bims-midtic 2024-04-14 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2024–04–14
25 papers selected by
Omkar Joshi, Turku Bioscience

GTPBP8 modulates mitochondrial fission through a Drp1-dependent process.
Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.
MITOCHONDRIAL IMPORT STRESS and PINK1-MEDIATED MITOPHAGY: THE ROLE of the PINK1-TOMM-TIMM23 SUPERCOMPLEX.
Miro GTPases at the Crossroads of Cytoskeletal Dynamics and Mitochondrial Trafficking.
Inhibition of Drp1-mediated mitochondrial fission improves contrast-induced acute kidney injury by targeting the mROS-TXNIP-NLRP3 inflammasome axis.
Mechanical regulation of mitochondrial morphodynamics in cancer cells by extracellular microenvironment.
DRP1 inhibition-mediated mitochondrial elongation abolishes cancer stemness, enhances glutaminolysis, and drives ferroptosis in oral squamous cell carcinoma.
Machine learning-based 3D segmentation of mitochondria in polarized epithelial cells.
Phosphoglycerate mutase 5 exacerbates liver ischemia-reperfusion injury by activating mitochondrial fission.
Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons.
Dramatic Changes in Mitochondrial Subcellular Location and Morphology Accompany Activation of the CO 2 Concentrating Mechanism.
Promoting mitochondrial dynamics by inhibiting the PINK1/PRKN pathway to relieve diabetic nephropathy.
Mdivi-1: Effective but complex mitochondrial fission inhibitor.
Cooperation of Various Cytoskeletal Components Orchestrates Intercellular Spread of Mitochondria between B-Lymphoma Cells through Tunnelling Nanotubes.
An Innovative Mitochondrial-targeted Gene Therapy for Cancer Treatment.
Inhibition of MFN1 restores tamoxifen-induced apoptosis in resistant cells by disrupting aberrant mitochondrial fusion dynamics.
Balbiani body of basal insects is potentially involved in multiplication and selective elimination of mitochondria.
Mitophagy Upregulation Occurs Early in the Neurodegenerative Process Mediated by α-Synuclein.
Mitochondrial morphology, distribution and activity during oocyte development.
Curcumin simultaneously improves mitochondrial dynamics and myocardial cell bioenergy after sepsis via the SIRT1-DRP1/PGC-1α pathway.
Contacting the gut: Mitochondria-associated Endoplasmic Reticulum Membranes in the Enteric Nervous System.
Elevated α-synuclein levels inhibit mitophagic flux.
A novel probe to monitor lysosome-mitochondria contact sites opens up a new path to study neurodegenerative diseases.
Right place at the right time: Mitochondrial shape, distribution and inter-organelle interaction during skeletal muscle postnatal development.
Mitochondrial Targeted Thermosensitive Nanocarrier for Near-Infrared-Triggered Precise Synergetic Photothermal Nitric Oxide Chemotherapy.

J Cell Sci. 2024 Apr 08. pii: jcs.261612. [Epub ahead of print]

GTPBP8 modulates mitochondrial fission through a Drp1-dependent process.

Xiumei He, Liang Wang, Hoi Ying Tsang, Xiaonan Liu, Xiaofeng Yang, Ziqi Guo, Cheng Yang, Qiong Wu, Zuping Zhou, Xiaobo Cen, Hongxia Zhao.

  Mitochondrial fission is a tightly regulated process involving multiple proteins and cell signaling. Despite extensive studies on mitochondrial fission factors, our understanding of the regulatory mechanisms remains limited. This study shows the critical role of a mitochondrial GTPase, GTPBP8, in orchestrating mitochondrial fission. Depletion of GTPBP8 resulted in drastic elongation and interconnectedness of mitochondria. Conversely, overexpression of GTPBP8 shifted mitochondrial morphology from tubular to fragmented. Notably, the induced mitochondrial fragmentation from GTPBP8 overexpression was inhibited in cells either depleted of the mitochondrial fission protein Drp1 or carrying mutated forms of Drp1. Importantly, downregulation of GTPBP8 caused an increase in oxidative stress, modulating cell signaling involved in the heightened phosphorylation of Drp1 at Ser637. This phosphorylation hindered the recruitment of Drp1 to mitochondria, leading to mitochondrial fission defects. On the other hand, GTPBP8 overexpression triggered enhanced recruitment and assembly of Drp1 to mitochondria. In summary, our study illuminates the cellular function of GTPBP8 as a pivotal modulator of the mitochondrial division apparatus, inherently reliant on its influence on Drp1.

Keywords:  Drp1; Fission; GTPBP8; Mitochondria; Phosphorylation

DOI:  https://doi.org/10.1242/jcs.261612
Nat Cell Biol. 2024 Apr 09.

Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.

Ao Liu, Frieda Kage, Asan F Abdulkareem, Mac Pholo Aguirre-Huamani, Gracie Sapp, Halil Aydin, Henry N Higgs.

Mitochondrial fission occurs in many cellular processes, but the regulation of fission is poorly understood. We show that long-chain acyl-coenzyme A (LCACA) activates two related mitochondrial fission proteins, MiD49 and MiD51, by inducing their oligomerization, which activates their ability to stimulate the DRP1 GTPase. The 1:1 stoichiometry of LCACA:MiD in the oligomer suggests interaction in the previously identified nucleotide-binding pocket, and a point mutation in this pocket reduces LCACA binding and LCACA-induced oligomerization for MiD51. In cells, this LCACA binding mutant does not assemble into puncta on mitochondria or rescue MiD49/51 knockdown effects on mitochondrial length and DRP1 recruitment. Furthermore, cellular treatment with BSA-bound oleic acid, which causes increased LCACA, promotes mitochondrial fission in an MiD49/51-dependent manner. These results suggest that LCACA is an endogenous ligand for MiDs, inducing mitochondrial fission and providing a potential mechanism for fatty-acid-induced mitochondrial division. Finally, MiD49 or MiD51 oligomers synergize with Mff, but not with actin filaments, in DRP1 activation, suggesting distinct pathways for DRP1 activation.

