bims-midtic 2024-03-10 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2024–03–10
seventeen papers selected by
Omkar Joshi, Turku Bioscience

ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission.
C5a-C5aR1 axis controls mitochondrial fission to promote podocyte injury in lupus nephritis.
The interplay between mitochondrial dynamics and autophagy: From a key homeostatic mechanism to a driver of pathology.
Mitochondrial fission enhances IL-6-induced metastatic potential in ovarian cancer via ERK1/2 activation.
Miro-mediated mitochondrial transport: A new dimension for disease-related abnormal cell metabolism?
Inhibition of Drp1- Fis1 interaction alleviates aberrant mitochondrial fragmentation and acute kidney injury.
CLU (clusterin) and PPARGC1A/PGC1α coordinately control mitophagy and mitochondrial biogenesis for oral cancer cell survival.
Drp1: Focus on Diseases Triggered by the Mitochondrial Pathway.
Two ancient membrane pores mediate mitochondrial-nucleus membrane contact sites.
Activity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo.
Defects of mitochondria-lysosomes communication induce secretion of mitochondria-derived vesicles and drive chemoresistance in ovarian cancer cells.
How and When to Measure Mitochondrial Inner Membrane Potentials.
A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.
Stem Leydig cells support macrophage immunological homeostasis through mitochondrial transfer in mice.
Targeting mitochondrial dynamics and redox regulation in cardiovascular diseases.
Localization of RNAs to the Mitochondria - Mechanisms and Functions.
Phase separation of SHP2E76K promotes malignant transformation of mesenchymal stem cells by activating mitochondrial complexes.

Cell Death Dis. 2024 Mar 02. 15(3): 184

ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission.

Palamou Das, Oishee Chakrabarti.

Dynamin related protein 1 (DRP1), a pivotal mitochondrial fission protein, is post-translationally modified by multiple mechanisms. Here we identify a new post-translational modification of DRP1 by the ubiquitin-like protein, interferon-stimulated gene 15 (ISG15). DRP1 ISGylation is mediated by ISG15 E3 ligase, HERC5; this promotes mitochondrial fission. DeISGylation of DRP1 however leads to hyperfusion. Heterologous expression of SARS-CoV2 PLpro, a deISGylating enzyme, results in similar mitochondrial filamentation, significant decrease in total DRP1 protein levels and efflux of mtDNA. We report that deISGylated DRP1 gets ubiquitylated and degraded by TRIM25, instead of PARKIN and MITOL. While the cytosolic pool of DRP1 is primarily ISGylated, both mitochondrial and cytosolic fractions may be ubiquitylated. It is known that phosphorylation of DRP1 at S616 residue regulates its mitochondrial localisation; we show that ISGylation of phospho-DRP1 (S616) renders fission competence at mitochondria. This is significant because DRP1 ISGylation affects its functionality and mitochondrial dynamics in Alzheimer's disease pathophysiology.

DOI: https://doi.org/10.1038/s41419-024-06543-7
Mol Ther. 2024 Mar 06. pii: S1525-0016(24)00144-8. [Epub ahead of print]

C5a-C5aR1 axis controls mitochondrial fission to promote podocyte injury in lupus nephritis.

Baokui Ye, Binfeng Chen, Chaohuan Guo, Ningjing Xiong, Yuefang Huang, Mengyuan Li, Yimei Lai, Jin Li, Mianjing Zhou, Shuang Wang, Shuyi Wang, Niansheng Yang, Hui Zhang.

