bims-celmim 2023-09-10 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2023–09–10
thirty-one papers selected by
Marc Segarra Mondejar, University of Cologne

2-Deoxy-d-ribose induces ferroptosis in renal tubular epithelial cells via ubiquitin-proteasome system-mediated xCT protein degradation.
Enhanced mitochondrial buffering prevents Ca2+ overload in naked mole-rat brain.
PTEN activates chaperone-mediated autophagy to regulate metabolism.
Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation.
Inhibition of mitochondrial fatty acid β-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of raptor in zebrafish.
Loss of Ptpmt1 limits mitochondrial utilization of carbohydrates and leads to muscle atrophy and heart failure in tissue-specific knockout mice.
Caspase-mediated nuclear pore complex trimming in cell differentiation and endoplasmic reticulum stress.
Glycolytic Metabolon Assembly on Mitochondria via Hexokinase O-GlcNAcylation Promotes Metabolic Efficiency.
Local and dynamic regulation of neuronal glycolysis in vivo.
Enhanced presynaptic mitochondrial energy production is required for memory formation.
Inhibition of ACSL4 ameliorates tubular ferroptotic cell death and protects against fibrotic kidney disease.
Brain-derived neurotrophic factor protects neurons by stimulating mitochondrial function through protein kinase A.
Differential intracellular management of fatty acids impacts on metabolic stress-stimulated glucose uptake in cardiomyocytes.
Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus.
Exploring a new mechanism between lactate and VSMC calcification: PARP1/POLG/UCP2 signaling pathway and imbalance of mitochondrial homeostasis.
CLPX regulates mitochondrial fatty acid β-oxidation in liver cells.
Role of STIM1 in the Regulation of Cardiac Energy Substrate Preference.
Lactate Metabolism, Signaling, and Function in Brain Development, Synaptic Plasticity, Angiogenesis, and Neurodegenerative Diseases.
Research progress of ferroptosis in Alzheimer disease: A review.
GLUT5: structure, functions, diseases and potential applications.
Mitochondrial Factors in the Cell Nucleus.
Potential benefits of medium chain fatty acids in aging and neurodegenerative disease.
Lipid and glucose metabolism in senescence.
Mitochondrial Properties in Skeletal Muscle Fiber.
Emerging role of metabolic reprogramming in hyperoxia-associated neonatal diseases.
Mitochondrial dynamics in health and disease: mechanisms and potential targets.
Biofactors regulating mitochondrial function and dynamics in podocytes and podocytopathies.
Cardiac Metabolism, Reprogramming, and Diseases.
Serine-associated one-carbon metabolic reprogramming: a new anti-cancer therapeutic strategy.
Autophagy/ferroptosis in colorectal cancer: Carcinogenic view and nanoparticle-mediated cell death regulation.
Metabolic control by AMPK in white adipose tissue.

Free Radic Biol Med. 2023 Sep 01. pii: S0891-5849(23)00607-X. [Epub ahead of print]208 384-393

2-Deoxy-d-ribose induces ferroptosis in renal tubular epithelial cells via ubiquitin-proteasome system-mediated xCT protein degradation.

Miyeon Kim, Ju Young Bae, Soyeon Yoo, Hyun Woo Kim, Sang Ah Lee, Eui Tae Kim, Gwanpyo Koh.

  Ferroptosis is a novel form of cell death triggered by iron-dependent lipid peroxidation. Recent findings suggest that inhibiting system χc-induces ferroptosis by reducing intracellular cystine levels, and that ferroptosis in renal tubular epithelial cells (RTECs) contributes to acute kidney injury (AKI) and diabetic nephropathy. Moreover, 2-deoxy-d-ribose (dRib) has been shown to inhibit cystine uptake through xCT, the functional unit of system χc-, in β-cells. This study aimed to investigate if dRib induces ferroptosis in RTECs and identify the underlying mechanisms. dRib treatment reduced cystine uptake and glutathione (GSH) content, and increased intracellular levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), lipid reactive oxygen species (ROS), and cell death in both NRK-52E cells and primary cultured RTECs. However, treatment with inhibitors of ferroptosis, such as deferoxamine (DFO), ferrostatin-1 (Fer-1), and liproxstatin-1 (Lip-1), counteracted the effects of dRib on GSH, MDA, 4-HNE, and lipid ROS levels, as well as cell death. Additionally, 2-mercaptoethanol (2-ME) treatment or xCT gene overexpression protected against dRib-induced changes. Moreover, transmission electron microscopy revealed dRib-induced mitochondrial shrinkage, decrease in cristae number, and outer membrane rupture. Furthermore, dRib treatment upregulated the expression of genes associated with ferroptosis, and downregulated xCT protein expression. The decrease in xCT protein caused by dRib was consistently observed even when treated with the protein synthesis inhibitor cycloheximide. However, treatment with the proteasome inhibitor MG132 reversed the dRib-induced decrease in xCT protein expression. Additionally, dRib increased xCT protein ubiquitination. Overall, dRib induces ferroptosis in RTECs by degrading xCT protein through ubiquitin-proteasome system (UPS), resulting in reduced intracellular cystine uptake. Therefore, targeting the regulation of system χc-through UPS could be a potential therapeutic approach for AKI and diabetic nephropathy.

Keywords:  2-Deoxy-d-ribose; Ferroptosis; Renal tubular epithelial cells; System χc-; Ubiquitin-proteasome system

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.08.027
J Physiol. 2023 Sep 05.

Enhanced mitochondrial buffering prevents Ca2+ overload in naked mole-rat brain.

Hang Cheng, Guy A Perkins, Saeyeon Ju, Keunyoung Kim, Mark H Ellisman, Matthew E Pamenter.

  Deleterious Ca2+ accumulation is central to hypoxic cell death in the brain of most mammals. Conversely, hypoxia-mediated increases in cytosolic Ca2+ are retarded in hypoxia-tolerant naked mole-rat brain. We hypothesized that naked mole-rat brain mitochondria have an enhanced capacity to buffer exogenous Ca2+ and examined Ca2+ handling in naked mole-rat cortical tissue. We report that naked mole-rat brain mitochondria buffer >2-fold more exogenous Ca2+ than mouse brain mitochondria, and that the half-maximal inhibitory concentration (IC50 ) at which Ca2+ inhibits aerobic oxidative phosphorylation is >2-fold higher in naked mole-rat brain. The primary driving force of Ca2+ uptake is the mitochondrial membrane potential (Δψm ), and the IC50 at which Ca2+ decreases Δψm is ∼4-fold higher in naked mole-rat than mouse brain. The ability of naked mole-rat brain mitochondria to safely retain large volumes of Ca2+ may be due to ultrastructural differences that support the uptake and physical storage of Ca2+ in mitochondria. Specifically, and relative to mouse brain, naked mole-rat brain mitochondria are larger and have higher crista density and increased physical interactions between adjacent mitochondrial membranes, all of which are associated with improved energetic homeostasis and Ca2+ management. We propose that excessive Ca2+ influx into naked mole-rat brain is buffered by physical storage in large mitochondria, which would reduce deleterious Ca2+ overload and may thus contribute to the hypoxia and ischaemia-tolerance of naked mole-rat brain. KEY POINTS: Unregulated Ca2+ influx is a hallmark of hypoxic brain death; however, hypoxia-mediated Ca2+ influx into naked mole-rat brain is markedly reduced relative to mice. This is important because naked mole-rat brain is robustly tolerant against in vitro hypoxia, and because Ca2+ is a key driver of hypoxic cell death in brain. We show that in hypoxic naked mole-rat brain, oxidative capacity and mitochondrial membrane integrity are better preserved following exogenous Ca2+ stress. This is due to mitochondrial buffering of exogenous Ca2+ and is driven by a mitochondrial membrane potential-dependant mechanism. The unique ultrastructure of naked mole-rat brain mitochondria, as a large physical storage space, may support increased Ca2+ buffering and thus hypoxia-tolerance.