DOI: https://doi.org/10.1038/s41556-024-01400-3
Autophagy. 2024 Apr 10.

MITOCHONDRIAL IMPORT STRESS and PINK1-MEDIATED MITOPHAGY: THE ROLE of the PINK1-TOMM-TIMM23 SUPERCOMPLEX.

Mohamed A Eldeeb, Armaan Fallahi, Andrea Soumbasis, Andrew N Bayne, Jean-François Trempe, Edward A Fon.

  Mutations in the PINK1 kinase cause Parkinson disease (PD) through physiological processes that are not yet fully elucidated. PINK1 kinase accumulates selectively on damaged mitochondria, where it recruits the E3 ubiquitin ligase PRKN/Parkin to mediate mitophagy. Upon mitochondrial import failure, PINK1 accumulates in association with the translocase of outer mitochondrial membrane (TOMM). However, the molecular basis of this PINK1 accumulation on the TOMM complex remain elusive. We recently demonstrated that TIMM23 (translocase of the inner mitochondrial membrane 23) is a component of the PINK1-supercomplex formed in response to mitochondrial stress. We also uncovered that PINK1 is required for the formation of this supercomplex and highlighted the biochemical regulation and significance of this supercomplex; expanding our understanding of mitochondrial quality control and PD pathogenesis.

Keywords:  Mitochondrial import; PINK1; Parkinson’s disease; mitochondrial quality control; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2340399
Cells. 2024 Apr 07. pii: 647. [Epub ahead of print]13(7):

Miro GTPases at the Crossroads of Cytoskeletal Dynamics and Mitochondrial Trafficking.

Pontus Aspenström.

  Miro GTPases are key components in the machinery responsible for transporting mitochondria and peroxisomes along microtubules, and also play important roles in regulating calcium homeostasis and organizing contact sites between mitochondria and the endoplasmic reticulum. Moreover, Miro GTPases have been shown to interact with proteins that actively regulate cytoskeletal organization and dynamics, suggesting that these GTPases participate in organizing cytoskeletal functions and organelle transport. Derailed mitochondrial transport is associated with neuropathological conditions such as Parkinson's and Alzheimer's diseases. This review explores our recent understanding of the diverse roles of Miro GTPases under cytoskeletal control, both under normal conditions and during the course of human diseases such as neuropathological disorders.

Keywords:  Miro GTPases; Parkinson’s disease; microtubules; mitochondrial dynamics; neuropathology

DOI:  https://doi.org/10.3390/cells13070647
Int Immunopharmacol. 2024 Apr 11. pii: S1567-5769(24)00519-8. [Epub ahead of print]133 112001

Inhibition of Drp1-mediated mitochondrial fission improves contrast-induced acute kidney injury by targeting the mROS-TXNIP-NLRP3 inflammasome axis.

Jiong Zhang, Qian Wei, Shu-Kun Wu, Fang Wang, Tong-Ling Yuan, Jia Wang.

  Acute kidney injury (AKI) is a critical complication known for their extremely high mortality rate and lack of effective clinical therapy. Disorders in mitochondrial dynamics possess a pivotal role in the occurrence and progression of contrast-induced nephropathy (CIN) by activating NLRP3 inflammasome. The activation of dynamin-related protein-1 (Drp1) can trigger mitochondrial dynamic disorders by regulating excessive mitochondrial fission. However, the precise role of Drp1 during CIN has not been clarified. In vivo experiments revealed that inhibiting Drp1 through Mdivi-1 (one selective inhibitor of Drp1) can significantly decrease the expression of p-Drp1 (Ser616), mitochondrial p-Drp1 (Ser616), mitochondrial Bax, mitochondrial reactive oxygen species (mROS), NLRP3, caspase-1, ASC, TNF-α, IL-1β, interleukin (IL)-18, IL-6, creatinine (Cr), malondialdehyde (MDA), blood urea nitrogen (BUN), and KIM-1. Moreover, Mdivi-1 reduced kidney pathological injury and downregulated the interaction between NLRP3 and thioredoxin-interacting protein (TXNIP), which was accompanied by decreased interactions between TRX and TXNIP. This resulted in increasing superoxide dismutase (SOD) and CAT activity, TRX expression, up-regulating mitochondrial membrane potential, and augmenting ATP contents and p-Drp1 (Ser616) levels in the cytoplasm. However, it did not bring impact on the expression of p-Drp1 (Ser637) and TXNIP. Activating Drp-1though Acetaldehyde abrogated the effects of Mdivi-1. In addition, the results of in vitro studies employing siRNA-Drp1 and plasmid-Drp1 intervention in HK-2 cells treated with iohexol were consistent with the in vivo experiments. Our findings revealed inhibiting Drp1 phosphorylation at Ser616 could ameliorate iohexol -induced acute kidney injury though alleviating the activation of the TXNIP-NLRP3 inflammasome pathway.

