bims-midtic 2023-10-01 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2023‒10‒01
seventeen papers selected by
Omkar Joshi, Turku Bioscience

The variable domain from dynamin-related protein 1 promotes liquid-liquid phase separation that enhances its interaction with cardiolipin-containing membranes.
Mitochondrial Dynamics and Insulin Secretion.
Mitochondrial PGAM5-Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses.
TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis.
Resveratrol prevents Drp1-mediated mitochondrial fission in the diabetic kidney through the PDE4D/PKA pathway.
All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ.
Alpha synuclein modulates mitochondrial Ca2+ uptake from ER during cell stimulation and under stress conditions.
Ubiquitin Ligase Nrdp1 Controls Autophagy-Associated Acrosome Biogenesis and Mitochondrial Arrangement during Spermiogenesis.
Roles of mitochondrial dynamics and mitophagy in diabetic myocardial microvascular injury.
Bavachin induces liver injury and cell apoptosis by targeting Wnt/β-catenin/DRP1 signaling pathway mediated mitochondrial dysfunction.
Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.
Reduced ER-mitochondrial contact sites and mitochondrial Ca2+ flux in PRKN-mutant patient tyrosine hydroxylase reporter iPSC lines.
Giant mitochondria in cardiomyocytes: cellular architecture in health and disease.
Microenvironmental stiffness induces metabolic reprogramming in glioblastoma.
Prognostic signature based on mitochondria quality control proteins for the prediction of lung adenocarcinoma patients survival.
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) drives angiotensin II-induced vascular remodeling through regulating mitochondrial fragmentation.
Cancer cells reprogram to metastatic state through the acquisition of platelet mitochondria.

Protein Sci. 2023 Sep 24. e4787

The variable domain from dynamin-related protein 1 promotes liquid-liquid phase separation that enhances its interaction with cardiolipin-containing membranes.

Ammon E Posey, Kyle A Ross, Mehran Bagheri, Elizabeth N Lanum, Misha A Khan, Christine E Jennings, Megan C Harwig, Nolan W Kennedy, Vincent J Hilser, James L Harden, R Blake Hill.

  Dynamins are an essential superfamily of mechanoenzymes that remodel membranes and often contain a "variable domain" important for regulation. For the mitochondrial fission dynamin, dynamin-related protein 1, a regulatory role for the variable domain is demonstrated by gain- and loss-of-function mutations, yet the basis for this is unclear. Here, the isolated variable domain is shown to be intrinsically disordered and undergo a cooperative transition in the stabilizing osmolyte trimethylamine N-oxide. However, the osmolyte-induced state is not folded and surprisingly appears as a condensed state. Other co-solutes including known molecular crowder Ficoll PM 70, also induce a condensed state. Fluorescence recovery after photobleaching experiments reveal this state to be liquid-like indicating the variable domain undergoes a liquid-liquid phase separation under crowding conditions. These crowding conditions also enhance binding to cardiolipin, a mitochondrial lipid, which appears to promote phase separation. Since dynamin-related protein 1 is found assembled into discrete punctate structures on the mitochondrial surface, the inference from the present work is that these structures might arise from a condensed state involving the variable domain that may enable rapid tuning of mechanoenzyme assembly necessary for fission. This article is protected by copyright. All rights reserved.

Keywords:  NMR; dynamin; fluorescence; intrinsically disordered protein; mitochondria; mitochondrial fission; phase separation; protein folding

DOI:  https://doi.org/10.1002/pro.4787
Int J Mol Sci. 2023 Sep 07. pii: 13782. [Epub ahead of print]24(18):

Mitochondrial Dynamics and Insulin Secretion.

Uma D Kabra, Martin Jastroch.

