bims-midtic 2023-07-02 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2023‒07‒02
twelve papers selected by
Omkar Joshi
Turku Bioscience

The unfolded protein response of the endoplasmic reticulum supports mitochondrial biogenesis by buffering non-imported proteins.
Interactome Analysis of the ER Stress Sensor Perk Uncovers Key Components of ER-Mitochondria Contact Sites and Ca2+ Signalling.
mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission.
Extracellular Vesicles and Cx43-Gap Junction Channels Are the Main Routes for Mitochondrial Transfer from Ultra-Purified Mesenchymal Stem Cells, RECs.
DOT1L Epigenetically Regulates Autophagy and Mitochondria Fusion in Cell Lines of Renal Cancer.
Implications of MCU complex in metabolic diseases.
Mitochondrial transfer from cancer associated fibroblasts increases migration in aggressive breast cancer.
A novel viscosity sensitive fluorescent probe for monitoring the changes of mitochondrial viscosity.
Mitochondria Transfer from Mesenchymal Stem Cells Confers Chemoresistance to Glioblastoma Stem Cells through Metabolic Rewiring.
Mitochondrial Fission as a Therapeutic Target for Metabolic Diseases: Insights into Antioxidant Strategies.
The bidirectional relationship between metabolism and cell cycle control.
Aurora kinase A/AURKA functionally interacts with the mitochondrial ATP synthase to regulate energy metabolism and cell death.

Mol Biol Cell. 2023 Jun 28. mbcE23050205

The unfolded protein response of the endoplasmic reticulum supports mitochondrial biogenesis by buffering non-imported proteins.

Katharina Knöringer, Carina Groh, Lena Krämer, Kevin C Stein, Katja G Hansen, Jannik Zimmermann, Bruce Morgan, Johannes M Herrmann, Judith Frydman, Felix Boos.

Almost all mitochondrial proteins are synthesized in the cytosol and subsequently targeted to mitochondria. The accumulation of non-imported precursor proteins occurring upon mitochondrial dysfunction can challenge cellular protein homeostasis. Here we show that blocking protein translocation into mitochondria results in the accumulation of mitochondrial membrane proteins at the endoplasmic reticulum, thereby triggering the unfolded protein response (UPRER). Moreover, we find that mitochondrial membrane proteins are also routed to the ER under physiological conditions. The level of ER-resident mitochondrial precursors is enhanced by import defects as well as metabolic stimuli that increase the expression of mitochondrial proteins. Under such conditions, the UPRER is crucial to maintain protein homeostasis and cellular fitness. We propose the ER serves as a physiological buffer zone for those mitochondrial precursors that cannot be immediately imported into mitochondria while engaging the UPRER to adjust the ER proteostasis capacity to the extent of precursor accumulation.

DOI: https://doi.org/10.1091/mbc.E23-05-0205
Contact (Thousand Oaks). 2021 Jan-Dec;4:4 25152564211052392

Interactome Analysis of the ER Stress Sensor Perk Uncovers Key Components of ER-Mitochondria Contact Sites and Ca2+ Signalling.

Maria Livia Sassano, Rita Derua, Etienne Waelkens, Patrizia Agostinis, Alexander R van Vliet.

  We recently reported that the ER stress kinase PERK regulates ER-mitochondria appositions and ER- plasma membrane (ER-PM) contact sites, independent of its canonical role in the unfolded protein response. PERK regulation of ER-PM contacts was revealed by a proximity biotinylation (BioID) approach and involved a dynamic PERK-Filamin A interaction supporting the formation of ER-PM contacts by actin-cytoskeleton remodeling in response to depletion of ER-Ca2+ stores. In this report, we further interrogated the PERK BioID interactome by validating through co-IP experiments the interaction between PERK and two proteins involved in Ca2+ handling and ER-mitochondria contact sites. These included the vesicle associated membrane (VAMP)-associated proteins (VAPA/B) and the main ER Ca2+ pump sarcoplasmic/endoplasmic reticulum Ca ATPase 2 (SERCA2). These data identify new putative PERK interacting proteins with a crucial role in membrane contact sites and Ca2+ signaling further supporting the uncanonical role of PERK in Ca2+ signaling through membrane contact sites (MCSs).

Keywords:  ER stress; cell biology; endoplasmic reticulum; mitochondrial associated membranes (MAM); sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)

DOI:  https://doi.org/10.1177/25152564211052392
Nat Cell Biol. 2023 Jun 29.

mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission.

