bims-mibica 2023-12-31 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2023‒12‒31
twenty-two papers selected by
Kelsey Fisher-Wellman, East Carolina University

Mitochondrial regulation of GPX4 inhibition-mediated ferroptosis in acute myeloid leukemia.
A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass.
Regulation of respiratory complex I assembly by FMN cofactor targeting.
Powering down the mitochondrial LonP1 protease: a novel strategy for anticancer therapeutics.
Protein N-myristoylation plays a critical role in the mitochondrial localization of human mitochondrial complex I accessory subunit NDUFB7.
Parkin enhances sensitivity of paclitaxel to nasopharyngeal carcinoma by activating BNIP3/NIX-mediated mitochondrial autophagy.
Interactome analysis identifies the role of BZW2 in promoting endoplasmic reticulum-mitochondrial contact and mitochondrial metabolism.
Cyclin D1 extensively reprograms metabolism to support biosynthetic pathways in hepatocytes.
Induction of Fatty Acid Oxidation Underlies DNA Damage-Induced Cell Death and Ameliorates Obesity-Driven Chemoresistance.
Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells.
Neither too much nor too little: mitochondrial calcium concentration as a balance between physiological and pathological conditions.
COX19 is a new target of MACC1 and promotes colorectal cancer progression by regulating copper transport in mitochondria.
p32/OPA1 axis-mediated mitochondrial dynamics contributes to cisplatin resistance in non-small cell lung cancer.
Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes.
Mitochondrial electron transport chain, ceramide, and coenzyme Q are linked in a pathway that drives insulin resistance in skeletal muscle.
Synthesis and biological evaluation of novel bi-gold mitocans in lung cancer cells.
Mitochondrial DNA copy number and cancer risks: A comprehensive Mendelian randomization analysis.
Up-regulation of TNF-alpha/NFkB/SIRT1 axis drives aggressiveness and cancer stem cells accumulation in chemoresistant oral squamous cell carcinoma.
Potassium ion efflux induces exaggerated mitochondrial damage and non-pyroptotic necrosis when energy metabolism is blocked.
Targeting Acid Ceramidase enhances antitumor immune response in colorectal cancer.
Suppression of the KRAS-NRF2 axis shifts arginine into the phosphocreatine energy system in pancreatic cancer cells.
Nutrition and dietary restrictions in cancer prevention.

Leukemia. 2023 Dec 26.

Mitochondrial regulation of GPX4 inhibition-mediated ferroptosis in acute myeloid leukemia.

Hiroki Akiyama, Ran Zhao, Lauren B Ostermann, Ziyi Li, Matthew Tcheng, Samar J Yazdani, Arman Moayed, Malcolm L Pryor, Sandeep Slngh, Natalia Baran, Edward Ayoub, Yuki Nishida, Po Yee Mak, Vivian R Ruvolo, Bing Z Carter, Aaron D Schimmer, Michael Andreeff, Jo Ishizawa.

Resistance to apoptosis in acute myeloid leukemia (AML) cells causes refractory or relapsed disease, associated with dismal clinical outcomes. Ferroptosis, a mode of non-apoptotic cell death triggered by iron-dependent lipid peroxidation, has been investigated as potential therapeutic modality against therapy-resistant cancers, but our knowledge of its role in AML is limited. We investigated ferroptosis in AML cells and identified its mitochondrial regulation as a therapeutic vulnerability. GPX4 knockdown induced ferroptosis in AML cells, accompanied with characteristic mitochondrial lipid peroxidation, exerting anti-AML effects in vitro and in vivo. Electron transport chains (ETC) are primary sources of coenzyme Q10 (CoQ) recycling for its function of anti-lipid peroxidation in mitochondria. We found that the mitochondria-specific CoQ potently inhibited GPX4 inhibition-mediated ferroptosis, suggesting that mitochondrial lipid redox regulates ferroptosis in AML cells. Consistently, Rho0 cells, which lack functional ETC, were more sensitive to GPX4 inhibition-mediated mitochondrial lipid peroxidation and ferroptosis than control cells. Furthermore, degradation of ETC through hyperactivation of a mitochondrial protease, caseinolytic protease P (ClpP), synergistically enhanced the anti-AML effects of GPX4 inhibition. Collectively, our findings indicate that in AML cells, GPX4 inhibition induces ferroptosis, which is regulated by mitochondrial lipid redox and ETC.

DOI: https://doi.org/10.1038/s41375-023-02117-2
Mol Cell. 2023 Dec 21. pii: S1097-2765(23)01014-6. [Epub ahead of print]

A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass.

Yuqiu Sun, Yu Cao, Huayun Wan, Adalet Memetimin, Yang Cao, Lin Li, Chongyang Wu, Meng Wang, She Chen, Qi Li, Yan Ma, Mengqiu Dong, Hui Jiang.

  Mitophagy mediated by BNIP3 and NIX critically regulates mitochondrial mass. Cellular BNIP3 and NIX levels are tightly controlled by SCFFBXL4-mediated ubiquitination to prevent excessive mitochondrial loss and lethal disease. Here, we report that knockout of PPTC7, a mitochondrial matrix protein, hyperactivates BNIP3-/NIX-mediated mitophagy and causes perinatal lethality that is rescued by NIX knockout in mice. Biochemically, the PPTC7 precursor is trapped by BNIP3 and NIX to the mitochondrial outer membrane, where PPTC7 scaffolds assembly of a substrate-PPTC7-SCFFBXL4 holocomplex to degrade BNIP3 and NIX, forming a homeostatic regulatory loop. PPTC7 possesses an unusually weak mitochondrial targeting sequence to facilitate its outer membrane retention and mitophagy control. Starvation upregulates PPPTC7 expression in mouse liver to repress mitophagy, which critically maintains hepatic mitochondrial mass, bioenergetics, and gluconeogenesis. Collectively, PPTC7 functions as a mitophagy sensor that integrates homeostatic and physiological signals to dynamically control BNIP3 and NIX degradation, thereby maintaining mitochondrial mass and cellular homeostasis.