  Mitochondria are involved in the regulation of cellular energy metabolism, calcium homeostasis, and apoptosis. For mitochondrial quality control, dynamic processes, such as mitochondrial fission and fusion, are necessary to maintain shape and function. Disturbances of mitochondrial dynamics lead to dysfunctional mitochondria, which contribute to the development and progression of numerous diseases, including Type 2 Diabetes (T2D). Compelling evidence has been put forward that mitochondrial dynamics play a significant role in the metabolism-secretion coupling of pancreatic β cells. The disruption of mitochondrial dynamics is linked to defects in energy production and increased apoptosis, ultimately impairing insulin secretion and β cell death. This review provides an overview of molecular mechanisms controlling mitochondrial dynamics, their dysfunction in pancreatic β cells, and pharmaceutical agents targeting mitochondrial dynamic proteins, such as mitochondrial division inhibitor-1 (mdivi-1), dynasore, P110, and 15-oxospiramilactone (S3).

Keywords:  diabetes; fission; fusion; glucose-stimulated insulin secretion; mitochondrial dynamics; pancreatic beta cell

DOI:  https://doi.org/10.3390/ijms241813782
Front Immunol. 2023 ;14 1243548

Mitochondrial PGAM5-Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses.

Bo-Ram Bang, Haruka Miki, Young Jun Kang.

  Macrophages play a critical role in the regulation of inflammation and tissue homeostasis. In addition to their vital functions for cell survival and physiology, mitochondria play a crucial role in innate immunity as a platform for the induction of inflammatory responses by regulating cell signaling and dynamics. Dynamin-related protein 1 (Drp1) plays a role in the induction of inflammatory responses and the subsequent development of various diseases. PGAM5 (phosphoglycerate mutase member 5) is a mitochondrial outer membrane phosphatase that dephosphorylates its substrate, Drp1. Previous studies showed that PGAM5 regulates the phosphorylation of Drp1 for the activation of NKT cells and T cells. However, it is not clear how PGAM5 regulates Drp1 activity for the induction of inflammation in macrophages. Here, we demonstrate that PGAM5 activity regulates the dephosphorylation of Drp1 in macrophages, leading to the induction of proinflammatory responses in macrophages. In TLR signaling, PGAM5 regulates the expression and production of inflammatory cytokines by regulating the activation of downstream signaling pathways, including the NF-κB and MAPK pathways. Upon LPS stimulation, PGAM5 interacts with Drp1 to form a complex, leading to the production of mtROS. Furthermore, PGAM5-Drp1 signaling promotes the polarization of macrophages toward a proinflammatory phenotype. Our study further demonstrates that PGAM5-Drp1 signaling promotes metabolic reprogramming by upregulating glycolysis and mitochondrial metabolism in macrophages. Altogether, PGAM5 signaling is a linker between alterations in Drp1-mediated mitochondrial dynamics and inflammatory responses in macrophages and may be a target for the treatment of inflammatory diseases.

Keywords:  inflammatory response; innate immunity; macrophages; metabolism; mitochondria; signaling/signaling pathways

DOI:  https://doi.org/10.3389/fimmu.2023.1243548
Nat Commun. 2023 Sep 29. 14(1): 6099

TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis.

Donghua Hu, Min Tan, Dongliang Lu, Brian Kleiboeker, Xuejing Liu, Hongsuk Park, Alexxai V Kravitz, Kooresh I Shoghi, Yu-Hua Tseng, Babak Razani, Akihiro Ikeda, Irfan J Lodhi.

Mitochondrial morphology, which is controlled by mitochondrial fission and fusion, is an important regulator of the thermogenic capacity of brown adipocytes. Adipose-specific peroxisome deficiency impairs thermogenesis by inhibiting cold-induced mitochondrial fission due to decreased mitochondrial membrane content of the peroxisome-derived lipids called plasmalogens. Here, we identify TMEM135 as a critical mediator of the peroxisomal regulation of mitochondrial fission and thermogenesis. Adipose-specific TMEM135 knockout in mice blocks mitochondrial fission, impairs thermogenesis, and increases diet-induced obesity and insulin resistance. Conversely, TMEM135 overexpression promotes mitochondrial division, counteracts obesity and insulin resistance, and rescues thermogenesis in peroxisome-deficient mice. Mechanistically, thermogenic stimuli promote association between peroxisomes and mitochondria and plasmalogen-dependent localization of TMEM135 in mitochondria, where it mediates PKA-dependent phosphorylation and mitochondrial retention of the fission factor Drp1. Together, these results reveal a previously unrecognized inter-organelle communication regulating mitochondrial fission and energy homeostasis and identify TMEM135 as a potential target for therapeutic activation of BAT.

