bims-nenemi 2021-10-24 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2021–10–24
25 papers selected by
Marco Tigano, Thomas Jefferson University

Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress.
Decreased mitochondrial membrane potential is an indicator of radioresistant cancer cells.
OMA1 High-Throughput Screen Reveals Protease Activation by Kinase Inhibitors.
Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts.
Control of host mitochondria by bacterial pathogens.
Genome instability independent of type I interferon signaling drives neuropathology caused by impaired ribonucleotide excision repair.
Balancing life and death: BCL-2 family members at diverse ER-mitochondria contact sites.
SOAT1 enhances lung cancer invasion through stimulating AKT-mediated mitochondrial fragmentation.
Cofilin1 oxidation links oxidative distress to mitochondrial demise and neuronal cell death.
BACE1 Inhibition Increases Susceptibility to Oxidative Stress by Promoting Mitochondrial Damage.
Neurogenic Potential of the 18-kDa Mitochondrial Translocator Protein (TSPO) in Pluripotent P19 Stem Cells.
ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis.
Metformin and arsenic trioxide synergize to trigger Parkin/pink1-dependent mitophagic cell death in human cervical cancer HeLa cells.
Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells.
Mitochondrial genome and its regulator TFAM modulates head and neck tumourigenesis through intracellular metabolic reprogramming and activation of oncogenic effectors.
DRP1-Mediated Mitochondrial Fission Regulates Lung Epithelial Response to Allergen.
Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity.
Targeting UPR branches, a potential strategy for enhancing efficacy of cancer chemotherapy.
The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor.
An in vitro system to silence mitochondrial gene expression.
Interferon induction held captive in tumor cells.
Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency.
Mitochondrial Translation Occurs Preferentially in the Peri-Nuclear Mitochondrial Network of Cultured Human Cells.
Nuclear PHGDH protects cancer cells from nutrient stress.
Mitochondrial Telomerase Reverse Transcriptase Protects from Myocardial Ischemia/reperfusion Injury by Improving Complex I Composition and Function.

Mol Cell. 2021 Oct 21. pii: S1097-2765(21)00798-X. [Epub ahead of print]81(20): 4191-4208.e8

Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress.

Raul Jobava, Yuanhui Mao, Bo-Jhih Guan, Di Hu, Dawid Krokowski, Chien-Wen Chen, Xin Erica Shu, Evelyn Chukwurah, Jing Wu, Zhaofeng Gao, Leah L Zagore, William C Merrick, Aleksandra Trifunovic, Andrew C Hsieh, Saba Valadkhan, Youwei Zhang, Xin Qi, Eckhard Jankowsky, Ivan Topisirovic, Donny D Licatalosi, Shu-Bing Qian, Maria Hatzoglou.

  To survive, mammalian cells must adapt to environmental challenges. While the cellular response to mild stress has been widely studied, how cells respond to severe stress remains unclear. We show here that under severe hyperosmotic stress, cells enter a transient hibernation-like state in anticipation of recovery. We demonstrate this adaptive pausing response (APR) is a coordinated cellular response that limits ATP supply and consumption through mitochondrial fragmentation and widespread pausing of mRNA translation. This pausing is accomplished by ribosome stalling at translation initiation codons, which keeps mRNAs poised to resume translation upon recovery. We further show that recovery from severe stress involves ISR (integrated stress response) signaling that permits cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. Our findings indicate that cells can respond to severe stress via a hibernation-like mechanism that preserves vital elements of cellular function under harsh environmental conditions.

Keywords:  ATF4; ISR; hypertonic; mTOR; mitochondria; neMito mRNAs; ribosome stalling; stress; translation

DOI:  https://doi.org/10.1016/j.molcel.2021.09.029
Life Sci. 2021 Oct 16. pii: S0024-3205(21)01038-9. [Epub ahead of print]286 120051

Decreased mitochondrial membrane potential is an indicator of radioresistant cancer cells.

Yoshikazu Kuwahara, Kazuo Tomita, Mehryar Habibi Roudkenar, Amaneh Mohammadi Roushandeh, Yusuke Urushihara, Kento Igarashi, Akihiro Kurimasa, Tomoaki Sato.

   AIMS: To overcome radioresistant cancer cells, clinically relevant radioresistant (CRR) cells were established. To maintain their radioresistance, CRR cells were exposed 2 Gy/day of X-rays daily (maintenance irradiation: MI). To understand whether the radioresistance induced by X-rays was reversible or irreversible, the difference between CRR cells and those without MI for a year (CRR-NoIR cells) was investigated by the mitochondrial function as an index.
MAIN METHODS: Radiation sensitivity was determined by modified high density survival assay. Mitochondrial membrane potential (Δψm) was determined by 5,5',6,6'-tetrachloro-1,1', tetraethylbenzimidazolocarbo-cyanine iodide (JC-1) staining. Rapid Glucose-Galactose assay was performed to determine the shift in their energy metabolism from aerobic glycolysis to oxidative phosphorylation in CRR cells. Involvement of prohibitin-1 (PHB1) in Δψm was evaluated by knockdown of PHB1 gene followed by real-time PCR.
KEY FINDINGS: CRR cells that exhibited resistant to 2 Gy/day X-ray lost their radioresistance after more than one year of culture without MI for a year. In addition, CRR cells lost their radioresistance when the mitochondria were activated by galactose. Furthermore, Δψm were increased and PHB1 expression was down-regulated, in the process of losing their radioresistance.
SIGNIFICANCE: Our finding reveled that tune regulation of mitochondrial function is implicated in radioresistance phenotype of cancer cells. Moreover, as our findings indicate, though further studies are required to clarify the precise mechanisms underlying cancer cell radioresistance, radioresistant cells induced by irradiation and cancer stem cells that are originally radioresistant should be considered separately, the radioresistance of CRR cells is reversible.

