bims-midtic 2023-09-17 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2023–09–17
twelve papers selected by
Omkar Joshi, Turku Bioscience

A nucleotide diphosphate kinase mediates tethering between mitochondria prior to fusion.
Mitochondrial degradation: Mitophagy and beyond.
Mitochondrial GTP metabolism controls reproductive aging in C. elegans.
Involvement of mitochondrial dynamics and mitophagy in diabetic endothelial dysfunction and cardiac microvascular injury.
Interleukin-6 Facilitates Acute Myeloid Leukemia Chemoresistance via Mitofusin 1-Mediated Mitochondrial Fusion.
Mesenchymal stem cell attenuates spinal cord injury by inhibiting mitochondrial quality control-associated neuronal ferroptosis.
Outer mitochondrial membrane E3 Ub ligase MARCH5 controls mitochondrial steps in peroxisome biogenesis.
Mitochondrial membrane potential acts as a retrograde signal to regulate cell cycle progression.
Enrichment of carcinogen-driven "mitochondria-primed" human skin stem cells and their identification using single-cell analyses.
The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation.
Mit.OnOff: A Science Communication Project for Public Awareness about Mitochondrial Cytopathies.
Mathematical reconstruction of the metabolic network in an in-vitro multiple myeloma model.

J Cell Biol. 2023 Oct 02. pii: e202309037. [Epub ahead of print]222(10):

A nucleotide diphosphate kinase mediates tethering between mitochondria prior to fusion.

Arisa Ikeda, Miho Iijima, Hiromi Sesaki.

Mitochondrial fusion plays an important role in both their structure and function. In this issue, Su et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202301091) report that a nucleoside diphosphate kinase, NME3, facilitates mitochondrial tethering prior to fusion through its direct membrane-binding and hexamerization but not its kinase activity.

DOI: https://doi.org/10.1083/jcb.202309037
Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00656-1. [Epub ahead of print]

Mitochondrial degradation: Mitophagy and beyond.

Louise Uoselis, Thanh Ngoc Nguyen, Michael Lazarou.

  Mitochondria are central hubs of cellular metabolism that also play key roles in signaling and disease. It is therefore fundamentally important that mitochondrial quality and activity are tightly regulated. Mitochondrial degradation pathways contribute to quality control of mitochondrial networks and can also regulate the metabolic profile of mitochondria to ensure cellular homeostasis. Here, we cover the many and varied ways in which cells degrade or remove their unwanted mitochondria, ranging from mitophagy to mitochondrial extrusion. The molecular signals driving these varied pathways are discussed, including the cellular and physiological contexts under which the different degradation pathways are engaged.

Keywords:  MDV; PINK1; Parkin; degradation; mitochondria; mitochondrial quality control; mitophagy; proteasome; selective autophagy; ubiquitin

DOI:  https://doi.org/10.1016/j.molcel.2023.08.021
Dev Cell. 2023 Sep 07. pii: S1534-5807(23)00435-5. [Epub ahead of print]

Mitochondrial GTP metabolism controls reproductive aging in C. elegans.

Yi-Tang Lee, Marzia Savini, Tao Chen, Jin Yang, Qian Zhao, Lang Ding, Shihong Max Gao, Mumine Senturk, Jessica N Sowa, Jue D Wang, Meng C Wang.

  Healthy mitochondria are critical for reproduction. During aging, both reproductive fitness and mitochondrial homeostasis decline. Mitochondrial metabolism and dynamics are key factors in supporting mitochondrial homeostasis. However, how they are coupled to control reproductive health remains unclear. We report that mitochondrial GTP (mtGTP) metabolism acts through mitochondrial dynamics factors to regulate reproductive aging. We discovered that germline-only inactivation of GTP- but not ATP-specific succinyl-CoA synthetase (SCS) promotes reproductive longevity in Caenorhabditis elegans. We further identified an age-associated increase in mitochondrial clustering surrounding oocyte nuclei, which is attenuated by GTP-specific SCS inactivation. Germline-only induction of mitochondrial fission factors sufficiently promotes mitochondrial dispersion and reproductive longevity. Moreover, we discovered that bacterial inputs affect mtGTP levels and dynamics factors to modulate reproductive aging. These results demonstrate the significance of mtGTP metabolism in regulating oocyte mitochondrial homeostasis and reproductive longevity and identify mitochondrial fission induction as an effective strategy to improve reproductive health.