Keywords:  Cullin; FBXL4; PPTC7; metabolism; mitochondrial mass; mitophagy receptors BNIP3 and NIX; ubiquitin

DOI:  https://doi.org/10.1016/j.molcel.2023.11.038
Redox Biol. 2023 Dec 20. pii: S2213-2317(23)00402-0. [Epub ahead of print]69 103001

Regulation of respiratory complex I assembly by FMN cofactor targeting.

Andrea Curtabbi, Adela Guarás, José Luis Cabrera-Alarcón, Maribel Rivero, Enrique Calvo, Marina Rosa-Moreno, Jesús Vázquez, Milagros Medina, José Antonio Enríquez.

  Respiratory complex I plays a crucial role in the mitochondrial electron transport chain and shows promise as a therapeutic target for various human diseases. While most studies focus on inhibiting complex I at the Q-site, little is known about inhibitors targeting other sites within the complex. In this study, we demonstrate that diphenyleneiodonium (DPI), a N-site inhibitor, uniquely affects the stability of complex I by reacting with its flavin cofactor FMN. Treatment with DPI blocks the final stage of complex I assembly, leading to the complete and reversible degradation of complex I in different cellular models. Growing cells in medium lacking the FMN precursor riboflavin or knocking out the mitochondrial flavin carrier gene SLC25A32 results in a similar complex I degradation. Overall, our findings establish a direct connection between mitochondrial flavin homeostasis and complex I stability and assembly, paving the way for novel pharmacological strategies to regulate respiratory complex I.

Keywords:  DPI; FMN; OXPHOS; Respiratory complex I

DOI:  https://doi.org/10.1016/j.redox.2023.103001
Expert Opin Ther Targets. 2023 Dec 29. 1-7

Powering down the mitochondrial LonP1 protease: a novel strategy for anticancer therapeutics.

Rahul Shetty, Roberto Noland, Ghata Nandi, Carolyn K Suzuki.

  INTRODUCTION: Mitochondrial LonP1 is an ATP-powered protease that also functions as an ATP-dependent chaperone. LonP1 plays a pivotal role in regulating mitochondrial proteostasis, metabolism and cell stress responses. Cancer cells exploit the functions of LonP1 to combat oncogenic stressors such as hypoxia, proteotoxicity, and oxidative stress, and to reprogram energy metabolism enabling cancer cell proliferation, chemoresistance, and metastasis.AREAS COVERED: LonP1 has emerged as a potential target for anti-cancer therapeutics. We review how cytoprotective functions of LonP1 can be leveraged by cancer cells to support oncogenic growth, proliferation, and survival. We also offer insights into small molecule inhibitors that target LonP1 by two distinct mechanisms: competitive inhibition of its protease activity and allosteric inhibition of its ATPase activity, both of which are crucial for its protease and chaperone functions.
EXPERT OPINION: We highlight advantages of identifying specific, high-affinity allosteric inhibitors blocking the ATPase activity of LonP1. The future discovery of such inhibitors has potential application either alone or in conjunction with other anticancer agents, presenting an innovative approach and target for cancer therapeutics.

Keywords:  AAA+ protease; ATP-powered protease; CDDO-Me; Cancer; Lon protease; LonP1; allosteric inhibitor; mitochondria

DOI:  https://doi.org/10.1080/14728222.2023.2298358
Sci Rep. 2023 12 27. 13(1): 22991

Protein N-myristoylation plays a critical role in the mitochondrial localization of human mitochondrial complex I accessory subunit NDUFB7.

Haruna Harada, Koko Moriya, Hirotsugu Kobuchi, Naotada Ishihara, Toshihiko Utsumi.

The present study examined human N-myristoylated proteins that specifically localize to mitochondria among the 1,705 human genes listed in MitoProteome, a mitochondrial protein database. We herein employed a strategy utilizing cellular metabolic labeling with a bioorthogonal myristic acid analog in transfected COS-1 cells established in our previous studies. Four proteins, DMAC1, HCCS, NDUFB7, and PLGRKT, were identified as N-myristoylated proteins that specifically localize to mitochondria. Among these proteins, DMAC1 and NDUFB7 play critical roles in the assembly of complex I of the mitochondrial respiratory chain. DMAC1 functions as an assembly factor, and NDUFB7 is an accessory subunit of complex I. An analysis of the intracellular localization of non-myristoylatable G2A mutants revealed that protein N-myristoylation occurring on NDUFB7 was important for the mitochondrial localization of this protein. Furthermore, an analysis of the role of the CHCH domain in NDUFB7 using Cys to Ser mutants revealed that it was essential for the mitochondrial localization of NDUFB7. Therefore, the present results showed that NDUFB7, a vital component of human mitochondrial complex I, was N-myristoylated, and protein N-myrisotylation and the CHCH domain were both indispensable for the specific targeting and localization of NDUFB7 to mitochondria.

DOI: https://doi.org/10.1038/s41598-023-50390-z
Chin J Physiol. 2023 Nov-Dec;66(6):66(6): 503-515

Parkin enhances sensitivity of paclitaxel to nasopharyngeal carcinoma by activating BNIP3/NIX-mediated mitochondrial autophagy.

Haifeng Ni, Renhui Liu, Zhen Zhou, Bo Jiang, Bin Wang.