Keywords:  Glycolysis; Hydrogen peroxide; Membrane potential; Mitochondria; Prohibitin; Radioresistance

DOI:  https://doi.org/10.1016/j.lfs.2021.120051
ACS Chem Biol. 2021 Oct 21.

OMA1 High-Throughput Screen Reveals Protease Activation by Kinase Inhibitors.

Marcel V Alavi.

Mitochondrial proteases are interesting but challenging drug targets for multifactorial diseases, such as neurodegeneration and cancer. The mitochondrial inner membrane protease OMA1 is a bona fide drug target for heart failure supported by data from human linkage analysis and animal disease models, but presumably relevant for more indications. OMA1 acts at the intersection of energy metabolism and stress signaling. The protease cleaves the structural protein OPA1, which organizes the cristae, as well as the signaling peptide DELE1, which can stimulate the integrated stress response. OMA1 shows little activity under physiological conditions but hydrolyzes OPA1 in mitochondria destined for mitophagy and during apoptosis. Little is known about OMA1, its structure has not been solved, let alone its context-dependent regulation. Autocatalytic processing and the lack of OMA1 inhibitors are thereby creating the biggest roadblocks. This study introduces a scalable, cellular OMA1 protease assay suitable for high-throughput drug screening. The assay utilizes an engineered luciferase targeted to the inner membrane as artificial OMA1 substrate, whereby the reporter signal inversely correlates to OMA1 activity. Testing different screening protocols and sampling different compound collections validated the reporter and demonstrated that both OMA1 activators as well as OMA1 inhibitors can be identified with the assay. Ten kinase-targeted cancer drugs triggered OMA1 in the assays, which suggests-considering cardiotoxicity as a rather common side-effect of this class of drugs-cross-reactivity with the OMA1 pathway.

DOI: https://doi.org/10.1021/acschembio.1c00350
Int J Mol Sci. 2021 Oct 13. pii: 11047. [Epub ahead of print]22(20):

Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts.

Dietrich Averbeck, Claire Rodriguez-Lafrasse.

  Until recently, radiation effects have been considered to be mainly due to nuclear DNA damage and their management by repair mechanisms. However, molecular biology studies reveal that the outcomes of exposures to ionizing radiation (IR) highly depend on activation and regulation through other molecular components of organelles that determine cell survival and proliferation capacities. As typical epigenetic-regulated organelles and central power stations of cells, mitochondria play an important pivotal role in those responses. They direct cellular metabolism, energy supply and homeostasis as well as radiation-induced signaling, cell death, and immunological responses. This review is focused on how energy, dose and quality of IR affect mitochondria-dependent epigenetic and functional control at the cellular and tissue level. Low-dose radiation effects on mitochondria appear to be associated with epigenetic and non-targeted effects involved in genomic instability and adaptive responses, whereas high-dose radiation effects (>1 Gy) concern therapeutic effects of radiation and long-term outcomes involving mitochondria-mediated innate and adaptive immune responses. Both effects depend on radiation quality. For example, the increased efficacy of high linear energy transfer particle radiotherapy, e.g., C-ion radiotherapy, relies on the reduction of anastasis, enhanced mitochondria-mediated apoptosis and immunogenic (antitumor) responses.

Keywords:  DNA damage response (DDR); ROS; adaptive response; apoptosis; cancer; carbon ions; carbon-ion radiotherapy (CIRT); epigenetics; genomic instability; high LET particle radiation; hormesis; innate and adaptive immune responses; ionizing radiation; metabolism; mitochondria; non-targeted effects (NTEs); radiation quality; radiotherapy; signaling

DOI:  https://doi.org/10.3390/ijms222011047
Trends Microbiol. 2021 Oct 13. pii: S0966-842X(21)00237-7. [Epub ahead of print]

Control of host mitochondria by bacterial pathogens.

Saverio Marchi, Gianluca Morroni, Paolo Pinton, Lorenzo Galluzzi.

  Mitochondria control various processes that are integral to cellular and organismal homeostasis, including Ca2+ fluxes, bioenergetic metabolism, and cell death. Perhaps not surprisingly, multiple pathogenic bacteria have evolved strategies to subvert mitochondrial functions in support of their survival and dissemination. Here, we discuss nonimmunological pathogenic mechanisms that converge on the ability of bacteria to control the mitochondrial compartment of host cells.

Keywords:  Listeria monocytogenes; Mycobacterium tuberculosis; autophagy; mitochondria-associated ER membranes; oxidative phosphorylation; regulated cell death

DOI:  https://doi.org/10.1016/j.tim.2021.09.010
Neuron. 2021 Oct 08. pii: S0896-6273(21)00713-3. [Epub ahead of print]

Genome instability independent of type I interferon signaling drives neuropathology caused by impaired ribonucleotide excision repair.

Aditi, Susanna M Downing, Patrick A Schreiner, Young Don Kwak, Yang Li, Timothy I Shaw, Helen R Russell, Peter J McKinnon.