Keywords:  electron transport system; membrane potential; mitochondrial permeability transition pore; oxidative phosphorylation

DOI:  https://doi.org/10.1113/JP285002
Autophagy. 2023 Sep 08. 1-2

PTEN activates chaperone-mediated autophagy to regulate metabolism.

S Joseph Endicott, Richard A Miller.

  PTEN is a negative modulator of the INS-PI3K-AKT pathway and is an essential regulator of metabolism and cell growth. PTEN is one of the most commonly mutated tumor suppressors in cancer. However, PTEN overexpression extends the lifespan of both sexes of mice. We recently showed that PTEN is necessary and sufficient to activate chaperone-mediated autophagy (CMA) in the mouse liver and cultured cells. Selective protein degradation via CMA is required to suppress glycolysis and fatty acid synthesis when PTEN is overexpressed. Thus, activation of CMA downstream of PTEN might modulate health and metabolism through selective degradation of key metabolic enzymes.

Keywords:  Aging; PTEN; autophagy; chaperone-mediated autophagy; metabolism

DOI:  https://doi.org/10.1080/15548627.2023.2255966
Cell Discov. 2023 Sep 07. 9(1): 92

Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation.

Terytty Yang Li, Qi Wang, Arwen W Gao, Xiaoxu Li, Yu Sun, Adrienne Mottis, Minho Shong, Johan Auwerx.

Lysosomes are central platforms for not only the degradation of macromolecules but also the integration of multiple signaling pathways. However, whether and how lysosomes mediate the mitochondrial stress response (MSR) remain largely unknown. Here, we demonstrate that lysosomal acidification via the vacuolar H+-ATPase (v-ATPase) is essential for the transcriptional activation of the mitochondrial unfolded protein response (UPRmt). Mitochondrial stress stimulates v-ATPase-mediated lysosomal activation of the mechanistic target of rapamycin complex 1 (mTORC1), which then directly phosphorylates the MSR transcription factor, activating transcription factor 4 (ATF4). Disruption of mTORC1-dependent ATF4 phosphorylation blocks the UPRmt, but not other similar stress responses, such as the UPRER. Finally, ATF4 phosphorylation downstream of the v-ATPase/mTORC1 signaling is indispensable for sustaining mitochondrial redox homeostasis and protecting cells from ROS-associated cell death upon mitochondrial stress. Thus, v-ATPase/mTORC1-mediated ATF4 phosphorylation via lysosomes links mitochondrial stress to UPRmt activation and mitochondrial function resilience.

DOI: https://doi.org/10.1038/s41421-023-00589-1
J Biol Chem. 2023 Sep 01. pii: S0021-9258(23)02248-2. [Epub ahead of print] 105220

Inhibition of mitochondrial fatty acid β-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of raptor in zebrafish.

Wen-Hao Zhou, Yuan Luo, Rui-Xin Li, Pascal Degrace, Tony Jourdan, Fang Qiao, Li-Qiao Chen, Mei-Ling Zhang, Zhen-Yu Du.

  Pharmacological inhibition of mitochondrial fatty acid oxidation (FAO) has been clinically used to alleviate certain metabolic diseases by remodeling cellular metabolism. However, mitochondrial FAO inhibition also leads to mTORC1 activation-related protein synthesis and tissue hypertrophy, but the mechanism remains unclear. Here, by using a mitochondrial FAO inhibitor (Mildronate or Etomoxir) or knocking out carnitine palmitoyltransferase-1, we revealed that mitochondrial FAO inhibition activated the mTORC1 pathway through Gcn5-dependent Raptor acetylation. Mitochondrial FAO inhibition significantly promoted glucose catabolism and increased intracellular acetyl-CoA levels. In response to the increased intracellular acetyl-CoA, acetyltransferase Gcn5 activated mTORC1 by catalyzing Raptor acetylation through direct interaction. Further investigation also screened Raptor deacetylases HDAC class II and identified HDAC7 as a potential regulator of Raptor. These results provide a possible mechanistic explanation for the mTORC1 activation after mitochondrial FAO inhibition and also bring light to reveal the roles of nutrient metabolic remodeling in regulating protein acetylation by affecting acetyl-CoA production.

Keywords:  Gcn5; Raptor; acetyl-CoA; mTORC1; mitochondrial FAO inhibition

DOI:  https://doi.org/10.1016/j.jbc.2023.105220
Elife. 2023 Sep 06. pii: RP86944. [Epub ahead of print]12

Loss of Ptpmt1 limits mitochondrial utilization of carbohydrates and leads to muscle atrophy and heart failure in tissue-specific knockout mice.

Hong Zheng, Qianjin Li, Shanhu Li, Zhiguo Li, Marco Brotto, Daiana Weiss, Domenick Prosdocimo, Chunhui Xu, Ashruth Reddy, Michelle Puchowicz, Xinyang Zhao, M Neale Weitzmann, Mukesh K Jain, Cheng-Kui Qu.

  While mitochondria in different tissues have distinct preferences for energy sources, they are flexible in utilizing competing substrates for metabolism according to physiological and nutritional circumstances. However, the regulatory mechanisms and significance of metabolic flexibility are not completely understood. Here, we report that the deletion of Ptpmt1, a mitochondria-based phosphatase, critically alters mitochondrial fuel selection - the utilization of pyruvate, a key mitochondrial substrate derived from glucose (the major simple carbohydrate), is inhibited, whereas the fatty acid utilization is enhanced. Ptpmt1 knockout does not impact the development of the skeletal muscle or heart. However, the metabolic inflexibility ultimately leads to muscular atrophy, heart failure, and sudden death. Mechanistic analyses reveal that the prolonged substrate shift from carbohydrates to lipids causes oxidative stress and mitochondrial destruction, which in turn results in marked accumulation of lipids and profound damage in the knockout muscle cells and cardiomyocytes. Interestingly, Ptpmt1 deletion from the liver or adipose tissue does not generate any local or systemic defects. These findings suggest that Ptpmt1 plays an important role in maintaining mitochondrial flexibility and that their balanced utilization of carbohydrates and lipids is essential for both the skeletal muscle and the heart despite the two tissues having different preferred energy sources.

