bims-midysc 2024-12-22 papers

bims-midysc

Biomed News

on Mitochondria dysfunction in cancer

Issue of 2024–12–22
ten papers selected by
Papachristodoulou Lab

Mitochondrial unfolded protein response-dependent β-catenin signaling promotes neuroendocrine prostate cancer.
Fis1 regulates mitochondrial morphology, bioenergetics, and removal of mtDNA damage in irradiated glioblastoma cells.
Exploring Aerobic Energy Metabolism in Breast Cancer: A Mutational Profile of Glycolysis and Oxidative Phosphorylation.
Mapping mitochondrial aging.
IFNγ-dependent metabolic reprogramming restrains an immature, pro-metastatic lymphatic state in melanoma.
Aging promotes an increase in mitochondrial fragmentation in astrocytes.
Mitochondrial DNA-activated cGAS-STING pathway in cancer: Mechanisms and therapeutic implications.
Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.
Inter- and intracellular mitochondrial communication: signaling hubs in aging and age-related diseases.
PGC1α is a key regulator of erastin-induced mitochondrial dysfunction during ferroptotic cell death.

Oncogene. 2024 Dec 17.

Mitochondrial unfolded protein response-dependent β-catenin signaling promotes neuroendocrine prostate cancer.

Jordan Alyse Woytash, Rahul Kumar, Ajay K Chaudhary, Cullan Donnelly, Adam Wojtulski, Murali Bethu, Jianmin Wang, Joseph Spernyak, Peter Bross, Neelu Yadav, Joseph R Inigo, Dhyan Chandra.

The mitochondrial unfolded protein response (UPRmt) maintains mitochondrial quality control and proteostasis under stress conditions. However, the role of UPRmt in aggressive and resistant prostate cancer is not clearly defined. We show that castration-resistant neuroendocrine prostate cancer (CRPC-NE) harbored highly dysfunctional oxidative phosphorylation (OXPHOS) Complexes. However, biochemical and protein analyses of CRPC-NE tumors showed upregulation of nuclear-encoded OXPHOS proteins and UPRmt in this lethal subset of prostate cancer suggestive of compensatory upregulation of stress signaling. Genetic deletion and pharmacological inhibition of the main chaperone of UPRmt heat shock protein 60 (HSP60) reduced neuroendocrine prostate cancer (NEPC) growth in vivo as well as reverted NEPC cells to a more epithelial-like state. HSP60-dependent aggressive NEPC phenotypes was associated with upregulation of β-catenin signaling both in cancer cells and in vivo tumors. HSP60 expression rendered enrichment of aggressive prostate cancer signatures and metastatic potential were inhibited upon suppression of UPRmt. We discovered that UPRmt promoted OXPHOS functions including mitochondrial bioenergetics in CRPC-NE via regulation of β-catenin signaling. Mitochondrial biogenesis facilitated cisplatin resistance and inhibition of UPRmt resensitizes CRPC-NE cells to cisplatin. Together, our findings demonstrated that UPRmt promotes mitochondrial health via upregulating β-catenin signaling and UPRmt represents viable therapeutic target for NEPC.

DOI: https://doi.org/10.1038/s41388-024-03261-4
J Cell Sci. 2024 Dec 20. pii: jcs.263459. [Epub ahead of print]

Fis1 regulates mitochondrial morphology, bioenergetics, and removal of mtDNA damage in irradiated glioblastoma cells.

Yuli Buckley, Maria S K Stoll, Charles L Hoppel, Jason A Mears.

  In response to external stress, mitochondrial dynamics is often disrupted, but the associated physiologic changes are often uncharacterized. In many cancers, including glioblastoma (GBM), mitochondrial dysfunction has been observed. Understanding how mitochondrial dynamics and physiology contribute to treatment resistance will lead to more targeted and effective therapeutics. This study aims to uncover how mitochondria in GBM cells adapt to and resist ionizing radiation (IR), a component of the standard of care for GBM. Using several approaches, we investigated how mitochondrial dynamics and physiology adapt to radiation stress and uncover a novel role for Fis1, a pro-fission protein, in regulating the stress response through mitochondrial DNA (mtDNA) maintenance and altered mitochondrial bioenergetics. Importantly, our data demonstrate that increased fission in response to IR leads to removal of mtDNA damage and more efficient oxygen consumption through altered ETC activities in intact mitochondria. These findings demonstrate a key role for Fis1 in targeting damaged mtDNA for degradation and regulating mitochondrial bioenergetics through altered dynamics.