  As a malignant head and neck cancer, nasopharyngeal carcinoma (NPC) has high morbidity. Parkin expression has been reported to be reduced in NPC tissues and its upregulation could enhance paclitaxel-resistant cell cycle arrest. This study was performed to explore the possible mechanism of Parkin related to B-cell lymphoma-2 (Bcl-2)/adenovirus E1B 19 kDa interacting protein 3 (BNIP3)/BNIP3-like (NIX)-mediated mitochondrial autophagy in NPC cells. Initially, after Parkin overexpression or silencing, cell viability and proliferation were evaluated by lactate dehydrogenase and colony formation assays. JC-1 staining was used to assess the mitochondrial membrane potential. In addition, the levels of cellular reactive oxygen species (ROS) and mitochondrial ROS were detected using DCFH-DA staining and mitochondrial ROS (MitoSOX) red staining. The expression of proteins was measured using Western blot. Results showed that Parkin overexpression inhibited, whereas Parkin knockdown promoted the proliferation of paclitaxel-treated NPC cells. Besides, Parkin overexpression induced, whereas Parkin knockdown inhibited mitochondrial apoptosis in paclitaxel-treated NPC cells, as evidenced by the changes of Cytochrome C (mitochondria), Cytochrome C (cytoplasm), BAK, and Bcl-2 expression. Moreover, the levels of ROS, mitochondrial membrane potential, and LC3II/LC3I in paclitaxel-treated C666-1 cells were hugely elevated by Parkin overexpression and were all declined by Parkin knockdown in CNE-3 cells. Furthermore, Parkin upregulation activated, whereas Parkin downregulation inactivated BNIP3/NIX signaling. Further, BNIP3 silencing or overexpression reversed the impacts of Parkin upregulation or downregulation on the proliferation and mitochondrial apoptosis of paclitaxel-treated NPC cells. Particularly, Mdivi-1 (mitophagy inhibitor) or rapamycin (an activator of autophagy) exerted the same effects on NPC cells as BNIP3 silencing or overexpression, respectively. Collectively, Parkin overexpression activated BNIP3/NIX-mediated mitochondrial autophagy to enhance sensitivity to paclitaxel in NPC.

Keywords:  BNIP3/NIX; Parkin; mitochondrial autophagy; nasopharyngeal carcinoma; paclitaxel

DOI:  https://doi.org/10.4103/cjop.CJOP-D-23-00076
Mol Cell Proteomics. 2023 Dec 26. pii: S1535-9476(23)00220-7. [Epub ahead of print] 100709

Interactome analysis identifies the role of BZW2 in promoting endoplasmic reticulum-mitochondrial contact and mitochondrial metabolism.

George Maio, Mike Smith, Ruchika Bhawal, Sheng Zhang, Jeremy M Baskin, Jenny Li, Hening Lin.

Understanding the molecular functions of less-studied proteins is an important task of life science research. Despite reports of BZW2 (Basic leucine zipper and W2 domain-containing protein 2) promoting cancer progression first emerging in 2017, little is known about its molecular function. Using a quantitative proteomic approach to identify its interacting proteins, we found that BZW2 interacts with both endoplasmic reticulum (ER) and mitochondrial proteins. We thus hypothesized that BZW2 localizes to and promotes the formation of ER-mitochondrial contact sites, and that such localization would promote calcium transport from ER to the mitochondria and promote ATP production. Indeed, we found that BZW2 localized to ER-mitochondria contact sites and that BZW2 knockdown decreased ER-mitochondrial contact, mitochondrial calcium levels, and ATP production. These findings provide key insights into molecular functions of BZW2, the potential role of BZW2 in cancer progression, and highlight the utility of interactome data in understanding the function of less-studied proteins.

DOI: https://doi.org/10.1016/j.mcpro.2023.100709
J Biol Chem. 2023 Dec;pii: S0021-9258(23)02435-3. [Epub ahead of print]299(12): 105407

Cyclin D1 extensively reprograms metabolism to support biosynthetic pathways in hepatocytes.

Heng Wu, Betsy T Kren, Andrew N Lane, Teresa A Cassel, Richard M Higashi, Teresa W M Fan, George S Scaria, Laurie L Shekels, Mark A Klein, Jeffrey H Albrecht.

  Cell proliferation requires metabolic reprogramming to accommodate biosynthesis of new cell components, and similar alterations occur in cancer cells. However, the mechanisms linking the cell cycle machinery to metabolism are not well defined. Cyclin D1, along with its main partner cyclin-dependent kinase 4 (Cdk4), is a pivotal cell cycle regulator and driver oncogene that is overexpressed in many cancers. Here, we examine hepatocyte proliferation to define novel effects of cyclin D1 on biosynthetic metabolism. Metabolomic studies reveal that cyclin D1 broadly promotes biosynthetic pathways including glycolysis, the pentose phosphate pathway, and the purine and pyrimidine nucleotide synthesis in hepatocytes. Proteomic analyses demonstrate that overexpressed cyclin D1 binds to numerous metabolic enzymes including those involved in glycolysis and pyrimidine synthesis. In the glycolysis pathway, cyclin D1 activates aldolase and GAPDH, and these proteins are phosphorylated by cyclin D1/Cdk4 in vitro. De novo pyrimidine synthesis is particularly dependent on cyclin D1. Cyclin D1/Cdk4 phosphorylates the initial enzyme of this pathway, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), and metabolomic analysis indicates that cyclin D1 depletion markedly reduces the activity of this enzyme. Pharmacologic inhibition of Cdk4 along with the downstream pyrimidine synthesis enzyme dihydroorotate dehydrogenase synergistically inhibits proliferation and survival of hepatocellular carcinoma cells. These studies demonstrate that cyclin D1 promotes a broad network of biosynthetic pathways in hepatocytes, and this model may provide insights into potential metabolic vulnerabilities in cancer cells.