  Podocytes are essential to maintaining the integrity of the glomerular filtration barrier, yet they are frequently affected in lupus nephritis (LN). Here, we show that the significant upregulation of Drp1S616 phosphorylation in podocytes promotes mitochondrial fission, leading to mitochondrial dysfunction and podocyte injury in LN. Inhibition or knockdown of Drp1 promotes mitochondrial fusion and protects podocytes from injury induced by LN serum. In vivo, pharmacological inhibition of Drp1 reduces the phosphorylation of Drp1S616 in podocytes in lupus-prone mice. Podocyte injury is reversed when Drp1 is inhibited, resulting in the alleviation of proteinuria. Mechanistically, complement component C5a (C5a) upregulates the phosphorylation of Drp1S616 and promotes mitochondrial fission in podocytes. Moreover, the expression of C5a receptor 1 (C5aR1) is notably upregulated in podocytes in LN. C5a-C5aR1 axis-controlled phosphorylation of Drp1S616 and mitochondrial fission are substantially suppressed when C5aR1 is knocked down by siRNA. Moreover, lupus-prone mice treated with C5aR inhibitor show reduced phosphorylation of Drp1S616 in podocytes, resulting in significantly less podocyte damage. Together, this study uncovers a novel mechanism by which the C5a-C5aR1 axis promotes podocyte injury by enhancing Drp1-mediated mitochondrial fission, which could have significant implications for the treatment of LN.

Keywords:  C5a-C5aR1 axis; Drp1; lupus nephritis; mitochondrial fission; podocyte injury

DOI:  https://doi.org/10.1016/j.ymthe.2024.03.003
Semin Cell Dev Biol. 2024 Mar 01. pii: S1084-9521(24)00022-3. [Epub ahead of print]161-162 1-19

The interplay between mitochondrial dynamics and autophagy: From a key homeostatic mechanism to a driver of pathology.

Alice Lacombe, Luca Scorrano.

  The complex relationship between mitochondrial dynamics and autophagy illustrates how two cellular housekeeping processes are intimately linked, illuminating fundamental principles of cellular homeostasis and shedding light on disparate pathological conditions including several neurodegenerative disorders. Here we review the basic tenets of mitochondrial dynamics i.e., the concerted balance between fusion and fission of the organelle, and its interplay with macroautophagy and selective mitochondrial autophagy, also dubbed mitophagy, in the maintenance of mitochondrial quality control and ultimately in cell viability. We illustrate how conditions of altered mitochondrial dynamics reverberate on autophagy and vice versa. Finally, we illustrate how altered interplay between these two key cellular processes participates in the pathogenesis of human disorders affecting multiple organs and systems.

Keywords:  Mitochondria; autophagy; diseases; fusion-fission; mitophagy

DOI:  https://doi.org/10.1016/j.semcdb.2024.02.001
Cancer Sci. 2024 Mar 03.

Mitochondrial fission enhances IL-6-induced metastatic potential in ovarian cancer via ERK1/2 activation.

Juwon Lee, Youngjin Han, Soochi Kim, HyunA Jo, Wenyu Wang, Untack Cho, Se Ik Kim, Boyun Kim, Yong Sang Song.

  Ovarian cancer is a lethal gynecologic cancer mostly diagnosed in an advanced stage with an accumulation of ascites. Interleukin-6 (IL-6), a pro-inflammatory cytokine is highly elevated in malignant ascites and plays a pleiotropic role in cancer progression. Mitochondria are dynamic organelles that undergo fission and fusion in response to external stimuli and dysregulation in their dynamics has been implicated in cancer progression and metastasis. Here, we investigate the effect of IL-6 on mitochondrial dynamics in ovarian cancer cells (OVCs) and its impact on metastatic potential. Treatment with IL-6 on ovarian cancer cell lines (SKOV3 and PA-1) led to an elevation in the metastatic potential of OVCs. Interestingly, a positive association was observed between dynamin-related protein 1 (Drp1), a regulator of mitochondrial fission, and IL-6R in metastatic ovarian cancer tissues. Additionally, IL-6 treatment on OVCs was linked to the activation of Drp1, with a notable increase in the ratio of the inhibitory form p-Drp1(S637) to the active form p-Drp1(S616), indicating enhanced mitochondrial fission. Moreover, IL-6 treatment triggered the activation of ERK1/2, and inhibiting ERK1/2 mitigated IL-6-induced mitochondrial fission. Suppressing mitochondrial fission through siRNA transfection and a pharmacological inhibitor reduced the IL-6-induced migration and invasion of OVCs. This was further supported by 3D invasion assays using patient-derived spheroids. Altogether, our study suggests the role of mitochondrial fission in the metastatic potential of OVCs induced by IL-6. The inhibition of mitochondrial fission could be a potential therapeutic approach to suppress the metastasis of ovarian cancer.