  Aicardi-Goutières syndrome (AGS) is a monogenic type I interferonopathy characterized by neurodevelopmental defects and upregulation of type I interferon signaling and neuroinflammation. Mutations in genes that function in nucleic acid metabolism, including RNASEH2, are linked to AGS. Ribonuclease H2 (RNASEH2) is a genome surveillance factor critical for DNA integrity by removing ribonucleotides incorporated into replicating DNA. Here we show that RNASEH2 is necessary for neurogenesis and to avoid activation of interferon-responsive genes and neuroinflammation. Cerebellar defects after RNASEH2B inactivation are rescued by p53 but not cGAS deletion, suggesting that DNA damage signaling, not neuroinflammation, accounts for neuropathology. Coincident inactivation of Atm and Rnaseh2 further affected cerebellar development causing ataxia, which was dependent upon aberrant activation of non-homologous end-joining (NHEJ). The loss of ATM also markedly exacerbates cGAS-dependent type I interferon signaling. Thus, DNA damage-dependent signaling rather than type I interferon signaling underlies neurodegeneration in this class of neurodevelopmental/neuroinflammatory disease.

Keywords:  ATM; Aicardi-Goutières syndrome; Cerebellum; DNA damage; Microglia; Neurodegeneration; Neurodevelopment; Neuroinflammation; RNaseH2; cGAS/STING

DOI:  https://doi.org/10.1016/j.neuron.2021.09.040
FEBS J. 2021 Oct 20.

Balancing life and death: BCL-2 family members at diverse ER-mitochondria contact sites.

Robert E Means, Samuel G Katz.

The outer mitochondrial membrane is a busy place. One essential activity for cellular survival is the regulation of membrane integrity by the BCL-2 family of proteins. Another critical facet of the outer mitochondrial membrane is its close approximation with the endoplasmic reticulum. These mitochondria associated membranes (MAMs) occupy a significant fraction of the mitochondrial surface and serve as key signaling hubs for multiple cellular processes. Each of these pathways may be considered as forming their own specialized MAM sub-type. Interestingly, like membrane permeabilization, most of these pathways play critical roles in regulating cellular survival and death. Recently, the pro-apoptotic BCL-2 family member BOK, has been found within MAMs where it plays important roles in their structure and function. This has led to a greater appreciation that multiple BCL-2 family proteins, which are known to participate in numerous functions throughout the cell, also have roles within MAMs. In this review we evaluate several MAM subsets, their role in cellular homeostasis and the contribution of BCL-2 family members to their functions.

DOI: https://doi.org/10.1111/febs.16241
Biochem Cell Biol. 2021 Oct 20.

SOAT1 enhances lung cancer invasion through stimulating AKT-mediated mitochondrial fragmentation.

Yijun Mo, Lina Lin, Jianhua Zhang, Changhui Yu.

Sterol O-acyltransferase 1 (SOAT1) is a key enzyme in lipid metabolism, which mediates cholesterol esterification metabolism and is closely associated with many cancers. However, the role of SOAT1 in lung cancer invasion remains unclear. We found that SOAT1 expression was positively correlated with lung cancer invasion. Downregulation of SOAT1 inhibited invasion, mitochondrial fragmentation, AKT phosphorylation, and phospho-Drp (Ser616) in lung cancer cells and promoted intracellular free cholesterol accumulation. Mechanistically, AKT phosphorylation inhibitor MK-2206 alleviated both SOAT1 overexpression or high expression-induced mitochondrial fragmentation and lung cancer cell invasion. Furthermore, intracellular free cholesterol accumulation reduced AKT phosphorylation, SREBP1 mRNA expression, cell invasion, and mitochondrial fragmentation in lung cancer cells with high SOAT1 expression. In summary, our findings suggest that SOAT1 promotes lung cancer invasion activates the PI3K/AKT signaling pathway by downregulating intracellular free cholesterol levels, thereby affecting the regulation of mitochondrial fragmentation.

DOI: https://doi.org/10.1139/bcb-2021-0175
Cell Death Dis. 2021 Oct 16. 12(11): 953

Cofilin1 oxidation links oxidative distress to mitochondrial demise and neuronal cell death.

Lena Hoffmann, Marcel S Waclawczyk, Stephan Tang, Eva-Maria Hanschmann, Manuela Gellert, Marco B Rust, Carsten Culmsee.

Many cell death pathways, including apoptosis, regulated necrosis, and ferroptosis, are relevant for neuronal cell death and share common mechanisms such as the formation of reactive oxygen species (ROS) and mitochondrial damage. Here, we present the role of the actin-regulating protein cofilin1 in regulating mitochondrial pathways in oxidative neuronal death. Cofilin1 deletion in neuronal HT22 cells exerted increased mitochondrial resilience, assessed by quantification of mitochondrial ROS production, mitochondrial membrane potential, and ATP levels. Further, cofilin1-deficient cells met their energy demand through enhanced glycolysis, whereas control cells were metabolically impaired when challenged by ferroptosis. Further, cofilin1 was confirmed as a key player in glutamate-mediated excitotoxicity and associated mitochondrial damage in primary cortical neurons. Using isolated mitochondria and recombinant cofilin1, we provide a further link to toxicity-related mitochondrial impairment mediated by oxidized cofilin1. Our data revealed that the detrimental impact of cofilin1 on mitochondria depends on the oxidation of cysteine residues at positions 139 and 147. Overall, our findings show that cofilin1 acts as a redox sensor in oxidative cell death pathways of ferroptosis, and also promotes glutamate excitotoxicity. Protective effects by cofilin1 inhibition are particularly attributed to preserved mitochondrial integrity and function. Thus, interfering with the oxidation and pathological activation of cofilin1 may offer an effective therapeutic strategy in neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41419-021-04242-1
Antioxidants (Basel). 2021 Sep 28. pii: 1539. [Epub ahead of print]10(10):

BACE1 Inhibition Increases Susceptibility to Oxidative Stress by Promoting Mitochondrial Damage.

Carolina Francelin, Sayak K Mitter, Qingwen Qian, Sandeep Kumar Barodia, Colin Ip, Xiaoping Qi, Hongmei Gu, Judith Quigley, Matthew S Goldberg, Maria B Grant, Michael E Boulton.

