bims-midysc 2024-12-29 papers

bims-midysc

Biomed News

on Mitochondria dysfunction in cancer

Issue of 2024–12–29
eleven papers selected by
Papachristodoulou Lab

Activated DRP1 promotes mitochondrial fission and induces glycolysis in ATII cells under hyperoxia.
Mitochondrial DNA mutations in human oocytes undergo frequency-dependent selection but do not increase with age.
Aging through the lens of mitochondrial DNA mutations and inheritance paradoxes.
Functionally conserved inner mitochondrial membrane proteins CCDC51 and Mdm33 demarcate a subset of fission events.
Senolysis by ABT-263 is associated with inherent apoptotic dependence of cancer cells derived from the non-senescent state.
Metabolic Adaptations To Acute Glucose Uptake Inhibition Converge Upon Mitochondrial Respiration For Leukemia Cell Survival.
A transcription network underlies the dual genomic coordination of mitochondrial biogenesis.
Increased phosphorylation of AMPKα1 S485 in colorectal cancer and identification of PKCα as a responsible kinase.
Estimating the proportion of beneficial mutations that are not adaptive in mammals.
Singlet Oxygen-Induced Mitochondrial Reset in Cancer: A Novel Approach for Ovarian Cancer Therapy.
3D culture inhibits replicative senescence of SCAPs via UQCRC2-mediated mitochondrial oxidative phosphorylation.

Respir Res. 2024 Dec 26. 25(1): 443

Activated DRP1 promotes mitochondrial fission and induces glycolysis in ATII cells under hyperoxia.

Tong Sun, Haiyang Yu, Dingning Zhang, Danni Li, Jianhua Fu.

   BACKGROUD: Recent studies have reported mitochondrial damage and metabolic dysregulation in BPD, but the changes in mitochondrial dynamics and glucose metabolic reprogramming in ATII cells and their regulatory relationship have not been reported.
METHODS: Neonatal rats in this study were divided into model (FIO2:85%) and control (FIO2: 21%) groups. Lung tissues were extracted at 3, 7, 10 and 14 postnatal days and then conducted HE staining for histopathological observation. We assessed the expression of mitochondria dynamic associated proteins and glycolysis associated enzymes in lung tissues, primary ATII cells and RLE-6TN cells. Double immunofluorescence staining was used to confirm the co-localization of DRP1 and ATII cells. Real-time analyses of ECAR and OCR were performed with primary ATII cells using Seahorse XF96. ATP concentration was measured using an ATP kit. We treated RLE-6TN cells at 85% hyperoxia for 48 h with mitochondrial fission inhibitor Mdivi-1 to verify the role of DRP1 in regulating glucose metabolic reprogramming.
FINDINGS: We found that hyperoxia causes ATII cells' mitochondrial morphological change. The expression of DRP1 and p-DRP1 increased in lung tissue and primary ATII cells of neonatal rats exposed to hyperoxia. Glycolysis related enzymes including PFKM, HK2, and LDHA were also increased. Hyperoxia inhibited ATP production in ATII cells. In RLE-6TN cells, we verified that the administration of Mdivi-1 could alleviate the enhancement of aerobic glycolysis and fragmentation of mitochondria caused by hyperoxia.
INTERPRETATIONS: Hyperoxia exposure leads to increased mitochondrial fission in ATII cells and mediates the reprogramming of glucose metabolism via the DRP1 signaling pathway. Inhibiting the activation of DRP1 signaling pathway may be a promising therapeutic target for BPD.

Keywords:  ATII cells; Bronchopulmonary dysplasia; DRP1 signaling pathway; Metabolic reprogramming; Mitochondrial fission

DOI:  https://doi.org/10.1186/s12931-024-03083-8
bioRxiv. 2024 Dec 12. pii: 2024.12.09.627454. [Epub ahead of print]

Mitochondrial DNA mutations in human oocytes undergo frequency-dependent selection but do not increase with age.