Keywords:  Ptpmt1; bioenergetics; heart; medicine; mitochondria; mouse; skeletal muscle

DOI:  https://doi.org/10.7554/eLife.86944
Elife. 2023 09 04. pii: RP89066. [Epub ahead of print]12

Caspase-mediated nuclear pore complex trimming in cell differentiation and endoplasmic reticulum stress.

Ukrae H Cho, Martin W Hetzer.

  During apoptosis, caspases degrade 8 out of ~30 nucleoporins to irreversibly demolish the nuclear pore complex. However, for poorly understood reasons, caspases are also activated during cell differentiation. Here, we show that sublethal activation of caspases during myogenesis results in the transient proteolysis of four peripheral Nups and one transmembrane Nup. 'Trimmed' NPCs become nuclear export-defective, and we identified in an unbiased manner several classes of cytoplasmic, plasma membrane, and mitochondrial proteins that rapidly accumulate in the nucleus. NPC trimming by non-apoptotic caspases was also observed in neurogenesis and endoplasmic reticulum stress. Our results suggest that caspases can reversibly modulate nuclear transport activity, which allows them to function as agents of cell differentiation and adaptation at sublethal levels.

Keywords:  caspase; cell biology; cell differentiation; developmental biology; mouse; nuclear pore complex

DOI:  https://doi.org/10.7554/eLife.89066
bioRxiv. 2023 Aug 26. pii: 2023.08.26.554955. [Epub ahead of print]

Glycolytic Metabolon Assembly on Mitochondria via Hexokinase O-GlcNAcylation Promotes Metabolic Efficiency.

Haoming Wang, John Vant, Youjun Wu, Richard Sánchez, Mary Lauren Micou, Andrew Zhang, Vincent Luczak, Seungyoon Blenda Yu, Mirna Jabbo, Seokjun Yoon, Ahmed Abdallah Abushawish, Majid Ghassemian, Eric Griffis, Marc Hammarlund, Abhishek Singharoy, Gulcin Pekkurnaz.

Glucose is the primary cellular energy substrate and its metabolism via glycolysis is initiated by the rate-limiting enzyme Hexokinase (HK). In energy-demanding tissues like the brain, HK1 is the prominent isoform, primarily localized on mitochondria, crucial for the efficient coupling of glycolysis and oxidative phosphorylation, thereby ensuring optimal energy generation. Here, we reveal a novel regulatory mechanism whereby metabolic sensor enzyme O-GlcNAc transferase (OGT) modulates HK1 activity and its mitochondrial association. OGT catalyzes reversible O-GlcNAcylation, a post-translational modification, influenced by glucose flux-mediated intracellular UDP-GlcNAc concentrations. Dynamic O-GlcNAcylation of HK1's regulatory domain occurs with increased OGT activity, promoting glycolytic metabolon assembly on the outer mitochondrial membrane. This modification enhances HK1's mitochondrial localization, orchestrating glycolytic and mitochondrial ATP production. Mutations in HK1's O-GlcNAcylation site reduce ATP generation, affecting presynaptic vesicle release in neurons. Our findings reveal a new pathway linking neuronal metabolism to mitochondrial function through OGT and glycolytic metabolon formation, and provide important insight into the previously unknown metabolism plasticity mechanism.

DOI: https://doi.org/10.1101/2023.08.26.554955
bioRxiv. 2023 Aug 26. pii: 2023.08.25.554774. [Epub ahead of print]

Local and dynamic regulation of neuronal glycolysis in vivo.

Aaron D Wolfe, John N Koberstein, Chadwick B Smith, Melissa L Stewart, Marc Hammarlund, Anthony Hyman, Philip Js Stork, Richard Goodman, Daniel A Colón-Ramos.

Energy metabolism supports neuronal function. While it is well established that changes in energy metabolism underpin brain plasticity and function, less is known about how individual neurons modulate their metabolic states to meet varying energy demands. This is because most approaches used to examine metabolism in living organisms lack the resolution to visualize energy metabolism within individual circuits, cells, or subcellular regions. Here we adapted a biosensor for glycolysis, HYlight, for use in C. elegans to image dynamic changes in glycolysis within individual neurons and in vivo . We determined that neurons perform glycolysis cell-autonomously, and modulate glycolytic states upon energy stress. By examining glycolysis in specific neurons, we documented a neuronal energy landscape comprising three general observations: 1) glycolytic states in neurons are diverse across individual cell types; 2) for a given condition, glycolytic states within individual neurons are reproducible across animals; and 3) for varying conditions of energy stress, glycolytic states are plastic and adapt to energy demands. Through genetic analyses, we uncovered roles for regulatory enzymes and mitochondrial localization in the cellular and subcellular dynamic regulation of glycolysis. Our study demonstrates the use of a single-cell glycolytic biosensor to examine how energy metabolism is distributed across cells and coupled to dynamic states of neuronal function, and uncovers new relationships between neuronal identities and metabolic landscapes in vivo .
Significance statement: While it is generally accepted that energy metabolism underpins neuronal function, how it is distributed and dynamically regulated in different tissues of the brain to meet varying energy demands is not well understood. Here we utilized a fluorescent biosensor, HYlight, to observe glycolytic metabolism at cellular and subcellular scales in vivo . By leveraging both the stereotyped identities of individual neurons in C. elegans, and genetic tools for manipulating glycolytic metabolism, we determined that neurons perform and dynamically regulate glycolysis to match changing cellular demands for energy. Our findings support a model whereby glycolytic states should be considered distinct and related to individual neuron identities in vivo , and introduce new questions about the interconnected nature of metabolism and neuronal function.

DOI: https://doi.org/10.1101/2023.08.25.554774
Sci Rep. 2023 Sep 02. 13(1): 14431

Enhanced presynaptic mitochondrial energy production is required for memory formation.

Erica L Underwood, John B Redell, Kimberly N Hood, Mark E Maynard, Michael Hylin, M Neal Waxham, Jing Zhao, Anthony N Moore, Pramod K Dash.

Some of the prominent features of long-term memory formation include protein synthesis, gene expression, enhanced neurotransmitter release, increased excitability, and formation of new synapses. As these processes are critically dependent on mitochondrial function, we hypothesized that increased mitochondrial respiration and dynamics would play a prominent role in memory formation. To address this possibility, we measured mitochondrial oxygen consumption (OCR) in hippocampal tissue punches from trained and untrained animals. Our results show that context fear training significantly increased basal, ATP synthesis-linked, and maximal OCR in the Shaffer collateral-CA1 synaptic region, but not in the CA1 cell body layer. These changes were recapitulated in synaptosomes isolated from the hippocampi of fear-trained animals. As dynamin-related protein 1 (Drp1) plays an important role in mitochondrial fission, we examined its role in the increased mitochondrial respiration observed after fear training. Drp1 inhibitors decreased the training-associated enhancement of OCR and impaired contextual fear memory, but did not alter the number of synaptosomes containing mitochondria. Taken together, our results show context fear training increases presynaptic mitochondria respiration, and that Drp-1 mediated enhanced energy production in CA1 pre-synaptic terminals is necessary for context fear memory that does not result from an increase in the number of synaptosomes containing mitochondria or an increase in mitochondrial mass within the synaptic layer.