  BACE1 is a key enzyme facilitating the generation of neurotoxic β-amyloid (Aβ) peptide. However, given that BACE1 has multiple substrates we explored the importance of BACE1 in the maintenance of retinal pigment epithelial (RPE) cell homeostasis under oxidative stress. Inhibition of BACE1 reduced mitochondrial membrane potential, increased mitochondrial fragmentation, and increased cleaved caspase-3 expression in cells under oxidative stress. BACE1 inhibition also resulted in significantly lower levels of mitochondrial fusion proteins OPA1 and MFN1 suggesting a higher rate of mitochondrial fission while increasing the levels of mitophagic proteins Parkin and PINK1 and autophagosome numbers. In contrast, BACE2 had minimal effect on cellular response to oxidative stress. In summary, our results emphasize the importance of BACE1 in augmenting cellular defense against oxidative stress by protecting mitochondrial dynamics.

Keywords:  ARPE19; BACE1; mitochondrial damage; oxidative stress

DOI:  https://doi.org/10.3390/antiox10101539
Cells. 2021 Oct 17. pii: 2784. [Epub ahead of print]10(10):

Neurogenic Potential of the 18-kDa Mitochondrial Translocator Protein (TSPO) in Pluripotent P19 Stem Cells.

Laura González-Blanco, Juan Carlos Bermejo-Millo, Gabriela Oliveira, Yaiza Potes, Eduardo Antuña, Iván Menéndez-Valle, Ignacio Vega-Naredo, Ana Coto-Montes, Beatriz Caballero.

  The 18-kDa translocator protein (TSPO) is a key mitochondrial target by which different TSPO ligands exert neuroprotective effects. We assayed the neurogenic potential of TSPO to induce the neuronal differentiation of pluripotent P19 stem cells in vitro. We studied changes in cell morphology, cell proliferation, cell death, the cell cycle, mitochondrial functionality, and the levels of pluripotency and neurogenesis of P19 stem cells treated with the TSPO ligand, PK 11195, in comparison to differentiation induced by retinoid acid (RA) and undifferentiated P19 stem cells. We observed that PK 11195 was able to activate the differentiation of P19 stem cells by promoting the development of embryoid bodies. PK 11195 also induced changes in the cell cycle, decreased cell proliferation, and activated cell death. Mitochondrial metabolism was also enhanced by PK 11195, thus increasing the levels of reactive oxygen species, Ca2+, and ATP as well as the mitochondrial membrane potential. Markers of pluripotency and neurogenesis were also altered during the cell differentiation process, as PK 11195 induced the differentiation of P19 stem cells with a high predisposition toward a neuronal linage, compared to cell differentiation induced by RA. Thus, we suggest a relevant neurogenic potential of TSPO along with broad therapeutic implications.

Keywords:  TSPO; mitochondria; neurogenesis; stem cells

DOI:  https://doi.org/10.3390/cells10102784
Cell Rep. 2021 Oct 19. pii: S2211-1247(21)01325-5. [Epub ahead of print]37(3): 109858

ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis.

Rajendra Karki, Balamurugan Sundaram, Bhesh Raj Sharma, SangJoon Lee, R K Subbarao Malireddi, Lam Nhat Nguyen, Shelbi Christgen, Min Zheng, Yaqiu Wang, Parimal Samir, Geoffrey Neale, Peter Vogel, Thirumala-Devi Kanneganti.

  Cell death provides host defense and maintains homeostasis. Zα-containing molecules are essential for these processes. Z-DNA binding protein 1 (ZBP1) activates inflammatory cell death, PANoptosis, whereas adenosine deaminase acting on RNA 1 (ADAR1) serves as an RNA editor to maintain homeostasis. Here, we identify and characterize ADAR1's interaction with ZBP1, defining its role in cell death regulation and tumorigenesis. Combining interferons (IFNs) and nuclear export inhibitors (NEIs) activates ZBP1-dependent PANoptosis. ADAR1 suppresses this PANoptosis by interacting with the Zα2 domain of ZBP1 to limit ZBP1 and RIPK3 interactions. Adar1fl/flLysMcre mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tumorigenesis in these mice. In addition, treating wild-type mice with IFN-γ and the NEI KPT-330 regresses melanoma in a ZBP1-dependent manner. Our findings suggest that ADAR1 suppresses ZBP1-mediated PANoptosis, promoting tumorigenesis. Defining the functions of ADAR1 and ZBP1 in cell death is fundamental to informing therapeutic strategies for cancer and other diseases.

Keywords:  ADAR1; IFN; PANoptosis; PANoptosome; ZBP1; apoptosis; inflammasome; necroptosis; pyroptosis; tumorigenesis

DOI:  https://doi.org/10.1016/j.celrep.2021.109858
J Cancer. 2021 ;12(21): 6310-6319

Metformin and arsenic trioxide synergize to trigger Parkin/pink1-dependent mitophagic cell death in human cervical cancer HeLa cells.

Jing Chen, Cunmin Zhou, Juan Yi, Jingjing Sun, Bei Xie, Zhewen Zhang, Qunfeng Wang, Gang Chen, Suya Jin, Jinxia Hou, Miao Qin, Lina Wang, Hulai Wei.