Barbara Arbeithuber, Kate Anthony, Bonnie Higgins, Peter Oppelt, Omar Shebl, Irene Tiemann-Boege, Francesca Chiaromonte, Thomas Ebner, Kateryna D Makova.

Mitochondria, cellular powerhouses, harbor DNA (mtDNA) inherited from the mothers. MtDNA mutations can cause diseases, yet whether they increase with age in human germline cells-oocytes-remains understudied. Here, using highly accurate duplex sequencing of full-length mtDNA, we detected de novo mutations in single oocytes, blood, and saliva in women between 20 and 42 years of age. We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies (≥1%) were less prevalent in coding than non-coding regions, whereas mutations with low allele frequencies (<1%) were more uniformly distributed along mtDNA, suggesting frequency-dependent purifying selection. In somatic tissues, mutations caused elevated amino acid changes in protein-coding regions, suggesting positive or destructive selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations having functional consequences and with aging. These findings are particularly timely as humans tend to reproduce later in life.

DOI: https://doi.org/10.1101/2024.12.09.627454
Biogerontology. 2024 Dec 27. 26(1): 33

Aging through the lens of mitochondrial DNA mutations and inheritance paradoxes.

Jia Chen, Hongyu Li, Runyu Liang, Yongyin Huang, Qiang Tang.

  Mitochondrial DNA encodes essential components of the respiratory chain complexes, serving as the foundation of mitochondrial respiratory function. Mutations in mtDNA primarily impair energy metabolism, exerting far-reaching effects on cellular physiology, particularly in the context of aging. The intrinsic vulnerability of mtDNA is increasingly recognized as a key driver in the initiation of aging and the progression of its related diseases. In the field of aging research, it is critical to unravel the intricate mechanisms underpinning mtDNA mutations in living organisms and to elucidate the pathological consequences they trigger. Interestingly, certain effects, such as oxidative stress and apoptosis, may not universally accelerate aging as traditionally perceived. These phenomena demand deeper investigation and a more nuanced reinterpretation of current findings to address persistent scientific uncertainties. By synthesizing recent insights, this review seeks to clarify how pathogenic mtDNA mutations drive cellular senescence and systemic health deterioration, while also exploring the complex dynamics of mtDNA inheritance that may propagate these mutations. Such a comprehensive understanding could ultimately inform the development of innovative therapeutic strategies to counteract mitochondrial dysfunctions associated with aging.

Keywords:  Aging; Evolutionary selection; Genetic bottleneck; Mitochondrial DNA mutations; Mother’s curse

DOI:  https://doi.org/10.1007/s10522-024-10175-x
J Cell Biol. 2025 Mar 03. pii: e202403140. [Epub ahead of print]224(3):

Functionally conserved inner mitochondrial membrane proteins CCDC51 and Mdm33 demarcate a subset of fission events.

Alia R Edington, Olivia M Connor, Abigail C Love, Madeleine Marlar-Pavey, Jonathan R Friedman.

While extensive work has examined the mechanisms of mitochondrial fission, it remains unclear whether internal mitochondrial proteins in metazoans play a direct role in the process. Previously, the yeast inner membrane protein Mdm33 was shown to be required for normal mitochondrial morphology and has been hypothesized to be involved in mitochondrial fission. However, it is unknown whether Mdm33 plays a direct role, and it is not thought to have a mammalian homolog. Here, we use a bioinformatic approach to identify a structural ortholog of Mdm33 in humans, CCDC51 (also called MITOK), whose depletion phenocopies loss of Mdm33. We find that knockdown of CCDC51 also leads to reduced rates of mitochondrial fission. Further, we spatially and temporally resolve Mdm33 and CCDC51 to a subset of mitochondrial fission events. Finally, we show that CCDC51 overexpression promotes its spatial association with Drp1 and induces mitochondrial fragmentation, suggesting it is a positive effector of mitochondrial fission. Together, our data reveal that Mdm33 and CCDC51 are functionally conserved and suggest that internal mitochondrial proteins are directly involved in at least a subset of mitochondrial fission events in human cells.