Keywords:  GTP metabolism; bacteria-host interaction; gene-environment interaction; mitochondrial distribution; mitochondrial dynamics; oocyte quality control; reproductive aging; succinyl-CoA synthetase; vitamin B12

DOI:  https://doi.org/10.1016/j.devcel.2023.08.019
Arch Toxicol. 2023 Sep 14.

Involvement of mitochondrial dynamics and mitophagy in diabetic endothelial dysfunction and cardiac microvascular injury.

Xiao Zhang, Hao Zhou, Xing Chang.

  Endothelial cells (ECs), found in the innermost layer of blood vessels, are crucial for maintaining the structure and function of coronary microcirculation. Dysregulated coronary microcirculation poses a fundamental challenge in diabetes-related myocardial microvascular injury, impacting myocardial blood perfusion, thrombogenesis, and inflammation. Extensive research aims to understand the mechanistic connection and functional relationship between cardiac EC dysfunction and the development, diagnosis, and treatment of diabetes-related myocardial microvascular injury. Despite the low mitochondrial content in ECs, mitochondria act as sensors of environmental and cellular stress, influencing EC viability, structure, and function. Mitochondrial dynamics and mitophagy play a vital role in orchestrating mitochondrial responses to various stressors by regulating morphology, localization, and degradation. Impaired mitochondrial dynamics or reduced mitophagy is associated with EC dysfunction, serving as a potential molecular basis and promising therapeutic target for diabetes-related myocardial microvascular injury. This review introduces newly recognized mechanisms of damaged coronary microvasculature in diabetes-related microvascular injury and provides updated insights into the molecular aspects of mitochondrial dynamics and mitophagy. Additionally, novel targeted therapeutic approaches against diabetes-related microvascular injury or endothelial dysfunction, focusing on mitochondrial fission and mitophagy in endothelial cells, are summarized.

Keywords:  Diabetes-related cardiac microvascular injury; Endothelial dysfunction; Mitochondrial dynamics; Mitophagy

DOI:  https://doi.org/10.1007/s00204-023-03599-w
Mol Cancer Res. 2023 Sep 12.

Interleukin-6 Facilitates Acute Myeloid Leukemia Chemoresistance via Mitofusin 1-Mediated Mitochondrial Fusion.

Diyu Hou, Xiaoming Zheng, Danni Cai, Ruolan You, Jingru Liu, Xiaoting Wang, Xinai Liao, Maoqing Tan, Liyan Lin, Jin Wang, Shuxia Zhang, Huifang Huang.

Acute myeloid leukemia (AML), an aggressive hematopoietic malignancy, exhibits poor prognosis and a high recurrence rate largely because of primary and secondary drug resistance. Elevated serum interleukin-6 (IL-6) levels have been observed in patients with AML and are associated with chemoresistance. Chemoresistant AML cells are highly dependent on oxidative phosphorylation (OXPHOS), and mitochondrial network remodeling is essential for mitochondrial function. However, IL-6-mediated regulation of mitochondrial remodeling and its effectiveness as a therapeutic target remain unclear. We aimed to determine the mechanisms through which IL-6 facilitates the development of chemoresistance in AML cells. IL-6 upregulated mitofusin 1 (MFN1)-mediated mitochondrial fusion, promoted OXPHOS, and induced chemoresistance in AML cells. MFN1 knockdown impaired the effects of IL-6 on mitochondrial function and chemoresistance in AML cells. In an MLL::AF9 fusion gene-induced AML mouse model, IL-6 reduced chemosensitivity to cytarabine (Ara-C), a commonly used anti-leukemia drug, accompanied by increased MFN1 expression, mitochondrial fusion, and OXPHOS status. In contrast, anti-IL-6 antibodies downregulated MFN1 expression, suppressed mitochondrial fusion and OXPHOS, enhanced the curative effects of Ara-C, and prolonged overall survival. In conclusion, IL-6 upregulated MFN1-mediated mitochondrial fusion in AML, which facilitated mitochondrial respiration, in turn, inducing chemoresistance. Thus, targeting IL-6 may have therapeutic implications in overcoming IL-6-mediated chemoresistance in AML. Implications: IL-6 treatment induces MFN1-mediated mitochondrial fusion, promotes OXPHOS, and confers chemoresistance in AML cells. Targeting IL-6 regulation in mitochondria is a promising therapeutic strategy to enhance the chemosensitivity of AML.