  Mitochondria are involved in various biological processes including intracellular homeostasis, proliferation, senescence, and death, and mitochondrial mitophagy is closely related to the development and regression of malignant tumors. Recent studies confirmed that the hypoglycemic drug metformin (Met) exerted various antitumor effects, protected neural cells, and improved immunity, while arsenic trioxide (ATO) is an effective chemotherapeutic agent for the clinical treatment of leukemia and various solid tumors. However, the possible combined antitumor effects of Met and ATO and their cellular molecular mechanisms are unclear. We investigated the role of Parkin-mediated mitochondrial mitophagy in the anti-tumor mechanism of Met and ATO by studying the effects of Met and/or ATO on the proliferation and apoptosis of cervical cancer HeLa cells. Both Met and ATO effectively inhibited the proliferative activity of HeLa cells and induced apoptosis by activating Bax and inhibiting Bcl-2. Met and ATO treatment alone or in combination stimulated mitophagosome accumulation in HeLa cells, increased the conversion of microtubule-associated protein light chain 3 (LC3)-I to LC3-II, and decreased levels of the mitophagic lysosomal substrate protein P62. The mitochondrial membrane potential of HeLa cells also decreased, accompanied by activation of the mitochondrial translocase TOM system and the Pink1/Parkin signaling pathway. These results suggested that Met and/or ATO could induce mitophagy in HeLa cells via the Pink1/Parkin signaling pathway, leading to mitophagic apoptosis and inhibition of tumor cell proliferation. The combination of Met and ATO thus has enhanced antitumor effects, suggesting that this combination has potential clinical applications for the treatment of cervical cancer and other tumors.

Keywords:  Arsenic Trioxide; HeLa; Metformin; Mitophagy; Pink1/Parkin

DOI:  https://doi.org/10.7150/jca.61299
Cell Death Dis. 2021 Oct 21. 12(11): 977

Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells.

Barbara Schroeder, Travis Vander Steen, Ingrid Espinoza, Chandra M Kurapaty Venkatapoorna, Zeng Hu, Fernando Martín Silva, Kevin Regan, Elisabet Cuyàs, X Wei Meng, Sara Verdura, Aina Arbusà, Paula A Schneider, Karen S Flatten, George Kemble, Joan Montero, Scott H Kaufmann, Javier A Menendez, Ruth Lupu.

Inhibitors of the lipogenic enzyme fatty acid synthase (FASN) have attracted much attention in the last decade as potential targeted cancer therapies. However, little is known about the molecular determinants of cancer cell sensitivity to FASN inhibitors (FASNis), which is a major roadblock to their therapeutic application. Here, we find that pharmacological starvation of endogenously produced FAs is a previously unrecognized metabolic stress that heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors. Evaluation of the death decision circuits controlled by the BCL-2 family of proteins revealed that FASN inhibition is accompanied by the upregulation of the pro-death BH3-only proteins BIM, PUMA, and NOXA. Cell death triggered by FASN inhibition, which causally involves a palmitate/NADPH-related redox imbalance, is markedly diminished by concurrent loss of BIM or PUMA, suggesting that FASN activity controls cancer cell survival by fine-tuning the BH3 only proteins-dependent mitochondrial threshold for apoptosis. FASN inhibition results in a heightened mitochondrial apoptosis priming, shifting cells toward a primed-for-death state "addicted" to the anti-apoptotic protein BCL-2. Accordingly, co-administration of a FASNi synergistically augments the apoptosis-inducing activity of the dual BCL-XL/BCL-2 inhibitor ABT-263 (navitoclax) and the BCL-2 specific BH3-mimetic ABT-199 (venetoclax). FASN inhibition, however, fails to sensitize breast cancer cells to MCL-1- and BCL-XL-selective inhibitors such as S63845 and A1331852. A human breast cancer xenograft model evidenced that oral administration of the only clinically available FASNi drastically sensitizes FASN-addicted breast tumors to ineffective single-agents navitoclax and venetoclax in vivo. In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.

DOI: https://doi.org/10.1038/s41419-021-04262-x
Cell Death Dis. 2021 Oct 18. 12(11): 961

Mitochondrial genome and its regulator TFAM modulates head and neck tumourigenesis through intracellular metabolic reprogramming and activation of oncogenic effectors.

Yi-Ta Hsieh, Hsi-Feng Tu, Muh-Hwa Yang, Yi-Fen Chen, Xiang-Yun Lan, Chien-Ling Huang, Hsin-Ming Chen, Wan-Chun Li.

Mitochondrial transcriptional factor A (TFAM) acts as a key regulatory to control mitochondrial DNA (mtDNA); the impact of TFAM and mtDNA in modulating carcinogenesis is controversial. Current study aims to define TFAM mediated regulations in head and neck cancer (HNC). Multifaceted analyses in HNC cells genetically manipulated for TFAM were performed. Clinical associations of TFAM and mtDNA encoded Electron Transport Chain (ETC) genes in regulating HNC tumourigenesis were also examined in HNC specimens. At cellular level, TFAM silencing led to an enhanced cell growth, motility and chemoresistance whereas enforced TFAM expression significantly reversed these phenotypic changes. These TFAM mediated cellular changes resulted from (1) metabolic reprogramming by directing metabolism towards aerobic glycolysis, based on the detection of less respiratory capacity in accompany with greater lactate production; and/or (2) enhanced ERK1/2-Akt-mTORC-S6 signalling activity in response to TFAM induced mtDNA perturbance. Clinical impacts of TFAM and mtDNA were further defined in carcinogen-induced mouse tongue cancer and clinical human HNC tissues; as the results showed that TFAM and mtDNA expression were significantly dropped in tumour compared with their normal counterparts and negatively correlated with disease progression. Collectively, our data uncovered a tumour-suppressing role of TFAM and mtDNA in determining HNC oncogenicity and potentially paved the way for development of TFAM/mtDNA based scheme for HNC diagnosis.