Keywords:  Drp13; IL-62; metastasis5; mitochondria1; ovarian cancer4

DOI:  https://doi.org/10.1111/cas.16064
Biochem Biophys Res Commun. 2024 Feb 27. pii: S0006-291X(24)00273-0. [Epub ahead of print]705 149737

Miro-mediated mitochondrial transport: A new dimension for disease-related abnormal cell metabolism?

Yanxing Li, Zhen Yang, Shumei Zhang, Jianjun Li.

  Mitochondria are versatile and highly dynamic organelles found in eukaryotic cells that play important roles in a variety of cellular processes. The importance of mitochondrial transport in cell metabolism, including variations in mitochondrial distribution within cells and intercellular transfer, has grown in recent years. Several studies have demonstrated that abnormal mitochondrial transport represents an early pathogenic alteration in a variety of illnesses, emphasizing its significance in disease development and progression. Mitochondrial Rho GTPase (Miro) is a protein found on the outer mitochondrial membrane that is required for cytoskeleton-dependent mitochondrial transport, mitochondrial dynamics (fusion and fission), and mitochondrial Ca2+ homeostasis. Miro, as a critical regulator of mitochondrial transport, has yet to be thoroughly investigated in illness. This review focuses on recent developments in recognizing Miro as a crucial molecule in controlling mitochondrial transport and investigates its roles in diverse illnesses. It also intends to shed light on the possibilities of targeting Miro as a therapeutic method for a variety of diseases.

Keywords:  Cancer; Cell metabolism; Central nervous system disease; Miro; Mitochondrial transport; Tunneling nanotuble

DOI:  https://doi.org/10.1016/j.bbrc.2024.149737
Cell Mol Biol Lett. 2024 Mar 04. 29(1): 31

Inhibition of Drp1- Fis1 interaction alleviates aberrant mitochondrial fragmentation and acute kidney injury.

Zhixia Song, Yao Xia, Lang Shi, Hongchu Zha, Jing Huang, Xiaohong Xiang, Huiming Li, Hua Huang, Ruchi Yue, Hongtao Wang, Jiefu Zhu.

   BACKGROUND: Acute kidney injury (AKI) is a common clinical disorder with complex etiology and poor prognosis, and currently lacks specific and effective treatment options. Mitochondrial dynamics dysfunction is a prominent feature in AKI, and modulation of mitochondrial morphology may serve as a potential therapeutic approach for AKI.
METHODS: We induced ischemia-reperfusion injury (IRI) in mice (bilateral) and Bama pigs (unilateral) by occluding the renal arteries. ATP depletion and recovery (ATP-DR) was performed on proximal renal tubular cells to simulate in vitro IRI. Renal function was evaluated using creatinine and urea nitrogen levels, while renal structural damage was assessed through histopathological staining. The role of Drp1 was investigated using immunoblotting, immunohistochemistry, immunofluorescence, and immunoprecipitation techniques. Mitochondrial morphology was evaluated using confocal microscopy.
RESULTS: Renal IRI induced significant mitochondrial fragmentation, accompanied by Dynamin-related protein 1 (Drp1) translocation to the mitochondria and Drp1 phosphorylation at Ser616 in the early stages (30 min after reperfusion), when there was no apparent structural damage to the kidney. The use of the Drp1 inhibitor P110 significantly improved kidney function and structural damage. P110 reduced Drp1 mitochondrial translocation, disrupted the interaction between Drp1 and Fis1, without affecting the binding of Drp1 to other mitochondrial receptors such as MFF and Mid51. High-dose administration had no apparent toxic side effects. Furthermore, ATP-DR induced mitochondrial fission in renal tubular cells, accompanied by a decrease in mitochondrial membrane potential and an increase in the translocation of the pro-apoptotic protein Bax. This process facilitated the release of dsDNA, triggering the activation of the cGAS-STING pathway and promoting inflammation. P110 attenuated mitochondrial fission, suppressed Bax mitochondrial translocation, prevented dsDNA release, and reduced the activation of the cGAS-STING pathway. Furthermore, these protective effects of P110 were also observed renal IRI model in the Bama pig and folic acid-induced nephropathy in mice.
CONCLUSIONS: Dysfunction of mitochondrial dynamics mediated by Drp1 contributes to renal IRI. The specific inhibitor of Drp1, P110, demonstrated protective effects in both in vivo and in vitro models of AKI.

