bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2024–04–07
nineteen papers selected by
Marc Segarra Mondejar, University of Cologne
  1. Hypoxic adaptation of mitochondria and its impact on tumor cell function.
  2. Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.
  3. Context-dependent modification of PFKFB3 in hematopoietic stem cells promotes anaerobic glycolysis and ensures stress hematopoiesis.
  4. Role of mitochondria in renal ischemia-reperfusion injury.
  5. Optical imaging reveals chemotherapy-induced metabolic reprogramming of residual disease and recurrence.
  6. Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.
  7. Endocytic vesicles act as vehicles for glucose uptake in response to growth factor stimulation.
  8. A spatiotemporal proteomic map of human adipogenesis.
  9. The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.
  10. Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice.
  11. Chronic replication stress invokes mitochondria dysfunction via impaired parkin activity.
  12. PDK1 promotes breast cancer progression by enhancing the stability and transcriptional activity of HIF-1α.
  13. Glucose controls lipolysis through Golgi PtdIns4P-mediated regulation of ATGL.
  14. Futile cycles: Emerging utility from apparent futility.
  15. Membrane fission via transmembrane contact.
  16. Renal Glutathione: Dual roles as antioxidant protector and bioactivation promoter.
  17. Leveraging continuous glucose monitoring for personalized modeling of insulin-regulated glucose metabolism.
  18. The Roles of CircRNAs in Mitochondria.
  19. Using an ER-specific optogenetic mechanostimulator to understand the mechanosensitivity of the endoplasmic reticulum.
  1. Semin Cancer Biol. 2024 Mar 30. pii: S1044-579X(24)00022-1. [Epub ahead of print]100 28-38
    Hypoxic adaptation of mitochondria and its impact on tumor cell function.
    Martin Benej, Ioanna Papandreou, Nicholas C Denko.
      Mitochondria are the major sink for oxygen in the cell, consuming it during ATP production. Therefore, when environmental oxygen levels drop in the tumor, significant adaptation is required. Mitochondrial activity is also a major producer of biosynthetic precursors and a regulator of cellular oxidative and reductive balance. Because of the complex biochemistry, mitochondrial adaptation to hypoxia occurs through multiple mechanisms and has significant impact on other cellular processes such as macromolecule synthesis and gene regulation. In tumor hypoxia, mitochondria shift their location in the cell and accelerate the fission and quality control pathways. Hypoxic mitochondria also undergo significant changes to fundamental metabolic pathways of carbon metabolism and electron transport. These metabolic changes further impact the nuclear epigenome because mitochondrial metabolites are used as enzymatic substrates for modifying chromatin. This coordinated response delivers physiological flexibility and increased tumor cell robustness during the environmental stress of low oxygen.
    Keywords:  Hypoxia; Mitochondria; Oxygen consumption; Reductive stress
    DOI:  https://doi.org/10.1016/j.semcancer.2024.03.004
  2. bioRxiv. 2024 Mar 20. pii: 2024.03.20.586011. [Epub ahead of print]
    Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.
    Anupama Tiwari, Jongyun Myeong, Arsalan Hashemiaghdam, Hao Zhang, Xianfeng Niu, Marissa A Laramie, Marion I Stunault, Jasmin Sponagel, Gary Patti, Leah Shriver, Vitaly Klyachko, Ghazaleh Ashrafi.
      Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep, intense circuit activity, or dietary restrictions, posing significant metabolic stress. Here, we demonstrate that the mammalian brain utilizes pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability within a neuron and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation which in turn modulates mitochondrial pyruvate uptake. Importantly, our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in synaptic transmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval, functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of synaptic transmission in hippocampal terminals.
    HIGHLIGHTS: Serum pyruvate is taken up by the brain and efficiently oxidized in the TCA cycle.The mitochondrial pyruvate carrier (MPC) is essential for presynaptic energy metabolism.Acetylation of the MPC complex modulates mitochondrial pyruvate uptake.MPC activity regulates the release and retrieval of synaptic vesicles in nerve terminals.