Keywords:  BAY 2402234; aldolase; anaerobic glycolysis; cell cycle; cyclin D1; glyceraldehyde-3-phosphate dehydrogenase (GAPDH); liver regeneration; palbociclib; pentose phosphate pathway (PPP); purine; pyrimidine

DOI:  https://doi.org/10.1016/j.jbc.2023.105407
Adv Sci (Weinh). 2023 Dec 25. e2304702

Induction of Fatty Acid Oxidation Underlies DNA Damage-Induced Cell Death and Ameliorates Obesity-Driven Chemoresistance.

Sunsook Hwang, Seungyeon Yang, Kyungsoo Park, Byungjoo Kim, Minjoong Kim, Seungmin Shin, Ahyoung Yoo, Jiyun Ahn, Juneil Jang, Yeong Shin Yim, Rho H Seong, Seung Min Jeong.

  The DNA damage response is essential for preserving genome integrity and eliminating damaged cells. Although cellular metabolism plays a central role in cell fate decision between proliferation, survival, or death, the metabolic response to DNA damage remains largely obscure. Here, this work shows that DNA damage induces fatty acid oxidation (FAO), which is required for DNA damage-induced cell death. Mechanistically, FAO induction increases cellular acetyl-CoA levels and promotes N-alpha-acetylation of caspase-2, leading to cell death. Whereas chemotherapy increases FAO related genes through peroxisome proliferator-activated receptor α (PPARα), accelerated hypoxia-inducible factor-1α stabilization by tumor cells in obese mice impedes the upregulation of FAO, which contributes to its chemoresistance. Finally, this work finds that improving FAO by PPARα activation ameliorates obesity-driven chemoresistance and enhances the outcomes of chemotherapy in obese mice. These findings reveal the shift toward FAO induction is an important metabolic response to DNA damage and may provide effective therapeutic strategies for cancer patients with obesity.

Keywords:  DNA damage; cell death; chemoresistance; fatty acid oxidation; obesity

DOI:  https://doi.org/10.1002/advs.202304702
Cell Rep. 2023 Dec 22. pii: S2211-1247(23)01624-8. [Epub ahead of print]43(1): 113612

Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells.

Wiktoria Blaszczak, Bobby White, Stefania Monterisi, Pawel Swietach.

  Malignancy is enabled by pro-growth mutations and adequate energy provision. However, global metabolic activation would be self-terminating if it depleted tumor resources. Cancer cells could avoid this by rationing resources, e.g., dynamically switching between "baseline" and "activated" metabolic states. Using single-cell metabolic phenotyping of pancreatic ductal adenocarcinoma cells, we identify MIA-PaCa-2 as having broad heterogeneity of fermentative metabolism. Sorting by a readout of lactic acid permeability separates cells by fermentative and respiratory rates. Contrasting phenotypes persist for 4 days and are unrelated to cell cycling or glycolytic/respiratory gene expression; however, transcriptomics links metabolically active cells with interleukin-6 receptor (IL-6R)-STAT3 signaling. We verify this by IL-6R/STAT3 knockdowns and sorting by IL-6R status. IL-6R/STAT3 activates fermentation and transcription of its inhibitor, SOCS3, resulting in delayed negative feedback that underpins transitions between metabolic states. Among cells manifesting wide metabolic heterogeneity, dynamic IL-6R/STAT3 signaling may allow cell cohorts to take turns in progressing energy-intense processes without depleting shared resources.

Keywords:  CP: Cancer; CP: Metabolism; PDAC; SOCS; feedback; fermentation; glycolysis; heterogeneity; homeostasis; interleukin-6; microenvironment; rationing; variation

DOI:  https://doi.org/10.1016/j.celrep.2023.113612
Front Mol Biosci. 2023 ;10 1336416

Neither too much nor too little: mitochondrial calcium concentration as a balance between physiological and pathological conditions.

Donato D'Angelo, Denis Vecellio Reane, Anna Raffaello.

  Ca2+ ions serve as pleiotropic second messengers in the cell, regulating several cellular processes. Mitochondria play a fundamental role in Ca2+ homeostasis since mitochondrial Ca2+ (mitCa2+) is a key regulator of oxidative metabolism and cell death. MitCa2+ uptake is mediated by the mitochondrial Ca2+ uniporter complex (MCUc) localized in the inner mitochondrial membrane (IMM). MitCa2+ uptake stimulates the activity of three key enzymes of the Krebs cycle, thereby modulating ATP production and promoting oxidative metabolism. As Paracelsus stated, "Dosis sola facit venenum,"in pathological conditions, mitCa2+ overload triggers the opening of the mitochondrial permeability transition pore (mPTP), enabling the release of apoptotic factors and ultimately leading to cell death. Excessive mitCa2+ accumulation is also associated with a pathological increase of reactive oxygen species (ROS). In this article, we review the precise regulation and the effectors of mitCa2+ in physiopathological processes.

Keywords:  calcium; cell death; metabolism; mitochondria; mitochondrial calcium uniporter (MCU)

DOI:  https://doi.org/10.3389/fmolb.2023.1336416
J Nutr. 2023 Dec 21. pii: S0022-3166(23)72821-6. [Epub ahead of print]

COX19 is a new target of MACC1 and promotes colorectal cancer progression by regulating copper transport in mitochondria.

Sheng Gao, Xiaodong Zhang, Jian Wang, Wenqi Bai, Bo Jiang.