DOI: https://doi.org/10.1038/s41419-021-04255-w
Int J Mol Sci. 2021 Oct 15. pii: 11125. [Epub ahead of print]22(20):

DRP1-Mediated Mitochondrial Fission Regulates Lung Epithelial Response to Allergen.

Sierra R Bruno, Amit Kumar, Zoe F Mark, Ravishankar Chandrasekaran, Emily Nakada, Nicolas Chamberlain, Bethany Mihavics, Joseph Walzer, Jonathon Cahoon, Anne E Dixon, Brian Cunniff, Vikas Anathy.

  Mitochondria regulate a myriad of cellular functions. Dysregulation of mitochondrial control within airway epithelial cells has been implicated in the pro-inflammatory response to allergens in asthma patients. Because of their multifaceted nature, mitochondrial structure must be tightly regulated through fission and fusion. Dynamin Related Protein 1 (DRP1) is a key driver of mitochondrial fission. During allergic asthma, airway epithelial mitochondria appear smaller and structurally altered. The role of DRP1-mediated mitochondrial fission, however, has not been fully elucidated in epithelial response to allergens. We used a Human Bronchial Epithelial Cell line (HBECs), primary Mouse Tracheal Epithelial Cells (MTECs), and conditional DRP1 ablation in lung epithelial cells to investigate the impact of mitochondrial fission on the pro-inflammatory response to house dust mite (HDM) in vitro and in vivo. Our data suggest that, following HDM challenge, mitochondrial fission is rapidly upregulated in airway epithelial cells and precedes production of pro-inflammatory cytokines and chemokines. Further, deletion of Drp1 in lung epithelial cells leads to decreased fission and enhanced pro-inflammatory signaling in response to HDM in vitro, as well as enhanced airway hyper-responsiveness (AHR), inflammation, differential mucin transcription, and epithelial cell death in vivo. Mitochondrial fission, therefore, regulates the lung epithelial pro-inflammatory response to HDM.

Keywords:  DRP1; HDM; allergic airway disease; epithelial cell; mitochondrial fission

DOI:  https://doi.org/10.3390/ijms222011125
Nat Immunol. 2021 Oct 22.

Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity.

Giusy Di Conza, Chin-Hsien Tsai, Hector Gallart-Ayala, Yi-Ru Yu, Fabien Franco, Lea Zaffalon, Xin Xie, Xiaoyun Li, Zhengtao Xiao, Lydia N Raines, Maryline Falquet, Antoine Jalil, Jason W Locasale, Piergiorgio Percipalle, David Masson, Stanley Ching-Cheng Huang, Fabio Martinon, Julijana Ivanisevic, Ping-Chih Ho.

Tumor-associated macrophages (TAMs) display pro-tumorigenic phenotypes for supporting tumor progression in response to microenvironmental cues imposed by tumor and stromal cells. However, the underlying mechanisms by which tumor cells instruct TAM behavior remain elusive. Here, we uncover that tumor-cell-derived glucosylceramide stimulated unconventional endoplasmic reticulum (ER) stress responses by inducing reshuffling of lipid composition and saturation on the ER membrane in macrophages, which induced IRE1-mediated spliced XBP1 production and STAT3 activation. The cooperation of spliced XBP1 and STAT3 reinforced the pro-tumorigenic phenotype and expression of immunosuppressive genes. Ablation of XBP1 expression with genetic manipulation or ameliorating ER stress responses by facilitating LPCAT3-mediated incorporation of unsaturated lipids to the phosphatidylcholine hampered pro-tumorigenic phenotype and survival in TAMs. Together, we uncover the unexpected roles of tumor-cell-produced lipids that simultaneously orchestrate macrophage polarization and survival in tumors via induction of ER stress responses and reveal therapeutic targets for sustaining host antitumor immunity.

DOI: https://doi.org/10.1038/s41590-021-01047-4
Acta Biochim Biophys Sin (Shanghai). 2021 Oct 19. pii: gmab131. [Epub ahead of print]

Targeting UPR branches, a potential strategy for enhancing efficacy of cancer chemotherapy.

Mengchao Yu, Jie Lun, Hongwei Zhang, Lei Wang, Gang Zhang, Haisheng Zhang, Jing Fang.

  Cancer cells are often exposed to cell intrinsic stresses and environmental perturbations that may lead to accumulation of unfolded and/or misfolded proteins in the lumen of endoplasmic reticulum (ER), a cellular condition known as ER stress. In response to ER stress, the cells elicit an adaptive process called unfolded protein response (UPR) to cope with the stress, supporting cellular homeostasis and survival. The ER stress sensors inositol requiring protein 1α (IRE1α), eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also called PERK), and activating transcription factor 6 (ATF6) constitute the three branches of UPR to resolve ER stress. IRE1α, PERK, and ATF6 play an important role in tumor cell growth and survival. They are also involved in chemotherapy resistance of cancers. These have generated widespread interest in targeting these UPR branches for cancer treatment. In this review, we provide an overview of the role of IRE1α, PERK, and ATF6 in cancer progression and drug resistance and we summarize the research advances in targeting these UPR branches to enhance the efficacy of chemotherapy of cancers.

Keywords:  ER stress; cancer; chemotherapy; drug resistance; unfolded protein response

DOI:  https://doi.org/10.1093/abbs/gmab131
BMC Biol. 2021 Oct 21. 19(1): 228

The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor.

Marie-Lise Lacombe, Frederic Lamarche, Olivier De Wever, Teresita Padilla-Benavides, Alyssa Carlson, Imran Khan, Anda Huna, Sophie Vacher, Claire Calmel, Céline Desbourdes, Cécile Cottet-Rousselle, Isabelle Hininger-Favier, Stéphane Attia, Béatrice Nawrocki-Raby, Joël Raingeaud, Christelle Machon, Jérôme Guitton, Morgane Le Gall, Guilhem Clary, Cedric Broussard, Philippe Chafey, Patrice Thérond, David Bernard, Eric Fontaine, Malgorzata Tokarska-Schlattner, Patricia Steeg, Ivan Bièche, Uwe Schlattner, Mathieu Boissan.