    DOI:  https://doi.org/10.1101/2024.03.20.586011
  3. Elife. 2024 Apr 04. pii: RP87674. [Epub ahead of print]12
    Context-dependent modification of PFKFB3 in hematopoietic stem cells promotes anaerobic glycolysis and ensures stress hematopoiesis.
    Shintaro Watanuki, Hiroshi Kobayashi, Yuki Sugiura, Masamichi Yamamoto, Daiki Karigane, Kohei Shiroshita, Yuriko Sorimachi, Shinya Fujita, Takayuki Morikawa, Shuhei Koide, Motohiko Oshima, Akira Nishiyama, Koichi Murakami, Miho Haraguchi, Shinpei Tamaki, Takehiro Yamamoto, Tomohiro Yabushita, Yosuke Tanaka, Go Nagamatsu, Hiroaki Honda, Shinichiro Okamoto, Nobuhito Goda, Tomohiko Tamura, Ayako Nakamura-Ishizu, Makoto Suematsu, Atsushi Iwama, Toshio Suda, Keiyo Takubo.
      Metabolic pathways are plastic and rapidly change in response to stress or perturbation. Current metabolic profiling techniques require lysis of many cells, complicating the tracking of metabolic changes over time after stress in rare cells such as hematopoietic stem cells (HSCs). Here, we aimed to identify the key metabolic enzymes that define differences in glycolytic metabolism between steady-state and stress conditions in murine HSCs and elucidate their regulatory mechanisms. Through quantitative 13C metabolic flux analysis of glucose metabolism using high-sensitivity glucose tracing and mathematical modeling, we found that HSCs activate the glycolytic rate-limiting enzyme phosphofructokinase (PFK) during proliferation and oxidative phosphorylation (OXPHOS) inhibition. Real-time measurement of ATP levels in single HSCs demonstrated that proliferative stress or OXPHOS inhibition led to accelerated glycolysis via increased activity of PFKFB3, the enzyme regulating an allosteric PFK activator, within seconds to meet ATP requirements. Furthermore, varying stresses differentially activated PFKFB3 via PRMT1-dependent methylation during proliferative stress and via AMPK-dependent phosphorylation during OXPHOS inhibition. Overexpression of Pfkfb3 induced HSC proliferation and promoted differentiated cell production, whereas inhibition or loss of Pfkfb3 suppressed them. This study reveals the flexible and multilayered regulation of HSC glycolytic metabolism to sustain hematopoiesis under stress and provides techniques to better understand the physiological metabolism of rare hematopoietic cells.
    Keywords:  PFKFB3; hematioietic stem cell; metabolomics; mouse; regenerative medicine; single-cell atp analysis; stem cell metabolism; stem cells; stress hematopoiesis
    DOI:  https://doi.org/10.7554/eLife.87674
  4. FEBS J. 2024 Apr 03.
    Role of mitochondria in renal ischemia-reperfusion injury.
    Ruizhen Huang, Chiyu Zhang, Zhengjie Xiang, Tao Lin, Jian Ling, Honglin Hu.
      Acute kidney injury (AKI) induced by renal ischemia-reperfusion injury (IRI) has a high morbidity and mortality, representing a worldwide problem. The kidney is an essential organ of metabolism that has high blood perfusion and is the second most mitochondria-rich organ after the heart because of the high ATP demands of its essential functions of nutrient reabsorption, acid-base and electrolyte balance, and hemodynamics. Thus, these energy-intensive cells are particularly vulnerable to mitochondrial dysfunction. As the bulk of glomerular ultrafiltrate reabsorption by proximal tubules occurs via active transport, the mitochondria of proximal tubules must be equipped for detecting and responding to fluctuations in energy availability to guarantee efficient basal metabolism. Any insults to mitochondrial quality control mechanisms may lead to biological disruption, blocking the clearance of damaged mitochondria and resulting in morphological change and tissue dysfunction. Extensive research has shown that mitochondria have pivotal roles in acute kidney disease, so in this article, we discuss the role of mitochondria, their dynamics and mitophagy in renal ischemia-reperfusion injury.