DOI: https://doi.org/10.1038/s41467-023-41849-8
Phytother Res. 2023 Sep 28.

Resveratrol prevents Drp1-mediated mitochondrial fission in the diabetic kidney through the PDE4D/PKA pathway.

Xia Zhu, Zongli Deng, Yanjuan Cao, Zihui Zhou, Wen Sun, Chang Liu, Siwen Fan, Xiao-Xing Yin.

  To explore the role of PDE4D in diabetic nephropathy (DN) and investigate whether resveratrol protects against DN via inhibiting PDE4D. Diabetic db/db mouse and glomerular mesangial cell line (GMCs) were used to investigate the role of PDE4D and the protective effect of resveratrol on renal fibrosis under high glucose (HG) environment. Resveratrol alleviated the progress of DN via inhibiting mitochondrial fragmentation and restoring the expression of PDE4D, PKA, phosphorylated Drp1-Ser637 and Drp1 in kidney of db/db mice. In HG-exposed GMCs, resveratrol treatment decreased the expression of PDE4D, increased PKA level, and inhibited Drp1-mediated mitochondrial fission. In contrast, PDE4D over-expression blunted the inhibitory effects of resveratrol on Drp1 expression and mitochondrial fission. Moreover, PKA inhibitor H89 blunted the effects of resveratrol on phosphorylated Drp1-Ser637 expression and mitochondrial fission in HG-treated GMCs. Inhibition of mitochondrial fission with Drp1 inhibitor Mdivi-1 alleviated mitochondrial dysfunction in GMCs under HG. These findings indicate PDE4D plays an important role in the process of DN. Resveratrol attenuates the development of DN by preventing mitochondrial fission through inhibiting PDE4D, which regulates the expression of phosphorylated Drp1-Ser637 directly.

Keywords:  Drp1; PDE4D; PKA; diabetic nephropathy; resveratrol

DOI:  https://doi.org/10.1002/ptr.8004
Nat Commun. 2023 Sep 27. 14(1): 6036

All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ.

Shon A Koren, Nada Ahmed Selim, Lizbeth De la Rosa, Jacob Horn, M Arsalan Farooqi, Alicia Y Wei, Annika Müller-Eigner, Jacen Emerson, Gail V W Johnson, Andrew P Wojtovich.

Hydrogen peroxide (H2O2) functions as a second messenger to signal metabolic distress through highly compartmentalized production in mitochondria. The dynamics of reactive oxygen species (ROS) generation and diffusion between mitochondrial compartments and into the cytosol govern oxidative stress responses and pathology, though these processes remain poorly understood. Here, we couple the H2O2 biosensor, HyPer7, with optogenetic stimulation of the ROS-generating protein KillerRed targeted into multiple mitochondrial microdomains. Single mitochondrial photogeneration of H2O2 demonstrates the spatiotemporal dynamics of ROS diffusion and transient hyperfusion of mitochondria due to ROS. This transient hyperfusion phenotype required mitochondrial fusion but not fission machinery. Measurement of microdomain-specific H2O2 diffusion kinetics reveals directionally selective diffusion through mitochondrial microdomains. All-optical generation and detection of physiologically-relevant concentrations of H2O2 between mitochondrial compartments provide a map of mitochondrial H2O2 diffusion dynamics in situ as a framework to understand the role of ROS in health and disease.

DOI: https://doi.org/10.1038/s41467-023-41682-z
NPJ Parkinsons Dis. 2023 Sep 23. 9(1): 137

Alpha synuclein modulates mitochondrial Ca2+ uptake from ER during cell stimulation and under stress conditions.