DOI: https://doi.org/10.1038/s41598-023-40877-0
Commun Biol. 2023 09 05. 6(1): 907

Inhibition of ACSL4 ameliorates tubular ferroptotic cell death and protects against fibrotic kidney disease.

Yue Dai, Yuting Chen, Dexiameng Mo, Rui Jin, Yi Huang, Le Zhang, Cuntai Zhang, Hongyu Gao, Qi Yan.

Ferroptosis is a recently recognized form of regulated cell death, characterized by iron-dependent accumulation of lipid peroxidation. Ample evidence has depicted that ferroptosis plays an essential role in the cause or consequence of human diseases, including cancer, neurodegenerative disease and acute kidney injury. However, the exact role and underlying mechanism of ferroptosis in fibrotic kidney remain unknown. Acyl-CoA synthetase long-chain family member 4 (ACSL4) has been demonstrated as an essential component in ferroptosis execution by shaping lipid composition. In this study, we aim to discuss the potential role and underlying mechanism of ACSL4-mediated ferroptosis of tubular epithelial cells (TECs) during renal fibrosis. The unbiased gene expression studies showed that ACSL4 expression was tightly associated with decreased renal function and the progression of renal fibrosis. To explore the role of ACSL4 in fibrotic kidney, ACSL4 specific inhibitor rosiglitazone (ROSI) was used to disturb the high expression of ACSL4 in TECs induced by TGF-β, unilateral ureteral obstruction (UUO) and fatty acid (FA)-modeled mice in vivo, and ACSL4 siRNA was used to knockdown ACSL4 in TGF-β-induced HK2 cells in vitro. The results demonstrated that inhibition and knockdown of ACSL4 effectively attenuated the occurrence of ferroptosis in TECs and alleviated the interstitial fibrotic response. In addition, the expression of various profibrotic cytokines all decreased after ROSI-treated in vivo and in vitro. Further investigation showed that inhibition of ACSL4 obviously attenuates the progression of renal fibrosis by reducing the proferroptotic precursors arachidonic acid- and adrenic acid- containing phosphatidylethanolamine (AA-PE and AdA-PE). In conclusion, these results suggest ACSL4 is essential for tubular ferroptotic death during kidney fibrosis development and ACSL4 inhibition is a viable therapeutic approach to preventing fibrotic kidney diseases.

DOI: https://doi.org/10.1038/s42003-023-05272-5
J Neurochem. 2023 Sep 09.

Brain-derived neurotrophic factor protects neurons by stimulating mitochondrial function through protein kinase A.

Maryann Swain, Smijin K Soman, Kylea Tapia, Raul Y Dagda, Ruben K Dagda.

  Brain-derived neurotrophic factor (BDNF) stimulates dendrite outgrowth and synaptic plasticity by activating downstream protein kinase A (PKA) signaling. Recently, BDNF has been shown to modulate mitochondrial respiration in isolated brain mitochondria, suggesting that BDNF can modulate mitochondrial physiology. However, the molecular mechanisms by which BDNF stimulates mitochondrial function in neurons remain to be elucidated. In this study, we surmised that BDNF binds to the TrkB receptor and translocates to mitochondria to govern mitochondrial physiology in a PKA-dependent manner. Confocal microscopy and biochemical subcellular fractionation assays confirm the localization of the TrkB receptor in mitochondria. The translocation of the TrkB receptor to mitochondria was significantly enhanced upon treating primary cortical neurons with exogenous BDNF, leading to rapid PKA activation. Showing a direct role of BDNF in regulating mitochondrial structure/function, time-lapse confocal microscopy in primary cortical neurons showed that exogenous BDNF enhances mitochondrial fusion, anterograde mitochondrial trafficking, and mitochondrial content within dendrites, which led to increased basal and ATP-linked mitochondrial respiration and glycolysis as assessed by an XF24e metabolic analyzer. BDNF-mediated regulation of mitochondrial structure/function requires PKA activity as treating primary cortical neurons with a pharmacological inhibitor of PKA or transiently expressing constructs that target an inhibitor peptide of PKA (PKI) to the mitochondrion abrogated BDNF-mediated mitochondrial fusion and trafficking. Mechanistically, western/Phos-tag blots show that BDNF stimulates PKA-mediated phosphorylation of Drp1 and Miro-2 to promote mitochondrial fusion and elevate mitochondrial content in dendrites, respectively. Effects of BDNF on mitochondrial function were associated with increased resistance of neurons to oxidative stress and dendrite retraction induced by rotenone. Overall, this study revealed new mechanisms of BDNF-mediated neuroprotection, which entails enhancing mitochondrial health and function of neurons.

Keywords:  BDNF; PKA; TrkB; bioenergetics; mitochondrial dynamics; mitochondrial trafficking

DOI:  https://doi.org/10.1111/jnc.15945
Sci Rep. 2023 Sep 08. 13(1): 14805

Differential intracellular management of fatty acids impacts on metabolic stress-stimulated glucose uptake in cardiomyocytes.

Ettore Vanni, Karina Lindner, Anne-Claude Gavin, Christophe Montessuit.

Stimulation of glucose uptake in response to ischemic metabolic stress is important for cardiomyocyte function and survival. Chronic exposure of cardiomyocytes to fatty acids (FA) impairs the stimulation of glucose uptake, whereas induction of lipid droplets (LD) is associated with preserved glucose uptake. However, the mechanisms by which LD induction prevents glucose uptake impairment remain elusive. We induced LD with either tetradecanoyl phorbol acetate (TPA) or 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). Triacylglycerol biosynthesis enzymes were inhibited in cardiomyocytes exposed to FA ± LD inducers, either upstream (glycerol-3-phosphate acyltransferases; GPAT) or downstream (diacylglycerol acyltransferases; DGAT) of the diacylglycerol step. Although both inhibitions reduced LD formation in cardiomyocytes treated with FA and LD inducers, only DGAT inhibition impaired metabolic stress-stimulated glucose uptake. DGAT inhibition in FA plus TPA-treated cardiomyocytes reduced triacylglycerol but not diacylglycerol content, thus increasing the diacylglycerol/triacylglycerol ratio. In cardiomyocytes exposed to FA alone, GPAT inhibition reduced diacylglycerol but not triacylglycerol, thus decreasing the diacylglycerol/triacylglycerol ratio, prevented PKCδ activation and improved metabolic stress-stimulated glucose uptake. Changes in AMP-activated Protein Kinase activity failed to explain variations in metabolic stress-stimulated glucose uptake. Thus, LD formation regulates metabolic stress-stimulated glucose uptake in a manner best reflected by the diacylglycerol/triacylglycerol ratio.