Nuria Martinez-Lopez, Pamela Mattar, Miriam Toledo, Henrietta Bains, Manu Kalyani, Marie Louise Aoun, Mridul Sharma, Laura Beth J McIntire, Leslie Gunther-Cummins, Frank P Macaluso, Jennifer T Aguilan, Simone Sidoli, Mathieu Bourdenx, Rajat Singh.

Fasting triggers diverse physiological adaptations including increases in circulating fatty acids and mitochondrial respiration to facilitate organismal survival. The mechanisms driving mitochondrial adaptations and respiratory sufficiency during fasting remain incompletely understood. Here we show that fasting or lipid availability stimulates mTORC2 activity. Activation of mTORC2 and phosphorylation of its downstream target NDRG1 at serine 336 sustains mitochondrial fission and respiratory sufficiency. Time-lapse imaging shows that NDRG1, but not the phosphorylation-deficient NDRG1Ser336Ala mutant, engages with mitochondria to facilitate fission in control cells, as well as in those lacking DRP1. Using proteomics, a small interfering RNA screen, and epistasis experiments, we show that mTORC2-phosphorylated NDRG1 cooperates with small GTPase CDC42 and effectors and regulators of CDC42 to orchestrate fission. Accordingly, RictorKO, NDRG1Ser336Ala mutants and Cdc42-deficient cells each display mitochondrial phenotypes reminiscent of fission failure. During nutrient surplus, mTOR complexes perform anabolic functions; however, paradoxical reactivation of mTORC2 during fasting unexpectedly drives mitochondrial fission and respiration.

DOI: https://doi.org/10.1038/s41556-023-01163-3
Int J Mol Sci. 2023 Jun 18. pii: 10294. [Epub ahead of print]24(12):

Extracellular Vesicles and Cx43-Gap Junction Channels Are the Main Routes for Mitochondrial Transfer from Ultra-Purified Mesenchymal Stem Cells, RECs.

Jiahao Yang, Lu Liu, Yasuaki Oda, Keisuke Wada, Mako Ago, Shinichiro Matsuda, Miho Hattori, Tsukimi Goto, Shuichi Ishibashi, Yuki Kawashima-Sonoyama, Yumi Matsuzaki, Takeshi Taketani.

  Mitochondria are essential organelles for maintaining intracellular homeostasis. Their dysfunction can directly or indirectly affect cell functioning and is linked to multiple diseases. Donation of exogenous mitochondria is potentially a viable therapeutic strategy. For this, selecting appropriate donors of exogenous mitochondria is critical. We previously demonstrated that ultra-purified bone marrow-derived mesenchymal stem cells (RECs) have better stem cell properties and homogeneity than conventionally cultured bone marrow-derived mesenchymal stem cells. Here, we explored the effect of contact and noncontact systems on three possible mitochondrial transfer mechanisms involving tunneling nanotubes, connexin 43 (Cx43)-mediated gap junction channels (GJCs), and extracellular vesicles (Evs). We show that Evs and Cx43-GJCs provide the main mechanism for mitochondrial transfer from RECs. Through these two critical mitochondrial transfer pathways, RECs could transfer a greater number of mitochondria into mitochondria-deficient (ρ0) cells and could significantly restore mitochondrial functional parameters. Furthermore, we analyzed the effect of exosomes (EXO) on the rate of mitochondrial transfer from RECs and recovery of mitochondrial function. REC-derived EXO appeared to promote mitochondrial transfer and slightly improve the recovery of mtDNA content and oxidative phosphorylation in ρ0 cells. Thus, ultrapure, homogenous, and safe stem cell RECs could provide a potential therapeutic tool for diseases associated with mitochondrial dysfunction.

Keywords:  Cx43-gap junction channels (Cx43-GJCs); extracellular vesicles (Evs); mesenchymal stem cells (MSCs); mitochondrial transfer; rapidly expanding clones (RECs)

DOI:  https://doi.org/10.3390/ijms241210294
Technol Cancer Res Treat. 2023 Jan-Dec;22:22 15330338231167249

DOT1L Epigenetically Regulates Autophagy and Mitochondria Fusion in Cell Lines of Renal Cancer.

Yanguang Hou, Jiachen Liu, Shiyu Huang, Lei Wang, Juncheng Hu, Xiuheng Liu.