Meraj Ramezani, Alice Wagenknecht-Wiesner, Tong Wang, David A Holowka, David Eliezer, Barbara A Baird.

Alpha synuclein (a-syn) is an intrinsically disordered protein prevalent in neurons, and aggregated forms are associated with synucleinopathies including Parkinson's disease (PD). Despite the biomedical importance and extensive studies, the physiological role of a-syn and its participation in etiology of PD remain uncertain. We showed previously in model RBL cells that a-syn colocalizes with mitochondrial membranes, depending on formation of N-terminal helices and increasing with mitochondrial stress1. We have now characterized this colocalization and functional correlates in RBL, HEK293, and N2a cells. We find that expression of a-syn enhances stimulated mitochondrial uptake of Ca2+ from the ER, depending on formation of its N-terminal helices but not on its disordered C-terminal tail. Our results are consistent with a-syn acting as a tether between mitochondria and ER, and we show increased contacts between these two organelles using structured illumination microscopy. We tested mitochondrial stress caused by toxins related to PD, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) and carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and found that a-syn prevents recovery of stimulated mitochondrial Ca2+ uptake. The C-terminal tail, and not N-terminal helices, is involved in this inhibitory activity, which is abrogated when phosphorylation site serine-129 is mutated (S129A). Correspondingly, we find that MPTP/MPP+ and CCCP stress is accompanied by both phosphorylation (pS129) and aggregation of a-syn. Overall, our results indicate that a-syn can participate as a tethering protein to modulate Ca2+ flux between ER and mitochondria, with potential physiological significance. A-syn can also prevent cellular recovery from toxin-induced mitochondrial dysfunction, which may represent a pathological role of a-syn in the etiology of PD.

DOI: https://doi.org/10.1038/s41531-023-00578-x
Cells. 2023 Sep 05. pii: 2211. [Epub ahead of print]12(18):

Ubiquitin Ligase Nrdp1 Controls Autophagy-Associated Acrosome Biogenesis and Mitochondrial Arrangement during Spermiogenesis.

Zi-Yu Luo, Tian-Xia Jiang, Tao Zhang, Ping Xu, Xiao-Bo Qiu.

  Autophagy is critical to acrosome biogenesis and mitochondrial quality control, but the underlying mechanisms remain unclear. The ubiquitin ligase Nrdp1/RNF41 promotes ubiquitination of the mitophagy-associated Parkin and interacts with the pro-autophagic protein SIP/CacyBP. Here, we report that global deletion of Nrdp1 leads to formation of the round-headed sperm and male infertility by disrupting autophagy. Quantitative proteome analyses demonstrated that the expression of many proteins associated with mitochondria, lysosomes, and acrosomes was dysregulated in either spermatids or sperm of the Nrdp1-deficient mice. Deletion of Nrdp1 increased the levels of Parkin but decreased the levels of SIP, the mitochondrial fission protein Drp1 and the mitochondrial protein Tim23 in sperm, accompanied by the inhibition of autophagy, the impairment of acrosome biogenesis and the disruption of mitochondrial arrangement in sperm. Thus, our results uncover an essential role of Nrdp1 in spermiogenesis and male fertility by promoting autophagy, providing important clues to cope with the related male reproductive diseases.

Keywords:  Nrdp1; Parkin; SIP/CacyBP; acrosome; autophagy; mitochondrium; mitophagy; spermiogenesis; ubiquitin ligase

DOI:  https://doi.org/10.3390/cells12182211
Cell Stress Chaperones. 2023 Sep 27.

Roles of mitochondrial dynamics and mitophagy in diabetic myocardial microvascular injury.

Tong Wang, Xinwei Wang, Tong Fu, Yanchun Ma, Qi Wang, Shuxiang Zhang, Xiao Zhang, Hao Zhou, Xing Chang, Ying Tong.