Keywords:  Contrast-induced acute kidney injury; Drp1; Mitochondrion; mROS-TXNIP-NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.intimp.2024.112001
Biomater Biosyst. 2024 Jun;14 100093

Mechanical regulation of mitochondrial morphodynamics in cancer cells by extracellular microenvironment.

Mariia Lunova, Milan Jirsa, Alexandr Dejneka, Gareth John Sullivan, Oleg Lunov.

  Recently, it has been recognized that physical abnormalities (e.g. elevated solid stress, elevated interstitial fluid pressure, increased stiffness) are associated with tumor progression and development. Additionally, these mechanical forces originating from tumor cell environment through mechanotransduction pathways can affect metabolism. On the other hand, mitochondria are well-known as bioenergetic, biosynthetic, and signaling organelles crucial for sensing stress and facilitating cellular adaptation to the environment and physical stimuli. Disruptions in mitochondrial dynamics and function have been found to play a role in the initiation and advancement of cancer. Consequently, it is logical to hypothesize that mitochondria dynamics subjected to physical cues may play a pivotal role in mediating tumorigenesis. Recently mitochondrial biogenesis and turnover, fission and fusion dynamics was linked to mechanotransduction in cancer. However, how cancer cell mechanics and mitochondria functions are connected, still remain poorly understood. Here, we discuss recent studies that link mechanical stimuli exerted by the tumor cell environment and mitochondria dynamics and functions. This interplay between mechanics and mitochondria functions may shed light on how mitochondria regulate tumorigenesis.

Keywords:  Cancer; Mechanotransduction; Mitochondria; Mitochondrial dynamics; Tumor metabolism

DOI:  https://doi.org/10.1016/j.bbiosy.2024.100093
Br J Cancer. 2024 Apr 06.

DRP1 inhibition-mediated mitochondrial elongation abolishes cancer stemness, enhances glutaminolysis, and drives ferroptosis in oral squamous cell carcinoma.

Zhen Wang, Shouyi Tang, Luyao Cai, Qing Wang, Dan Pan, Yunmei Dong, Hao Zhou, Jing Li, Ning Ji, Xin Zeng, Yu Zhou, Ying-Qiang Shen, Qianming Chen.

BACKGROUND: Mitochondrial dynamics play a fundamental role in determining stem cell fate. However, the underlying mechanisms of mitochondrial dynamics in the stemness acquisition of cancer cells are incompletely understood.
METHODS: Metabolomic profiling of cells were analyzed by MS/MS. The genomic distribution of H3K27me3 was measured by CUT&Tag. Oral squamous cell carcinoma (OSCC) cells depended on glucose or glutamine fueling TCA cycle were monitored by 13C-isotope tracing. Organoids and tumors from patients and mice were treated with DRP1 inhibitors mdivi-1, ferroptosis inducer erastin, or combination with mdivi-1 and erastin to evaluate treatment effects.
RESULTS: Mitochondria of OSCC stem cells own fragment mitochondrial network and DRP1 is required for maintenance of their globular morphology. Imbalanced mitochondrial dynamics induced by DRP1 knockdown suppressed stemness of OSCC cells. Elongated mitochondria increased α-ketoglutarate levels and enhanced glutaminolysis to fuel the TCA cycle by increasing glutamine transporter ASCT2 expression. α-KG promoted the demethylation of histone H3K27me3, resulting in downregulation of SNAI2 associated with stemness and EMT. Significantly, suppressing DRP1 enhanced the anticancer effects of ferroptosis.
CONCLUSION: Our study reveals a novel mechanism underlying mitochondrial dynamics mediated cancer stemness acquisition and highlights the therapeutic potential of mitochondria elongation to increase the susceptibility of cancer cells to ferroptosis.

DOI: https://doi.org/10.1038/s41416-024-02670-2
Mitochondrion. 2024 Apr 08. pii: S1567-7249(24)00040-0. [Epub ahead of print] 101882

Machine learning-based 3D segmentation of mitochondria in polarized epithelial cells.

Nan W Hultgren, Tianli Zhou, David S Williams.

  Mitochondria are dynamic organelles that alter their morphological characteristics in response to functional needs. Therefore, mitochondrial morphology is an important indicator of mitochondrial function and cellular health. Reliable segmentation of mitochondrial networks in microscopy images is a crucial initial step for further quantitative evaluation of their morphology. However, 3D mitochondrial segmentation, especially in cells with complex network morphology, such as in highly polarized cells, remains challenging. To improve the quality of 3D segmentation of mitochondria in super-resolution microscopy images, we took a machine learning approach, using 3D Trainable Weka, an ImageJ plugin. We demonstrated that, compared with other commonly used methods, our approach segmented mitochondrial networks effectively, with improved accuracy in different polarized epithelial cell models, including differentiated human retinal pigment epithelial (RPE) cells. Furthermore, using several tools for quantitative analysis following segmentation, we revealed mitochondrial fragmentation in bafilomycin-treated RPE cells.

Keywords:  3D segmentation; ImageJ; Machine learning algorithm; Mitochondrial morphology; Retinal pigment epithelium

DOI:  https://doi.org/10.1016/j.mito.2024.101882
Sci Rep. 2024 Apr 12. 14(1): 8535

Phosphoglycerate mutase 5 exacerbates liver ischemia-reperfusion injury by activating mitochondrial fission.

Hongwei Tang, Qiwen Yu, Xu Chen, Jiakai Zhang, Danfeng Guo, Wenzhi Guo, Shuijun Zhang, Xiaoyi Shi.