    Keywords:  mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitophagy; renal ischemia–reperfusion injury
    DOI:  https://doi.org/10.1111/febs.17130
  5. Sci Adv. 2024 Apr 05. 10(14): eadj7540
    Optical imaging reveals chemotherapy-induced metabolic reprogramming of residual disease and recurrence.
    Enakshi D Sunassee, Riley J Deutsch, Victoria W D'Agostino, Pol Castellano-Escuder, Elizabeth A Siebeneck, Olga Ilkayeva, Brian T Crouch, Megan C Madonna, Jeffrey Everitt, James V Alvarez, Gregory M Palmer, Matthew D Hirschey, Nirmala Ramanujam.
      Fewer than 20% of triple-negative breast cancer patients experience long-term responses to mainstay chemotherapy. Resistant tumor subpopulations use alternative metabolic pathways to escape therapy, survive, and eventually recur. Here, we show in vivo, longitudinal metabolic reprogramming in residual disease and recurrence of triple-negative breast cancer xenografts with varying sensitivities to the chemotherapeutic drug paclitaxel. Optical imaging coupled with metabolomics reported an increase in non-glucose-driven mitochondrial metabolism and an increase in intratumoral metabolic heterogeneity during regression and residual disease in resistant MDA-MB-231 tumors. Conversely, sensitive HCC-1806 tumors were primarily reliant on glucose uptake and minimal changes in metabolism or heterogeneity were observed over the tumors' therapeutic life cycles. Further, day-matched resistant HCC-1806 tumors revealed a higher reliance on mitochondrial metabolism and elevated metabolic heterogeneity compared to sensitive HCC-1806 tumors. Together, metabolic flexibility, increased reliance on mitochondrial metabolism, and increased metabolic heterogeneity are defining characteristics of persistent residual disease, features that will inform the appropriate type and timing of therapies.
    DOI:  https://doi.org/10.1126/sciadv.adj7540
  6. Sci Adv. 2024 Apr 05. 10(14): eadl0389
    Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.
    Zhenqi Zhou, Alice Ma, Timothy M Moore, Dane M Wolf, Nicole Yang, Peter Tran, Mayuko Segawa, Alexander R Strumwasser, Wenjuan Ren, Kai Fu, Jonathan Wanagat, Alexander M van der Bliek, Rachelle Crosbie-Watson, Marc Liesa, Linsey Stiles, Rebecca Acin-Perez, Sushil Mahata, Orian Shirihai, Mark O Goodarzi, Michal Handzlik, Christian M Metallo, David W Walker, Andrea L Hevener.
      The dynamin-related guanosine triphosphatase, Drp1 (encoded by Dnm1l), plays a central role in mitochondrial fission and is requisite for numerous cellular processes; however, its role in muscle metabolism remains unclear. Here, we show that, among human tissues, the highest number of gene correlations with DNM1L is in skeletal muscle. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and impaired insulin action along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2 normalized complex II activity, lipid oxidation, and insulin action in Drp1-KD myocytes. Drp1 is critical in maintaining mitochondrial complex II assembly, lipid oxidation, and insulin sensitivity, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle metabolism, which is clinically relevant in combatting metabolic-related diseases.
    DOI:  https://doi.org/10.1126/sciadv.adl0389
  7. Nat Commun. 2024 Apr 02. 15(1): 2843
    Endocytic vesicles act as vehicles for glucose uptake in response to growth factor stimulation.
    Ryouhei Tsutsumi, Beatrix Ueberheide, Feng-Xia Liang, Benjamin G Neel, Ryuichi Sakai, Yoshiro Saito.
      Glycolysis is a fundamental cellular process, yet its regulatory mechanisms remain incompletely understood. Here, we show that a subset of glucose transporter 1 (GLUT1/SLC2A1) co-endocytoses with platelet-derived growth factor (PDGF) receptor (PDGFR) upon PDGF-stimulation. Furthermore, multiple glycolytic enzymes localize to these endocytosed PDGFR/GLUT1-containing vesicles adjacent to mitochondria. Contrary to current models, which emphasize the importance of glucose transporters on the cell surface, we find that PDGF-stimulated glucose uptake depends on receptor/transporter endocytosis. Our results suggest that growth factors generate glucose-loaded endocytic vesicles that deliver glucose to the glycolytic machinery in proximity to mitochondria, and argue for a new layer of regulation for glycolytic control governed by cellular membrane dynamics.