  OBJECTIVES: DOT1L, a histone methylase, is overexpression in renal cell cancer. However, the role and detailed molecular mechanism of DOT1L involved in renal cancer development remain unknown.METHODS: The inhibition of DOT1L was used by SGC0946 and short hairpin RNA silencing. Monodansylcadaverine staining and transmission electron microscope were performed to detect autophagy changes as a result of the inhibition of DOT1L. MitoTracker Red assay was used to analyze mitochondrial morphology. The autophagy markers and mitochondria-related proteins were analyzed by Western blot, qPCR, or immunofluorescence. ChIP assay was performed to demonstrate H3K79me2 is involved in the direct regulation of Farnesoid X receptor transcription.
RESULTS: DOT1L inhibition increased autophagy activity and promoted mito chondria fusion in cell lines of renal cancer. Inhibition of DOT1L upregulated levels of LC3α/β, P62, MFN1, and MFN2, which contributed to autophagy activity or mitochondria fusion. DOT1L knockdown showed a similar the above process. DOT1L inhibition or silencing resulted in AMP-activated protein kinase activation and mammalian target of rapamycin inhibition. Mechanistically, the DOT1L inhibitor and its short hairpin RNAs decreased the expression of Farnesoid X receptor in a histone methylase-dependent manner.
CONCLUSION: We revealed the essential role of Farnesoid X receptor in regulating DOT1L-induced autophagy and mitochondrial fission through the AMP-activated protein kinase/mammalian target of rapamycin pathway in cell lines of renal cancer, which may provide new insights into the pathogenesis of renal cell cancer.

Keywords:  DOT1L; FXR; autophagy; mitochondria fusion; renal cancer

DOI:  https://doi.org/10.1177/15330338231167249
FASEB J. 2023 Aug;37(8): e23046

Implications of MCU complex in metabolic diseases.

Chen Li, Jiyu Sun, Xidan Zhang, Min Zhou, Xueqi Gan.

  Metabolic diseases are considered the primary culprit for physical and mental health of individuals. Although the diagnosis of these diseases is relatively easy, more effective and convenient potent drugs are still being explored. Ca2+ across the inner mitochondrial membrane is a vital intracellular messenger that regulates energy metabolism and cellular Ca2+ homeostasis and is involved in cell death. Mitochondria rely on a selective mitochondrial Ca2+ unidirectional transport complex (MCU complex) in their inner membrane for Ca2+ uptake. We found that the channel contains several subunits and undergoes dramatic transformations in various pathological processes, especially in metabolic diseases. In this way, we believe that the MCU complex becomes a target with significant potential for these diseases. However, there is no review linking the two factors, thus hindering the possibility of new drug production. Here, we highlight the connection between MCU complex-related Ca2+ transport and the pathophysiology of metabolic diseases, adding understanding and insight at the molecular level to provide new insights for targeting MCU to reverse metabolism-related diseases.

Keywords:  MCU complex; homeostasis; metabolic disease; mitochondrial; structure

DOI:  https://doi.org/10.1096/fj.202300218R
J Cell Sci. 2023 Jun 26. pii: jcs.260419. [Epub ahead of print]

Mitochondrial transfer from cancer associated fibroblasts increases migration in aggressive breast cancer.

Kayla F Goliwas, Sarah Libring, Emily Berestesky, Shayan Gholizadeh, Samantha C Schwager, Andra R Frost, Thomas R Gaborski, Jian Zhang, Cynthia A Reinhart-King.

  Cancer associated fibroblasts (CAFs) have distinct roles within the tumor microenvironment, which may impact the mode and efficacy of tumor cell migration. CAFs are known to increase invasion of less-aggressive breast cancer cells through matrix remodeling and leader-follower dynamics. Here, we demonstrate that CAFs communicate with breast cancer cells through the formation of contact-dependent tunneling nanotubes (TNTs) that allow for the exchange of cargo between cell types. The transferring of CAF mitochondria is an integral cargo component, and CAF mitochondria are sufficient to increase the 3D migration of cancer cells. This cargo transfer results in an increase in mitochondrial ATP production in cancer cells while having negligible impact on glycolytic ATP production. Manually increasing mitochondrial oxidative phosphorylation (OXPHOS) by providing extra substrates for OXPHOS fails to enhance cancer cell migration unless glycolysis is maintained at a constant level. Together, these data indicate that tumor-stromal crosstalk via TNTs and the associated metabolic symbiosis is a finely controlled mechanism by which tumor cells co-opt their microenvironment to promote cancer progression and may become a potential therapeutic target.