DOI: https://doi.org/10.1158/1541-7786.MCR-23-0382
Redox Biol. 2023 Sep 07. pii: S2213-2317(23)00272-0. [Epub ahead of print]67 102871

Mesenchymal stem cell attenuates spinal cord injury by inhibiting mitochondrial quality control-associated neuronal ferroptosis.

Senyu Yao, Mao Pang, Yanheng Wang, Xiaokang Wang, Yaobang Lin, Yanyan Lv, Ziqi Xie, Jianfeng Hou, Cong Du, Yuan Qiu, Yuanjun Guan, Bin Liu, Jiancheng Wang, Andy Peng Xiang, Limin Rong.

  Ferroptosis is a newly discovered form of iron-dependent oxidative cell death and drives the loss of neurons in spinal cord injury (SCI). Mitochondrial damage is a critical contributor to neuronal death, while mitochondrial quality control (MQC) is an essential process for maintaining mitochondrial homeostasis to promote neuronal survival. However, the role of MQC in neuronal ferroptosis has not been clearly elucidated. Here, we further demonstrate that neurons primarily suffer from ferroptosis in SCI at the single-cell RNA sequencing level. Mechanistically, disordered MQC aggravates ferroptosis through excessive mitochondrial fission and mitophagy. Furthermore, mesenchymal stem cells (MSCs)-mediated mitochondrial transfer restores neuronal mitochondria pool and inhibits ferroptosis through mitochondrial fusion by intercellular tunneling nanotubes. Collectively, these results not only suggest that neuronal ferroptosis is regulated in an MQC-dependent manner, but also fulfill the molecular mechanism by which MSCs attenuate neuronal ferroptosis at the subcellular organelle level. More importantly, it provides a promising clinical translation strategy based on stem cell-mediated mitochondrial therapy for mitochondria-related central nervous system disorders.

Keywords:  Intercellular mitochondrial transfer; Mesenchymal stem cells; Mitochondrial quality control; Neuronal ferroptosis; Spinal cord injury

DOI:  https://doi.org/10.1016/j.redox.2023.102871
bioRxiv. 2023 Sep 01. pii: 2023.08.31.555756. [Epub ahead of print]

Outer mitochondrial membrane E3 Ub ligase MARCH5 controls mitochondrial steps in peroxisome biogenesis.

Nicolas Verhoeven, Yumiko Oshima, Etienne Cartier, Albert Neutzner, Liron Boyman, Mariusz Karbowski.

Peroxisome de novo biogenesis requires yet unidentified mitochondrial proteins. We report that the outer mitochondrial membrane (OMM)-associated E3 Ub ligase MARCH5 is vital for generating mitochondria-derived pre-peroxisomes. MARCH5 knockout results in accumulation of immature peroxisomes and lower expression of various peroxisomal proteins. Upon fatty acid-induced peroxisomal biogenesis, MARCH5 redistributes to newly formed peroxisomes; the peroxisomal biogenesis under these conditions is inhibited in MARCH5 knockout cells. MARCH5 activity-deficient mutants are stalled on peroxisomes and induce accumulation of peroxisomes containing high levels of the OMM protein Tom20 (mitochondria-derived pre-peroxisomes). Furthermore, depletion of peroxisome biogenesis factor Pex14 leads to the formation of MARCH5- and Tom20-positive peroxisomes, while no peroxisomes are detected in Pex14/MARCH5 dko cells. Reexpression of WT, but not MARCH5 mutants, restores Tom20-positive pre-peroxisomes in Pex14/MARCH5 dko cells. Thus, MARCH5 acts upstream of Pex14 in mitochondrial steps of peroxisome biogenesis. Our data validate the hybrid, mitochondria-dependent model of peroxisome biogenesis and reveal that MARCH5 is an essential mitochondrial protein in this process.
Summary: The authors found that mitochondrial E3 Ub ligase MARCH5 controls the formation of mitochondria-derived pre-peroxisomes. The data support the hybrid, mitochondria-dependent model of peroxisome biogenesis and reveal that MARCH5 is an essential mitochondrial protein in this process.

DOI: https://doi.org/10.1101/2023.08.31.555756
Life Sci Alliance. 2023 Dec;pii: e202302091. [Epub ahead of print]6(12):

Mitochondrial membrane potential acts as a retrograde signal to regulate cell cycle progression.