    DOI:  https://doi.org/10.1038/s41467-024-46971-9
  8. Nat Metab. 2024 Apr 02.
    A spatiotemporal proteomic map of human adipogenesis.
    Felix Klingelhuber, Scott Frendo-Cumbo, Muhmmad Omar-Hmeadi, Lucas Massier, Pamela Kakimoto, Austin J Taylor, Morgane Couchet, Sara Ribicic, Martin Wabitsch, Ana C Messias, Arcangela Iuso, Timo D Müller, Mikael Rydén, Niklas Mejhert, Natalie Krahmer.
      White adipocytes function as major energy reservoirs in humans by storing substantial amounts of triglycerides, and their dysfunction is associated with metabolic disorders; however, the mechanisms underlying cellular specialization during adipogenesis remain unknown. Here, we generate a spatiotemporal proteomic atlas of human adipogenesis, which elucidates cellular remodelling as well as the spatial reorganization of metabolic pathways to optimize cells for lipid accumulation and highlights the coordinated regulation of protein localization and abundance during adipocyte formation. We identify compartment-specific regulation of protein levels and localization changes of metabolic enzymes to reprogramme branched-chain amino acids and one-carbon metabolism to provide building blocks and reduction equivalents. Additionally, we identify C19orf12 as a differentiation-induced adipocyte lipid droplet protein that interacts with the translocase of the outer membrane complex of lipid droplet-associated mitochondria and regulates adipocyte lipid storage by determining the capacity of mitochondria to metabolize fatty acids. Overall, our study provides a comprehensive resource for understanding human adipogenesis and for future discoveries in the field.
    DOI:  https://doi.org/10.1038/s42255-024-01025-8
  9. EMBO Rep. 2024 Apr 02.
    The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.
    Christian Koch, Svenja Lenhard, Markus Räschle, Cristina Prescianotto-Baschong, Anne Spang, Johannes M Herrmann.
      Most mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria in a post-translational reaction. Mitochondrial precursor proteins which use the ER-SURF pathway employ the surface of the endoplasmic reticulum (ER) as an important sorting platform. How they reach the mitochondrial import machinery from the ER is not known. Here we show that mitochondrial contact sites play a crucial role in the ER-to-mitochondria transfer of precursor proteins. The ER mitochondria encounter structure (ERMES) and Tom70, together with Djp1 and Lam6, are part of two parallel and partially redundant ER-to-mitochondria delivery routes. When ER-to-mitochondria transfer is prevented by loss of these two contact sites, many precursors of mitochondrial inner membrane proteins are left stranded on the ER membrane, resulting in mitochondrial dysfunction. Our observations support an active role of the ER in mitochondrial protein biogenesis.
    Keywords:  Contact sites; ERMES; Endoplasmic reticulum; Mitochondria; Protein import
    DOI:  https://doi.org/10.1038/s44319-024-00113-w
  10. PNAS Nexus. 2024 Apr;3(4): pgae116
    Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice.
    Darren J Walsh, David J Bernard, Joanna L Fiddler, Faith Pangilinan, Madison Esposito, Denise Harold, Martha S Field, Anne Parle-McDermott, Lawrence C Brody.