DOI: https://doi.org/10.1038/s41598-023-42072-7
Dev Cell. 2023 Sep 01. pii: S1534-5807(23)00411-2. [Epub ahead of print]

Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus.

Alexandra MacColl Garfinkel, Nelli Mnatsakanyan, Jeet H Patel, Andrea E Wills, Amy Shteyman, Peter J S Smith, Kambiz N Alavian, Elizabeth Ann Jonas, Mustafa K Khokha.

  An instructive role for metabolism in embryonic patterning is emerging, although a role for mitochondria is poorly defined. We demonstrate that mitochondrial oxidative metabolism establishes the embryonic patterning center, the Spemann-Mangold Organizer, via hypoxia-inducible factor 1α (Hif-1α) in Xenopus. Hypoxia or decoupling ATP production from oxygen consumption expands the Organizer by activating Hif-1α. In addition, oxygen consumption is 20% higher in the Organizer than in the ventral mesoderm, indicating an elevation in mitochondrial respiration. To reconcile increased mitochondrial respiration with activation of Hif-1α, we discovered that the "free" c-subunit ring of the F1Fo ATP synthase creates an inner mitochondrial membrane leak, which decouples ATP production from respiration at the Organizer, driving Hif-1α activation there. Overexpression of either the c-subunit or Hif-1α is sufficient to induce Organizer cell fates even when β-catenin is inhibited. We propose that mitochondrial leak metabolism could be a general mechanism for activating Hif-1α and Wnt signaling.

Keywords:  F(1)F(o) ATP synthase; Hif-1α; LRPPRC; Spemann-Mangold Organizer; Wnt/β-catenin signaling; Xenopus; free c-subunit; hypoxia; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.devcel.2023.08.015
Cell Death Dis. 2023 Sep 07. 14(9): 598

Exploring a new mechanism between lactate and VSMC calcification: PARP1/POLG/UCP2 signaling pathway and imbalance of mitochondrial homeostasis.

Yi Zhu, Jia-Li Zhang, Xue-Jiao Yan, Yuan Ji, Fang-Fang Wang.

Lactate leads to the imbalance of mitochondria homeostasis, which then promotes vascular calcification. PARP1 can upregulate osteogenic genes and accelerate vascular calcification. However, the relationship among lactate, PARP1, and mitochondrial homeostasis is unclear. The present study aimed to explore the new molecular mechanism of lactate to promote VSMC calcification by evaluating PARP1 as a breakthrough molecule. A coculture model of VECs and VSMCs was established, and the model revealed that the glycolysis ability and lactate production of VECs were significantly enhanced after incubation in DOM. Osteogenic marker expression, calcium deposition, and apoptosis in VSMCs were decreased after lactate dehydrogenase A knockdown in VECs. Mechanistically, exogenous lactate increased the overall level of PARP and PARylation in VSMCs. PARP1 knockdown inhibited Drp1-mediated mitochondrial fission and partially restored PINK1/Parkin-mediated mitophagy, thereby reducing mitochondrial oxidative stress. Moreover, lactate induced the translocation of PARP1 from the nucleus to the mitochondria, which then combined with POLG and inhibited POLG-mediated mitochondrial DNA synthesis. This process led to the downregulation of mitochondria-encoded genes, disturbance of mitochondrial respiration, and inhibition of oxidative phosphorylation. The knockdown of PARP1 could partially reverse the damage of mitochondrial gene expression and function caused by lactate. Furthermore, UCP2 was upregulated by the PARP1/POLG signal, and UCP2 knockdown inhibited Drp1-mediated mitochondrial fission and partially recovered PINK1/Parkin-mediated mitophagy. Finally, UCP2 knockdown in VSMCs alleviated DOM-caused VSMC calcification in the coculture model. The study results thus suggest that upregulated PARP1 is involved in the mechanism through which lactate accelerates VSMC calcification partly via POLG/UCP2-caused unbalanced mitochondrial homeostasis.

DOI: https://doi.org/10.1038/s41419-023-06113-3
J Biol Chem. 2023 Sep 01. pii: S0021-9258(23)02238-X. [Epub ahead of print] 105210

CLPX regulates mitochondrial fatty acid β-oxidation in liver cells.

Ko Suzuki, Yoshiko Kubota, Kiriko Kaneko, Costantine Chasama Kamata, Kazumichi Furuyama.

  Mitochondrial fatty acid oxidation (β-oxidation) is an essential metabolic process for energy production in eukaryotic cells, but the regulatory mechanisms of this pathway are largely unknown. In the present study, we found that several enzymes involved in β-oxidation are associated with CLPX, the AAA+ unfoldase that is a component of the mitochondrial matrix protease ClpXP. The suppression of CLPX expression increased β-oxidation activity in the HepG2 cell line and in primary human hepatocytes without glucagon treatment. However, the protein levels of enzymes involved in β-oxidation did not significantly increase in CLPX-deleted HepG2 cells (CLPX-KO cells). Coimmunoprecipitation experiments revealed that the protein level in the immunoprecipitates of each antibody changed after the treatment of wild-type cells with glucagon, and a part of these changes was also observed in the comparison of wild-type and CLPX-KO cells without glucagon treatment. Although the exogenous expression of wild-type or ATP-hydrolysis mutant CLPX suppressed β-oxidation activity in CLPX-KO cells, glucagon treatment induced β-oxidation activity only in CLPX-KO cells expressing wild-type CLPX. These results suggest that the dissociation of CLPX from its target proteins is essential for the induction of β-oxidation in HepG2 cells. Moreover, specific phosphorylation of AMP-activated protein kinase (AMPK) and a decrease in the expression of acetyl-CoA carboxylase 2 were observed in CLPX-KO cells, suggesting that CLPX might participate in the regulation of the cytosolic signaling pathway for β-oxidation. The mechanism for AMPK phosphorylation remains elusive; however, our results uncovered the hitherto unknown role of CLPX in mitochondrial β-oxidation in human liver cells.

Keywords:  CLPX; beta-oxidation; glucagon; hepatocyte; mitochondria; protein‒protein interaction

DOI:  https://doi.org/10.1016/j.jbc.2023.105210
Int J Mol Sci. 2023 Aug 25. pii: 13188. [Epub ahead of print]24(17):

Role of STIM1 in the Regulation of Cardiac Energy Substrate Preference.

Panpan Liu, Zhuli Yang, Youjun Wang, Aomin Sun.