DOI: https://doi.org/10.1083/jcb.202403140
Cell Death Differ. 2024 Dec 21.

Senolysis by ABT-263 is associated with inherent apoptotic dependence of cancer cells derived from the non-senescent state.

Fleur Jochems, Chrysiida Baltira, Julie A MacDonald, Veerle Daniels, Abhijeet Mathur, Mark C de Gooijer, Olaf van Tellingen, Anthony Letai, René Bernards.

Cellular senescence is a stress response that cells can employ to resist cell death. Senescent cells rely on anti-apoptotic signaling for their survival, which can be targeted by senolytic agents, like the BCL-XL, BCL-2, BCL-W inhibitor ABT-263. However, the response to ABT-263 of senescent cancer cells ranges from highly sensitive to refractory. Using BH3 profiling, we identify here apoptotic blocks in cancer cells that are resistant to this senolytic treatment and discover a correlation between mitochondrial apoptotic priming and cellular sensitivity to ABT-263 in senescence. Intriguingly, ABT-263 sensitivity correlates with overall mitochondrial apoptotic priming, not only in senescence but also in the parental state. Moreover, we confirm that ABT-263 exposure increases dependency on MCL-1, which is most enhanced in ABT-263 sensitive cells. ABT-263 resistant cells however upregulate MCL-1, while sensitive cells exhibit low levels of this anti-apoptotic protein. Overall, our data indicate that the response of senescent cells to ABT-263 is predetermined by the mitochondrial apoptotic priming state of the parental cells, which could serve as a predictive biomarker for response to senolytic therapy.

DOI: https://doi.org/10.1038/s41418-024-01439-7
bioRxiv. 2024 Nov 22. pii: 2024.11.20.624567. [Epub ahead of print]

Metabolic Adaptations To Acute Glucose Uptake Inhibition Converge Upon Mitochondrial Respiration For Leukemia Cell Survival.

Monika Komza, Jesminara Khatun, Jesse D Gelles, Andrew P Trotta, Ioana Abraham-Enachescu, Juan Henao, Ahmed Elsaadi, Andriana G Kotini, Cara Clementelli, JoAnn Arandela, Sebastian El Ghaity-Beckley, Agneesh Barua, Yiyang Chen, Bridget K Marcellino, Eirini P Papapetrou, Masha V Poyurovsky, Jerry Edward Chipuk.

One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.

DOI: https://doi.org/10.1101/2024.11.20.624567
Elife. 2024 Dec 27. pii: RP96536. [Epub ahead of print]13

A transcription network underlies the dual genomic coordination of mitochondrial biogenesis.

Fan Zhang, Annie Lee, Anna V Freitas, Jake T Herb, Zong-Heng Wang, Snigdha Gupta, Zhe Chen, Hong Xu.

  Mitochondrial biogenesis requires the expression of genes encoded by both the nuclear and mitochondrial genomes. However, aside from a handful transcription factors regulating specific subsets of mitochondrial genes, the overall architecture of the transcriptional control of mitochondrial biogenesis remains to be elucidated. The mechanisms coordinating these two genomes are largely unknown. We performed a targeted RNAi screen in developing eyes with reduced mitochondrial DNA content, anticipating a synergistic disruption of tissue development due to impaired mitochondrial biogenesis and mitochondrial DNA (mtDNA) deficiency. Among 638 transcription factors annotated in the Drosophila genome, 77 were identified as potential regulators of mitochondrial biogenesis. Utilizing published ChIP-seq data of positive hits, we constructed a regulatory network revealing the logic of the transcription regulation of mitochondrial biogenesis. Multiple transcription factors in core layers had extensive connections, collectively governing the expression of nearly all mitochondrial genes, whereas factors sitting on the top layer may respond to cellular cues to modulate mitochondrial biogenesis through the underlying network. CG1603, a core component of the network, was found to be indispensable for the expression of most nuclear mitochondrial genes, including those required for mtDNA maintenance and gene expression, thus coordinating nuclear genome and mtDNA activities in mitochondrial biogenesis. Additional genetic analyses validated YL-1, a transcription factor upstream of CG1603 in the network, as a regulator controlling CG1603 expression and mitochondrial biogenesis.