      One-carbon metabolism is a complex network of metabolic reactions that are essential for cellular function including DNA synthesis. Vitamin B12 and folate are micronutrients that are utilized in this pathway and their deficiency can result in the perturbation of one-carbon metabolism and subsequent perturbations in DNA replication and repair. This effect has been well characterized in nuclear DNA but to date, mitochondrial DNA (mtDNA) has not been investigated extensively. Mitochondrial variants have been associated with several inherited and age-related disease states; therefore, the study of factors that impact heteroplasmy are important for advancing our understanding of the mitochondrial genome's impact on human health. Heteroplasmy studies require robust and efficient mitochondrial DNA enrichment to carry out in-depth mtDNA sequencing. Many of the current methods for mtDNA enrichment can introduce biases and false-positive results. Here, we use a method that overcomes these limitations and have applied it to assess mitochondrial heteroplasmy in mouse models of altered one-carbon metabolism. Vitamin B12 deficiency was found to cause increased levels of mitochondrial DNA heteroplasmy across all tissues that were investigated. Folic acid supplementation also contributed to elevated mitochondrial DNA heteroplasmy across all mouse tissues investigated. Heteroplasmy analysis of human data from the Framingham Heart Study suggested a potential sex-specific effect of folate and vitamin B12 status on mitochondrial heteroplasmy. This is a novel relationship that may have broader consequences for our understanding of one-carbon metabolism, mitochondrial-related disease and the influence of nutrients on DNA mutation rates.
    Keywords:  cobalamin; folic acid; heteroplasmy; mitochondria; vitamin B12
    DOI:  https://doi.org/10.1093/pnasnexus/pgae116
  11. Sci Rep. 2024 Apr 03. 14(1): 7877
    Chronic replication stress invokes mitochondria dysfunction via impaired parkin activity.
    Tsuyoshi Kawabata, Reiko Sekiya, Shinji Goto, Tao-Sheng Li.
      Replication stress is a major contributor to tumorigenesis because it provides a source of chromosomal rearrangements via recombination events. PARK2, which encodes parkin, a regulator of mitochondrial homeostasis, is located on one of the common fragile sites that are prone to rearrangement by replication stress, indicating that replication stress may potentially impact mitochondrial homeostasis. Here, we show that chronic low-dose replication stress causes a fixed reduction in parkin expression, which is associated with mitochondrial dysfunction, indicated by an increase in mtROS. Consistent with the major role of parkin in mitophagy, reduction in parkin protein expression was associated with a slight decrease in mitophagy and changes in mitochondrial morphology. In contrast, cells expressing ectopic PARK2 gene does not show mtROS increases and changes in mitochondrial morphology even after exposure to chronic replication stress, suggesting that intrinsic fragility at PARK2 loci associated with parkin reduction is responsible for mitochondrial dysfunction caused by chronic replication stress. As endogenous replication stress and mitochondrial dysfunction are both involved in multiple pathophysiology, our data support the therapeutic development of recovery of parkin expression in human healthcare.
    DOI:  https://doi.org/10.1038/s41598-024-58656-w
  12. Genes Dis. 2024 Jul;11(4): 101041
    PDK1 promotes breast cancer progression by enhancing the stability and transcriptional activity of HIF-1α.
    Yu Wei, Dian Zhang, He Shi, Husun Qian, Hongling Chen, Qian Zeng, Fangfang Jin, Yan Ye, Zuli Ou, Minkang Guo, Bianqin Guo, Tingmei Chen.
      Pyruvate dehydrogenase kinase 1 (PDK1) phosphorylates the pyruvate dehydrogenase complex, which inhibits its activity. Inhibiting pyruvate dehydrogenase complex inhibits the tricarboxylic acid cycle and the reprogramming of tumor cell metabolism to glycolysis, which plays an important role in tumor progression. This study aims to elucidate how PDK1 promotes breast cancer progression. We found that PDK1 was highly expressed in breast cancer tissues, and PDK1 knockdown reduced the proliferation, migration, and tumorigenicity of breast cancer cells and inhibited the HIF-1α (hypoxia-inducible factor 1α) pathway. Further investigation showed that PDK1 promoted the protein stability of HIF-1α by reducing the level of ubiquitination of HIF-1α. The HIF-1α protein levels were dependent on PDK1 kinase activity. Furthermore, HIF-1α phosphorylation at serine 451 was detected in wild-type breast cancer cells but not in PDK1 knockout breast cancer cells. The phosphorylation of HIF-1α at Ser 451 stabilized its protein levels by inhibiting the interaction of HIF-1α with von Hippel-Lindau and prolyl hydroxylase domain. We also found that PDK1 enhanced HIF-1α transcriptional activity. In summary, PDK1 enhances HIF-1α protein stability by phosphorylating HIF-1α at Ser451 and promotes HIF-1α transcriptional activity by enhancing the binding of HIF-1α to P300. PDK1 and HIF-1α form a positive feedback loop to promote breast cancer progression.
