bims-nenemi 2021-12-05 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2021‒12‒05
fourteen papers selected by
Marco Tigano
Thomas Jefferson University

Global mitochondrial protein import proteomics reveal distinct regulation by translation and translocation machinery.
ER-misfolded proteins become sequestered with mitochondria and impair mitochondrial function.
Peroxisomal support of mitochondrial respiratory efficiency promotes ER stress survival.
Malignancy and NF-κB signalling strengthen coordination between expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes.
Pharmacological reduction of mitochondrial iron triggers a non-canonical BAX/BAK dependent cell death.
Movement of mitochondria with mutant DNA through extracellular vesicles helps to acquire chemo-resistance of cancer cells.
METTLing in the right place: METTL8 is a mitochondrial tRNA-specific methyltransferase.
Ultrafine black carbon caused mitochondrial oxidative stress, mitochondrial dysfunction and mitophagy in SH-SY5Y cells.
The FusX TALE Base Editor (FusXTBE) for Rapid Mitochondrial DNA Programming of Human Cells In Vitro and Zebrafish Disease Models In Vivo.
[Risk of Multiple Sclerosis: Analysis of Interactions Between Variants of Nuclear and Mitochondrial Genomes].
Lutein activates downstream signaling pathways of unfolded protein response in hyperglycemic ARPE-19 cells.
RNA-binding protein Mub1 and the nuclear RNA exosome act to fine-tune environmental stress response.
Mitochondrial acute oxygen sensing and signaling.
Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis.

Mol Cell. 2021 Nov 19. pii: S1097-2765(21)00954-0. [Epub ahead of print]

Global mitochondrial protein import proteomics reveal distinct regulation by translation and translocation machinery.

Jasmin Adriana Schäfer, Süleyman Bozkurt, Jonas Benjamin Michaelis, Kevin Klann, Christian Münch.

  Most mitochondrial proteins are translated in the cytosol and imported into mitochondria. Mutations in the mitochondrial protein import machinery cause human pathologies. However, a lack of suitable tools to measure protein uptake across the mitochondrial proteome has prevented the identification of specific proteins affected by import perturbation. Here, we introduce mePRODmt, a pulsed-SILAC based proteomics approach that includes a booster signal to increase the sensitivity for mitochondrial proteins selectively, enabling global dynamic analysis of endogenous mitochondrial protein uptake in cells. We applied mePRODmt to determine protein uptake kinetics and examined how inhibitors of mitochondrial import machineries affect protein uptake. Monitoring changes in translation and uptake upon mitochondrial membrane depolarization revealed that protein uptake was extensively modulated by the import and translation machineries via activation of the integrated stress response. Strikingly, uptake changes were not uniform, with subsets of proteins being unaffected or decreased due to changes in translation or import capacity.

Keywords:  SILAC; TMT; disease; integrated stress response; mitochondria; protein translocation; proteomics; proteostasis; respiratory chain complexes; translation

DOI:  https://doi.org/10.1016/j.molcel.2021.11.004
Commun Biol. 2021 Dec 02. 4(1): 1350

ER-misfolded proteins become sequestered with mitochondria and impair mitochondrial function.

Adrián Cortés Sanchón, Harshitha Santhosh Kumar, Matilde Mantovani, Ivan Osinnii, José María Mateos, Andres Kaech, Dimitri Shcherbakov, Rashid Akbergenov, Erik C Böttger.

Proteostasis is a challenge for cellular organisms, as all known protein synthesis machineries are error-prone. Here we show by cell fractionation and microscopy studies that misfolded proteins formed in the endoplasmic reticulum can become associated with and partly transported into mitochondria, resulting in impaired mitochondrial function. Blocking the endoplasmic reticulum-mitochondria encounter structure (ERMES), but not the mitochondrial sorting and assembly machinery (SAM) or the mitochondrial surveillance pathway components Msp1 and Vms1, abrogated mitochondrial sequestration of ER-misfolded proteins. We term this mitochondria-associated proteostatic mechanism for ER-misfolded proteins ERAMS (ER-associated mitochondrial sequestration). We testify to the relevance of this pathway by using mutant α-1-antitrypsin as an example of a human disease-related misfolded ER protein, and we hypothesize that ERAMS plays a role in pathological features such as mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s42003-021-02873-w
J Cell Sci. 2021 Dec 02. pii: jcs.259254. [Epub ahead of print]

Peroxisomal support of mitochondrial respiratory efficiency promotes ER stress survival.