Keywords:  Bioenergetics; Fis1; Ionizing radiation; Mitochondrial fission; MtDNA

DOI:  https://doi.org/10.1242/jcs.263459
Int J Mol Sci. 2024 Nov 23. pii: 12585. [Epub ahead of print]25(23):

Exploring Aerobic Energy Metabolism in Breast Cancer: A Mutational Profile of Glycolysis and Oxidative Phosphorylation.

Ricardo Cunha de Oliveira, Giovanna C Cavalcante, Giordano B Soares-Souza.

  Energy metabolism is a fundamental aspect of the aggressiveness and invasiveness of breast cancer (BC), the neoplasm that most affects women worldwide. Nonetheless, the impact of genetic somatic mutations on glycolysis and oxidative phosphorylation (OXPHOS) genes in BC remains unclear. To fill these gaps, the mutational profiles of 205 screened genes related to glycolysis and OXPHOS in 968 individuals with BC from The Cancer Genome Atlas (TCGA) project were performed. We carried out analyses to characterize the mutational profile of BC, assess the clonality of tumors, identify somatic mutation co-occurrence, and predict the pathogenicity of these alterations. In total, 408 mutations in 132 genes related to the glycolysis and OXPHOS pathways were detected. The PGK1, PC, PCK1, HK1, DONSON, GPD1, NDUFS1, and FOXRED1 genes are also associated with the tumorigenesis process in other types of cancer, as are the genes BRCA1, BRCA2, and HMCN1, which had been previously described as oncogenes in BC, with whom the target genes of this work were associated. Seven mutations were identified and highlighted due to the high pathogenicity, which are present in more than one of our results and are documented in the literature as being correlated with other diseases. These mutations are rs267606829 (FOXRED1), COSV53860306 (HK1), rs201634181 (NDUFS1), rs774052186 (DONSON), rs119103242 (PC), rs1436643226 (PC), and rs104894677 (ETFB). They could be further investigated as potential biomarkers for diagnosis, prognosis, and treatment of BC patients.

Keywords:  biomarkers; glycolysis; mitochondria; oncogenes; oxidative phosphorylation

DOI:  https://doi.org/10.3390/ijms252312585
Elife. 2024 Dec 20. pii: e105191. [Epub ahead of print]13

Mapping mitochondrial aging.

Alessandro Bitto.

  Measuring mitochondrial respiration in frozen tissue samples provides the first comprehensive atlas of how aging affects mitochondrial function in mice.

Keywords:  aging; cellular respiration; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology

DOI:  https://doi.org/10.7554/eLife.105191
bioRxiv. 2024 Dec 05. pii: 2024.12.02.626426. [Epub ahead of print]

IFNγ-dependent metabolic reprogramming restrains an immature, pro-metastatic lymphatic state in melanoma.

Triantafyllia Karakousi, Vanessa Cristaldi, Maria Luiza Lopes de Oliveira, Luiz Henrique Medeiros Geraldo, Tania J González-Robles, Gabrielle da Silva, Alec P Breazeale, Joel Encarnacion-Rosado, Joanna Pozniak, Alec C Kimmelman, Kelly V Ruggles, J Chris Marine, Navdeep S Chandel, Amanda W Lund.

Lymphatic vessels play a crucial role in activating anti-tumor immune surveillance but also contribute to metastasis and systemic tumor progression. Whether distinct lymphatic phenotypes exist that govern the switch between immunity and metastasis remains unclear. Here we reveal that cytotoxic immunity normalizes lymphatic function and uncouples immune and metastatic potential. We find that in mice and humans, intratumoral lymphatic vessel density negatively correlates with productive cytotoxic immune responses and identify IFNγ as an intrinsic inhibitor of lymphangiogenesis. Specific deletion of the Ifngr1 in lymphatic endothelial cells (LECs) greatly expanded the intratumoral lymphatic network and drove the emergence of a tip-like endothelial state, promoting lymph node metastasis but not dendritic cell migration. IFNγ inhibits oxidative phosphorylation, which is required for proliferation and acquisition of the pathologic transcriptional state. Our data indicate that IFNγ induces a phenotypic switch in tumor-associated lymphatic vessels to reinforce canonical immune surveillance and block metastasis.

DOI: https://doi.org/10.1101/2024.12.02.626426
Front Cell Neurosci. 2024 ;18 1496163

Aging promotes an increase in mitochondrial fragmentation in astrocytes.

Ana Paula Bergamo Araujo, Gabriele Vargas, Lívia de Sá Hayashide, Isadora Matias, Cherley Borba Vieira Andrade, Jorge José de Carvalho, Flávia Carvalho Alcantara Gomes, Luan Pereira Diniz.