  Myocardial microvessels are composed of a monolayer of endothelial cells, which play a crucial role in maintaining vascular barrier function, luminal latency, vascular tone, and myocardial perfusion. Endothelial dysfunction is a key factor in the development of cardiac microvascular injury and diabetic cardiomyopathy. In addition to their role in glucose oxidation and energy metabolism, mitochondria also participate in non-metabolic processes such as apoptosis, intracellular ion handling, and redox balancing. Mitochondrial dynamics and mitophagy are responsible for regulating the quality and quantity of mitochondria in response to hyperglycemia. However, these endogenous homeostatic mechanisms can both preserve and/or disrupt non-metabolic mitochondrial functions during diabetic endothelial damage and cardiac microvascular injury. This review provides an overview of the molecular features and regulatory mechanisms of mitochondrial dynamics and mitophagy. Furthermore, we summarize findings from various investigations that suggest abnormal mitochondrial dynamics and defective mitophagy contribute to the development of diabetic endothelial dysfunction and myocardial microvascular injury. Finally, we discuss different therapeutic strategies aimed at improving endothelial homeostasis and cardiac microvascular function through the enhancement of mitochondrial dynamics and mitophagy.

Keywords:  Cardiac microvascular injury; Diabetes; Endothelial cells; Mitochondrial dynamics; Mitophagy

DOI:  https://doi.org/10.1007/s12192-023-01384-3
Toxicol Lett. 2023 Sep 23. pii: S0378-4274(23)01043-3. [Epub ahead of print]387 1-13

Bavachin induces liver injury and cell apoptosis by targeting Wnt/β-catenin/DRP1 signaling pathway mediated mitochondrial dysfunction.

Ying Yang, Wei Zhou, Yihao Wang, Yunxuan Ge, Zheng Fan, Qingquan Liu, Yue Gao.

  Psraleae Fructus (PF) is a well-known traditional Chinese medicine in China. While numerous liver injury reports caused by PF limits its clinical application. Bavachin, a flavonoid compound isolated from the fruits of Psoralea corylifolia L., has been validated to induce direct apoptosis in hepatocytes and liver tissues in our previous studies. However, the subcellular mechanisms of bavachin induced liver injury is still elusive. Here, utilizing 6-week-old C57BL/6 J mice and human embryonic hepatocytes (L02 cells), we report that bavachin activates dynamic-related protein 1 (DRP1) mediated excess mitochondrial fission and endoplasmic reticulum (ER) stress related apoptosis via Wnt/β-catenin signaling pathway. Notably, DRP1 knockdown or XAV-939 induced Wnt/β-catenin inhibition decreased bavachin-induced ER stress and cell apoptosis in L02 cells. In addition, bavachin impaired mitochondrial structural and function in the mice liver tissues. Mdivi-1, a mitochondrial fission inhibitor targeting DRP1, prevented bavachin-induced mitochondrial and ER structural damage, ER stress, and liver injury. Our results demonstrated that bavachin induced mitochondrial fission plays a crucial role in bavachin induced ER stress related liver injury, via the mechanism that involved activation of Wnt/β-catenin signaling pathway.

Keywords:  Bavachin; DRP1; Liver injury; Mitochondrial dysfunction; Wnt/β-catenin

DOI:  https://doi.org/10.1016/j.toxlet.2023.09.006
Nat Cell Biol. 2023 Sep 28.

Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.

Nicholas J Kramer, Gyan Prakash, R Stefan Isaac, Karine Choquet, Iliana Soto, Boryana Petrova, Hope E Merens, Naama Kanarek, L Stirling Churchman.

Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells requiring coordinated gene expression across organelles. To identify genes involved in dual-origin protein complex synthesis, we performed fluorescence-activated cell-sorting-based genome-wide screens analysing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of Complex IV. We identified genes involved in OXPHOS biogenesis, including two uncharacterized genes: PREPL and NME6. We found that PREPL specifically impacts Complex IV biogenesis by acting at the intersection of mitochondrial lipid metabolism and protein synthesis, whereas NME6, an uncharacterized nucleoside diphosphate kinase, controls OXPHOS biogenesis through multiple mechanisms reliant on its NDPK domain. Firstly, NME6 forms a complex with RCC1L, which together perform nucleoside diphosphate kinase activity to maintain local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Secondly, NME6 modulates the activity of mitoribosome regulatory complexes, altering mitoribosome assembly and mitochondrial RNA pseudouridylation. Taken together, we propose that NME6 acts as a link between compartmentalized mitochondrial metabolites and mitochondrial gene expression.

DOI: https://doi.org/10.1038/s41556-023-01244-3
Front Cell Dev Biol. 2023 ;11 1171440

Reduced ER-mitochondrial contact sites and mitochondrial Ca2+ flux in PRKN-mutant patient tyrosine hydroxylase reporter iPSC lines.

Mutsumi Yokota, Yutaro Yoshino, Mitsuko Hosoi, Ryota Hashimoto, Soichiro Kakuta, Takahiro Shiga, Kei-Ichi Ishikawa, Hideyuki Okano, Nobutaka Hattori, Wado Akamatsu, Masato Koike.

  Endoplasmic reticulum-mitochondrial contact sites (ERMCS) play an important role in mitochondrial dynamics, calcium signaling, and autophagy. Disruption of the ERMCS has been linked to several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, the etiological role of ERMCS in these diseases remains unclear. We previously established tyrosine hydroxylase reporter (TH-GFP) iPSC lines from a PD patient with a PRKN mutation to perform correlative light-electron microscopy (CLEM) analysis and live cell imaging in GFP-expressing dopaminergic neurons. Here, we analyzed ERMCS in GFP-expressing PRKN-mutant dopaminergic neurons from patients using CLEM and a proximity ligation assay (PLA). The PLA showed that the ERMCS were significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control under normal conditions. The reduction of the ERMCS in PRKN-mutant patient dopaminergic neurons was further enhanced by treatment with a mitochondrial uncoupler. In addition, mitochondrial calcium imaging showed that mitochondrial Ca2+ flux was significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control. These results suggest a defect in calcium flux from ER to mitochondria is due to the decreased ERMCS in PRKN-mutant patient dopaminergic neurons. Our study of ERMCS using TH-GFP iPSC lines would contribute to further understanding of the mechanisms of dopaminergic neuron degeneration in patients with PRKN mutations.

Keywords:  ER-mitochondrial contact sites; PRKN; dopaminergic neurons; iPSC; tyrosine hydroxylase reporter

DOI:  https://doi.org/10.3389/fcell.2023.1171440
Basic Res Cardiol. 2023 Sep 29. 118(1): 39

Giant mitochondria in cardiomyocytes: cellular architecture in health and disease.

Amy Li, Gerald J Shami, Lisa Griffiths, Sean Lal, Helen Irving, Filip Braet.

  Giant mitochondria are frequently observed in different disease models within the brain, kidney, and liver. In cardiac muscle, these enlarged organelles are present across diverse physiological and pathophysiological conditions including in ageing and exercise, and clinically in alcohol-induced heart disease and various cardiomyopathies. This mitochondrial aberration is widely considered an early structural hallmark of disease leading to adverse organ function. In this thematic paper, we discuss the current state-of-knowledge on the presence, structure and functional implications of giant mitochondria in heart muscle. Despite its demonstrated reoccurrence in different heart diseases, the literature on this pathophysiological phenomenon remains relatively sparse since its initial observations in the early 60s. We review historical and contemporary investigations from cultured cardiomyocytes to human tissue samples to address the role of giant mitochondria in cardiac health and disease. Finally, we discuss their significance for the future development of novel mitochondria-targeted therapies to improve cardiac metabolism and functionality.

Keywords:  Cardiomyopathy; Giant and megamitochondria; Histopathological marker; Mitochondrial aberrations; Mitochondrion pathophysiology; Muscle disease

DOI:  https://doi.org/10.1007/s00395-023-01011-3
Cell Rep. 2023 Sep 26. pii: S2211-1247(23)01187-7. [Epub ahead of print]42(10): 113175

Microenvironmental stiffness induces metabolic reprogramming in glioblastoma.