  BACKGROUND: Recent studies have demonstrated that Cu plays an important role in the progression of tumor diseases. Metastasis associated with colon cancer protein 1 (MACC1) promotes the transcription and expression of various tumor-related genes. Cytochrome c oxidase (COX) 19, present in the cytoplasm and intermembrane space of mitochondria, may transport Cu within the mitochondria. However, the mechanism through which MACC1 regulates the Cu homeostasis mediated by COX19 remains unclear.OBJECTIVES: The aim of this study was to elucidate the mechanism through which MACC1 initiates the transcription and expression of COX19, and promotes malignant behavior in tumor cells.
METHODS: Immunohistochemistry, western blotting, and real-time PCR analyses were conducted to analyze the expression of MACC1 and COX19 proteins and genes in tumor and normal tissues. RNA-CHIP was used to detect the transcriptional initiation of COX19 by MACC1. The effects of MACC1 and COX19 on mitochondrial activity were determined using an ATP assay kit and Cytochrome c Oxidase Assay Kit. A CCK-8 kit was used to detect the effect of high-dose Cu or overexpression of MACC1 and COX19 on tumor cell proliferation. A xenograft mouse model was used to analyze the effect of COX19 overexpression on the malignant behavior of the tumors.
RESULTS: Cu enhanced the proliferation, invasion, and migration and inhibited apoptosis of SW480 cells. MACC1 was highly expressed in colorectal cancer tissues and activated the expression of COX19 by binding to its promoter region of COX19. The overexpression of COX19 increased mitochondrial Cu content and enhanced the activity of mitochondrial COX and ATP content, and inhibited apoptosis, promoted tumor growth of mice.
CONCLUSIONS: Our results indicate that COX19 functions as a target gene of MACC1 and regulates mitochondrial activity and promotes the progression of colorectal cancer. MACC1/COX19 may provide a novel therapeutic target for colorectal cancer.

Keywords:  COX19; Colorectal cancer; Copper metabolic; MACC1

DOI:  https://doi.org/10.1016/j.tjnut.2023.12.032
Acta Biochim Biophys Sin (Shanghai). 2023 Dec 27.

p32/OPA1 axis-mediated mitochondrial dynamics contributes to cisplatin resistance in non-small cell lung cancer.

Chun-Xia Yu, Zhe-Qing Peng, Tao Wang, Xin-Hui Qu, Ping Yang, Shao-Rong Huang, Li-Ping Jiang, Fang-Fang Tou, Xiao-Jian Han.

  Cisplatin resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). p32 and OPA1 are the key regulators of mitochondrial morphology and function. This study aims to investigate the role of the p32/OPA1 axis in cisplatin resistance in NSCLC and its underlying mechanism. The levels of p32 protein and mitochondrial fusion protein OPA1 are higher in cisplatin-resistant A549/DDP cells than in cisplatin-sensitive A549 cells, which facilitates mitochondrial fusion in A549/DDP cells. In addition, the expression of p32 and OPA1 protein is also upregulated in A549 cells during the development of cisplatin resistance. Moreover, p32 knockdown effectively downregulates the expression of OPA1, stimulates mitochondrial fission, decreases ATP generation and sensitizes A549/DDP cells to cisplatin-induced apoptosis. Furthermore, metformin significantly downregulates the expressions of p32 and OPA1 and induces mitochondrial fission and a decrease in ATP level in A549/DDP cells. The co-administration of metformin and cisplatin shows a significantly greater decrease in A549/DDP cell viability than cisplatin treatment alone. Moreover, D-erythro-Sphingosine, a potent p32 kinase activator, counteracts the metformin-induced downregulation of OPA1 and mitochondrial fission in A549/DDP cells. Taken together, these findings indicate that p32/OPA1 axis-mediated mitochondrial dynamics contributes to the acquired cisplatin resistance in NSCLC and that metformin resensitizes NSCLC to cisplatin, suggesting that targeting p32 and mitochondrial dynamics is an effective strategy for the prevention of cisplatin resistance.

Keywords:  OPA1; cisplatin resistance; metformin; mitochondrial dynamics; non-small cell lung cancer; p32

DOI:  https://doi.org/10.3724/abbs.2023247
Mol Metab. 2023 Dec 23. pii: S2212-8778(23)00193-X. [Epub ahead of print] 101859

Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes.

Anna Janz, Katharina Walz, Alexandra Cirnu, Jessica Surjanto, Daniela Urlaub, Miriam Leskien, Michael Kohlhaas, Alexander Nickel, Theresa Brand, Naoko Nose, Philipp Wörsdörfer, Nicole Wagner, Takahiro Higuchi, Christoph Maack, Jan Dudek, Kristina Lorenz, Eva Klopocki, Süleyman Ergün, Henry J Duff, Brenda Gerull.