Imadeddin Hijazi, Emily Wang, Michelle Orozco, Sarah Pelton, Amy Chang.

  Endoplasmic reticulum stress (ERS) occurs when cellular demand for protein folding exceeds the capacity of the organelle. Adaptation and cell survival in response to ERS requires a critical contribution by mitochondria and peroxisomes. During ERS response, mitochondrial respiration increases to ameliorate reactive oxygen species (ROS) accumulation; we now show in yeast that peroxisome abundance also increases to promote an adaptive response. In pox1▵ cells, defective in peroxisomal ß oxidation of fatty acids, respiratory response to ERS is impaired, and ROS accrues. However, respiratory response to ERS is rescued, and ROS production is mitigated in pox1▵ cells by overexpression of Mpc1, the mitochondrial pyruvate carrier that provides another source of acetyl CoA to fuel the TCA cycle and oxidative phosphorylation. Using proteomics, select mitochondrial proteins were identified that undergo upregulation by ERS to remodel respiratory machinery. Several peroxisome-based proteins were also increased, corroborating the peroxisomal role in ERS adaptation. Finally, ERS stimulates assembly of respiratory complexes into higher order supercomplexes, underlying increased electron transfer efficiency. Our results highlight peroxisomal and mitochondrial support for ERS adaptation to favor cell survival.

Keywords:  Endoplasmic reticulum; Mitochondria; Stress survival

DOI:  https://doi.org/10.1242/jcs.259254
Genome Biol. 2021 Dec 02. 22(1): 328

Malignancy and NF-κB signalling strengthen coordination between expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes.

Marcos Francisco Perez, Peter Sarkies.

BACKGROUND: Mitochondria are ancient endosymbiotic organelles crucial to eukaryotic growth and metabolism. The mammalian mitochondrial genome encodes for 13 mitochondrial proteins, and the remaining mitochondrial proteins are encoded by the nuclear genome. Little is known about how coordination between the expression of the two sets of genes is achieved.RESULTS: Correlation analysis of RNA-seq expression data from large publicly available datasets is a common method to leverage genetic diversity to infer gene co-expression modules. Here we use this method to investigate nuclear-mitochondrial gene expression coordination. We identify a pitfall in correlation analysis that results from the large variation in the proportion of transcripts from the mitochondrial genome in RNA-seq data. Commonly used normalisation techniques based on total read counts, such as FPKM or TPM, produce artefactual negative correlations between mitochondrial- and nuclear-encoded transcripts. This also results in artefactual correlations between pairs of nuclear-encoded genes, with important consequences for inferring co-expression modules beyond mitochondria. We show that these effects can be overcome by normalizing using the median-ratio normalisation (MRN) or trimmed mean of M values (TMM) methods. Using these normalisations, we find only weak and inconsistent correlations between mitochondrial and nuclear-encoded mitochondrial genes in the majority of healthy human tissues from the GTEx database.
CONCLUSIONS: We show that a subset of healthy tissues with high expression of NF-κB show significant coordination, suggesting a role for NF-κB in ensuring balanced expression between mitochondrial and nuclear genes. Contrastingly, most cancer types show robust coordination of nuclear and mitochondrial OXPHOS gene expression, identifying this as a feature of gene regulation in cancer.

DOI: https://doi.org/10.1186/s13059-021-02541-6
Cancer Discov. 2021 Dec 03. pii: candisc.0522.2021. [Epub ahead of print]

Pharmacological reduction of mitochondrial iron triggers a non-canonical BAX/BAK dependent cell death.