Alireza Sohrabi, Austin E Y T Lefebvre, Mollie J Harrison, Michael C Condro, Talia M Sanazzaro, Gevick Safarians, Itay Solomon, Soniya Bastola, Shadi Kordbacheh, Nadia Toh, Harley I Kornblum, Michelle A Digman, Stephanie K Seidlits.

  The mechanical properties of solid tumors influence tumor cell phenotype and the ability to invade surrounding tissues. Using bioengineered scaffolds to provide a matrix microenvironment for patient-derived glioblastoma (GBM) spheroids, this study demonstrates that a soft, brain-like matrix induces GBM cells to shift to a glycolysis-weighted metabolic state, which supports invasive behavior. We first show that orthotopic murine GBM tumors are stiffer than peritumoral brain tissues, but tumor stiffness is heterogeneous where tumor edges are softer than the tumor core. We then developed 3D scaffolds with μ-compressive moduli resembling either stiffer tumor core or softer peritumoral brain tissue. We demonstrate that the softer matrix microenvironment induces a shift in GBM cell metabolism toward glycolysis, which manifests in lower proliferation rate and increased migration activities. Finally, we show that these mechanical cues are transduced from the matrix via CD44 and integrin receptors to induce metabolic and phenotypic changes in cancer cells.

Keywords:  CP: Cancer; CP: Metabolism; extracellular matrix; tissue mechanics

DOI:  https://doi.org/10.1016/j.celrep.2023.113175
Cell Death Discov. 2023 Sep 25. 9(1): 352

Prognostic signature based on mitochondria quality control proteins for the prediction of lung adenocarcinoma patients survival.

Anna S Gorbunova, Alexey V Zamaraev, Maria A Yapryntseva, Olga V Kovaleva, Elena M Tchevkina, Maria V Turkina, Boris Zhivotovsky, Gelina S Kopeina.

Lung cancer is the leading cause of cancer mortality worldwide. In recent years, the incidence of lung cancer subtype lung adenocarcinoma (LUAD) has steadily increased. Mitochondria, as a pivotal site of cell bioenergetics, metabolism, cell signaling, and cell death, are often dysregulated in lung cancer cells. Mitochondria maintenance and integrity depend on mitochondrial quality control proteins (MQCPs). During lung cancer progression, the levels of MQCPs could change and promote cancer cell adaptation to the microenvironment and stresses. Here, univariate and multivariate proportional Cox regression analyses were applied to develop a signature based on the level of MQCPs (dimeric form of BNIP3, DRP1, and SIRT3) in tumorous and non-tumorous samples of 80 patients with LUAD. The MQCP signature could be used to separate the patients with LUAD into high- and low-risk groups. Survival analysis indicated that patients in the high-risk group had dramatically shorter overall survival compared with the low-risk patients. Moreover, a nomogram combining clinicopathologic features and the MQCP signature was constructed and validated to predict 1-, 3-, and 5-year overall survival of the patients. Thus, this study presents a novel signature based on MQCPs as a reliable prognostic tool to predict overall survival for patients with LUAD.

DOI: https://doi.org/10.1038/s41420-023-01649-x
Redox Biol. 2023 Sep 16. pii: S2213-2317(23)00294-X. [Epub ahead of print]67 102893

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) drives angiotensin II-induced vascular remodeling through regulating mitochondrial fragmentation.

Litao Wang, Lin Wu, Yuxin Du, Xiang Wang, Bingsheng Yang, Shuai Guo, Yuan Zhou, Yiming Xu, Shuofei Yang, Yingmei Zhang, Jun Ren.