  Although the death of hepatocytes is a crucial trigger of liver ischemia-reperfusion (I/R) injury, the regulation of liver I/R-induced hepatocyte death is still poorly understood. Phosphoglycerate mutase 5 (PGAM5), a mitochondrial Serine/Threonine protein phosphatase, regulates mitochondrial dynamics and is involved in the process of both apoptosis and necrotic. However, it is still unclear what role PGAM5 plays in the death of hepatocytes induced by I/R. Using a PGAM5-silence mice model, we investigated the role of PGAM5 in liver I/R injury and its relevant molecular mechanisms. Our data showed that PGAM5 was highly expressed in mice with liver I/R injury. Silence of PGAM5 could decrease I/R-induced hepatocyte death in mice. In subcellular levels, the silence of PGAM5 could restore mitochondrial membrane potential, increase mitochondrial DNA copy number and transcription levels, inhibit ROS generation, and prevent I/R-induced opening of abnormal mPTP. As for the molecular mechanisms, we indicated that the silence of PGAM5 could inhibit Drp1(S616) phosphorylation, leading to a partial reduction of mitochondrial fission. In addition, Mdivi-1 could inhibit mitochondrial fission, decrease hepatocyte death, and attenuate liver I/R injury in mice. In conclusion, our data reveal the molecular mechanism of PGAM5 in driving hepatocyte death through activating mitochondrial fission in liver I/R injury.

Keywords:  Liver I/R injury; Mitochondrial fission; Mitochondrial quality control; PGAM5

DOI:  https://doi.org/10.1038/s41598-024-58748-7
Neuron. 2024 Mar 26. pii: S0896-6273(24)00167-3. [Epub ahead of print]

Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons.

Sandra M V Kochan, Meret Cepero Malo, Milica Jevtic, Hannah M Jahn-Kelleter, Gulzar A Wani, Kristiano Ndoci, Laura Pérez-Revuelta, Felix Gaedke, Iris Schäffner, Dieter Chichung Lie, Astrid Schauss, Matteo Bergami.

  Integration of new neurons into adult hippocampal circuits is a process coordinated by local and long-range synaptic inputs. To achieve stable integration and uniquely contribute to hippocampal function, immature neurons are endowed with a critical period of heightened synaptic plasticity, yet it remains unclear which mechanisms sustain this form of plasticity during neuronal maturation. We found that as new neurons enter their critical period, a transient surge in fusion dynamics stabilizes elongated mitochondrial morphologies in dendrites to fuel synaptic plasticity. Conditional ablation of fusion dynamics to prevent mitochondrial elongation selectively impaired spine plasticity and synaptic potentiation, disrupting neuronal competition for stable circuit integration, ultimately leading to decreased survival. Despite profuse mitochondrial fragmentation, manipulation of competition dynamics was sufficient to restore neuronal survival but left neurons poorly responsive to experience at the circuit level. Thus, by enabling synaptic plasticity during the critical period, mitochondrial fusion facilitates circuit remodeling by adult-born neurons.

Keywords:  LTP; Mfn2; adult neurogenesis; competition; experience; hippocampus; mitochondria; mitochondrial fusion; neural stem cell; synaptic plasticity

DOI:  https://doi.org/10.1016/j.neuron.2024.03.013
bioRxiv. 2024 Mar 27. pii: 2024.03.25.586705. [Epub ahead of print]

Dramatic Changes in Mitochondrial Subcellular Location and Morphology Accompany Activation of the CO 2 Concentrating Mechanism.

Justin Findinier, Lydia-Marie Joubert, Michael F Schmid, Andrey Malkovskiy, Wah Chiu, Adrien Burlacot, Arthur R Grossman.

Dynamic changes in intracellular ultrastructure can be critical for the ability of organisms to acclimate to environmental conditions. Microalgae, which are responsible for ∼50% of global photosynthesis, compartmentalize their Rubisco into a specialized structure known as the pyrenoid when the cells experience limiting CO 2 conditions; this compartmentalization appears to be a component of the CO 2 Concentrating Mechanism (CCM), which facilitates photosynthetic CO 2 fixation as environmental levels of inorganic carbon (Ci) decline. Changes in the spatial distribution of mitochondria in green algae have also been observed under CO 2 limiting conditions, although a role for this reorganization in CCM function remains unclear. We used the green microalgae Chlamydomonas reinhardtii to monitor changes in the position and ultrastructure of mitochondrial membranes as cells transition between high CO 2 (HC) and Low/Very Low CO 2 (LC/VLC). Upon transferring cells to VLC, the mitochondria move from a central to a peripheral location, become wedged between the plasma membrane and chloroplast envelope, and mitochondrial membranes orient in parallel tubular arrays that extend from the cell's apex to its base. We show that these ultrastructural changes require protein and RNA synthesis, occur within 90 min of shifting cells to VLC conditions, correlate with CCM induction and are regulated by the CCM master regulator CIA5. The apico-basal orientation of the mitochondrial membrane, but not the movement of the mitochondrion to the cell periphery, is dependent on microtubules and the MIRO1 protein, which is involved in membrane-microtubule interactions. Furthermore, blocking mitochondrial electron transport in VLC acclimated cells reduces the cell's affinity for inorganic carbon. Overall, our results suggest that CIA5-dependent mitochondrial repositioning/reorientation functions in integrating cellular architecture and energetics with CCM activities and invite further exploration of how intracellular architecture can impact fitness under dynamic environmental conditions.

DOI: https://doi.org/10.1101/2024.03.25.586705
Dis Model Mech. 2024 Apr 11. pii: dmm.050471. [Epub ahead of print]

Promoting mitochondrial dynamics by inhibiting the PINK1/PRKN pathway to relieve diabetic nephropathy.