Keywords:  Acute kidney injury; Drp1; Fis1; Ischemia reperfusion injury; Mitochondria

DOI:  https://doi.org/10.1186/s11658-024-00553-1
Autophagy. 2024 Mar 06. 1-25

CLU (clusterin) and PPARGC1A/PGC1α coordinately control mitophagy and mitochondrial biogenesis for oral cancer cell survival.

Prakash P Praharaj, Srimanta Patra, Amruta Singh, Debasna P Panigrahi, Hwa Y Lee, Mohammad F Kabir, Muhammad K Hossain, Samir K Patra, Birija S Patro, Shankargouda Patil, Daniel J Klionsky, Han J Chae, Sujit K Bhutia.

  Mitophagy involves the selective elimination of defective mitochondria during chemotherapeutic stress to maintain mitochondrial homeostasis and sustain cancer growth. Here, we showed that CLU (clusterin) is localized to mitochondria to induce mitophagy controlling mitochondrial damage in oral cancer cells. Moreover, overexpression and knockdown of CLU establish its mitophagy-specific role, where CLU acts as an adaptor protein that coordinately interacts with BAX and LC3 recruiting autophagic machinery around damaged mitochondria in response to cisplatin treatment. Interestingly, CLU triggers class III phosphatidylinositol 3-kinase (PtdIns3K) activity around damaged mitochondria, and inhibition of mitophagic flux causes the accumulation of excessive mitophagosomes resulting in reactive oxygen species (ROS)-dependent apoptosis during cisplatin treatment in oral cancer cells. In parallel, we determined that PPARGC1A/PGC1α (PPARG coactivator 1 alpha) activates mitochondrial biogenesis during CLU-induced mitophagy to maintain the mitochondrial pool. Intriguingly, PPARGC1A inhibition through small interfering RNA (siPPARGC1A) and pharmacological inhibitor (SR-18292) treatment counteracts CLU-dependent cytoprotection leading to mitophagy-associated cell death. Furthermore, co-treatment of SR-18292 with cisplatin synergistically suppresses tumor growth in oral cancer xenograft models. In conclusion, CLU and PPARGC1A are essential for sustained cancer cell growth by activating mitophagy and mitochondrial biogenesis, respectively, and their inhibition could provide better therapeutic benefits against oral cancer.

Keywords:  Clusterin; PPARGC1A/PGC1α; mitochondrial biogenesis; mitophagy; mitophagy-associated cell death

DOI:  https://doi.org/10.1080/15548627.2024.2309904
Cell Biochem Biophys. 2024 Mar 04.

Drp1: Focus on Diseases Triggered by the Mitochondrial Pathway.

Fulin Sun, Min Fang, Huhu Zhang, Qinghang Song, Shuang Li, Ya Li, Shuyao Jiang, Lina Yang.

  Drp1 (Dynamin-Related Protein 1) is a cytoplasmic GTPase protein encoded by the DNM1L gene that influences mitochondrial dynamics by mediating mitochondrial fission processes. Drp1 has been demonstrated to play an important role in a variety of life activities such as cell survival, proliferation, migration, and death. Drp1 has been shown to play different physiological roles under different physiological conditions, such as normal and inflammation. Recently studies have revealed that Drp1 plays a critical role in the occurrence, development, and aggravation of a series of diseases, thereby it serves as a potential therapeutic target for them. In this paper, we review the structure and biological properties of Drp1, summarize the biological processes that occur in the inflammatory response to Drp1, discuss its role in various cancers triggered by the mitochondrial pathway and investigate effective methods for targeting Drp1 in cancer treatment. We also synthesized the phenomena of Drp1 involving in the triggering of other diseases. The results discussed herein contribute to our deeper understanding of mitochondrial kinetic pathway-induced diseases and their therapeutic applications. It is critical for advancing the understanding of the mechanisms of Drp1-induced mitochondrial diseases and preventive therapies.