  BACKGROUND: Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19 for the development of cardiomyopathy.METHODS: We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two affected siblings with DCMA and a gene-edited truncation variant (tv) of DNAJC19which all lack the conserved DnaJ interaction domain. The mutant iPSC-CMs and their respective control cells were subjected to various analyses, including assessments of morphology, metabolic function, and physiological consequences such as Ca2+ kinetics, contractility, and arrhythmic potential. Validation of respiration analysis was done in a gene-edited HeLa cell line (DNAJC19tvHeLa).
RESULTS: Structural analyses revealed mitochondrial fragmentation and abnormal cristae formation associated with an overall reduced mitochondrial protein expression in mutant iPSC-CMs. Morphological alterations were associated with higher oxygen consumption rates (OCRs) in all three mutant iPSC-CMs, indicating higher electron transport chain activity to meet cellular ATP demands. Additionally, increased extracellular acidification rates suggested an increase in overall metabolic flux, while radioactive tracer uptake studies revealed decreased fatty acid uptake and utilization of glucose. Mutant iPSC-CMs also showed increased reactive oxygen species (ROS) and an elevated mitochondrial membrane potential. Increased mitochondrial respiration with pyruvate and malate as substrates was observed in mutant DNAJC19tv HeLa cells in addition to an upregulation of respiratory chain complexes, while cellular ATP-levels remain the same. Moreover, mitochondrial alterations were associated with increased beating frequencies, elevated diastolic Ca2+ concentrations, reduced sarcomere shortening and an increased beat-to-beat rate variability in mutant cell lines in response to β-adrenergic stimulation.
CONCLUSIONS: Loss of the DnaJ domain disturbs cardiac mitochondrial structure with abnormal cristae formation and mitochondrial function, which suggests that DNAJC19 plays an essential role in mitochondrial morphogenesis and biogenesis. Moreover, increased mitochondrial respiration, altered substrate utilization, increased ROS production and abnormal Ca2+ kinetics provide insights into the pathogenesis of DCMA-related cardiomyopathy.

Keywords:  Contractility; Dilated cardiomyopathy with ataxia; Genetics; Metabolism; Mitochondria; OXPHOS; ROS

DOI:  https://doi.org/10.1016/j.molmet.2023.101859
Elife. 2023 Dec 27. pii: RP87340. [Epub ahead of print]12

Mitochondrial electron transport chain, ceramide, and coenzyme Q are linked in a pathway that drives insulin resistance in skeletal muscle.

Alexis Diaz-Vegas, Søren Madsen, Kristen C Cooke, Luke Carroll, Jasmine X Y Khor, Nigel Turner, Xin Y Lim, Miro A Astore, Jonathan C Morris, Anthony S Don, Amanda Garfield, Simona Zarini, Karin A Zemski Berry, Andrew P Ryan, Bryan C Bergman, Joseph T Brozinick, David E James, James G Burchfield.

  Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Previously we showed that deficiency of coenzyme Q (CoQ) is necessary and sufficient for IR in adipocytes and skeletal muscle (Fazakerley et al., 2018). Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, CoQ deficiency, mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells result in CoQ depletion and loss of mitochondrial respiratory chain components, leading to mitochondrial dysfunction and IR. Further, decreasing mitochondrial ceramide levels in vitro and in animal models (mice, C57BL/6J) (under chow and high-fat diet) increased CoQ levels and was protective against IR. CoQ supplementation also rescued ceramide-associated IR. Examination of the mitochondrial proteome from human muscle biopsies revealed a strong correlation between the respirasome system and mitochondrial ceramide as key determinants of insulin sensitivity. Our findings highlight the mitochondrial ceramide-CoQ-respiratory chain nexus as a potential foundation of an IR pathway that may also play a critical role in other conditions associated with ceramide accumulation and mitochondrial dysfunction, such as heart failure, cancer, and aging. These insights may have important clinical implications for the development of novel therapeutic strategies for the treatment of IR and related metabolic disorders.

Keywords:  biochemistry; cell biology; ceramides; chemical biology; coenzyme Q; human; insulin resistance; mitochondria; mouse; muscle; rat

DOI:  https://doi.org/10.7554/eLife.87340
Front Chem. 2023 ;11 1292115

Synthesis and biological evaluation of novel bi-gold mitocans in lung cancer cells.

Wenwen Ding, Qingbin Cui, Wenhua Lu, Yongliang Du, Yao Luo, Yumin Hu, Peng Huang, Shijun Wen.

  Mitochondria are promising drug target for cancer treatment. We previously demonstrated that a bi-gold compound BGC2a was more potent than the mono-gold drug auranofin in suppressing cancer cells due to increased gold atom number that led to higher drug accumulation in and thereby inhibition of mitochondria. To exploit the potential of this new strategy, we further designed and synthesized a series of bi-gold mitocans, the compounds targeting mitochondria. The results showed that most of the newly synthesized mitocans exhibited obviously lower IC50 than auranofin, an old drug that is repurposed in clinical trials for cancer treatment. The best mitocan C3P4 was nearly 2-fold more potent than BGC2a in human non-small cell lung cancer A549 cells and mantle cell lymphoma Jeko-1 cells, exhibiting substantial colony formation-suppressing and tumor-suppressing effects in A549 cells xenograft model. C3P4 induced apoptosis in a dose-dependent manner and arrested cell cycle at G0/G1 phase. The mechanistic study showed that C3P4 significantly increased the global reactive oxygen species and mitochondrial superoxide level, and reduced the mitochondrial membrane potential. C3P4 preferentially accumulated in mitochondria as measured by the gold content and substantially inhibited oxygen consumption rate and ATP production. These results further validated our hypothesis that targeting mitochondria would be promising to develop more potent anticancer agents. C3P4 may be further evaluated as a drug candidate for lung cancer treatment.

Keywords:  anticancer; apoptosis; bi-gold mitocans; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.3389/fchem.2023.1292115
Int J Cancer. 2023 Dec 27.

Mitochondrial DNA copy number and cancer risks: A comprehensive Mendelian randomization analysis.

Xianlei Cai, Chao Liang, Miaozun Zhang, Zhebin Dong, Yihui Weng, Weiming Yu.