Keywords:  ChIP-seq; D. melanogaster; RNA-seq; SDHA; TFAM; genetics; genomics; mitochondrial biogenesis; transcription factors

DOI:  https://doi.org/10.7554/eLife.96536
Cancer Lett. 2024 Dec 24. pii: S0304-3835(24)00813-9. [Epub ahead of print] 217418

Increased phosphorylation of AMPKα1 S485 in colorectal cancer and identification of PKCα as a responsible kinase.

Yan Zhou, Tingting Lei, Zhimin Tang, Pei Guo, Deqiang Huang, Zhijun Luo, Linyu Luo.

  The present study attempts to examine the biological effect of phosphorylation of AMPKα1 S485 and identify the responsible kinase in colon cancer cells. Thus, our results showed that S485 phosphorylation was increased in colorectal cancer specimens as compared with adjacent normal tissues, which was inversely correlated to phosphorylation of T172. Our study further revealed that phosphorylation of S485 on AMPKα1 plays a promoting role in cell proliferation, colony formation, migration and growth of Xenograft tumor. Furthermore, we identified PKCα as a kinase specific for phosphorylation of S485. First, under the basal condition, S485 phosphorylation was blunted by Gö6983, a pan PKC inhibitor, but not by Akt inhibitor, MK2206, although the latter countered off the insulin-stimulated phosphorylation. Second, the phosphorylation was enhanced by PMA and attenuated by sgRNA for PKCα, but not by PKCγ and PKCδ, neither by siRNA for Akt1. Third, the phosphorylation was suppressed by shRNA for PLCγ1. Fourth, the phosphorylation was enhanced by ectopically expressing a constitutively active mutant of PKCα, but not PKCγ. Finally, the increase of S485 phosphorylation by high glucose or palmitic acid was almost completely abolished by Gö6983. Altogether, our data reinforced the tumor suppressive function of AMPK and demonstrated that PKCα is a major kinase responsible for phosphorylation of S485, which contributes to one of the mechanisms underlying the regulation of AMPK in cancer cells in response to nutritional conditions.

Keywords:  cancer metabolism; glucose; oncogene; palmitate; tumor suppressor

DOI:  https://doi.org/10.1016/j.canlet.2024.217418
PLoS Genet. 2024 Dec 26. 20(12): e1011536

Estimating the proportion of beneficial mutations that are not adaptive in mammals.

Thibault Latrille, Julien Joseph, Diego A Hartasánchez, Nicolas Salamin.

Mutations can be beneficial by bringing innovation to their bearer, allowing them to adapt to environmental change. These mutations are typically unpredictable since they respond to an unforeseen change in the environment. However, mutations can also be beneficial because they are simply restoring a state of higher fitness that was lost due to genetic drift in a stable environment. In contrast to adaptive mutations, these beneficial non-adaptive mutations can be predicted if the underlying fitness landscape is stable and known. The contribution of such non-adaptive mutations to molecular evolution has been widely neglected mainly because their detection is very challenging. We have here reconstructed protein-coding-gene fitness landscapes shared between mammals, using mutation-selection models and a multi-species alignments across 87 mammals. These fitness landscapes have allowed us to predict the fitness effect of polymorphisms found in 28 mammalian populations. Using methods that quantify selection at the population level, we have confirmed that beneficial non-adaptive mutations are indeed positively selected in extant populations. Our work confirms that deleterious substitutions are accumulating in mammals and are being reverted, generating a balance in which genomes are damaged and restored simultaneously at different loci. We observe that beneficial non-adaptive mutations represent between 15% and 45% of all beneficial mutations in 24 of 28 populations analyzed, suggesting that a substantial part of ongoing positive selection is not driven solely by adaptation to environmental change in mammals.