    Keywords:  Breast cancer; HIF-1α; PDK1; Protein phosphorylation; Transcriptional activity
    DOI:  https://doi.org/10.1016/j.gendis.2023.06.013
  13. Nat Cell Biol. 2024 Apr 01.
    Glucose controls lipolysis through Golgi PtdIns4P-mediated regulation of ATGL.
    Lianggong Ding, Florian Huwyler, Fen Long, Wu Yang, Jonas Binz, Kendra Wernlé, Matthias Pfister, Manuel Klug, Miroslav Balaz, Barbara Ukropcova, Jozef Ukropec, Chunyan Wu, Tongtong Wang, Min Gao, Pierre-Alain Clavien, Philipp Dutkowski, Mark W Tibbitt, Christian Wolfrum.
      Metabolic crosstalk of the major nutrients glucose, amino acids and fatty acids (FAs) ensures systemic metabolic homeostasis. The coordination between the supply of glucose and FAs to meet various physiological demands is especially important as improper nutrient levels lead to metabolic disorders, such as diabetes and metabolic dysfunction-associated steatohepatitis (MASH). In response to the oscillations in blood glucose levels, lipolysis is thought to be mainly regulated hormonally to control FA liberation from lipid droplets by insulin, catecholamine and glucagon. However, whether general cell-intrinsic mechanisms exist to directly modulate lipolysis via glucose sensing remains largely unknown. Here we report the identification of such an intrinsic mechanism, which involves Golgi PtdIns4P-mediated regulation of adipose triglyceride lipase (ATGL)-driven lipolysis via intracellular glucose sensing. Mechanistically, depletion of intracellular glucose results in lower Golgi PtdIns4P levels, and thus reduced assembly of the E3 ligase complex CUL7FBXW8 in the Golgi apparatus. Decreased levels of the E3 ligase complex lead to reduced polyubiquitylation of ATGL in the Golgi and enhancement of ATGL-driven lipolysis. This cell-intrinsic mechanism regulates both the pool of intracellular FAs and their extracellular release to meet physiological demands during fasting and glucose deprivation. Moreover, genetic and pharmacological manipulation of the Golgi PtdIns4P-CUL7FBXW8-ATGL axis in mouse models of simple hepatic steatosis and MASH, as well as during ex vivo perfusion of a human steatotic liver graft leads to the amelioration of steatosis, suggesting that this pathway might be a promising target for metabolic dysfunction-associated steatotic liver disease and possibly MASH.
    DOI:  https://doi.org/10.1038/s41556-024-01386-y
  14. Cell Metab. 2024 Mar 27. pii: S1550-4131(24)00087-1. [Epub ahead of print]
    Futile cycles: Emerging utility from apparent futility.
    Anand Kumar Sharma, Radhika Khandelwal, Christian Wolfrum.
      Futile cycles are biological phenomena where two opposing biochemical reactions run simultaneously, resulting in a net energy loss without appreciable productivity. Such a state was presumed to be a biological aberration and thus deemed an energy-wasting "futile" cycle. However, multiple pieces of evidence suggest that biological utilities emerge from futile cycles. A few established functions of futile cycles are to control metabolic sensitivity, modulate energy homeostasis, and drive adaptive thermogenesis. Yet, the physiological regulation, implication, and pathological relevance of most futile cycles remain poorly studied. In this review, we highlight the abundance and versatility of futile cycles and propose a classification scheme. We further discuss the energetic implications of various futile cycles and their impact on basal metabolic rate, their bona fide and tentative pathophysiological implications, and putative drug interactions.
    Keywords:  BMR; energy expenditure; futile calcium cycling; futile creatine cycle; futile cycle; futile lipid cycle; obesity; uncoupler
    DOI:  https://doi.org/10.1016/j.cmet.2024.03.008
  15. Nat Commun. 2024 Mar 30. 15(1): 2793
    Membrane fission via transmembrane contact.