   BACKGROUND: Mitochondrial nucleoside diphosphate kinase (NDPK-D, NME4, NM23-H4) is a multifunctional enzyme mainly localized in the intermembrane space, bound to the inner membrane.
RESULTS: We constructed loss-of-function mutants of NDPK-D, lacking either NDP kinase activity or membrane interaction and expressed mutants or wild-type protein in cancer cells. In a complementary approach, we performed depletion of NDPK-D by RNA interference. Both loss-of-function mutations and NDPK-D depletion promoted epithelial-mesenchymal transition and increased migratory and invasive potential. Immunocompromised mice developed more metastases when injected with cells expressing mutant NDPK-D as compared to wild-type. This metastatic reprogramming is a consequence of mitochondrial alterations, including fragmentation and loss of mitochondria, a metabolic switch from respiration to glycolysis, increased ROS generation, and further metabolic changes in mitochondria, all of which can trigger pro-metastatic protein expression and signaling cascades. In human cancer, NME4 expression is negatively associated with markers of epithelial-mesenchymal transition and tumor aggressiveness and a good prognosis factor for beneficial clinical outcome.
CONCLUSIONS: These data demonstrate NME4 as a novel metastasis suppressor gene, the first localizing to mitochondria, pointing to a role of mitochondria in metastatic dissemination.

Keywords:  Invasion; Metabolic reprogramming; Metastasis; Mitochondrial dynamics; NME4; Nucleoside diphosphate kinase; Prognosis biomarker; Retrograde signaling

DOI:  https://doi.org/10.1186/s12915-021-01155-5
Cell. 2021 Oct 11. pii: S0092-8674(21)01116-8. [Epub ahead of print]

An in vitro system to silence mitochondrial gene expression.

Luis Daniel Cruz-Zaragoza, Sven Dennerlein, Andreas Linden, Roya Yousefi, Elena Lavdovskaia, Abhishek Aich, Rebecca R Falk, Ridhima Gomkale, Thomas Schöndorf, Markus T Bohnsack, Ricarda Richter-Dennerlein, Henning Urlaub, Peter Rehling.

  The human mitochondrial genome encodes thirteen core subunits of the oxidative phosphorylation system, and defects in mitochondrial gene expression lead to severe neuromuscular disorders. However, the mechanisms of mitochondrial gene expression remain poorly understood due to a lack of experimental approaches to analyze these processes. Here, we present an in vitro system to silence translation in purified mitochondria. In vitro import of chemically synthesized precursor-morpholino hybrids allows us to target translation of individual mitochondrial mRNAs. By applying this approach, we conclude that the bicistronic, overlapping ATP8/ATP6 transcript is translated through a single ribosome/mRNA engagement. We show that recruitment of COX1 assembly factors to translating ribosomes depends on nascent chain formation. By defining mRNA-specific interactomes for COX1 and COX2, we reveal an unexpected function of the cytosolic oncofetal IGF2BP1, an RNA-binding protein, in mitochondrial translation. Our data provide insight into mitochondrial translation and innovative strategies to investigate mitochondrial gene expression.

Keywords:  IGF2BP1; antisense; mitochondria; mitochondrial ribosome; morpholino; oxidative phosphorylation; translation

DOI:  https://doi.org/10.1016/j.cell.2021.09.033
Mol Cell. 2021 Oct 21. pii: S1097-2765(21)00833-9. [Epub ahead of print]81(20): 4109-4110

Interferon induction held captive in tumor cells.

Anne Bridgeman, Jan Rehwinkel.

Unusual nucleic acids activate innate immunity and may be present in transformed cells. Meng et al. (2021) find that cancer-associated mutations in NF2 turn this tumor suppressor into a potent antagonist of DNA- and RNA-induced innate immune signaling.

DOI: https://doi.org/10.1016/j.molcel.2021.10.004
Proc Natl Acad Sci U S A. 2021 Oct 26. pii: e2025347118. [Epub ahead of print]118(43):

Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency.

Melissa Vos, Marija Dulovic-Mahlow, Frida Mandik, Lisa Frese, Yuliia Kanana, Sokhna Haissatou Diaw, Julia Depperschmidt, Claudia Böhm, Jonas Rohr, Thora Lohnau, Inke R König, Christine Klein.

  Energy production via the mitochondrial electron transport chain (ETC) and mitophagy are two important processes affected in Parkinson's disease (PD). Interestingly, PINK1, mutations of which cause early-onset PD, plays a key role in both processes, suggesting that these two mechanisms are connected. However, the converging link of both pathways currently remains enigmatic. Recent findings demonstrated that lipid aggregation, along with defective mitochondria, is present in postmortem brains of PD patients. In addition, an increasing body of evidence shows that sphingolipids, including ceramide, are altered in PD, supporting the importance of lipids in the pathophysiology of PD. Here, we identified ceramide to play a crucial role in PINK1-related PD that was previously linked almost exclusively to mitochondrial dysfunction. We found ceramide to accumulate in mitochondria and to negatively affect mitochondrial function, most notably the ETC. Lowering ceramide levels improved mitochondrial phenotypes in pink1-mutant flies and PINK1-deficient patient-derived fibroblasts, showing that the effects of ceramide are evolutionarily conserved. In addition, ceramide accumulation provoked ceramide-induced mitophagy upon PINK1 deficiency. As a result of the ceramide accumulation, β-oxidation in PINK1 mutants was decreased, which was rescued by lowering ceramide levels. Furthermore, stimulation of β-oxidation was sufficient to rescue PINK1-deficient phenotypes. In conclusion, we discovered a cellular mechanism resulting from PD-causing loss of PINK1 and found a protective role of β-oxidation in ETC dysfunction, thus linking lipids and mitochondria in the pathophysiology of PINK1-related PD. Furthermore, our data nominate β-oxidation and ceramide as therapeutic targets for PD.

