STOML2 Restricts Mitophagy and Increases Chemosensitivity in Pancreatic Cancer through Stabilizing PARL-induced PINK1 degradation

Cheng, Qi; Wang, Yuanyang; Zhao, Bangbo; Li, Zeru; Li, Tianyu; Yang, Xiaoying; Zhao, Yutong; Wang, Weibin

doi:10.21203/rs.3.rs-1952708/v1

Cited by 3 publications

(3 citation statements)

References 48 publications

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“…STOML2 is involved in maintaining coupled mitochondrial respiration and the formation of respiratory chain complexes [72,73] and has been shown to profoundly alter the metabolic profile and proliferative capacity of cancer cells [74]. Moreover, independent studies have demonstrated an interaction between STOML2 and PINK1 that modulates mitophagy [75,76]. Notably, it has been reported that STOML2 directly interacts with and stabilizes MFN2 and another central fusion gene, OPA1 [60,77].…”

Section: Discussionmentioning

confidence: 99%

Transmission Electron Microscopy Reveals Propionic Acid-induced Alterations to Mitochondrial Morphology in SH-SY5Y Cells

Buchanan¹,

Mahony²,

Bam³

et al. 2022

Preprint

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Mitochondrial dysregulation is implicated in numerous neurological disorders. Mitochondrial dynamics, including biogenesis, fusion and fission, are essential components of mitostasis which is modulated by complex regulatory mechanisms. Although expression studies are often used to investigate mitochondrial dynamics, these studies may be limited by the interdependent and temporal nature of mitostasis. Transmission electron microscopy (TEM) and cryogenic preparation methods provide a direct approach to examine mitochondrial ultrastructure in neurons. We investigated the utility of TEM to visualize mitochondrial morphological changes in SH-SY5Y cells treated with propionic acid (PPA). We examined whether morphological alterations were associated with differences in membrane potential or expression of biogenesis, fusion and fission genes. PPA induced a significant decrease in mitochondrial area (p<0.01 5mM), Feret's diameter and perimeter (p<0.05 5mM), and in area2 (p<0.05 3mM, p<0.01 5mM) – consistent with a shift towards fission. Morphological changes were not associated with significant differences in mitochondrial membrane potential. However, we observed decreased gene expression of NRF1 (p<0.01), TFAM (p<0.05), and STOML2 (p<0.0001). These data support a disruption of the balance in dynamics to preserve function under stress. This demonstrates the utility of TEM to provide insight into mitochondrial dynamics and function which can inform targeted mechanistic investigations into neuropathology.

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Section: Discussionmentioning

confidence: 99%

Transmission Electron Microscopy Reveals Propionic Acid-induced Alterations to Mitochondrial Morphology in SH-SY5Y Cells

Buchanan¹,

Mahony²,

Bam³

et al. 2022

Preprint

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“…[28] It have been reported that Stomatin-like protein 2 (STOML2), which is located in the mitochondrial inner membrane, too, is highly expressed in cancer cells and correlated with higher survival of patients with PAAD, stabilized PARL and prevented gemcitabine-induced mitophagy and reduced the chemoresistance in pancreatic cancer. [29] Correspondingly, PLD6, also known as phospholipase D6, plays pivotal roles in mitochondrial dynamics. [30] In tumor, PLD6 alters mitochondrial fusion and fission dynamics downstream of myelocytomatosis oncogene, which activates AMPK and inhibits YAP/TAZ in breast cancer, [30] piRNA pathway genes PLD6 also play roles in clear cell renal cell carcinoma and ovarian cancer.…”

Section: Tablementioning

confidence: 99%

Construction of prognostic markers for pancreatic adenocarcinoma based on mitochondrial fusion-related genes

Chen,

Zhang,

Jiang

et al. 2024

Medicine

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Early detection of pancreatic adenocarcinoma (PAAD) remains a pressing clinical problem. Information on the clinical prognostic value of mitochondrial fusion-related genes in PAAD remains limited. In this study, we investigated mitochondrial fusion-related genes of PAAD to establish an optimal signature plate for the early diagnosis and prognosis of PAAD. The cancer genome atlas database was used to integrate the Fragments Per Kilobase Million data and related clinical data for patients with PAAD. Least absolute shrinkage and selection operator regression, cox regression, operating characteristic curves, and cBioPortal database was used to evaluate model performance, assess the prognostic ability and sensitivity. The levels of immune infiltration were compared by CIBERSORT, QUANTISEQ, and EPIC. Chemotherapy sensitivity between the different risk groups was compared by the Genomics of Drug Sensitivity in Cancer database and the “pRRophetic” R package. At last, a total of 4 genes were enrolled in multivariate Cox regression analysis. The risk-predictive signature was constructed as: (0.5438 × BAK1) + (‐1.0259 × MIGA2) + (1.1140 × PARL) + (‐0.4300 × PLD6). The area under curve of these 4 genes was 0.89. Cox regression analyses indicates the signature was an independent prognostic indicator (P < .001, hazard ratio [HR] = 1.870, 95% CI = 1.568–2.232). Different levels of immune cell infiltration in the 2 risk groups were observed using the 3 algorithms, with tumor mutation load (P = .0063), tumor microenvironment score (P = .01), and Tumor Immune Dysfunction and Exclusion score (P = .0012). The chemotherapeutic sensitivity analysis also revealed that the half-maximal inhibitory concentration of 5-fluorouracil (P = .0127), cisplatin (P = .0099), docetaxel (P < .0001), gemcitabine (P = .0047), and pacilataxel (P < .0001) were lower in the high-risk groups, indicating that the high-risk group patients had a greater sensitivity to chemotherapy. In conclude, we established a gene signature plate comprised of 4 mitochondrial fusion related genes to facilitate early diagnosis and prognostic prediction of PAAD.

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“…Essential role in mitochondrial quality control by mediating mitochondrial clearance by transducing hypoxia signals [107] Presenilin-associated rhomboid-like protein (PARL) Regulator of PINK1 and Parkin [108]…”

Section: Role In Mitophagy Referencesmentioning

confidence: 99%

Mitophagy Induced by Metal Nanoparticles for Cancer Treatment

Mundekkad

Cho

2022

Pharmaceutics

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Research on nanoparticles, especially metal nanoparticles, in cancer therapy is gaining momentum. The versatility and biocompatibility of metal nanoparticles make them ideal for various applications in cancer therapy. They can bring about apoptotic cell death in cancer cells. In addition to apoptosis, nanoparticles mediate a special type of autophagy facilitated through mitochondria called mitophagy. Interestingly, nanoparticles with antioxidant properties are capable of inducing mitophagy by altering the levels of reactive oxygen species and by influencing signaling pathways like PINK/Parkin pathway and P13K/Akt/mTOR pathway. The current review presents various roles of metal nanoparticles in inducing mitophagy in cancer cells. We envision this review sheds some light on the blind spots in the research related to mitophagy induced by nanoparticles for cancer treatment.

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STOML2 Restricts Mitophagy and Increases Chemosensitivity in Pancreatic Cancer through Stabilizing PARL-induced PINK1 degradation

Cited by 3 publications

References 48 publications

Transmission Electron Microscopy Reveals Propionic Acid-induced Alterations to Mitochondrial Morphology in SH-SY5Y Cells

Transmission Electron Microscopy Reveals Propionic Acid-induced Alterations to Mitochondrial Morphology in SH-SY5Y Cells

Construction of prognostic markers for pancreatic adenocarcinoma based on mitochondrial fusion-related genes

Mitophagy Induced by Metal Nanoparticles for Cancer Treatment

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