Jun-Yi Zhu, Joyce van de Leemput, Zhe Han.

  Diabetes is a metabolic disorder characterized by high blood glucose levels and is a leading cause of kidney disease. Diabetic nephropathy has been attributed to dysfunctional mitochondria. However, many questions remain about the exact mechanism. The structure, function, and molecular pathways between mammalian podocytes and Drosophila nephrocytes are highly conserved, therefore we used flies on a high-sucrose diet to model type 2 diabetic nephropathy. The nephrocytes of high-sucrose diet flies showed significant functional decline and decreased cell size, associated with a shortened lifespan. Structurally, the nephrocytes filtration structure known as the slit diaphragm was disorganized. At the cellular level, we found altered mitochondrial dynamics and dysfunction. Regulating mitochondrial dynamics by either genetic modification of the Pink1/Park (mammalian PINK1/PRKN) pathway or treatment with BGP-15, mitigated the mitochondrial defects and nephrocyte functional decline. These findings support a role for Pink1/Park-mediated mitophagy and associated control of mitochondrial dynamics, essential for function, in diabetic nephropathy; and demonstrate that targeting this pathway might provide therapeutic benefits in type 2 diabetic nephropathy.

Keywords:   Drosophila ; Diabetes; Mitochondria; Nephrocyte; PINK1; PRKN

DOI:  https://doi.org/10.1242/dmm.050471
Biochem Biophys Res Commun. 2024 Apr 03. pii: S0006-291X(24)00422-4. [Epub ahead of print]710 149886

Mdivi-1: Effective but complex mitochondrial fission inhibitor.

Seor I Ahn, Sung Kyung Choi, Myoung Jun Kim, Jinhong Wie, Jueng Soo You.

  Mdivi-1, Mitochondrial DIVIsion inhibitor 1, has been widely employed in research under the assumption that it exclusively influences mitochondrial fusion, but effects other than mitochondrial dynamics have been underinvestigated. This paper provides transcriptome and DNA methylome-wide analysis for Mdivi-1 treated SH-SY5Y human neuroblastoma cells using RNA sequencing (RNA-seq) and methyl capture sequencing (MC-seq) methods. Gene ontology analysis of RNA sequences revealed that p53 transcriptional gene network and DNA replication initiation-related genes were significantly up and down-regulated, respectively, showing the correlation with the arrest cell cycle in the G1 phase. MC-seq, a powerful sequencing method for capturing DNA methylation status in CpG sites, revealed that although Mdivi-1 does not induce dramatic DNA methylation change, the subtle alterations were concentrated within the CpG island. Integrative analysis of both sequencing data disclosed that the p53 transcriptional network was activated while the Parkinson's disease pathway was halted. Next, we investigated several changes in mitochondria in response to Mdivi-1. Copy number and transcription of mitochondrial DNA were suppressed. ROS levels increased, and elevated ROS triggered mitochondrial retrograde signaling rather than inducing direct DNA damage. In this study, we could better understand the molecular network of Mdivi-1 by analyzing DNA methylation and mRNA transcription in the nucleus and further investigating various changes in mitochondria, providing inspiration for studying nuclear-mitochondrial communications.

Keywords:  DNA methylome; Mdivi-1; Mitochondrial dynamics; Mitochondrial retrograde signaling; Transcriptome

DOI:  https://doi.org/10.1016/j.bbrc.2024.149886
Cells. 2024 Mar 30. pii: 607. [Epub ahead of print]13(7):

Cooperation of Various Cytoskeletal Components Orchestrates Intercellular Spread of Mitochondria between B-Lymphoma Cells through Tunnelling Nanotubes.

Henriett Halász, Viktória Tárnai, János Matkó, Miklós Nyitrai, Edina Szabó-Meleg.

  Membrane nanotubes (NTs) are dynamic communication channels connecting spatially separated cells even over long distances and promoting the transport of different cellular cargos. NTs are also involved in the intercellular spread of different pathogens and the deterioration of some neurological disorders. Transport processes via NTs may be controlled by cytoskeletal elements. NTs are frequently observed membrane projections in numerous mammalian cell lines, including various immune cells, but their functional significance in the 'antibody factory' B cells is poorly elucidated. Here, we report that as active channels, NTs of B-lymphoma cells can mediate bidirectional mitochondrial transport, promoted by the cooperation of two different cytoskeletal motor proteins, kinesin along microtubules and myosin VI along actin, and bidirectional transport processes are also supported by the heterogeneous arrangement of the main cytoskeletal filament systems of the NTs. We revealed that despite NTs and axons being different cell extensions, the mitochondrial transport they mediate may exhibit significant similarities. Furthermore, we found that microtubules may improve the stability and lifespan of B-lymphoma-cell NTs, while F-actin strengthens NTs by providing a structural framework for them. Our results may contribute to a better understanding of the regulation of the major cells of humoral immune response to infections.

Keywords:  actin; membrane nanotube; microtubule; mitochondria; motor proteins; transport

DOI:  https://doi.org/10.3390/cells13070607
bioRxiv. 2024 Mar 27. pii: 2024.03.24.584499. [Epub ahead of print]

An Innovative Mitochondrial-targeted Gene Therapy for Cancer Treatment.

Kai Chen, Patrick Ernst, Seulhee Kim, Yingnan Si, Tanvi Varadkar, Matthew D Ringel, Xiaoguang Margaret Liu, Lufang Zhou.