  The heart requires a variety of energy substrates to maintain proper contractile function. Glucose and long-chain fatty acids (FA) are the major cardiac metabolic substrates under physiological conditions. Upon stress, a shift of cardiac substrate preference toward either glucose or FA is associated with cardiac diseases. For example, in pressure-overloaded hypertrophic hearts, there is a long-lasting substrate shift toward glucose, while in hearts with diabetic cardiomyopathy, the fuel is switched toward FA. Stromal interaction molecule 1 (STIM1), a well-established calcium (Ca2+) sensor of endoplasmic reticulum (ER) Ca2+ store, is increasingly recognized as a critical player in mediating both cardiac hypertrophy and diabetic cardiomyopathy. However, the cause-effect relationship between STIM1 and glucose/FA metabolism and the possible mechanisms by which STIM1 is involved in these cardiac metabolic diseases are poorly understood. In this review, we first discussed STIM1-dependent signaling in cardiomyocytes and metabolic changes in cardiac hypertrophy and diabetic cardiomyopathy. Second, we provided examples of the involvement of STIM1 in energy metabolism to discuss the emerging role of STIM1 in the regulation of energy substrate preference in metabolic cardiac diseases and speculated the corresponding underlying molecular mechanisms of the crosstalk between STIM1 and cardiac energy substrate preference. Finally, we briefly discussed and presented future perspectives on the possibility of targeting STIM1 to rescue cardiac metabolic diseases. Taken together, STIM1 emerges as a key player in regulating cardiac energy substrate preference, and revealing the underlying molecular mechanisms by which STIM1 mediates cardiac energy metabolism could be helpful to find novel targets to prevent or treat cardiac metabolic diseases.

Keywords:  STIM1; cardiac energy metabolism; cardiac hypertrophy; diabetic cardiomyopathy; fatty acid; glucose

DOI:  https://doi.org/10.3390/ijms241713188
Int J Mol Sci. 2023 Aug 29. pii: 13398. [Epub ahead of print]24(17):

Lactate Metabolism, Signaling, and Function in Brain Development, Synaptic Plasticity, Angiogenesis, and Neurodegenerative Diseases.

Anika Wu, Daehoon Lee, Wen-Cheng Xiong.

  Neural tissue requires a great metabolic demand despite negligible intrinsic energy stores. As a result, the central nervous system (CNS) depends upon a continuous influx of metabolic substrates from the blood. Disruption of this process can lead to impairment of neurological functions, loss of consciousness, and coma within minutes. Intricate neurovascular networks permit both spatially and temporally appropriate metabolic substrate delivery. Lactate is the end product of anaerobic or aerobic glycolysis, converted from pyruvate by lactate dehydrogenase-5 (LDH-5). Although abundant in the brain, it was traditionally considered a byproduct or waste of glycolysis. However, recent evidence indicates lactate may be an important energy source as well as a metabolic signaling molecule for the brain and astrocytes-the most abundant glial cell-playing a crucial role in energy delivery, storage, production, and utilization. The astrocyte-neuron lactate-shuttle hypothesis states that lactate, once released into the extracellular space by astrocytes, can be up-taken and metabolized by neurons. This review focuses on this hypothesis, highlighting lactate's emerging role in the brain, with particular emphasis on its role during development, synaptic plasticity, angiogenesis, and disease.

Keywords:  development; dysmetabolism; energy; lactate; neurodegeneration; neuroprotective; synaptic plasticity

DOI:  https://doi.org/10.3390/ijms241713398
Medicine (Baltimore). 2023 Sep 08. 102(36): e35142

Research progress of ferroptosis in Alzheimer disease: A review.

Qi Han, Li Sun, Ke Xiang.

Ferroptosis is an emerging form of programmed cell death triggered by iron-dependent lipid peroxidation and reactive oxygen species (ROS). Alzheimer disease (AD), a neurodegenerative disorder, is characterized by the degeneration of nerve cells. Recent research has indicated a significant association between ferroptosis and AD; however, the precise underlying mechanism remains elusive. It is postulated that ferroptosis may impact the accumulation of iron ions within the body by influencing iron metabolism, amino acid metabolism, and lipid metabolism, ultimately leading to the induction of ferroptosis in nerve cells. This article centers on the attributes and regulatory mechanism of ferroptosis, the correlation between ferroptosis and AD, and the recent advancements in the therapeutic approach of targeting ferroptosis for the treatment of AD. These results suggest that ferroptosis could potentially serve as a pivotal focus in future research on AD.

DOI: https://doi.org/10.1097/MD.0000000000035142
Acta Biochim Biophys Sin (Shanghai). 2023 Sep 07.

GLUT5: structure, functions, diseases and potential applications.

Aqian Song, Yuanpeng Mao, Hongshan Wei.

  Glucose transporter 5 (GLUT5) is a membrane transporter that specifically transports fructose and plays a key role in dietary fructose uptake and metabolism. In recent years, a high fructose diet has occupied an important position in the daily intake of human beings, resulting in a significant increase in the incidence of obesity and metabolic diseases worldwide. Over the past few decades, GLUT5 has been well understood to play a significant role in the pathogenesis of human digestive diseases. Recently, the role of GLUT5 in human cancer has received widespread attention, and a large number of studies have focused on exploring the effects of changes in GLUT5 expression levels on cancer cell survival, metabolism and metastasis. However, due to various difficulties and shortcomings, the molecular structure and mechanism of GLUT5 have not been fully elucidated, which to some extent prevents us from revealing the relationship between GLUT5 expression and cell carcinogenesis at the protein molecular level. In this review, we summarize the current understanding of the structure and function of mammalian GLUT5 and its relationship to intestinal diseases and cancer and suggest that GLUT5 may be an important target for cancer therapy.

Keywords:  GLUT5; cancers; fructose; intestinal diseases

DOI:  https://doi.org/10.3724/abbs.2023158
Int J Mol Sci. 2023 Sep 04. pii: 13656. [Epub ahead of print]24(17):

Mitochondrial Factors in the Cell Nucleus.

Katiuska González-Arzola, Antonio Díaz-Quintana.

  The origin of eukaryotic organisms involved the integration of mitochondria into the ancestor cell, with a massive gene transfer from the original proteobacterium to the host nucleus. Thus, mitochondrial performance relies on a mosaic of nuclear gene products from a variety of genomes. The concerted regulation of their synthesis is necessary for metabolic housekeeping and stress response. This governance involves crosstalk between mitochondrial, cytoplasmic, and nuclear factors. While anterograde and retrograde regulation preserve mitochondrial homeostasis, the mitochondria can modulate a wide set of nuclear genes in response to an extensive variety of conditions, whose response mechanisms often merge. In this review, we summarise how mitochondrial metabolites and proteins-encoded either in the nucleus or in the organelle-target the cell nucleus and exert different actions modulating gene expression and the chromatin state, or even causing DNA fragmentation in response to common stress conditions, such as hypoxia, oxidative stress, unfolded protein stress, and DNA damage.

Keywords:  DNA damage; hypoxia; mito-nuclear crosstalk; oxidative stress; stress response; unfolded stress response

DOI:  https://doi.org/10.3390/ijms241713656
Front Aging Neurosci. 2023 ;15 1230467

Potential benefits of medium chain fatty acids in aging and neurodegenerative disease.

Ella Dunn, Biqin Zhang, Virender K Sahota, Hrvoje Augustin.