    Russell K W Spencer, Isaac Santos-Pérez, Izaro Rodríguez-Renovales, Juan Manuel Martinez Galvez, Anna V Shnyrova, Marcus Müller.
      Division of intracellular organelles often correlates with additional membrane wrapping, e.g., by the endoplasmic reticulum or the outer mitochondrial membrane. Such wrapping plays a vital role in proteome and lipidome organization. However, how an extra membrane impacts the mechanics of the division has not been investigated. Here we combine fluorescence and cryo-electron microscopy experiments with self-consistent field theory to explore the stress-induced instabilities imposed by membrane wrapping in a simple double-membrane tubular system. We find that, at physiologically relevant conditions, the outer membrane facilitates an alternative pathway for the inner-tube fission through the formation of a transient contact (hemi-fusion) between both membranes. A detailed molecular theory of the fission pathways in the double membrane system reveals the topological complexity of the process, resulting both in leaky and leakless intermediates, with energies and topologies predicting physiological events.
    DOI:  https://doi.org/10.1038/s41467-024-47122-w
  16. Biochem Pharmacol. 2024 Mar 29. pii: S0006-2952(24)00164-3. [Epub ahead of print] 116181
    Renal Glutathione: Dual roles as antioxidant protector and bioactivation promoter.
    Lawrence H Lash.
      The tripeptide glutathione (GSH) possesses two key structural features, namely the nucleophilic sulfur and the γ-glutamyl isopeptide bond. The former allows GSH to serve as a critical antioxidant and anti-electrophile. The latter allows GSH to translocate throughout the systemic circulation without being degraded. The kidneys exhibit several unique processes for handling GSH. This includes the extraction of 80% of plasma GSH, in part by glomerular filtration but mostly by transport across the basolateral plasma membrane. Studies on the protective effect of exogenous GSH are summarized, showing the different inherent susceptibility of proximal tubular and distal tubular cells and the impact on pathological or disease states, including hypoxia, diabetic nephropathy, and compensatory renal growth associated with uninephrectomy. Studies on mitochondrial GSH transport show the coordination between the citric acid cycle and oxidative phosphorylation in generating driving forces for both plasma membrane and mitochondrial carriers. The strong protective effects of increasing expression and activity of these carriers against oxidants and mitochondrial toxicants are summarized. Although GSH plays a cytoprotective role in most situations, two distinct exceptions to this are presented. In contrast to expectations, overexpression of the mitochondrial 2-oxoglutarate carrier markedly increased cell death from exposure to the nephrotoxic chemotherapeutic drug cisplatin (CDDP). Another key example of GSH serving a bioactivation role in the kidneys, rather than a detoxification role, is the metabolism of halogenated alkenes such as trichloroethylene (TCE). Although considerable research has gone into this topic, unanswered questions and emerging topics remain and are discussed.
    Keywords:  Antioxidant; Bioactivation; Glutathione; Kidney; Membrane transport; Trichloroethylene
    DOI:  https://doi.org/10.1016/j.bcp.2024.116181
  17. Sci Rep. 2024 Apr 05. 14(1): 8037
    Leveraging continuous glucose monitoring for personalized modeling of insulin-regulated glucose metabolism.
    Balázs Erdős, Shauna D O'Donovan, Michiel E Adriaens, Anouk Gijbels, Inez Trouwborst, Kelly M Jardon, Gijs H Goossens, Lydia A Afman, Ellen E Blaak, Natal A W van Riel, Ilja C W Arts.
      Continuous glucose monitoring (CGM) is a promising, minimally invasive alternative to plasma glucose measurements for calibrating physiology-based mathematical models of insulin-regulated glucose metabolism, reducing the reliance on in-clinic measurements. However, the use of CGM glucose, particularly in combination with insulin measurements, to develop personalized models of glucose regulation remains unexplored. Here, we simultaneously measured interstitial glucose concentrations using CGM as well as plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT) in individuals with overweight or obesity to calibrate personalized models of glucose-insulin dynamics. We compared the use of interstitial glucose with plasma glucose in model calibration, and evaluated the effects on model fit, identifiability, and model parameters' association with clinically relevant metabolic indicators. Models calibrated on both plasma and interstitial glucose resulted in good model fit, and the parameter estimates associated with metabolic indicators such as insulin sensitivity measures in both cases. Moreover, practical identifiability of model parameters was improved in models estimated on CGM glucose compared to plasma glucose. Together these results suggest that CGM glucose may be considered as a minimally invasive alternative to plasma glucose measurements in model calibration to quantify the dynamics of glucose regulation.