Keywords:  Alzheimer’s disease; Cancer; Dynamin-Related Protein 1; Inflammation response; Mitochondrial dynamics; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12013-024-01245-5
J Cell Biol. 2024 Apr 01. pii: e202304075. [Epub ahead of print]223(4):

Two ancient membrane pores mediate mitochondrial-nucleus membrane contact sites.

Jana Ovciarikova, Shikha Shikha, Alice Lacombe, Flavie Courjol, Rosalind McCrone, Wasim Hussain, Andrew Maclean, Leandro Lemgruber, Erica S Martins-Duarte, Mathieu Gissot, Lilach Sheiner.

Coordination between nucleus and mitochondria is essential for cell survival, and thus numerous communication routes have been established between these two organelles over eukaryotic cell evolution. One route for organelle communication is via membrane contact sites, functional appositions formed by molecular tethers. We describe a novel nuclear-mitochondrial membrane contact site in the protozoan Toxoplasma gondii. We have identified specific contacts occurring at the nuclear pore and demonstrated an interaction between components of the nuclear pore and the mitochondrial protein translocon, highlighting them as molecular tethers. Genetic disruption of the nuclear pore or the TOM translocon components, TgNup503 or TgTom40, respectively, result in contact site reduction, supporting their potential involvement in this tether. TgNup503 depletion further leads to specific mitochondrial morphology and functional defects, supporting a role for nuclear-mitochondrial contacts in mediating their communication. The discovery of a contact formed through interaction between two ancient mitochondrial and nuclear complexes sets the ground for better understanding of mitochondrial-nuclear crosstalk in eukaryotes.

DOI: https://doi.org/10.1083/jcb.202304075
Nat Commun. 2024 Mar 08. 15(1): 2142

Activity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo.

Daniel M Virga, Stevie Hamilton, Bertha Osei, Abigail Morgan, Parker Kneis, Emiliano Zamponi, Natalie J Park, Victoria L Hewitt, David Zhang, Kevin C Gonzalez, Fiona M Russell, D Grahame Hardie, Julien Prudent, Erik Bloss, Attila Losonczy, Franck Polleux, Tommy L Lewis.

Neuronal mitochondria play important roles beyond ATP generation, including Ca2+ uptake, and therefore have instructive roles in synaptic function and neuronal response properties. Mitochondrial morphology differs significantly between the axon and dendrites of a given neuronal subtype, but in CA1 pyramidal neurons (PNs) of the hippocampus, mitochondria within the dendritic arbor also display a remarkable degree of subcellular, layer-specific compartmentalization. In the dendrites of these neurons, mitochondria morphology ranges from highly fused and elongated in the apical tuft, to more fragmented in the apical oblique and basal dendritic compartments, and thus occupy a smaller fraction of dendritic volume than in the apical tuft. However, the molecular mechanisms underlying this striking degree of subcellular compartmentalization of mitochondria morphology are unknown, precluding the assessment of its impact on neuronal function. Here, we demonstrate that this compartment-specific morphology of dendritic mitochondria requires activity-dependent, Ca2+ and Camkk2-dependent activation of AMPK and its ability to phosphorylate two direct effectors: the pro-fission Drp1 receptor Mff and the recently identified anti-fusion, Opa1-inhibiting protein, Mtfr1l. Our study uncovers a signaling pathway underlying the subcellular compartmentalization of mitochondrial morphology in dendrites of neurons in vivo through spatially precise and activity-dependent regulation of mitochondria fission/fusion balance.

DOI: https://doi.org/10.1038/s41467-024-46463-w
Cell Commun Signal. 2024 Mar 06. 22(1): 165

Defects of mitochondria-lysosomes communication induce secretion of mitochondria-derived vesicles and drive chemoresistance in ovarian cancer cells.

Sinforosa Gagliardi, Marco Mitruccio, Riccardo Di Corato, Roberta Romano, Alessandra Aloisi, Rosaria Rinaldi, Pietro Alifano, Flora Guerra, Cecilia Bucci.