Keywords:  ATP production.; Bioenergetics; CAF; Reverse Warburg effect; Tumor microenvironment; Tumor spheroid; Tunneling nanotube

DOI:  https://doi.org/10.1242/jcs.260419
Luminescence. 2023 Jun 28.

A novel viscosity sensitive fluorescent probe for monitoring the changes of mitochondrial viscosity.

Xiaoya Li, Rui Guo, Xi Gong, Yingjie Yang, Weiying Lin.

  As a fundamental physical parameter, viscosity influences diffusion in biological processes. The changes in intracellular viscosity leads to the occurrence of relevant diseases. Monitoring changes in cellular viscosity is important for distinguishing abnormal cells in cell biology and oncologic pathology. Herein, we devised and synthesized a viscosity sensitive fluorescent probe LBX-1. LBX-1 showed high sensitivity, providing a large Stokes shift as well as an enhancement of fluorescent intensity (16.1-fold) from methanol solution to glycerol solution. Furthermore, the probe LBX-1 can localize in mitochondria because of the ability of the probe to penetrate the cell membrane and accumulate in mitochondria. These results suggested that the probe could be utilized in monitoring the changes of mitochondrial viscosity in complex biological systems.

Keywords:  fluorescent probe; living cell; viscosity

DOI:  https://doi.org/10.1002/bio.4547
Cancer Res Commun. 2023 Jun;3(6): 1041-1056

Mitochondria Transfer from Mesenchymal Stem Cells Confers Chemoresistance to Glioblastoma Stem Cells through Metabolic Rewiring.

Jean Nakhle, Khattar Khattar, Tülin Özkan, Adel Boughlita, Daouda Abba Moussa, Amélie Darlix, Frédérique Lorcy, Valérie Rigau, Luc Bauchet, Sabine Gerbal-Chaloin, Martine Daujat-Chavanieu, Floriant Bellvert, Laurent Turchi, Thierry Virolle, Jean-Philippe Hugnot, Nicolas Buisine, Mireille Galloni, Valérie Dardalhon, Anne-Marie Rodriguez, Marie-Luce Vignais.

Glioblastomas (GBM) are heterogeneous tumors with high metabolic plasticity. Their poor prognosis is linked to the presence of glioblastoma stem cells (GSC), which support resistance to therapy, notably to temozolomide (TMZ). Mesenchymal stem cells (MSC) recruitment to GBM contributes to GSC chemoresistance, by mechanisms still poorly understood. Here, we provide evidence that MSCs transfer mitochondria to GSCs through tunneling nanotubes, which enhances GSCs resistance to TMZ. More precisely, our metabolomics analyses reveal that MSC mitochondria induce GSCs metabolic reprograming, with a nutrient shift from glucose to glutamine, a rewiring of the tricarboxylic acid cycle from glutaminolysis to reductive carboxylation and increase in orotate turnover as well as in pyrimidine and purine synthesis. Metabolomics analysis of GBM patient tissues at relapse after TMZ treatment documents increased concentrations of AMP, CMP, GMP, and UMP nucleotides and thus corroborate our in vitro analyses. Finally, we provide a mechanism whereby mitochondrial transfer from MSCs to GSCs contributes to GBM resistance to TMZ therapy, by demonstrating that inhibition of orotate production by Brequinar (BRQ) restores TMZ sensitivity in GSCs with acquired mitochondria. Altogether, these results identify a mechanism for GBM resistance to TMZ and reveal a metabolic dependency of chemoresistant GBM following the acquisition of exogenous mitochondria, which opens therapeutic perspectives based on synthetic lethality between TMZ and BRQ.Significance: Mitochondria acquired from MSCs enhance the chemoresistance of GBMs. The discovery that they also generate metabolic vulnerability in GSCs paves the way for novel therapeutic approaches.

DOI: https://doi.org/10.1158/2767-9764.CRC-23-0144
Antioxidants (Basel). 2023 May 27. pii: 1163. [Epub ahead of print]12(6):

Mitochondrial Fission as a Therapeutic Target for Metabolic Diseases: Insights into Antioxidant Strategies.

Tianzheng Yu, Li Wang, Lei Zhang, Patricia A Deuster.