Targeting cancer cell mitochondria holds great therapeutic promise, yet current strategies to specifically and effectively destroy cancer mitochondria in vivo are limited. Here, we introduce mLumiOpto, an innovative mitochondrial-targeted luminoptogenetics gene therapy designed to directly disrupt the inner mitochondrial membrane (IMM) potential and induce cancer cell death. We synthesize a blue light-gated channelrhodopsin (CoChR) in the IMM and co-express a blue bioluminescence-emitting Nanoluciferase (NLuc) in the cytosol of the same cells. The mLumiOpto genes are selectively delivered to cancer cells in vivo by using adeno-associated virus (AAV) carrying a cancer-specific promoter or cancer-targeted monoclonal antibody-tagged exosome-associated AAV. Induction with NLuc luciferin elicits robust endogenous bioluminescence, which activates mitochondrial CoChR, triggering cancer cell IMM permeability disruption, mitochondrial damage, and subsequent cell death. Importantly, mLumiOpto demonstrates remarkable efficacy in reducing tumor burden and killing tumor cells in glioblastoma or triple-negative breast cancer xenografted mouse models. These findings establish mLumiOpto as a novel and promising therapeutic strategy by targeting cancer cell mitochondria in vivo .

DOI: https://doi.org/10.1101/2024.03.24.584499
Cancer Lett. 2024 Apr 05. pii: S0304-3835(24)00240-4. [Epub ahead of print]590 216847

Inhibition of MFN1 restores tamoxifen-induced apoptosis in resistant cells by disrupting aberrant mitochondrial fusion dynamics.

Yuxuan Song, Shuang Ren, Xingmei Chen, Xuhong Li, Lin Chen, Shijie Zhao, Yue Zhang, Xiangchun Shen, Yan Chen.

  Tamoxifen (TAM) resistance presents a major clinical obstacle in the management of estrogen-sensitive breast cancer, highlighting the need to understand the underlying mechanisms and potential therapeutic approaches. We showed that dysregulated mitochondrial dynamics were involved in TAM resistance by protecting against mitochondrial apoptosis. The dysregulated mitochondrial dynamics were associated with increased mitochondrial fusion and decreased fission, thus preventing the release of mitochondrial cytochrome c to the cytoplasm following TAM treatment. Dynamin-related GTPase protein mitofusin 1 (MFN1), which promotes fusion, was upregulated in TAM-resistant cells, and high MFN1 expression indicated a poor prognosis in TAM-treated patients. Mitochondrial translocation of MFN1 and interaction between MFN1 and mitofusin 2 (MFN2) were enhanced to promote mitochondrial outer membrane fusion. The interaction of MFN1 and cristae-shaping protein optic atrophy 1 (OPA1) and OPA1 oligomerization were reduced due to augmented OPA1 proteolytic cleavage, and their apoptosis-promoting function was reduced due to cristae remodeling. Furthermore, the interaction of MFN1 and BAK were increased, which restrained BAK activation following TAM treatment. Knockdown or pharmacological inhibition of MFN1 blocked mitochondrial fusion, restored BAK oligomerization and cytochrome c release, and amplified activation of caspase-3/9, thus sensitizing resistant cells to apoptosis and facilitating the therapeutic effects of TAM both in vivo and in vitro. Conversely, overexpression of MFN1 alleviated TAM-induced mitochondrial apoptosis and promoted TAM resistance in sensitive cells. These results revealed that dysregulated mitochondrial dynamics contributes to the development of TAM resistance, suggesting that targeting MFN1-mediated mitochondrial fusion is a promising strategy to circumvent TAM resistance.

Keywords:  Fusion; Mitochondrial dynamics; Mitofusin 1; Optic atrophy 1; Tamoxifen resistance

DOI:  https://doi.org/10.1016/j.canlet.2024.216847
Sci Rep. 2024 04 09. 14(1): 8263

Balbiani body of basal insects is potentially involved in multiplication and selective elimination of mitochondria.

Malgorzata Sekula, Waclaw Tworzydlo, Szczepan M Bilinski.

Oocytes of both vertebrates and invertebrates often contain an intricate organelle assemblage, termed the Balbiani body (Bb). It has previously been suggested that this assemblage is involved in the delivery of organelles and macromolecules to the germ plasm, formation of oocyte reserve materials, and transfer of mitochondria to the next generation. To gain further insight into the function of the Bb, we performed a series of analyses and experiments, including computer-aided 3-dimensional reconstructions, detection of DNA (mtDNA) synthesis as well as immunolocalization studies. We showed that in orthopteran Meconema meridionale, the Bb comprises a network of mitochondria and perinuclear nuage aggregations. As oogenesis progresses, the network expands filling almost entire ooplasm, then partitions into several smaller entities, termed micro-networks, and ultimately into individual mitochondria. As in somatic cells, this process involves microfilaments and elements of endoplasmic reticulum. We showed also that at least some of the individual mitochondria are surrounded by phagophores and eliminated via mitophagy. These findings support the idea that the Bb is implicated in the multiplication and selective elimination of (defective) mitochondria and therefore may participate in the transfer of undamaged (healthy) mitochondria to the next generation.

DOI: https://doi.org/10.1038/s41598-024-58997-6
Mol Neurobiol. 2024 Apr 06.

Mitophagy Upregulation Occurs Early in the Neurodegenerative Process Mediated by α-Synuclein.

Sarah Hui, Jimmy George, Minesh Kapadia, Hien Chau, Zahn Bariring, Rebecca Earnshaw, Kashfia Shafiq, Lorraine V Kalia, Suneil K Kalia.