   Introduction: Brain aging involves a complex interplay of cellular and molecular changes, including metabolic alterations and the accumulation of senescent cells. These changes frequently manifest as dysregulation in glucose metabolism and mitochondrial function, leading to reduced energy production, increased oxidative stress, and mitochondrial dysfunction-key contributors to age-related neurodegenerative diseases.
Methods: We conducted experiments on two models: young (3-4 months) and aged (over 18 months) mice, as well as cultures of senescent and control mouse astrocytes. Mitochondrial content and biogenesis were analyzed in astrocytes and neurons from aged and young animals. Cultured senescent astrocytes were examined for mitochondrial membrane potential and fragmentation. Quantitative PCR (qPCR) and immunocytochemistry were used to measure fusion- and fission-related protein levels. Additionally, transmission electron microscopy provided morphological data on mitochondria.
Results: Astrocytes and neurons from aged animals showed a significant reduction in mitochondrial content and a decrease in mitochondrial biogenesis. Senescent astrocytes in culture exhibited lower mitochondrial membrane potential and increased mitochondrial fragmentation. qPCR and immunocytochemistry analyses revealed a 68% increase in fusion-related proteins (mitofusin 1 and 2) and a 10-fold rise in DRP1, a key regulator of mitochondrial fission. Transmission electron microscopy showed reduced perimeter, area, and length-to-diameter ratio of mitochondria in astrocytes from aged mice, supported by elevated DRP1 phosphorylation in astrocytes of the cerebral cortex.
Discussion: Our findings provide novel evidence of increased mitochondrial fragmentation in astrocytes from aged animals. This study sheds light on mechanisms of astrocytic metabolic dysfunction and mitochondrial dysregulation in brain aging, highlighting mitochondrial fragmentation as a potential target for therapeutic interventions in age-related neurodegenerative diseases.

Keywords:  astrocytes; brain aging; mitochondrial biogenesis and neurodegeneration; mitochondrial dysfunction; mitochondrial fragmentation

DOI:  https://doi.org/10.3389/fncel.2024.1496163
Biochim Biophys Acta Rev Cancer. 2024 Dec 17. pii: S0304-419X(24)00180-X. [Epub ahead of print] 189249

Mitochondrial DNA-activated cGAS-STING pathway in cancer: Mechanisms and therapeutic implications.

Lintao Xia, Xiuli Yan, Hui Zhang.

  Mitochondrial DNA (mtDNA), a circular double-stranded DNA located within mitochondria, plays a pivotal role in mitochondrial-induced innate immunity, particularly via the cyclic GMP-AMP synthase (cGAS)-STING pathway, which recognizes double-stranded DNA and is crucial for pathogen resistance. Recent studies elucidate the interplay among mtDNA, the cGAS-STING pathway, and neutrophil extracellular traps (NETs) in the context of cancer. mtDNA uptake by recipient cells activates the cGAS-STING pathway, while mtDNA leakage reciprocally regulates NET release, amplifying inflammation and promoting NETosis, a mechanism of tumor cell death. Autophagy modulates these processes by clearing damaged mitochondria and degrading cGAS, thus preventing mtDNA recognition. Tumor microenvironmental factors, such as metabolic reprogramming and lipid accumulation, induce mitochondrial stress, ROS production, and further mtDNA leakage. This review explores strategies in cancer drug development that leverage mtDNA leakage to activate the cGAS-STING pathway, potentially converting 'cold tumors' into 'hot tumors,' while discussing advancements in targeted therapies and proposing new research methodologies.

Keywords:  Cancer; Innate immune; Mitochondria DNA; cGAS-STING

DOI:  https://doi.org/10.1016/j.bbcan.2024.189249
Elife. 2024 Dec 20. pii: RP96926. [Epub ahead of print]13

Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.

Dylan C Sarver, Muzna Saqib, Fangluo Chen, G William Wong.