  Mitochondrial fission is a crucial process in maintaining metabolic homeostasis in normal physiology and under conditions of stress. Its dysregulation has been associated with several metabolic diseases, including, but not limited to, obesity, type 2 diabetes (T2DM), and cardiovascular diseases. Reactive oxygen species (ROS) serve a vital role in the genesis of these conditions, and mitochondria are both the main sites of ROS production and the primary targets of ROS. In this review, we explore the physiological and pathological roles of mitochondrial fission, its regulation by dynamin-related protein 1 (Drp1), and the interplay between ROS and mitochondria in health and metabolic diseases. We also discuss the potential therapeutic strategies of targeting mitochondrial fission through antioxidant treatments for ROS-induced conditions, including the effects of lifestyle interventions, dietary supplements, and chemicals, such as mitochondrial division inhibitor-1 (Mdivi-1) and other mitochondrial fission inhibitors, as well as certain commonly used drugs for metabolic diseases. This review highlights the importance of understanding the role of mitochondrial fission in health and metabolic diseases, and the potential of targeting mitochondrial fission as a therapeutic approach to protecting against these conditions.

Keywords:  Coenzyme Q10; Drp1; L-citrulline; astaxanthin; curcumin; exercise; lifestyle interventions; mitochondrial integrity; pharmacological management; reactive oxygen species; resveratrol

DOI:  https://doi.org/10.3390/antiox12061163
Trends Cell Biol. 2023 Jun 27. pii: S0962-8924(23)00110-1. [Epub ahead of print]

The bidirectional relationship between metabolism and cell cycle control.

Frances F Diehl, Kiera M Sapp, Matthew G Vander Heiden.

  The relationship between metabolism and cell cycle progression is complex and bidirectional. Cells must rewire metabolism to meet changing biosynthetic demands across cell cycle phases. In turn, metabolism can influence cell cycle progression through direct regulation of cell cycle proteins, through nutrient-sensing signaling pathways, and through its impact on cell growth, which is linked to cell division. Furthermore, metabolism is a key player in mediating quiescence-proliferation transitions in physiologically important cell types, such as stem cells. How metabolism impacts cell cycle progression, exit, and re-entry, as well as how these processes impact metabolism, is not fully understood. Recent advances uncovering mechanistic links between cell cycle regulators and metabolic processes demonstrate a complex relationship between metabolism and cell cycle control, with many questions remaining.

Keywords:  cell growth; mitochondria; mitosis; proliferation; quiescence; translation

DOI:  https://doi.org/10.1016/j.tcb.2023.05.012
Cell Death Discov. 2023 Jun 29. 9(1): 203

Aurora kinase A/AURKA functionally interacts with the mitochondrial ATP synthase to regulate energy metabolism and cell death.

Rakesh Kumar Sharma, Abderrahman Chafik, Giulia Bertolin.

Cancer cells often hijack metabolic pathways to obtain the energy required to sustain their proliferation. Understanding the molecular mechanisms underlying cancer cell metabolism is key to fine-tune the metabolic preference of specific tumors, and potentially offer new therapeutic strategies. Here, we show that the pharmacological inhibition of mitochondrial Complex V delays the cell cycle by arresting breast cancer cell models in the G0/G1 phase. Under these conditions, the abundance of the multifunctional protein Aurora kinase A/AURKA is specifically lowered. We then demonstrate that AURKA functionally interacts with the mitochondrial Complex V core subunits ATP5F1A and ATP5F1B. Altering the AURKA/ATP5F1A/ATP5F1B nexus is sufficient to trigger G0/G1 arrest, and this is accompanied by decreased glycolysis and mitochondrial respiration rates. Last, we discover that the roles of the AURKA/ATP5F1A/ATP5F1B nexus depend on the specific metabolic propensity of triple-negative breast cancer cell lines, where they correlate with cell fate. On one hand, the nexus induces G0/G1 arrest in cells relying on oxidative phosphorylation as the main source of energy. On the other hand, it allows to bypass cell cycle arrest and it triggers cell death in cells with a glycolytic metabolism. Altogether, we provide evidence that AURKA and mitochondrial Complex V subunits cooperate to maintain cell metabolism in breast cancer cells. Our work paves the way to novel anti-cancer therapies targeting the AURKA/ATP5F1A/ATP5F1B nexus to lower cancer cell metabolism and proliferation.

DOI: https://doi.org/10.1038/s41420-023-01501-2