  Neurodegenerative diseases are a large class of neurological disorders characterized by progressive dysfunction and death of neurones. Examples include Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Aging is the primary risk factor for neurodegeneration; individuals over 65 are more likely to suffer from a neurodegenerative disease, with prevalence increasing with age. As the population ages, the social and economic burden caused by these diseases will increase. Therefore, new therapies that address both aging and neurodegeneration are imperative. Ketogenic diets (KDs) are low carbohydrate, high-fat diets developed initially as an alternative treatment for epilepsy. The classic ketogenic diet provides energy via long-chain fatty acids (LCFAs); naturally occurring medium chain fatty acids (MCFAs), on the other hand, are the main components of the medium-chain triglyceride (MCT) ketogenic diet. MCT-based diets are more efficient at generating the ketone bodies that are used as a secondary energy source for neurones and astrocytes. However, ketone levels alone do not closely correlate with improved clinical symptoms. Recent findings suggest an alternative mode of action for the MCFAs, e.g., via improving mitochondrial biogenesis and glutamate receptor inhibition. MCFAs have been linked to the treatment of both aging and neurodegenerative disease via their effects on metabolism. Through action on multiple disease-related pathways, MCFAs are emerging as compounds with notable potential to promote healthy aging and ameliorate neurodegeneration. MCFAs have been shown to stimulate autophagy and restore mitochondrial function, which are found to be disrupted in aging and neurodegeneration. This review aims to provide insight into the metabolic benefits of MCFAs in neurodegenerative disease and healthy aging. We will discuss the use of MCFAs to combat dysregulation of autophagy and mitochondrial function in the context of "normal" aging, Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease.

Keywords:  Alzheimer’s disease; Parkinson’ s disease; ageing; amyotrophic lateral sclerosis; autophagy; ketogenic diet (KD); medium chain fatty acid (MCFA); mitochondria

DOI:  https://doi.org/10.3389/fnagi.2023.1230467
Front Nutr. 2023 ;10 1157352

Lipid and glucose metabolism in senescence.

Bin Liu, Qingfei Meng, Xin Gao, Huihui Sun, Zhixiang Xu, Yishu Wang, Honglan Zhou.

  Senescence is an inevitable biological process. Disturbances in glucose and lipid metabolism are essential features of cellular senescence. Given the important roles of these types of metabolism, we review the evidence for how key metabolic enzymes influence senescence and how senescence-related secretory phenotypes, autophagy, apoptosis, insulin signaling pathways, and environmental factors modulate glucose and lipid homeostasis. We also discuss the metabolic alterations in abnormal senescence diseases and anti-cancer therapies that target senescence through metabolic interventions. Our work offers insights for developing pharmacological strategies to combat senescence and cancer.

Keywords:  ACC; ACOX1; CPT1; PPP; TCA; glycolysis; lipid metabolism; senescence

DOI:  https://doi.org/10.3389/fnut.2023.1157352
Cells. 2023 Aug 30. pii: 2183. [Epub ahead of print]12(17):

Mitochondrial Properties in Skeletal Muscle Fiber.

Han Dong, Shih-Yin Tsai.

  Mitochondria are the primary source of energy production and are implicated in a wide range of biological processes in most eukaryotic cells. Skeletal muscle heavily relies on mitochondria for energy supplements. In addition to being a powerhouse, mitochondria evoke many functions in skeletal muscle, including regulating calcium and reactive oxygen species levels. A healthy mitochondria population is necessary for the preservation of skeletal muscle homeostasis, while mitochondria dysregulation is linked to numerous myopathies. In this review, we summarize the recent studies on mitochondria function and quality control in skeletal muscle, focusing mainly on in vivo studies of rodents and human subjects. With an emphasis on the interplay between mitochondrial functions concerning the muscle fiber type-specific phenotypes, we also discuss the effect of aging and exercise on the remodeling of skeletal muscle and mitochondria properties.

Keywords:  mitochondria; skeletal muscle physiology

DOI:  https://doi.org/10.3390/cells12172183
Redox Biol. 2023 Aug 29. pii: S2213-2317(23)00266-5. [Epub ahead of print]66 102865

Emerging role of metabolic reprogramming in hyperoxia-associated neonatal diseases.

Tong Sun, Haiyang Yu, Danni Li, He Zhang, Jianhua Fu.

  Oxygen therapy is common during the neonatal period to improve survival, but it can increase the risk of oxygen toxicity. Hyperoxia can damage multiple organs and systems in newborns, commonly causing lung conditions such as bronchopulmonary dysplasia and pulmonary hypertension, as well as damage to other organs, including the brain, gut, and eyes. These conditions are collectively referred to as newborn oxygen radical disease to indicate the multi-system damage caused by hyperoxia. Hyperoxia can also lead to changes in metabolic pathways and the production of abnormal metabolites through a process called metabolic reprogramming. Currently, some studies have analyzed the mechanism of metabolic reprogramming induced by hyperoxia. The focus has been on mitochondrial oxidative stress, mitochondrial dynamics, and multi-organ interactions, such as the lung-gut, lung-brain, and brain-gut axes. In this article, we provide an overview of the major metabolic pathway changes reported in hyperoxia-associated neonatal diseases and explore the potential mechanisms of metabolic reprogramming. Metabolic reprogramming induced by hyperoxia can cause multi-organ metabolic disorders in newborns, including abnormal glucose, lipid, and amino acid metabolism. Moreover, abnormal metabolites may predict the occurrence of disease, suggesting their potential as therapeutic targets. Although the mechanism of metabolic reprogramming caused by hyperoxia requires further elucidation, mitochondria and the gut-lung-brain axis may play a key role in metabolic reprogramming.

Keywords:  Bronchopulmonary dysplasia; Hyperoxia; Metabolic reprogramming; Mitochondria; Neonate

DOI:  https://doi.org/10.1016/j.redox.2023.102865
Signal Transduct Target Ther. 2023 Sep 06. 8(1): 333

Mitochondrial dynamics in health and disease: mechanisms and potential targets.

Wen Chen, Huakan Zhao, Yongsheng Li.

Mitochondria are organelles that are able to adjust and respond to different stressors and metabolic needs within a cell, showcasing their plasticity and dynamic nature. These abilities allow them to effectively coordinate various cellular functions. Mitochondrial dynamics refers to the changing process of fission, fusion, mitophagy and transport, which is crucial for optimal function in signal transduction and metabolism. An imbalance in mitochondrial dynamics can disrupt mitochondrial function, leading to abnormal cellular fate, and a range of diseases, including neurodegenerative disorders, metabolic diseases, cardiovascular diseases and cancers. Herein, we review the mechanism of mitochondrial dynamics, and its impacts on cellular function. We also delve into the changes that occur in mitochondrial dynamics during health and disease, and offer novel perspectives on how to target the modulation of mitochondrial dynamics.

DOI: https://doi.org/10.1038/s41392-023-01547-9
J Cell Physiol. 2023 Sep 02.

Biofactors regulating mitochondrial function and dynamics in podocytes and podocytopathies.