    DOI:  https://doi.org/10.1038/s41598-024-58703-6
  18. J Cancer. 2024 ;15(9): 2759-2769
    The Roles of CircRNAs in Mitochondria.
    Donghong Liu, Xinyu Zhou, Yida He, Jun Zhao.
      Mitochondria participate in varieties of cellular events. It is widely accepted that human mitochondrial genome encodes 13 proteins, 2 rRNAs, and 22 tRNAs. Gene variation derived from human nuclear genome cannot completely explain mitochondrial diseases. The advent of high-throughput sequencing coupled with novel bioinformatic analyses decode the complexity of mitochondria-derived transcripts. Recently, circular RNAs (circRNAs) from both human mitochondrial genome and nuclear genome have been found to be located at mitochondria. Studies about the roles and molecular mechanisms underlying trafficking of the nucleus encoded circRNAs to mitochondria and mitochondria encoded circRNAs to the nucleus or cytoplasm in mammals are only beginning to emerge. These circRNAs have been associated with a variety of diseases, especially cancers. Here, we discuss the emerging field of mitochondria-located circRNAs by reviewing their identification, expression patterns, regulatory roles, and functional mechanisms. Mitochondria-located circRNAs have regulatory roles in cellular physiology and pathology. We also highlight future perspectives and challenges in studying mitochondria-located circRNAs, as well as their potential biomedical applications.
    Keywords:  circular RNAs; mitochondria; mitochondrial genome; noncoding RNAs; nuclear genome
    DOI:  https://doi.org/10.7150/jca.92111
  19. Dev Cell. 2024 Apr 01. pii: S1534-5807(24)00180-1. [Epub ahead of print]
    Using an ER-specific optogenetic mechanostimulator to understand the mechanosensitivity of the endoplasmic reticulum.
    Yutong Song, Zhihao Zhao, Linyu Xu, Peiyuan Huang, Jiayang Gao, Jingxuan Li, Xuejie Wang, Yiren Zhou, Jinhui Wang, Wenting Zhao, Likun Wang, Chaogu Zheng, Bo Gao, Liwen Jiang, Kai Liu, Yusong Guo, Xiaoqiang Yao, Liting Duan.
      The ability of cells to perceive and respond to mechanical cues is essential for numerous biological activities. Emerging evidence indicates important contributions of organelles to cellular mechanosensitivity and mechanotransduction. However, whether and how the endoplasmic reticulum (ER) senses and reacts to mechanical forces remains elusive. To fill the knowledge gap, after developing a light-inducible ER-specific mechanostimulator (LIMER), we identify that mechanostimulation of ER elicits a transient, rapid efflux of Ca2+ from ER in monkey kidney COS-7 cells, which is dependent on the cation channels transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and polycystin-2 (PKD2) in an additive manner. This ER Ca2+ release can be repeatedly stimulated and tuned by varying the intensity and duration of force application. Moreover, ER-specific mechanostimulation inhibits ER-to-Golgi trafficking. Sustained mechanostimuli increase the levels of binding-immunoglobulin protein (BiP) expression and phosphorylated eIF2α, two markers for ER stress. Our results provide direct evidence for ER mechanosensitivity and tight mechanoregulation of ER functions, placing ER as an important player on the intricate map of cellular mechanotransduction.
    Keywords:  ER Ca(2+) signaling; ER mechanostimulator; ER stress; ER-Golgi transport; light-gated hetero-dimerization; optical dimerizer; optogenetics; organelle mechanobiology
    DOI:  https://doi.org/10.1016/j.devcel.2024.03.014
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