  BACKGROUND: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a novel instigator for mitochondrial dysfunction, and plays an important role in the pathogenesis of cardiovascular diseases. However, the role and mechanism of DNA-PKcs in angiotensin II (Ang II)-induced vascular remodeling remains obscure.METHODS: Rat aortic smooth muscle cells (SMC) and VSMC-specific DNA-PKcs knockout (DNA-PKcsΔVSMC) mice were employed to examine the role of DNA-PKcs in vascular remodeling and the underlying mechanisms. Blood pressure of mice was monitored using the tail-cuff and telemetry methods. The role of DNA-PKcs in vascular function was evaluated using vascular relaxation assessment.
RESULTS: In the tunica media of remodeled mouse thoracic aortas, and renal arteries from hypertensive patients, elevated DNA-PKcs expression was observed along with its cytoplasmic translocation from nucleus, suggesting a role for DNA-PKcs in vascular remodeling. We then infused wild-type (DNA-PKcsfl/fl) and DNA-PKcsΔVSMC mice with Ang II for 14 days to establish vascular remodeling, and demonstrated that DNA-PKcsΔVSMC mice displayed attenuated vascular remodeling through inhibition of dedifferentiation of VSMCs. Moreover, deletion of DNA-PKcs in VSMCs alleviated Ang II-induced vasodilation dysfunction and hypertension. Mechanistic investigations denoted that Ang II-evoked rises in cytoplasmic DNA-PKcs interacted with dynamin-related protein 1 (Drp1) at its TQ motif to phosphorylate Drp1S616, subsequently promoting mitochondrial fragmentation and dysfunction, as well as reactive oxygen species (ROS) production. Treatment of irbesartan, an Ang II type 1 receptor (AT1R) blocker, downregulated DNA-PKcs expression in VSMCs and aortic tissues following Ang II administration.
CONCLUSION: Our data revealed that cytoplasmic DNA-PKcs in VSMCs accelerated Ang II-induced vascular remodeling by interacting with Drp1 at its TQ motif and phosphorylating Drp1S616 to provoke mitochondrial fragmentation. Maneuvers targeting DNA-PKcs might be a valuable therapeutic option for the treatment of vascular remodeling and hypertension.

Keywords:  DNA-PKcs; Drp1; Hypertension; Mitochondrial fragmentation; Vascular remodeling

DOI:  https://doi.org/10.1016/j.redox.2023.102893
Cell Rep. 2023 Sep 19. pii: S2211-1247(23)01159-2. [Epub ahead of print]42(9): 113147

Cancer cells reprogram to metastatic state through the acquisition of platelet mitochondria.

Wenkan Zhang, Hao Zhou, Hengyuan Li, Haochen Mou, Eloy Yinwang, Yucheng Xue, Shengdong Wang, Yongxing Zhang, Zenan Wang, Tao Chen, Hangxiang Sun, Fangqian Wang, Jiahao Zhang, Xupeng Chai, Shixin Chen, Binghao Li, Changqing Zhang, Junjie Gao, Zhaoming Ye.

  Metastasis is the major cause of cancer deaths, and cancer cells evolve to adapt to various tumor microenvironments, which hinders the treatment of tumor metastasis. Platelets play critical roles in tumor development, especially during metastasis. Here, we elucidate the role of platelet mitochondria in tumor metastasis. Cancer cells are reprogrammed to a metastatic state through the acquisition of platelet mitochondria via the PINK1/Parkin-Mfn2 pathway. Furthermore, platelet mitochondria regulate the GSH/GSSG ratio and reactive oxygen species (ROS) in cancer cells to promote lung metastasis of osteosarcoma. Impairing platelet mitochondrial function has proven to be an efficient approach to impair metastasis, providing a direction for osteosarcoma therapy. Our findings demonstrate mitochondrial transfer between platelets and cancer cells and suggest a role for platelet mitochondria in tumor metastasis.

Keywords:  CP: Cancer; CP: Cell biology; glutathione; metabolic reprogram; mitochondria transfer; osteosarcoma metastasis; oxidative stress; platelets

DOI:  https://doi.org/10.1016/j.celrep.2023.113147