandre Cornet d'Elzius, Frédéric Pincet, David Pérez-Morga, Etienne Pays.
      Apolipoproteins L1 and L3 (APOLs) are associated at the Golgi with the membrane fission factors phosphatidylinositol 4-kinase-IIIB (PI4KB) and non-muscular myosin 2A. Either APOL1 C-terminal truncation (APOL1Δ) or APOL3 deletion (APOL3-KO [knockout]) reduces PI4KB activity and triggers actomyosin reorganization. We report that APOL3, but not APOL1, controls PI4KB activity through interaction with PI4KB and neuronal calcium sensor-1 or calneuron-1. Both APOLs are present in Golgi-derived autophagy-related protein 9A vesicles, which are involved in PI4KB trafficking. Like APOL3-KO, APOL1Δ induces PI4KB dissociation from APOL3, linked to reduction of mitophagy flux and production of mitochondrial reactive oxygen species. APOL1 and APOL3, respectively, can interact with the mitophagy receptor prohibitin-2 and the mitophagosome membrane fusion factor vesicle-associated membrane protein-8 (VAMP8). While APOL1 conditions PI4KB and APOL3 involvement in mitochondrion fission and mitophagy, APOL3-VAMP8 interaction promotes fusion between mitophagosomal and endolysosomal membranes. We propose that APOL3 controls mitochondrial membrane dynamics through interactions with the fission factor PI4KB and the fusion factor VAMP8.
    Keywords:  APOL1 risk variants; COVAN; COVID-19-associated nephropathy; CP: Cell biology; HIV-associated nephropathy; HIVAN; inflammation; interferon 1; kidney disease; mitochondrion fission/fusion; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2023.113528
  14. bioRxiv. 2023 Nov 21. pii: 2023.11.21.568136. [Epub ahead of print]
    Reactive Oxygen Species Generation by Reverse Electron Transfer at Mitochondrial Complex I Under Simulated Early Reperfusion Conditions.
    Caio Tabata Fukushima, Ian-Shika Dancil, Hannah Clary, Nidhi Shah, Sergiy M Nadtochiy, Paul S Brookes.
      Ischemic tissues accumulate succinate, which is rapidly oxidized upon reperfusion, driving a burst of mitochondrial reactive oxygen species (ROS) generation that triggers cell death. In isolated mitochondria with succinate as the sole metabolic substrate under non-phosphorylating conditions, 90% of ROS generation is from reverse electron transfer (RET) at the Q site of respiratory complex I (Cx-I). Together, these observations suggest Cx-I RET is the source of pathologic ROS in reperfusion injury. However, numerous factors present in early reperfusion may impact Cx-I RET, including: (i) High [NADH]; (ii) High [lactate]; (iii) Mildly acidic pH; (iv) Defined ATP/ADP ratios; (v) Presence of the nucleosides adenosine and inosine; and (vi) Defined free [Ca 2+ ]. Herein, experiments with mouse cardiac mitochondria revealed that under simulated early reperfusion conditions including these factors, overall mitochondrial ROS generation was only 56% of that seen with succinate alone, and only 52% of this ROS was assignable to Cx-I RET. The residual non-RET ROS could be partially assigned to complex III (Cx-III) with the remainder likely originating from other ROS sources upstream of the Cx-I Q site. Together, these data suggest the relative contribution of Cx-I RET ROS to reperfusion injury may be overestimated, and other ROS sources may contribute a significant fraction of ROS in early reperfusion.
    DOI:  https://doi.org/10.1101/2023.11.21.568136
  15. J Theor Biol. 2023 Dec 02. pii: S0022-5193(23)00281-3. [Epub ahead of print] 111684
    Predicting pathways for old and new metabolites through clustering.
    Thiru Siddharth, Nathan E Lewis.
      The diverse metabolic pathways are fundamental to all living organisms, as they harvest energy, synthesize biomass components, produce molecules to interact with the microenvironment, and neutralize toxins. While the discovery of new metabolites and pathways continues, the prediction of pathways for new metabolites can be challenging. It can take vast amounts of time to elucidate pathways for new metabolites; thus, according to HMDB (Human Metabolome Database), only 60% of metabolites get assigned to pathways. Here, we present an approach to identify pathways based on metabolite structure. We extracted 201 features from SMILES annotations and identified new metabolites from PubMed abstracts and HMDB. After applying clustering algorithms to both groups of features, we quantified correlations between metabolites, and found the clusters accurately linked 92% of known metabolites to their respective pathways. Thus, this approach could be valuable for predicting metabolic pathways for new metabolites.
    Keywords:  AdaBoostClassifier; K-mode clustering; K-prototype clustering; Metabolites prediction; Pathways prediction
    DOI:  https://doi.org/10.1016/j.jtbi.2023.111684
  16. Cell Cycle. 2023 Dec 05. 1-19
    The mystery of phospho-Drp1 with four adaptors in cell cycle: when mitochondrial fission couples to cell fate decisions.
    Nian-Siou Wu, I-Chu Ma, Yi-Fan Lin, Huey-Jiun Ko, Joon-Khim Loh, Yi-Ren Hong.
      Recent study had deepened our knowledge of the mitochondrial dynamics to classify mitochondrial fission into two types. To further clarify the relationship between the two distinct fission machinery and the four major adaptors of Drp1, we propose a model of mechanism elucidating the multiple functions of phospho-Drp1 with its adaptors during cell cycle and providing in-depth insights into the molecular basis and evolutionary implications in depth. The model highlights not only the clustering characteristics of different phospho-Drp1 with respective subsets of mitochondrial pro-fission adaptors but also the correlation, crosstalk and shifting between different clustering of phosphorylated Drp1-adaptors during different key fission situations. Particularly, phospho-Drp1 (Ser616) couples with Mff/MiD51 to exert mitochondrial division and phospho-Drp1 (Ser637) couples with MiD49/Fis1 to execute mitophagy in M-phase. We then apply the model to address the relationship of mitochondrial dynamics to Parkinson's disease (PD) and carcinogenesis. Our proposed model is indeed compatible with current research results and pathological observations, providing promising directions for future treatment design.
    Keywords:  Drp1; Mitochondrial Adaptors; cell cycle; mitophagy; phosphorylation
    DOI:  https://doi.org/10.1080/15384101.2023.2289753
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