Sylvain Garciaz, Andrew A Guirguis, Sebastian Muller, Fiona C Brown, Yih-Chih Chan, Ali Motazedian, Caitlin L Rowe, James A Kuzich, Kah Lok Chan, Kevin Tran, Lorey Smith, Laura MacPherson, Brian Liddicoat, Enid Y N Lam, Tatiana Caneque, Marian L Burr, Veronique Litalien, Giovanna Pomilio, Mathilde Poplineau, Estelle Duprez, Sarah-Jane Dawson, Georg Ramm, Andrew G Cox, Kristin K Brown, David C S Huang, Andrew H Wei, Kate McArthur, Raphael Rodriguez, Mark A Dawson.

Cancer cell metabolism is increasingly recognised as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small molecule ironomycin (AM5) reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent non-redundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples.

DOI: https://doi.org/10.1158/2159-8290.CD-21-0522
ChemMedChem. 2021 Nov 30.

Movement of mitochondria with mutant DNA through extracellular vesicles helps to acquire chemo-resistance of cancer cells.

Alex Lyakhovich, Etna Abad.

  Triple negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer with the worst prognosis after chemo or radiation therapy. This is mainly due to the development of cancer chemoresistance accompanied by tumor recurrence. In this work, we investigated a new mechanism of acquired chemoresistance of TNBC cells. We showed that extracellular vehicles (EVs) of chemoresistant TNBC cells can transfer mitochondria to sensitive cancer cells, thus increasing their chemoresistance. Such transfer, but with less efficiency, can be carried out over short distances using tunneling nanotubes. In addition, we showed that exosome fractions carrying mitochondria from resistant TNBC cells contribute to acquired chemoresistance by increasing mtDNA levels with mutations in the mtND4 gene responsible for tumorigenesis. Blocking mitochondrial transport by exosome inhibitors, including GW4869, reduced acquired TNBC chemoresistance. These results could lead to the identification of new molecular targets necessary for more effective treatment of this type of cancer.

Keywords:  acquired chemoresistance; exosomes; extracellular vesicles; mitochondrial horizontal transfer; tunnelling nanotubes

DOI:  https://doi.org/10.1002/cmdc.202100642
Mol Cell. 2021 Dec 02. pii: S1097-2765(21)00978-3. [Epub ahead of print]81(23): 4765-4767

METTLing in the right place: METTL8 is a mitochondrial tRNA-specific methyltransferase.

Eva Kowalinski, Juan D Alfonzo.

Schöller et al. (2021) discovered that METTL8, thought of as an mRNA modifier, is a tRNA-specific mitochondrial enzyme important for mitochondrial translation and function. Paradoxically, increased expression of METTL8 is associated with high respiratory rates in pancreatic cancers.

DOI: https://doi.org/10.1016/j.molcel.2021.11.009
Sci Total Environ. 2021 Nov 24. pii: S0048-9697(21)06975-8. [Epub ahead of print] 151899

Ultrafine black carbon caused mitochondrial oxidative stress, mitochondrial dysfunction and mitophagy in SH-SY5Y cells.

Yu Shang, Wanlei Xue, Jiexing Kong, Yingjun Chen, Xinghua Qiu, Xingqin An, Yi Li, Hongli Wang, Jing An.

  Exposure to ambient ultrafine black carbon (uBC, with aerodynamic diameter less than 100 nm) is associated with many neurodegenerative diseases. Oxidative stress is the predominantly reported neurotoxic effects caused by uBC exposure. Mitochondrion is responsible for production of majority of ROS in cells and mitochondrial dysfunction is closely related to adverse nervous outcomes. Mitophagy is an important cellular process to eliminate dysfunctional or damaged mitochondria. However, the mechanisms that modulate mitophagy and mitochondrial dysfunction initiated by uBC remain to be elucidated. The purpose of this study was to investigate how mitochondrial oxidative stress regulated mitochondrial dysfunction and mitophagy in human neuroblastoma cell line (SH-SY5Y) after uBC treatment. RNA interference was further applied to explore the roles of mitophagy in mitochondrial dysfunction. We found uBC triggered cell apoptosis via ROS-mitochondrial apoptotic pathway. The uBC also caused serious mitochondrial damage and respiratory dysfunction, indicated by the abnormalities in mitochondrial division and fusion related proteins, decreased mitochondria number and ATP level. Increased PTEN induced putative kinase 1 (PINK1) and Parkin protein levels and the autolysosome numbers suggested uBC could promote Pink1/Parkin-dependent mitophagy process in SH-SY5Y cells. Mitophagy inhibition could reserve mitochondria number and ATP activity, but not fusion and division related protein levels in SH-SY5Y cells exposed to uBC. Administration of a mitochondria-targeted antioxidant (mitoquinone) significantly eliminated uBC caused apoptosis, mitochondrial dysfunction and mitophagy. Our data suggested mitochondrial oxidative stress regulated uBC induced mitochondrial dysfunction and PINK1/Parkin-dependent mitophagy. PINK1/Parkin-dependent mitophagy probably participated in regulating uBC caused mitochondrial dysfunction but not by controlling mitochondrial fusion and division related proteins. Our results may provide some new insights and evidences to understand the mechanisms of neurotoxicity induced by uBC.