Seyyedeh Mina Hejazian, Mohammadreza Ardalan, Seyed Mahdi Hosseiniyan Khatibi, Yalda Rahbar Saadat, Abolfazl Barzegari, Virginie Gueguen, Anne Meddahi-Pellé, Fani Anagnostou, Sepideh Zununi Vahed, Graciela Pavon-Djavid.

  Podocytes are terminally differentiated kidney cells acting as the main gatekeepers of the glomerular filtration barrier; hence, inhibiting proteinuria. Podocytopathies are classified as kidney diseases caused by podocyte damage. Different genetic and environmental risk factors can cause podocyte damage and death. Recent evidence shows that mitochondrial dysfunction also contributes to podocyte damage. Understanding alterations in mitochondrial metabolism and function in podocytopathies and whether altered mitochondrial homeostasis/dynamics is a cause or effect of podocyte damage are issues that need in-depth studies. This review highlights the roles of mitochondria and their bioenergetics in podocytes. Then, factors/signalings that regulate mitochondria in podocytes are discussed. After that, the role of mitochondrial dysfunction is reviewed in podocyte injury and the development of different podocytopathies. Finally, the mitochondrial therapeutic targets are considered.

Keywords:  diabetic nephropathy; mitochondrial dynamics; mitochondrial dysfunction; podocyte injury; podocytopathies

DOI:  https://doi.org/10.1002/jcp.31110
J Cardiovasc Transl Res. 2023 Sep 05.

Cardiac Metabolism, Reprogramming, and Diseases.

Haichang Wang, Min Shen, Xiaofei Shu, Baolin Guo, Tengfei Jia, Jiaxu Feng, Zuocheng Lu, Yanyan Chen, Jie Lin, Yue Liu, Jiye Zhang, Xuan Zhang, Dongdong Sun.

  Cardiovascular diseases (CVD) account for the largest bulk of deaths worldwide, posing a massive burden on societies and the global healthcare system. Besides, the incidence and prevalence of these diseases are on the rise, demanding imminent action to revert this trend. Cardiovascular pathogenesis harbors a variety of molecular and cellular mechanisms among which dysregulated metabolism is of significant importance and may even proceed other mechanisms. The healthy heart metabolism primarily relies on fatty acids for the ultimate production of energy through oxidative phosphorylation in mitochondria. Other metabolites such as glucose, amino acids, and ketone bodies come next. Under pathological conditions, there is a shift in metabolic pathways and the preference of metabolites, termed metabolic remodeling or reprogramming. In this review, we aim to summarize cardiovascular metabolism and remodeling in different subsets of CVD to come up with a new paradigm for understanding and treatment of these diseases.

Keywords:  Branched-chain amino acids; Cardiac metabolism; Cardiovascular diseases; Fatty acids; Glucose; Ketone bodies; Metabolic reprogramming

DOI:  https://doi.org/10.1007/s12265-023-10432-3
Front Oncol. 2023 ;13 1184626

Serine-associated one-carbon metabolic reprogramming: a new anti-cancer therapeutic strategy.

Jing Zhang, Jian Bai, Chen Gong, Jianhua Wang, Yi Cheng, Jing Zhao, Huihua Xiong.

  Tumour metabolism is a major focus of cancer research, and metabolic reprogramming is an important feature of malignant tumours. Serine is an important non-essential amino acid, which is a main resource of one-carbon units in tumours. Cancer cells proliferate more than normal cells and require more serine for proliferation. The cancer-related genes that are involved in serine metabolism also show changes corresponding to metabolic alterations. Here, we reviewed the serine-associated one-carbon metabolism and its potential as a target for anti-tumour therapeutic strategies.

Keywords:  SERINE; immunotherapy; metabolism reprogramming; molecular targeted therapy; one-carbon units

DOI:  https://doi.org/10.3389/fonc.2023.1184626
Environ Res. 2023 Sep 03. pii: S0013-9351(23)01810-8. [Epub ahead of print] 117006

Autophagy/ferroptosis in colorectal cancer: Carcinogenic view and nanoparticle-mediated cell death regulation.

Zhibin Zhang, Yintao Zhao, Yuman Wang, Yutang Zhao, Jianen Guo.

  The cell death mechanisms have a long history of being evaluated in diseases and pathological events. The ability of triggering cell death is considered to be a promising strategy in cancer therapy, but some mechanisms have dual functions in cancer, requiring more elucidation of underlying factors. Colorectal cancer (CRC) is a disease and malignant condition of colon and rectal that causes high mortality and morbidity. The autophagy targeting in CRC is therapeutic importance and this cell death mechanism can interact with apoptosis in inhibiting or increasing apoptosis. Autophagy has interaction with ferroptosis as another cell death pathway in CRC and can accelerate ferroptosis in suppressing growth and invasion. The dysregulation of autophagy affects the drug resistance in CRC and pro-survival autophagy can induce drug resistance. Therefore, inhibition of protective autophagy enhances chemosensitivity in CRC cells. Moreover, autophagy displays interaction with metastasis and EMT as a potent regulator of invasion in CRC cells. The same is true for ferroptosis, but the difference is that function of ferroptosis is determined and it can reduce viability. The lack of ferroptosis can cause development of chemoresistance in CRC cells and this cell death mechanism is regulated by various pathways and mechanisms that autophagy is among them. Therefore, current review paper provides a state-of-art analysis of autophagy, ferroptosis and their crosstalk in CRC. The nanoparticle-mediated regulation of cell death mechanisms in CRC causes changes in progression. The stimulation of ferroptosis and control of autophagy (induction or inhibition) by nanoparticles can impair CRC progression. The engineering part of nanoparticle synthesis to control autophagy and ferroptosis in CRC still requires more attention.

Keywords:  Cancer therapy; Colorectal cancer; Ferroptosis; Nanoparticles; autophagy

DOI:  https://doi.org/10.1016/j.envres.2023.117006
Trends Endocrinol Metab. 2023 Sep 04. pii: S1043-2760(23)00164-9. [Epub ahead of print]

Metabolic control by AMPK in white adipose tissue.

Olga Göransson, Franziska Kopietz, Mark H Rider.

  White adipose tissue (WAT) plays an important role in the integration of whole-body metabolism by storing fat and mobilizing triacylglycerol when needed. The released free fatty acids can then be oxidized by other tissues to provide ATP. AMP-activated protein kinase (AMPK) is a key regulator of metabolic pathways, and can be targeted by a new generation of direct, small-molecule activators. AMPK activation in WAT inhibits insulin-stimulated lipogenesis and in some situations also inhibits insulin-stimulated glucose uptake, but AMPK-induced inhibition of β-adrenergic agonist-stimulated lipolysis might need to be re-evaluated in vivo. The lack of dramatic effects of AMPK activation on basal metabolism in WAT could be advantageous when treating type 2 diabetes with pharmacological pan-AMPK activators.

Keywords:  AMPK; Drug targeting; adipocyte; glucose uptake; lipogenesis; lipolysis

DOI:  https://doi.org/10.1016/j.tem.2023.08.011