DOI: https://doi.org/10.1371/journal.pgen.1011536
Metabolites. 2024 Nov 21. pii: 648. [Epub ahead of print]14(12):

Singlet Oxygen-Induced Mitochondrial Reset in Cancer: A Novel Approach for Ovarian Cancer Therapy.

Jorgelindo da Veiga Moreira, Laurent Schwartz, Mario Jolicoeur.

  Background/Objectives: This study explores the generation of singlet oxygen (SO) through methylene blue (MB) activation as a metabolic intervention for ovarian cancer. We aimed to examine the role of SO in modulating mitochondrial function, cellular metabolism, and proliferation in ovarian cancer cell lines compared to control cells. Methods: The study utilized two ovarian cancer cell lines, OV1369-R2 and TOV1369, along with ARPE-19 control cells. Following MB treatment and light activation, mitochondrial function and ATP synthesis were assessed. Metabolomic analyses were performed to evaluate changes in central carbon metabolism, particularly focusing on markers of the Warburg effect. Results: TOV1369 cells exhibited a pronounced sensitivity to MB treatment, resulting in significant inhibition of ATP synthesis and reduced proliferation. Metabolomic analysis indicated that MB-induced SO production partially reversed the Warburg effect, suggesting a shift from glycolysis to oxidative phosphorylation. These effects were less pronounced in OV1369-R2 and ARPE-19 cells, correlating with their lower MB sensitivity. Conclusions: MB-generated SO selectively modulates mitochondrial energetics in ovarian cancer cells, driving a metabolic reorganization that curtails their proliferative capacity. This approach, leveraging the bacterial-like features of cancer metabolism, offers a promising therapeutic avenue to induce apoptosis and enhance treatment outcomes in ovarian cancer.

Keywords:  metabolic bistability; methylene blue; mitochondrial involution; ovarian cancer; singlet oxygen

DOI:  https://doi.org/10.3390/metabo14120648
J Transl Med. 2024 Dec 20. 22(1): 1129

3D culture inhibits replicative senescence of SCAPs via UQCRC2-mediated mitochondrial oxidative phosphorylation.

Yijia Shi, Tong Xiao, Yingying Weng, Ya Xiao, Jintao Wu, Jing Wang, Wenmin Wang, Maoshen Yan, Ming Yan, Zehan Li, Jinhua Yu.

  Stem cells derived from the apical papilla (SCAPs) play a crucial role in tooth root development and dental pulp regeneration. They are important seed cells for bone/tooth tissue engineering. However, replicative senescence remains an unavoidable issue as in vitro amplification increases. This study investigated the effect of a three-dimensional (3D) culture environment constructed with methylcellulose on SCAPs senescence. It was observed that 3D culture conditions can delay cellular senescence, potentially due to changes in mitochondrial function and oxidative phosphorylation. Transcriptome high-throughput sequencing technology revealed that the different mitochondrial states may be related to UQCRC2. Knocking down UQCRC2 expression in the 3D culture group resulted in increased production of mitochondrial reactive oxygen species, decreased mitochondrial membrane potential, and a decline in the oxygen consumption rate for oxidative phosphorylation, accelerating cell senescence. The results of this study indicated that 3D culture can mitigate SCAPs aging by maintaining UQCRC2-mediated mitochondrial homeostasis. These findings provide a new solution for the senescence of SCAPs during in vitro amplification and can promote the applications of SCAPs-based clinical translation.

Keywords:   UQCRC2 ; 3D culture; Energy metabolism; Mitochondria; SCAPs

DOI:  https://doi.org/10.1186/s12967-024-05953-7