  Mitochondrial DNA plays a critical role in the pathophysiology of cancer. However, the associations between mitochondrial DNA copy number (mtDNA-CN) and cancer risk are controversial. Mendelian randomization (MR) analyses were performed using three independent instrumental variables (IVs) to explore potential associations between mtDNA-CN and 20 types of cancer. The three sets of IVs were primarily obtained from participants in the UK Biobank and the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium using different methods. The outcome data of cancers were investigated using summary statistics from the FinnGen cohort. The potential causal associations were evaluated using the MR-Egger regression, weighted median, inverse-variance weighted (IVW), and weighted mode methods. The robustness of IVW estimates was validated using leave-one-out sensitivity analysis. Additionally, a meta-analysis was conducted to pool results from three sets of IVs. The results revealed that genetically predicted mtDNA-CN was not associated with cancer risk (odds ratio = 1.02; 95% confidence interval: 0.95-1.10). Subgroup analyses indicated no causal association between mtDNA-CN and breast, lung, prostate, skin, colorectal, gastric, liver, cervical uteri, esophageal, thyroid, bladder, pancreas, kidney, corpus uteri, ovary, brain, larynx, and anus cancers. It was observed that mtDNA-CN was associated with lip, oral cavity, and testis cancers. However, these results should be interpreted with caution because a small number of patients with lip and oral cavity or testis cancers were included. The comprehensive MR analysis demonstrated that mtDNA-CN is not a suitable biomarker for tumor risk assessment.

Keywords:  Mendelian randomization; cancer risk; mitochondrial DNA

DOI:  https://doi.org/10.1002/ijc.34833
J Cell Physiol. 2023 Dec 27.

Up-regulation of TNF-alpha/NFkB/SIRT1 axis drives aggressiveness and cancer stem cells accumulation in chemoresistant oral squamous cell carcinoma.

Letícia Rodrigues de Castro, Lucas Dias de Oliveira, Thaís Moré Milan, Ana Patrícia Espaladori Eskenazi, Rayana Longo Bighetti-Trevisan, Otávio Guilherme Gonçalves de Almeida, Marcio Luis Munhoz Amorim, Cristiane Helena Squarize, Rogerio Moraes Castilho, Luciana Oliveira de Almeida.

  Tumor resistance remains an obstacle to successfully treating oral squamous cell carcinoma (OSCC). Cisplatin is widely used as a cytotoxic drug to treat solid tumors, including advanced OSCC, but with low efficacy due to chemoresistance. Therefore, identifying the pathways that contribute to chemoresistance may show new possibilities for improving the treatment. This work explored the role of the tumor necrosis factor-alpha (TNF-alpha)/NFkB signaling in driving the cisplatin resistance of OSCC and its potential as a pharmacological target to overcome chemoresistance. Differential accessibility analysis demonstrated the enrichment of opened chromatin regions in members of the TNF-alpha/NFkB signaling pathway, and RNA-Seq confirmed the upregulation of TNF-alpha/NFkB signaling in cisplatin-resistant cell lines. NFkB was accumulated in cisplatin-resistant cell lines and in cancer stem cells (CSC), and the administration of TNF-alpha increased the CSC, suggesting that TNF-alpha/NFkB signaling is involved in the accumulation of CSC. TNF-alpha stimulation also increased the histone deacetylases HDAC1 and SIRT1. Cisplatin-resistant cell lines were sensitive to the pharmacological inhibition of NFkB, and low doses of the NFkB inhibitors, CBL0137, and emetine, efficiently reduced the CSC and the levels of SIRT1, increasing histone acetylation. The NFkB inhibitors decreased stemness potential, clonogenicity, migration, and invasion of cisplatin-resistant cell lines. The administration of the emetine significantly reduced the tumor growth of cisplatin-resistant xenograft models, decreasing NFkB and SIRT1, increasing histone acetylation, and decreasing CSC. TNF-alpha/NFkB/SIRT1 signaling regulates the epigenetic machinery by modulating histone acetylation, CSC, and aggressiveness of cisplatin-resistant OSCC and the NFkB inhibition is a potential strategy to treat chemoresistant OSCC.

Keywords:  NFkB; SIRT1; cancer stem cells; cisplatin resistance; oral squamous cell carcinoma

DOI:  https://doi.org/10.1002/jcp.31164
Free Radic Biol Med. 2023 Dec 25. pii: S0891-5849(23)01186-3. [Epub ahead of print]

Potassium ion efflux induces exaggerated mitochondrial damage and non-pyroptotic necrosis when energy metabolism is blocked.

Rong Xu, Li-Sha Yuan, Ying-Qing Gan, Na Lu, Ya-Ping Li, Zhi-Ya Zhou, Qing-Bing Zha, Xian-Hui He, Tak-Sui Wong, Dong-Yun Ouyang.

  Damage-associated molecular patterns (DAMPs) such as extracellular ATP and nigericin (a bacterial toxin) not only act as potassium ion (K+) efflux inducers to activate NLRP3 inflammasome, leading to pyroptosis, but also induce cell death independently of NLRP3 expression. However, the roles of energy metabolism in determining NLRP3-dependent pyroptosis and -independent necrosis upon K+ efflux are incompletely understood. Here we established cellular models by pharmacological blockade of energy metabolism, followed by stimulation with a K+ efflux inducer (ATP or nigericin). Two energy metabolic inhibitors, namely CPI-613 that targets α-ketoglutarate dehydrogenase and pyruvate dehydrogenase (a rate-limiting enzyme) and 2-deoxy-d-glucose (2-DG) that targets hexokinase, are recruited in this study, and Nlrp3 gene knockout macrophages were used. Our data showed that CPI-613 and 2-DG dose-dependently inhibited NLRP3 inflammasome activation, but profoundly increased cell death in the presence of ATP or nigericin. The cell death was K+ efflux-induced but NLRP3-indendent, which was associated with abrupt reactive oxygen species (ROS) production, reduction of mitochondrial membrane potential, and oligomerization of mitochondrial proteins, all indicating mitochondrial damage. Notably, the cell death induced by K+ efflux and blockade of energy metabolism was distinct from pyroptosis, apoptosis, necroptosis or ferroptosis. Furthermore, fructose 1,6-bisphosphate, a high-energy intermediate of glycolysis, significantly suppressed CPI-613+nigericin-induced mitochondrial damage and cell death. Collectively, our data show that energy deficiency diverts NLRP3 inflammasome activation-dependent pyroptosis to Nlrp3-independent necrosis upon K+ efflux inducers, which can be dampened by high-energy intermediate, highlighting a critical role of energy metabolism in cell survival and death under inflammatory conditions.