Keywords:  Air pollution; Mitochondrial dysfunction; Mitophagy; Oxidative stress; Ultrafine black carbon

DOI:  https://doi.org/10.1016/j.scitotenv.2021.151899
CRISPR J. 2021 Nov 30.

The FusX TALE Base Editor (FusXTBE) for Rapid Mitochondrial DNA Programming of Human Cells In Vitro and Zebrafish Disease Models In Vivo.

Ankit Sabharwal, Bibekananda Kar, Santiago Restrepo-Castillo, Shannon R Holmberg, Neal D Mathew, Benjamin Luke Kendall, Ryan P Cotter, Zachary WareJoncas, Christoph Seiler, Eiko Nakamaru-Ogiso, Karl J Clark, Stephen C Ekker.

Functional analyses of mitochondria have been hampered by few effective approaches to manipulate mitochondrial DNA (mtDNA) and a lack of existing animal models. Recently a TALE-derived base editor was shown to induce C-to-T (or G-to-A) sequence changes in mtDNA. We report here the FusX TALE Base Editor (FusXTBE) to facilitate broad-based access to TALE mitochondrial base editing technology. TALE Writer is a de novo in silico design tool to map potential mtDNA base editing sites. FusXTBE was demonstrated to function with comparable activity to the initial base editor in human cells in vitro. Zebrafish embryos were used as a pioneering in vivo test system, with FusXTBE inducing 90+% editing efficiency in mtDNA loci as an example of near-complete induction of mtDNA heteroplasmy in vivo. Gene editing specificity as precise as a single nucleotide was observed for a protein-coding gene. Nondestructive genotyping enables single-animal mtDNA analyses for downstream biological functional genomic applications. FusXTBE is a new gene editing toolkit for exploring important questions in mitochondrial biology and genetics.

DOI: https://doi.org/10.1089/crispr.2021.0061
Mol Biol (Mosk). 2021 Nov-Dec;55(6):55(6): 956-964

[Risk of Multiple Sclerosis: Analysis of Interactions Between Variants of Nuclear and Mitochondrial Genomes].

M S Kozin, I S Kiselev, N M Baulina, G V Pavlova, A N Boyko, O G Kulakova, O O Favorova.

  There is increasing evidence that the interaction of the mitochondrial and nuclear genomes substantially affects the risk of neurodegenerative diseases. The role of mitonuclear interactions in the development of multiple sclerosis, a severe chronic neurodegenerative disease of a polygenic nature, is poorly understood. In this work, we analyzed the association of multiple sclerosis with two-component mitonuclear combinations that include each of seven polymorphic variants of the nuclear genome localized in the region of the UCP2, and KIF1B genes and in the PVT1 locus (MYC, PVT1, and MIR1208 genes) and each often polymorphisms of the mitochondrial genome, as well as individual genetic variants that make up these combinations. Association of the individual components of these combinations with multiple sclerosis was also evaluated. 507 patients with multiple sclerosis and 321 healthy individuals were enrolled in the study, all participants were ethnic Russians. Two mitonuclear combinations associated with multiple sclerosis were identified: the UCP2 (rs660339)*A + MT-ATP6 (rs193303045)*G combination was characterized by p-value = 0.015 and OR= 1.39 [95% CI 1.05-1.87], and the PVT1 (rs2114358)*G + MT-ND1 (rs1599988)*С combination - by p-value = 0.012 and OR = 1.77 [95% CI 1.10-2.84]. Only one of the individual components of these combinations, allele rs660339*A of the nuclear gene UCP2 encoding uncoupling protein 2 of the mitochondrial anion carrier family, was independently associated with multiple sclerosis (p = 0.028; OR = 1.36 [95% CI 1.01-1.84]). This study expands the current understanding of the role of mitonuclear interactions and variance of nuclear genes, whose products function in mitochondria, and in risk of MS.