Choco Michael Gorospe, Gustavo Carvalho, Alicia Herrera Curbelo, Lisa Marchhart, Isabela C Mendes, Katarzyna Niedźwiecka, Paulina H Wanrooij.

Mitochondria are central to numerous metabolic pathways whereby mitochondrial dysfunction has a profound impact and can manifest in disease. The consequences of mitochondrial dysfunction can be ameliorated by adaptive responses that rely on crosstalk from the mitochondria to the rest of the cell. Such mito-cellular signalling slows cell cycle progression in mitochondrial DNA-deficient (ρ0) Saccharomyces cerevisiae cells, but the initial trigger of the response has not been thoroughly studied. Here, we show that decreased mitochondrial membrane potential (ΔΨm) acts as the initial signal of mitochondrial stress that delays G1-to-S phase transition in both ρ0 and control cells containing mtDNA. Accordingly, experimentally increasing ΔΨm was sufficient to restore timely cell cycle progression in ρ0 cells. In contrast, cellular levels of oxidative stress did not correlate with the G1-to-S delay. Restored G1-to-S transition in ρ0 cells with a recovered ΔΨm is likely attributable to larger cell size, whereas the timing of G1/S transcription remained delayed. The identification of ΔΨm as a regulator of cell cycle progression may have implications for disease states involving mitochondrial dysfunction.

DOI: https://doi.org/10.26508/lsa.202302091
STAR Protoc. 2023 Sep 09. pii: S2666-1667(23)00512-9. [Epub ahead of print]4(3): 102545

Enrichment of carcinogen-driven "mitochondria-primed" human skin stem cells and their identification using single-cell analyses.

Swati Agarwala, Mayank Saini, Danitra Parker, Kasturi Mitra.

  Previous work has shown that mitochondria play a critical role in priming stem cells to self-renew and proliferate. Here, we describe a protocol for enriching and identifying the mitochondria-primed stem cells (mpSCs) for their characterization and applications. We describe steps for enriching mpSCs with the environmental carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin in a skin keratinocyte lineage and for identifying mpSCs using single-cell transcriptomics and single-cell microscopy analyses of expression of relevant stem cell markers. For complete details on the use and execution of this protocol, please refer to Spurlock et al.1.

Keywords:  Bioinformatics; Cancer; Cell Biology; Genomics; Metabolism; Microscopy; RNA-seq

DOI:  https://doi.org/10.1016/j.xpro.2023.102545
Cell Rep. 2023 Sep 06. pii: S2211-1247(23)01092-6. [Epub ahead of print] 113081

The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation.

Rowan A Boyd, Saurav Majumder, Johnny Stiban, Grace Mavodza, Alexandra J Straus, Sachin K Kempelingaiah, Varun Reddy, Yusuf A Hannun, Lina M Obeid, Can E Senkal.

  Sphingolipids have key functions in membrane structure and cellular signaling. Ceramide is the central molecule of the sphingolipid metabolism and is generated by ceramide synthases (CerS) in the de novo pathway. Despite their critical function, mechanisms regulating CerS remain largely unknown. Using an unbiased proteomics approach, we find that the small heat shock protein 27 (Hsp27) interacts specifically with CerS1 but not other CerS. Functionally, our data show that Hsp27 acts as an endogenous inhibitor of CerS1. Wild-type Hsp27, but not a mutant deficient in CerS1 binding, inhibits CerS1 activity. Additionally, silencing of Hsp27 enhances CerS1-generated ceramide accumulation in cells. Moreover, phosphorylation of Hsp27 modulates Hsp27-CerS1 interaction and CerS1 activity in acute stress-response conditions. Biologically, we show that Hsp27 knockdown impedes mitochondrial function and induces lethal mitophagy in a CerS1-dependent manner. Overall, we identify an important mode of CerS1 regulation and CerS1-mediated mitophagy through protein-protein interaction with Hsp27.

Keywords:  C18-ceramide; CP: Molecular biology; CerS1; Hsp27; ceramide; ceramide synthase; mitophagy; sphingolipids

DOI:  https://doi.org/10.1016/j.celrep.2023.113081
Endocr Metab Immune Disord Drug Targets. 2023 Sep 14.