   BACKGROUND: Among the mechanisms of mitochondrial quality control (MQC), generation of mitochondria-derived vesicles (MDVs) is a process to avoid complete failure of mitochondria determining lysosomal degradation of mitochondrial damaged proteins. In this context, RAB7, a late endocytic small GTPase, controls delivery of MDVs to late endosomes for subsequent lysosomal degradation. We previously demonstrated that RAB7 has a pivotal role in response to cisplatin (CDDP) regulating resistance to the drug by extracellular vesicle (EVs) secretion.
METHODS: Western blot and immunofluorescence analysis were used to analyze structure and function of endosomes and lysosomes in CDDP chemosensitive and chemoresistant ovarian cancer cell lines. EVs were purified from chemosensitive and chemoresistant cells by ultracentrifugation or immunoisolation to analyze their mitochondrial DNA and protein content. Treatment with cyanide m-chlorophenylhydrazone (CCCP) and RAB7 modulation were used, respectively, to understand the role of mitochondrial and late endosomal/lysosomal alterations on MDV secretion. Using conditioned media from chemoresistant cells the effect of MDVs on the viability after CDDP treatment was determined. Seahorse assays and immunofluorescence analysis were used to study the biochemical role of MDVs and the uptake and intracellular localization of MDVs, respectively.
RESULTS: We observed that CDDP-chemoresistant cells are characterized by increased MDV secretion, impairment of late endocytic traffic, RAB7 downregulation, an increase of RAB7 in EVs, compared to chemosensitive cells, and downregulation of the TFEB-mTOR pathway overseeing lysosomal and mitochondrial biogenesis and turnover. We established that MDVs can be secreted rather than delivered to lysosomes and are able to deliver CDDP outside the cells. We showed increased secretion of MDVs by chemoresistant cells ultimately caused by the extrusion of RAB7 in EVs, resulting in a dramatic drop in its intracellular content, as a novel mechanism to regulate RAB7 levels. We demonstrated that MDVs purified from chemoresistant cells induce chemoresistance in RAB7-modulated process, and, after uptake from recipient cells, MDVs localize to mitochondria and slow down mitochondrial activity.
CONCLUSIONS: Dysfunctional MQC in chemoresistant cells determines a block in lysosomal degradation of MDVs and their consequent secretion, suggesting that MQC is not able to eliminate damaged mitochondria whose components are secreted becoming effectors and potential markers of chemoresistance.

Keywords:  Cisplatin chemoresistance; Extracellular vesicles; Mitochondria-derived vesicles; Ovarian cancer; RAB7

DOI:  https://doi.org/10.1186/s12964-024-01507-y
Biophys J. 2024 Mar 06. pii: S0006-3495(24)00176-0. [Epub ahead of print]

How and When to Measure Mitochondrial Inner Membrane Potentials.

Alicia J Kowaltowski, Fernando Abdulkader.

The scientific literature on mitochondria has increased significantly over the years, due to findings that these organelles have widespread roles in the onset and progression of pathological conditions such as metabolic disorders, neurodegenerative and cardiovascular diseases, inflammation, and cancer. Researchers have extensively explored how mitochondrial properties and functions are modified in different models, often using fluorescent inner mitochondrial membrane potential (ΔΨm) probes to assess functional mitochondrial aspects such as protonmotive force and oxidative phosphorylation. This review provides an overview of existing techniques to measure ΔpH and ΔΨm, highlighting their advantages, limitations, and applications. It discusses drawbacks of ΔΨm probes, especially when used without calibration, and conditions where alternative methods should replace ΔΨm measurements for the benefit of the specific scientific objectives entailed. Studies investigating mitochondria and their vast biological roles would be significantly advanced by the understanding of the correct applications as well as limitations of protonmotive force measurements and use of fluorescent ΔΨm probes, adopting more precise, artifact-free, sensitive, and quantitative measurements of mitochondrial functionality.

DOI: https://doi.org/10.1016/j.bpj.2024.03.011
Cell Stem Cell. 2024 Mar 07. pii: S1934-5909(24)00047-X. [Epub ahead of print]31(3): 359-377.e10

A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.