Keywords:  association; genetic predisposition; mitochondrial genome; mitonuclear interaction; multiple sclerosis; nuclear genome; single nucleotide polymorphism

DOI:  https://doi.org/10.31857/S0026898421060070
Eur J Pharmacol. 2021 Nov 30. pii: S0014-2999(21)00819-0. [Epub ahead of print] 174663

Lutein activates downstream signaling pathways of unfolded protein response in hyperglycemic ARPE-19 cells.

Arpitha Haranahalli Shivarudrappa, Kunal Sharan, Ganesan Ponesakki.

  We have earlier demonstrated that lutein effectively prevents hyperglycemia generated sustained oxidative stress in ARPE-19 cells by activating Nrf2 (nuclear factor erythroid 2-related factor 2) signaling. Since evidence portrays an intricate connection between ER (endoplasmic reticulum) stress and hyperglycemia-mediated oxidative stress, we aimed to explore the protective mechanism of lutein on hyperglycemia-induced ER stress in ARPE-19 cells. To determine the effect of lutein, we probed three major downstream branches of unfolded protein response (UPR) signaling pathways using western blot, immunofluorescent and RT-PCR techniques. The data showed a reduction (38%) in protein expression of an imperative ER chaperon, BiP (binding immunoglobulin protein), in glucose-treated ARPE-19 cells. At the same time, lutein pretreatment blocked this glucose-mediated effect, leading to a significant increase in BiP expression. Lutein promoted the phosphorylation of IRE1 (inositol requiring enzyme 1) and subsequent splicing of XBP1 (X-box binding protein 1), leading to enhanced nuclear translocation. Likewise, lutein activated the expression and translocation of transcription factors, ATF6 (activating transcription factor 6) and ATF4 (activating transcription factor 4) suppressed by hyperglycemia. Lutein also increased CHOP (C/EBP-homologous protein) levels in ARPE-19 cultured under high glucose conditions. The mRNA expression study showed that lutein pretreatment upregulates downstream UPR genes HRD1 (ERAD-associated E3 ubiquitin-protein ligase HRD1), p58IPK (protein kinase inhibitor p58) compared to high glucose treatment alone. From our study, it is clear that lutein show protection against hyperglycemia-mediated ER stress in ARPE-19 cells by activating IRE1-XBP1, ATF6, and ATF4 pathways and their downstream activators. Thus, lutein may have the pharmacological potential for protection against widespread disease conditions of ER stress.

Keywords:  ARPE-19; ER stress; Hyperglycemia; Lutein; UPR pathways

DOI:  https://doi.org/10.1016/j.ejphar.2021.174663
Life Sci Alliance. 2022 Feb;pii: e202101111. [Epub ahead of print]5(2):

RNA-binding protein Mub1 and the nuclear RNA exosome act to fine-tune environmental stress response.

Adrien Birot, Krzysztof Kus, Emily Priest, Ahmad Al Alwash, Alfredo Castello, Shabaz Mohammed, Lidia Vasiljeva, Cornelia Kilchert.