  Organ function declines with age, and large-scale transcriptomic analyses have highlighted differential aging trajectories across tissues. The mechanism underlying shared and organ-selective functional changes across the lifespan, however, still remains poorly understood. Given the central role of mitochondria in powering cellular processes needed to maintain tissue health, we therefore undertook a systematic assessment of respiratory activity across 33 different tissues in young (2.5 months) and old (20 months) mice of both sexes. Our high-resolution mitochondrial respiration atlas reveals: (1) within any group of mice, mitochondrial activity varies widely across tissues, with the highest values consistently seen in heart, brown fat, and kidney; (2) biological sex is a significant but minor contributor to mitochondrial respiration, and its contributions are tissue-specific, with major differences seen in the pancreas, stomach, and white adipose tissue; (3) age is a dominant factor affecting mitochondrial activity, especially across most brain regions, different fat depots, skeletal muscle groups, eyes, and different regions of the gastrointestinal tract; (4) age effects can be sex- and tissue-specific, with some of the largest effects seen in pancreas, heart, adipose tissue, and skeletal muscle; and (5) while aging alters the functional trajectories of mitochondria in a majority of tissues, some are remarkably resilient to age-induced changes. Altogether, our data provide the most comprehensive compendium of mitochondrial respiration and illuminate functional signatures of aging across diverse tissues and organ systems.

Keywords:  aging; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology

DOI:  https://doi.org/10.7554/eLife.96926
Cell Mol Biol Lett. 2024 Dec 18. 29(1): 153

Inter- and intracellular mitochondrial communication: signaling hubs in aging and age-related diseases.

Meng Zhang, Jin Wei, Chang He, Liutao Sui, Chucheng Jiao, Xiaoyan Zhu, Xudong Pan.

  Mitochondria are versatile and complex organelles that can continuously communicate and interact with the cellular milieu. Deregulated communication between mitochondria and host cells/organelles has significant consequences and is an underlying factor of many pathophysiological conditions, including the process of aging. During aging, mitochondria lose function, and mitocellular communication pathways break down; mitochondrial dysfunction interacts with mitochondrial dyscommunication, forming a vicious circle. Therefore, strategies to protect mitochondrial function and promote effective communication of mitochondria can increase healthy lifespan and longevity, which might be a new treatment paradigm for age-related disorders. In this review, we comprehensively discuss the signal transduction mechanisms of inter- and intracellular mitochondrial communication, as well as the interactions between mitochondrial communication and the hallmarks of aging. This review emphasizes the indispensable position of inter- and intracellular mitochondrial communication in the aging process of organisms, which is crucial as the cellular signaling hubs. In addition, we also specifically focus on the status of mitochondria-targeted interventions to provide potential therapeutic targets for age-related diseases.

Keywords:  Age-related diseases; Aging; Mitochondrial communication; Mitochondrial dysfunction; Signaling hubs

DOI:  https://doi.org/10.1186/s11658-024-00669-4
BMB Rep. 2024 Dec 17. pii: 6336. [Epub ahead of print]

PGC1α is a key regulator of erastin-induced mitochondrial dysfunction during ferroptotic cell death.

Byeong Geun Seok, Eunhee Park, Young-Jun Park, Young-Jun Park, Hyuk Nam Kwon, Su Wol Chung.

A type of programmed cell death called ferroptosis is defined by increased iron-dependent lipid peroxidation. Mitochondria play a central role in iron metabolism. Mitochondrial defects include decreased cristae density, membrane rupture, and decreased mitochondrial membrane density, which occur as a result of ferroptosis. One of the important regulator of mitochondrial biogenesis is PGC1α. While recent studies have begun to explore the association between PGC1α and ferroptosis, the specific role of PGC1α in erastin-induced mitochondrial dysfunction during ferroptotic cell death has not been fully elucidated. In this study, we demonstrate for the first time that PGC1α is a key regulator of erastin-induced mitochondrial-dependent lipid peroxidation and dysfunction during ferroptosis in HT1080 fibrosarcoma cells. In this study, we examined PGC1α function in ferroptosis. Erastin, an inducer of ferroptosis, boosted the expression of PGC1α. Moreover, PGC1α down-regulation reduced erastin-induced ferroptosis. The most important biochemical feature of ferroptosis is the increase in iron ion (Fe2+)-dependent lipid peroxide (LOOH) concentration. Mitochondrial-dependent lipid peroxidation was abolished by PGC1α downregulation. In addition, PGC1α was induced during mitochondrial dysfunction in erastin-induced ferroptosis. Mitochondrial membrane potential loss and mitochondrial ROS production associated with erastin-induced mitochondrial dysfunction were blocked by PGC1α inhibition. In addition, erastin-induced lipid peroxidation in HT1080 fibrosarcoma cells was regulated by PGC1α inhibitor. This phenomenon was also consistent in HT1080 cells transfected with PGC1α shRNA transfected cells. Taken together, these results suggest that PGC1α is a key factor in erastin-induced mitochondrial-dependent lipid peroxidation and dysfunction during ferroptosis cell death.