Keywords:  PINK1; Parkinson’s disease; ceramide; mitochondria; β-oxidation

DOI:  https://doi.org/10.1073/pnas.2025347118
Biology (Basel). 2021 Oct 15. pii: 1050. [Epub ahead of print]10(10):

Mitochondrial Translation Occurs Preferentially in the Peri-Nuclear Mitochondrial Network of Cultured Human Cells.

Christin A Albus, Rolando Berlinguer-Palmini, Caroline Hewison, Fiona McFarlane, Elisabeta-Ana Savu, Robert N Lightowlers, Zofia M Chrzanowska-Lightowlers, Matthew Zorkau.

  Human mitochondria are highly dynamic organelles, fusing and budding to maintain reticular networks throughout many cell types. Although extending to the extremities of the cell, the majority of the network is concentrated around the nucleus in most of the commonly cultured cell lines. This organelle harbours its own genome, mtDNA, with a different gene content to the nucleus, but the expression of which is critical for maintaining oxidative phosphorylation. Recent advances in click chemistry have allowed us to visualise sites of mitochondrial protein synthesis in intact cultured cells. We show that the majority of translation occurs in the peri-nuclear region of the network. Further analysis reveals that whilst there is a slight peri-nuclear enrichment in the levels of mitoribosomal protein and mitochondrial rRNA, it is not sufficient to explain this substantial heterogeneity in the distribution of translation. Finally, we also show that in contrast, a mitochondrial mRNA does not show such a distinct gradient in distribution. These data suggest that the relative lack of translation in the peripheral mitochondrial network is not due to an absence of mitoribosomes or an insufficient supply of the mt-mRNA transcripts.

Keywords:  co-localisation; heterogeneity; mammalian; mitochondria; peri-nuclear; peripheral; protein synthesis

DOI:  https://doi.org/10.3390/biology10101050
Nat Metab. 2021 Oct;3(10): 1284-1285

Nuclear PHGDH protects cancer cells from nutrient stress.

Daniela Annibali, Sarah-Maria Fendt.

DOI: https://doi.org/10.1038/s42255-021-00448-x
Circulation. 2021 Oct 21.

Mitochondrial Telomerase Reverse Transcriptase Protects from Myocardial Ischemia/reperfusion Injury by Improving Complex I Composition and Function.

Niloofar Ale-Agha, Philipp Jakobs, Christine Goy, Mark Zurek, Julia Rosen, Nadine Dyballa-Rukes, Sabine Metzger, Jan Greulich, Florian von Ameln, Olaf Eckermann, Klaus Unfried, Fedor Brack, Maria Grandoch, Matthias Thielmann, Markus Kamler, Nilgün Gedik, Petra Kleinbongard, Andre Heinen, Gerd Heusch, Axel Gödecke, Joachim Altschmied, Judith Haendeler.

Background: The catalytic subunit of telomerase, Telomerase Reverse Transcriptase (TERT) has protective functions in the cardiovascular system. TERT is not only present in the nucleus, but also in mitochondria. However, it is unclear whether nuclear or mitochondrial TERT is responsible for the observed protection and appropriate tools are missing to dissect this. Methods: We generated new mouse models containing TERT exclusively in the mitochondria (mitoTERT mice) or the nucleus (nucTERT mice) to finally distinguish between the functions of nuclear and mitochondrial TERT. Outcome after ischemia/reperfusion, mitochondrial respiration in the heart as well as cellular functions of cardiomyocytes, fibroblasts, and endothelial cells were determined. Results: All mice were phenotypically normal. While respiration was reduced in cardiac mitochondria from TERT-deficient and nucTERT mice, it was increased in mitoTERT animals. The latter also had smaller infarcts than wildtype mice, whereas nucTERT animals had larger infarcts. The decrease in ejection fraction after one, two and four weeks of reperfusion was attenuated in mitoTERT mice. Scar size was also reduced and vascularization increased. Mitochondrial TERT protected a cardiomyocyte cell line from apoptosis. Myofibroblast differentiation, which depends on complex I activity, was abrogated in TERT-deficient and nucTERT cardiac fibroblasts and completely restored in mitoTERT cells. In endothelial cells, mitochondrial TERT enhanced migratory capacity and activation of endothelial NO synthase. Mechanistically, mitochondrial TERT improved the ratio between complex I matrix arm and membrane subunits explaining the enhanced complex I activity. In human right atrial appendages, TERT was localized in mitochondria and there increased by remote ischemic preconditioning. The Telomerase activator, TA-65 evoked a similar effect in endothelial cells, thereby increasing their migratory capacity, and enhanced myofibroblast differentiation. Conclusions: Mitochondrial, but not nuclear TERT, is critical for mitochondrial respiration and during ischemia/reperfusion injury. Mitochondrial TERT improves complex I subunit composition. TERT is present in human heart mitochondria, and remote ischemic preconditioning increases its level in those organelles. TA-65 has comparable effects ex vivo and improves migratory capacity of endothelial cells and myofibroblast differentiation. We conclude that mitochondrial TERT is responsible for cardioprotection and its increase could serve as a therapeutic strategy.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.120.051923