The nuclear RNA exosome plays a key role in controlling the levels of multiple protein-coding and non-coding RNAs. Recruitment of the exosome to specific RNA substrates is mediated by RNA-binding co-factors. The transient interaction between co-factors and the exosome as well as the rapid decay of RNA substrates make identification of exosome co-factors challenging. Here, we use comparative poly(A)+ RNA interactome capture in fission yeast expressing three different mutants of the exosome to identify proteins that interact with poly(A)+ RNA in an exosome-dependent manner. Our analyses identify multiple RNA-binding proteins whose association with RNA is altered in exosome mutants, including the zinc-finger protein Mub1. Mub1 is required to maintain the levels of a subset of exosome RNA substrates including mRNAs encoding for stress-responsive proteins. Removal of the zinc-finger domain leads to loss of RNA suppression under non-stressed conditions, altered expression of heat shock genes in response to stress, and reduced growth at elevated temperature. These findings highlight the importance of exosome-dependent mRNA degradation in buffering gene expression networks to mediate cellular adaptation to stress.

DOI: https://doi.org/10.26508/lsa.202101111
Crit Rev Biochem Mol Biol. 2021 Dec 01. 1-21

Mitochondrial acute oxygen sensing and signaling.

José López-Barneo, Patricia Ortega-Sáenz.

  Oxygen (O2) is essential for life and therefore the supply of sufficient O2 to the tissues is a major physiological challenge. In mammals, a deficit of O2 (hypoxia) triggers rapid cardiorespiratory reflexes (e.g. hyperventilation and increased heart output) that within a few seconds increase the uptake of O2 by the lungs and its distribution throughout the body. The prototypical acute O2-sensing organ is the carotid body (CB), which contains sensory glomus cells expressing O2-regulated ion channels. In response to hypoxia, glomus cells depolarize and release transmitters which activate afferent fibers terminating at the brainstem respiratory and autonomic centers. In this review, we summarize the basic properties of CB chemoreceptor cells and the essential role played by their specialized mitochondria in acute O2 sensing and signaling. We focus on recent data supporting a "mitochondria-to-membrane signaling" model of CB chemosensory transduction. The possibility that the differential expression of specific subunit isoforms and enzymes could allow mitochondria to play a generalized adaptive O2-sensing and signaling role in a wide variety of cells is also discussed.

Keywords:  arterial chemoreceptors; carotid body; cell physiology; cute hypoxia; glomus cells; itochondria; mitochondrial subunit isoforms; o; xygen sensing

DOI:  https://doi.org/10.1080/10409238.2021.2004575
Signal Transduct Target Ther. 2021 Dec 01. 6(1): 401

Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis.

Yan Yu, Xiao-Dan Peng, Xiao-Jun Qian, Kai-Ming Zhang, Xiang Huang, Yu-Hong Chen, Yun-Tian Li, Gong-Kan Feng, Hai-Liang Zhang, Xue-Lian Xu, Shun Li, Xuan Li, Jia Mai, Zhi-Ling Li, Yun Huang, Dong Yang, Li-Huan Zhou, Zhuo-Yan Zhong, Jun-Dong Li, Rong Deng, Xiao-Feng Zhu.

Met tyrosine kinase, a receptor for a hepatocyte growth factor (HGF), plays a critical role in tumor growth, metastasis, and drug resistance. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network. Dysregulated mitochondrial dynamics are responsible for the progression and metastasis of many cancers. Here, using structured illumination microscopy (SIM) and high spatial and temporal resolution live cell imaging, we identified mitochondrial trafficking of receptor tyrosine kinase Met. The contacts between activated Met kinase and mitochondria formed dramatically, and an intact HGF/Met axis was necessary for dysregulated mitochondrial fission and cancer cell movements. Mechanically, we found that Met directly phosphorylated outer mitochondrial membrane protein Fis1 at Tyr38 (Fis1 pY38). Fis1 pY38 promoted mitochondrial fission by recruiting the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) to mitochondria. Fragmented mitochondria fueled actin filament remodeling and lamellipodia or invadopodia formation to facilitate cell metastasis in hepatocellular carcinoma (HCC) cells both in vitro and in vivo. These findings reveal a novel and noncanonical pathway of Met receptor tyrosine kinase in the regulation of mitochondrial activities, which may provide a therapeutic target for metastatic HCC.

DOI: https://doi.org/10.1038/s41392-021-00790-2