Massimo Bonora, Claudia Morganti, Nick van Gastel, Kyoko Ito, Enrica Calura, Ilaria Zanolla, Letizia Ferroni, Yang Zhang, Yookyung Jung, Gabriele Sales, Paolo Martini, Takahisa Nakamura, Francesco Massimo Lasorsa, Toren Finkel, Charles P Lin, Barbara Zavan, Paolo Pinton, Irene Georgakoudi, Chiara Romualdi, David T Scadden, Keisuke Ito.

  Mitochondrial fatty acid oxidation (FAO) is essential for hematopoietic stem cell (HSC) self-renewal; however, the mechanism by which mitochondrial metabolism controls HSC fate remains unknown. Here, we show that within the hematopoietic lineage, HSCs have the largest mitochondrial NADPH pools, which are required for proper HSC cell fate and homeostasis. Bioinformatic analysis of the HSC transcriptome, biochemical assays, and genetic inactivation of FAO all indicate that FAO-generated NADPH fuels cholesterol synthesis in HSCs. Interference with FAO disturbs the segregation of mitochondrial NADPH toward corresponding daughter cells upon single HSC division. Importantly, we have found that the FAO-NADPH-cholesterol axis drives extracellular vesicle (EV) biogenesis and release in HSCs, while inhibition of EV signaling impairs HSC self-renewal. These data reveal the existence of a mitochondrial NADPH-cholesterol axis for EV biogenesis that is required for hematopoietic homeostasis and highlight the non-stochastic nature of HSC fate determination.

Keywords:  HSC self-renewal; NADPH; cholesterol; exosomes; extracellular vesicles; fate determination; fatty acid oxidation; hematopoietic stem cell; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.stem.2024.02.004
Nat Commun. 2024 Mar 08. 15(1): 2120

Stem Leydig cells support macrophage immunological homeostasis through mitochondrial transfer in mice.

Ani Chi, Bicheng Yang, Hao Dai, Xinyu Li, Jiahui Mo, Yong Gao, Zhihong Chen, Xin Feng, Menghui Ma, Yanqing Li, Chao Yang, Jie Liu, Hanchao Liu, Zhenqing Wang, Feng Gao, Yan Liao, Xuetao Shi, Chunhua Deng, Min Zhang.

As testicular mesenchymal stromal cells, stem Leydig cells (SLCs) show great promise in the treatment of male hypogonadism. The therapeutic functions of mesenchymal stromal cells are largely determined by their reciprocal regulation by immune responses. However, the immunoregulatory properties of SLCs remain unclear. Here, we observe that SLCs transplantation restore male fertility and testosterone production in an ischemia‒reperfusion injury mouse model. SLCs prevent inflammatory cascades through mitochondrial transfer to macrophages. Reactive oxygen species (ROS) released from activated macrophages inducing mitochondrial transfer from SLCs to macrophages in a transient receptor potential cation channel subfamily member 7 (TRPM7)-mediated manner. Notably, knockdown of TRPM7 in transplanted SLCs compromised therapeutic outcomes in both testicular ischemia‒reperfusion and testicular aging mouse models. These findings reveal a new mechanism of SLCs transplantation that may contribute to preserve testis function in male patients with hypogonadism related to immune disorders.

DOI: https://doi.org/10.1038/s41467-024-46190-2
Trends Pharmacol Sci. 2024 Mar 07. pii: S0165-6147(24)00028-2. [Epub ahead of print]

Targeting mitochondrial dynamics and redox regulation in cardiovascular diseases.

Mirza Ahmar Beg, Minqi Huang, Lance Vick, K N Shashanka Rao, Jue Zhang, Yiliang Chen.

  Accumulating evidence highlights the pivotal role of mitochondria in cardiovascular diseases (CVDs). Understanding the molecular mechanisms underlying mitochondrial dysfunction is crucial for developing targeted therapeutics. Recent years have seen substantial advancements in unraveling mitochondrial regulatory pathways in both normal and pathological states and the development of potent drugs. However, specific delivery of drugs into the mitochondria is still a challenge. We present recent findings on regulators of mitochondrial dynamics and reactive oxygen species (ROS), critical factors influencing mitochondrial function in CVDs. We also discuss advancements in drug delivery strategies aimed at overcoming the technical barrier in targeting mitochondria for CVD treatment.