  Parkinson's disease (PD) is a progressive neurogenerative movement disorder characterized by dopaminergic cell death within the substantia nigra pars compacta (SNpc) due to the aggregation-prone protein α-synuclein. Accumulation of α-synuclein is implicated in mitochondrial dysfunction and disruption of the autophagic turnover of mitochondria, or mitophagy, which is an essential quality control mechanism proposed to preserve mitochondrial fidelity in response to aging and stress. Yet, the precise relationship between α-synuclein accumulation, mitochondrial autophagy, and dopaminergic cell loss remains unresolved. Here, we determine the kinetics of α-synuclein overexpression and mitophagy using the pH-sensitive fluorescent mito-QC reporter. We find that overexpression of mutant A53T α-synuclein in either human SH-SY5Y cells or rat primary cortical neurons induces mitophagy. Moreover, the accumulation of mutant A53T α-synuclein in the SNpc of rats results in mitophagy dysregulation that precedes the onset of dopaminergic neurodegeneration. This study reveals a role for mutant A53T α-synuclein in inducing mitochondrial dysfunction, which may be an early event contributing to neurodegeneration.

Keywords:  Alpha-synuclein; Lysosomes; Mitochondria dysfunction; Mitophagy; Neurodegeneration; Parkinson’s disease; Substantia nigra pars compacta

DOI:  https://doi.org/10.1007/s12035-024-04131-6
Trends Endocrinol Metab. 2024 Apr 09. pii: S1043-2760(24)00064-X. [Epub ahead of print]

Mitochondrial morphology, distribution and activity during oocyte development.

Devesh Bahety, Elvan Böke, Aida Rodríguez-Nuevo.

  Mitochondria have a crucial role in cellular function and exhibit remarkable plasticity, adjusting both their structure and activity to meet the changing energy demands of a cell. Oocytes, female germ cells that become eggs, undergo unique transformations: the extended dormancy period, followed by substantial increase in cell size and subsequent maturation involving the segregation of genetic material for the next generation, present distinct metabolic challenges necessitating varied mitochondrial adaptations. Recent findings in dormant oocytes challenged the established respiratory complex hierarchies and underscored the extent of mitochondrial plasticity in long-lived oocytes. In this review, we discuss mitochondrial adaptations observed during oocyte development across three vertebrate species (Xenopus, mouse, and human), emphasising current knowledge, acknowledging limitations, and outlining future research directions.

Keywords:  metabolism; mitochondria; oocyte; plasticity

DOI:  https://doi.org/10.1016/j.tem.2024.03.002
Heliyon. 2024 Apr 15. 10(7): e28501

Curcumin simultaneously improves mitochondrial dynamics and myocardial cell bioenergy after sepsis via the SIRT1-DRP1/PGC-1α pathway.

Dongyao Hou, Haitang Liao, Shuai Hao, Ruixue Liu, He Huang, Chenyang Duan.

  Septic cardiomyopathy (SCM) is associated with an imbalance in mitochondrial quality and high mortality rates, with no effective treatment developed to date. Curcumin provides antioxidant, anti-inflammatory, cardiovascular, and mitochondrial protection. However, curcumin has not been confirmed to improve cardiac dysfunction in sepsis. We hypothesized that curcumin can reduce abnormal inflammatory responses by improving mitochondrial function as a novel mechanism to improve SCM. To explore this hypothesis, we used an in vivo male C57BL/6 mouse sepsis model and an in vitro model of lipopolysaccharide-stimulated HL-1 cells. The effects of curcumin on sepsis-induced cardiac dysfunction, inflammatory responses, and mitochondrial quality of cardiac cells were observed using quantitative polymerase chain reaction, western blotting, echocardiography, and transmission electron microscopy. Curcumin activated sirtuin 1 (SIRT1); increased expression of the mitochondrial biogenesis-related genes Pgc1α, Tfam, and Nrf2; reduced dynamin-related protein 1 translocation from the cytoplasm to mitochondria; and restored the mitochondrial morphology and function in cardiac cells. Accordingly, curcumin protected heart function after septic shock and alleviated the effects of SCM. SIRT1 knockdown reversed the protective effects of curcumin on mitochondria. Therefore, curcumin promotes mitochondrial biogenesis and inhibits mitochondrial fragmentation by activating SIRT1, thereby improving the mitochondrial quality and reducing oxidative stress in cardiomyocytes and sepsis-induced cardiac dysfunction. These findings provide new evidence supporting the use of curcumin to treat SCM.

Keywords:  Cardiac dysfunction; Inflammation; Mitochondrial biogenesis; Oxidative stress

DOI:  https://doi.org/10.1016/j.heliyon.2024.e28501
Contact (Thousand Oaks). 2024 Jan-Dec;7:7 25152564241244941

Contacting the gut: Mitochondria-associated Endoplasmic Reticulum Membranes in the Enteric Nervous System.

Jenny Greig, Giada Delfino, Pascal Derkinderen, Sébastien Paillusson.

  Changes in the connections between the endoplasmic reticulum (ER) and mitochondria, as well as alterations in mitochondria-associated ER membrane (MAM) signalling, have been documented in various neurodegenerative diseases affecting the brain. Despite the growing recognition of the significance of the gut-brain axis in neurodegenerative conditions, there has been no prior investigation into the biology of MAM within the enteric nervous system (ENS). Our recent research reveals, for the first time, the existence of connections between the ER and mitochondria within enteric neurons. Additionally, we observed alterations in the dynamics of these connections in the enteric neurons from a mouse model exhibiting age-related neurodegeneration. These findings provide the first detailed characterization of MAM in the ENS under physiological conditions and in a mouse model of age-associated neurodegeneration and shed new light on the potential role of enteric MAM in the context of neurodegenerative disorders.