Mit.OnOff: A Science Communication Project for Public Awareness about Mitochondrial Cytopathies.

Manuela Grazina, Sara Martins, Maria João Santos, Marta Simões, Carolina Caetano, Beatriz Neves, Sara Varela Amaral, Laurence A Bindoff.

   INTRODUCTION: Mitochondrial diseases are rare, heterogeneous, incurable and complex to diagnose. Probably due to their rareness, there is still a lack of literacy in this area, especially in society, but also in schools and in general, health care services. Accordingly, tools that may bring advancement in science and health literacy are needed. Mit.OnOff is a science communication project based on a bilateral partnership between the University of Coimbra (Portugal) and the University of Bergen (Norway). It aims to inform society about rare diseases related to mitochondrial cytopathies with an emphasis on LHON.
METHODS: The initiative focuses on the creation of an illustrated book explaining the diseases caused by the failure of energy production in simple and accessible language. The aim is to raise awareness (particularly in Portugal and Norway) and provide in-depth knowledge to people suffering from these diseases.
RESULTS/CASE REPORT: This project involves expert scientists in the field of mitochondrial disease, science communicators and artists in alignment with the United Nations SDGs, Agenda 2030. Mit.OnOff is a bilateral partnership (Portugal and Norway) established to address the lack of knowledge and health literacy on the subject of mitochondrial disease. The book will be distributed in both countries, creating a sense of inclusion and visibility and influencing decisions regarding these diseases. It is a relevant educational medium (e.g., schools, health care provision). The distribution of the book is complemented with other communication materials. Oral communications are made, together with public involvement, in which special glasses will be distributed to simulate a mitochondrial disease that leads to blindness (LHON) for the public to experience what it is like living with a rare disease.
CONCLUSION: It is hoped that the production of this book will give patients a sense of inclusion and representation in the media. This, in turn, will contribute to achieving the SDG targets (3,4,5,8,10,12), i.e., ensuring people live healthy lives, reducing child mortality, and increasing life expectancy, ensuring access to inclusive, equitable and quality education for all, ensuring gender equality, and contributing to a peaceful and prosperous world.

Keywords:  LHON; health literacy; mitochondria; mitochondrial cytopathies; mitochondrial diseases; rare diseases; science communication

DOI:  https://doi.org/10.2174/1871530323666230914114434
PLoS Comput Biol. 2023 Sep;19(9): e1011374

Mathematical reconstruction of the metabolic network in an in-vitro multiple myeloma model.

Elias Vera-Siguenza, Cristina Escribano-Gonzalez, Irene Serrano-Gonzalo, Kattri-Liis Eskla, Fabian Spill, Daniel Tennant.

It is increasingly apparent that cancer cells, in addition to remodelling their metabolism to survive and proliferate, adapt and manipulate the metabolism of other cells. This property may be a telling sign that pre-clinical tumour metabolism studies exclusively utilising in-vitro mono-culture models could prove to be limited for uncovering novel metabolic targets able to translate into clinical therapies. Although this is increasingly recognised, and work towards addressing the issue is becoming routinary much remains poorly understood. For instance, knowledge regarding the biochemical mechanisms through which cancer cells manipulate non-cancerous cell metabolism, and the subsequent impact on their survival and proliferation remains limited. Additionally, the variations in these processes across different cancer types and progression stages, and their implications for therapy, also remain largely unexplored. This study employs an interdisciplinary approach that leverages the predictive power of mathematical modelling to enrich experimental findings. We develop a functional multicellular in-silico model that facilitates the qualitative and quantitative analysis of the metabolic network spawned by an in-vitro co-culture model of bone marrow mesenchymal stem- and myeloma cell lines. To procure this model, we devised a bespoke human genome constraint-based reconstruction workflow that combines aspects from the legacy mCADRE & Metabotools algorithms, the novel redHuman algorithm, along with 13C-metabolic flux analysis. Our workflow transforms the latest human metabolic network matrix (Recon3D) into two cell-specific models coupled with a metabolic network spanning a shared growth medium. When cross-validating our in-silico model against the in-vitro model, we found that the in-silico model successfully reproduces vital metabolic behaviours of its in-vitro counterpart; results include cell growth predictions, respiration rates, as well as support for observations which suggest cross-shuttling of redox-active metabolites between cells.

DOI: https://doi.org/10.1371/journal.pcbi.1011374