Keywords:  atherosclerosis; cardiovascular disease; drug delivery; fission/fusion; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.1016/j.tips.2024.02.001
RNA. 2024 Mar 06. pii: rna.079999.124. [Epub ahead of print]

Localization of RNAs to the Mitochondria - Mechanisms and Functions.

Surbhi Sharma, Furqan M Fazal.

  The mammalian mitochondrial proteome comprises over 1000 proteins, with the majority translated from nuclear-encoded messenger RNAs (mRNAs). Mounting evidence suggests many of these mRNAs are localized to the outer mitochondrial membrane (OMM) in a pre-or co-translational state. Upon reaching the mitochondrial surface, these mRNAs are locally translated to produce proteins that are co-translationally imported into mitochondria. Here, we summarize various mechanisms cells employ to localize RNAs, including transfer RNAs (tRNAs), to the OMM and recent technological advancements in the field to study these processes. While most early studies in the field were carried out in yeast, recent studies reveal RNA localization to the OMM and their regulation in higher organisms. Various factors regulate this localization process, including RNA sequence elements, RNA binding proteins (RBPs), cytoskeletal motors, and translation machinery. In this review, we also highlight the role of RNA structures and modifications in mitochondrial RNA localization and discuss how these features can alter the binding properties of RNAs. Finally, in addition to RNAs related to mitochondrial function, RNAs involved in other cellular processes can also localize to the OMM, including those implicated in the innate immune response and piRNA biogenesis. As impairment of mRNA localization and regulation compromise mitochondrial function, future studies will undoubtedly expand our understanding of how RNAs localize to the OMM and investigate the consequences of their mislocalization in disorders, particularly neurodegenerative diseases, muscular dystrophies, and cancers.

Keywords:  Imaging; Mitochondrial Biology; RNA Subcellular Localization; Technologies; Transcriptomics

DOI:  https://doi.org/10.1261/rna.079999.124
JCI Insight. 2024 Mar 07. pii: e170340. [Epub ahead of print]

Phase separation of SHP2E76K promotes malignant transformation of mesenchymal stem cells by activating mitochondrial complexes.

Chen Kan, Zhenya Tan, Liwei Liu, Bo Liu, Li Zhan, Jicheng Zhu, Xiaofei Li, Keqiong Lin, Jia Liu, Yakun Liu, Fan Yang, Mandy Wong, Siying Wang, Hong Zheng.

  Mesenchymal stem cells, suffering from diverse gene hits, undergoes malignant transformation and aberrant osteochondral differentiation. Src homology region 2- (SH2-) containing protein tyrosine phosphatase 2 (SHP2), a non-receptor protein tyrosine phosphatase, regulates multicellular differentiation, proliferation, and transformation. However, the role of SHP2 in MSC fate determination remains unclear. Here, we showed that MSCs bearing the activating SHP2E76K mutation underwent malignant transformation into sarcoma stem-like cells (SSCs). We revealed that the SHP2E76K mutation in mouse MSCs led to hyperactive mitochondrial metabolism by activating mitochondrial complexes I and III. Inhibition of complexes I and III prevented hyperactive mitochondrial metabolism and malignant transformation of SHP2E76K MSCs. Mechanistically, we confirmed that SHP2 underwent liquid-liquid phase separation (LLPS) in SHP2E76K MSCs. SHP2 LLPS led to its dissociation from complexes I and III, causing their hyperactivation. Blockade of SHP2 LLPS by LLPS‒defective mutations or allosteric inhibitors suppressed complex I and III hyperactivation as well as malignant transformation of SHP2E76K MSCs. These findings reveal that complex I and III hyperactivation driven by SHP2 LLPS promotes malignant transformation of SHP2E76K MSCs and suggest that inhibition of SHP2 LLPS could be a potential therapeutic target for the treatment of activating SHP2‒associated cancers.

Keywords:  Adult stem cells; Cancer; Mouse stem cells; Oncology; Stem cells

DOI:  https://doi.org/10.1172/jci.insight.170340