Keywords:  Alzheimer's disease; Parkinson's disease; ageing; enteric nervous system; mitochondria-associated ER membranes

DOI:  https://doi.org/10.1177/25152564241244941
NPJ Parkinsons Dis. 2024 Apr 09. 10(1): 80

Elevated α-synuclein levels inhibit mitophagic flux.

Inge Kinnart, Liselot Manders, Thibaut Heyninck, Dorien Imberechts, Roman Praschberger, Nils Schoovaerts, Catherine Verfaillie, Patrik Verstreken, Wim Vandenberghe.

The pathogenic effect of SNCA gene multiplications indicates that elevation of wild-type α-synuclein levels is sufficient to cause Parkinson's disease (PD). Mitochondria have been proposed to be a major target of α-synuclein-induced damage. PINK1/parkin/DJ-1-mediated mitophagy is a defense strategy that allows cells to selectively eliminate severely damaged mitochondria. Here, we quantified mitophagic flux and non-mitochondrial autophagic flux in three models of increased α-synuclein expression: 1/Drosophila melanogaster that transgenically express human wild-type and mutant α-synuclein in flight muscle; 2/human skin fibroblasts transfected with α-synuclein or β-synuclein; and 3/human induced pluripotent stem cell (iPSC)-derived neurons carrying an extra copy of wild-type SNCA under control of a doxycycline-inducible promoter, allowing titratable α-synuclein upregulation. In each model, elevated α-synuclein levels potently suppressed mitophagic flux, while non-mitochondrial autophagy was preserved. In human neurons, a twofold increase in wild-type α-synuclein was already sufficient to induce this effect. PINK1 and parkin activation and mitochondrial translocation of DJ-1 after mitochondrial depolarization were not affected by α-synuclein upregulation. Overexpression of the actin-severing protein cofilin or treatment with CK666, an inhibitor of the actin-related protein 2/3 (Arp2/3) complex, rescued mitophagy in neurons with increased α-synuclein, suggesting that excessive actin network stabilization mediated the mitophagy defect. In conclusion, elevated α-synuclein levels inhibit mitophagic flux. Disruption of actin dynamics may play a key role in this effect.

DOI: https://doi.org/10.1038/s41531-024-00696-0
Cell Calcium. 2024 Apr 08. pii: S0143-4160(24)00045-9. [Epub ahead of print]120 102887

A novel probe to monitor lysosome-mitochondria contact sites opens up a new path to study neurodegenerative diseases.

Mai Makino, Shuhei Nakamura.

DOI: https://doi.org/10.1016/j.ceca.2024.102887
J Physiol. 2024 Apr 11.

Right place at the right time: Mitochondrial shape, distribution and inter-organelle interaction during skeletal muscle postnatal development.

Itamar C G Jesus, Marcos Eliezeck, Débora L Scheffer.



Keywords:  inter‐organelle interaction; lipid droplet; mitochondria; postnatal development; skeletal muscle

DOI:  https://doi.org/10.1113/JP286517
ACS Appl Mater Interfaces. 2024 Apr 06.

Mitochondrial Targeted Thermosensitive Nanocarrier for Near-Infrared-Triggered Precise Synergetic Photothermal Nitric Oxide Chemotherapy.

Mi Wang, Mo Zhang, Jianyi Bi, Jincan Li, Xiaoxiao Hu, Lina Zhang, Yao Zhang, Wenli Wang, Yuan Lin, Hong-Bo Cheng, Jing Wang.

  Nitric oxide (NO) intervenes, that is, a potential treatment strategy, and has attracted wide attention in the field of tumor therapy. However, the therapeutic effect of NO is still poor, due to its short half-life and instability. Therapeutic concentration ranges of NO should be delivered to the target tissue sites, cell, and even subcellular organelles and to control NO generation. Mitochondria have been considered a major target in cancer therapy for their essential roles in cancer cell metabolism and apoptosis. In this study, mesoporous silicon-coated gold nanorods encapsulated with a mitochondria targeted and the thermosensitive lipid layer (AuNR@MSN-lipid-DOX) served as the carrier to load NO prodrug (BNN6) to build the near-infrared-triggered synergetic photothermal NO-chemotherapy platform (AuNR@MSN(BNN6)-lipid-DOX). The core of AuNR@MSN exhibited excellent photothermal conversion capability and high loading efficiency in terms of BNN6, reaching a high value of 220 mg/g (w/w), which achieved near-infrared-triggered precise release of NO. The outer biocompatible lipid layer, comprising thermosensitive phospholipid DPPC and mitochondrial-targeted DSPE-PEG2000-DOX, guided the whole nanoparticle to the mitochondria of 4T1 cells observed through confocal microscopy. In the mitochondria, the nanoparticles increased the local temperature over 42 °C under NIR irradiation, and a high NO concentration from BNN6 detected by the NO probe and DSPE-PEG2000-DOX significantly inhibited 4T1 cancer cells in vitro and in vivo under the synergetic photothermal therapy (PTT)-NO therapy-chemotherapy modes. The built NIR-triggered combination therapy nanoplatform can serve as a strategy for multimodal collaboration.

Keywords:  gas therapy; gold nanorods; mesoporous silicon; mitochondria targeting; photothermal therapy; synergistic therapy

DOI:  https://doi.org/10.1021/acsami.3c09997