Keywords:  Fructose-1,6-bisphosphate; Glucose metabolism; Mitochondrial damage; NLRP3 inflammasome activation; Potassium efflux; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.029
J Adv Res. 2023 Dec 21. pii: S2090-1232(23)00403-4. [Epub ahead of print]

Targeting Acid Ceramidase enhances antitumor immune response in colorectal cancer.

Yadu Vijayan, Shirley James, Arun Viswanathan, Jayasekharan S Aparna, Anu Bindu, Narayanan N Namitha, Devasena Anantharaman, Manendra Babu Lankadasari, Kuzhuvelil B Harikumar.

  INTRODUCTION: Acid ceramidase (hereafter referred as ASAH1) is an enzyme in sphingolipid metabolism that converts pro-survival ceramide into sphingosine. ASAH1 has been shown to be overexpressed in certain cancers. However, the role of ASAH1 in colorectal cancer is still remain elusive OBJECTIVE: The present study is aimed to understand how ASAH1 regulates colorectal cancer (CRC) progression and resistance to checkpoint inhibitor therapy.METHODS: Both pharmacological and genetic silencing of ASAH1 was used in the study. In vitro experiments were done on human and mouse CRC cell lines. The in vivo studies were conducted in NOD-SCID and BALB/c mice models. The combination of ASAH1 inhibitor and checkpoint inhibitor was tested using a syngeneic tumor model of CRC. Transcriptomic and metabolomic analyses were done to understand the effect of ASAH1 silencing.
RESULTS: ASAH1 is overexpressed in human CRC cases, and silencing the expression resulted in the induction of immunological cell death (ICD) and mitochondrial stress. The ASAH1 inhibitor (LCL-521), either as monotherapy or in combination with an anti-PD-1 antibody, resulted in a reduction of tumors and, through induction of type I and II interferon response, activation of M1 macrophages and T cells, leading to enhanced infiltration of cytotoxic T cells. Our findings supported that the combination of LCL-521 and ICIs, which enhances the antitumor responses, and ASAH1 can be a druggable target in CRC.

Keywords:  Acid ceramidase; Colorectal cancer; Glutathione; Immunological cell death; LCL-521; T cells; checkpoint inhibitor

DOI:  https://doi.org/10.1016/j.jare.2023.12.013
iScience. 2023 Dec 15. 26(12): 108566

Suppression of the KRAS-NRF2 axis shifts arginine into the phosphocreatine energy system in pancreatic cancer cells.

Eros Di Giorgio, Himanshi Choudhary, Annalisa Ferino, Ylenia Cortolezzis, Emiliano Dalla, Francesca D'Este, Marina Comelli, Valentina Rapozzi, Luigi E Xodo.

  In pancreatic ductal adenocarcinomas (PDAC), the KRASG12D-NRF2 axis controls cellular functions such as redox homeostasis and metabolism. Disruption of this axis through suppression of NRF2 leads to profound reprogramming of metabolism. Unbiased transcriptome and metabolome analyses showed that PDAC cells with disrupted KRASG12D-NRF2 signaling (NRF2-/- cells) shift from aerobic glycolysis to metabolic pathways fed by amino acids. Metabolome, RNA-seq and qRT-PCR analyses revealed a blockade of the urea cycle, making NRF2-/- cells dependent on exogenous arginine for survival. Arginine is channeled into anabolic pathways, including the synthesis of phosphocreatine, which generates an energy buffer essential for cell growth. A similar switch was observed in tumor clones that had survived FOLFIRINOX therapy or blockade of KRAS signaling. Inhibition of the creatine pathway with cyclocreatine reduced both ATP and invasion rate in 3D spheroids from NRF2-deficient PDAC cells. Our study provides basis for the rational development of combination therapies for pancreatic cancer.

Keywords:  Cancer; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2023.108566
Biochim Biophys Acta Rev Cancer. 2023 Dec 24. pii: S0304-419X(23)00212-3. [Epub ahead of print] 189063

Nutrition and dietary restrictions in cancer prevention.

Amrendra Mishra, Giacomo Giuliani, Valter D Longo.

  The composition and pattern of dietary intake have emerged as key factors influencing aging, regeneration, and consequently, healthspan and lifespan. Cancer is one of the major diseases more tightly linked with aging, and age-related mortality. Although the role of nutrition in cancer incidence is generally well established, we are far from a consensus on how diet influences tumour development in different tissues. In this review, we will discuss how diet and dietary restrictions affect cancer risk and the molecular mechanisms potentially responsible for their effects. We will cover calorie restriction, intermittent fasting, prolonged fasting, fasting-mimicking diet, time-restricted eating, ketogenic diet, high protein diet, Mediterranean diet, and the vegan and vegetarian diets.

Keywords:  Calorie restriction; Cancer prevention; Dietary restrictions; Fasting mimicking diet; Intermittent fasting; Mediterranean diet

DOI:  https://doi.org/10.1016/j.bbcan.2023.189063