Opa1 and Drp1 reciprocally regulate cristae morphology, ETC function, and NAD+ regeneration in KRas-mutant lung adenocarcinoma

Sessions, Dane; Kim, Kee-Beom; Kashatus, Jennifer A.; Churchill, Nikolas; Park, Kwon-Sik; Mayo, Marty W.; Sesaki, Hiromi; Kashatus, David F.

doi:10.1016/j.celrep.2022.111818

Cited by 21 publications

(13 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, OXPHOS High state-specific vulnerabilities included genes encoding enzymes that mediate the mitochondrial membrane respiratory chain and ATP synthesis, as well as genes with key roles in the control and maintenance of mitochondrial shape, crista junctions, and architecture. These findings are consistent with various evidences, indicating a tight connection between mitochondrial network structure and bioenergetics 21,42,43 , and suggest that mitochondrial network dynamics are linked to metabolic state-specific therapeutic vulnerabilities 44 .…”

Section: Discussionsupporting

confidence: 91%

Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations

Abecunas,

Kidd,

Jiang

et al. 2023

Preprint

View full text Add to dashboard Cite

Targeting the distinct metabolic needs of tumor cells has recently emerged as a promising strategy for cancer therapy. The heterogeneous, context-dependent nature of cancer cell metabolism, however, poses challenges in identifying effective therapeutic interventions. Here, we utilize various unsupervised and supervised multivariate modeling approaches to systematically pinpoint recurrent metabolic states within hundreds of cancer cell lines, elucidate their association with tissue lineage and growth environments, and uncover vulnerabilities linked to their metabolic states across diverse genetic and tissue contexts. We validate key findings using data from an independent set of cell lines, pharmacological screens, and via single-cell analysis of patient-derived tumors. Our analysis uncovers new synthetically lethal associations between the tumor metabolic state (e.g., oxidative phosphorylation), driver mutations (e.g., loss of tumor suppressor PTEN), and actionable biological targets (e.g., mitochondrial electron transport chain). Investigating these relationships could inform the development of more precise and context-specific, metabolism-targeted cancer therapies.

show abstract

Section: Discussionsupporting

confidence: 91%

Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations

Abecunas,

Kidd,

Jiang

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Similarly, high DRP1 levels are associated with worse prognosis. However, deletion of Drp1 does not affect growth of K-Ras mutated LUAD [ 26 ]. Thus, high Opa1 LUAD might be less responsive to therapy and/or prone to relapse because of OPA1 overexpression, calling for an analysis of the role of this mitochondria-shaping protein in LUAD resistance to therapy.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of the mitochondria-shaping protein Opa1 restores sensitivity to Gefitinib in a lung adenocarcinomaresistant cell line

et al. 2023

View full text Add to dashboard Cite

Drug resistance limits the efficacy of chemotherapy and targeted cancer treatments, calling for the identification of druggable targets to overcome it. Here we show that the mitochondria-shaping protein Opa1 participates in resistance against the tyrosine kinase inhibitor gefitinib in a lung adenocarcinoma cell line. Respiratory profiling revealed that oxidative metabolism was increased in this gefitinib-resistant lung cancer cell line. Accordingly, resistant cells depended on mitochondrial ATP generation, and their mitochondria were elongated with narrower cristae. In the resistant cells, levels of Opa1 were increased and its genetic or pharmacological inhibition reverted the mitochondrial morphology changes and sensitized them to gefitinib-induced cytochrome c release and apoptosis. In vivo, the size of gefitinib-resistant lung orthotopic tumors was reduced when gefitinib was combined with the specific Opa1 inhibitor MYLS22. The combo gefitinib-MYLS22 treatment increased tumor apoptosis and reduced its proliferation. Thus, the mitochondrial protein Opa1 participates in gefitinib resistance and can be targeted to overcome it.

show abstract

“…Mitochondrial clustering in Drp1-depleted cells requires the activity of mitochondrial fusion proteins Opa1 and Marf (Dubal et al, 2022; Sessions et al, 2022). We depleted Opa1 using an shRNA to inhibit mitochondrial clustering in Drp1-depleted FCs.…”

Section: Resultsmentioning

confidence: 99%

“…Mitochondrial clustering in Drp1-depleted cells requires the activity of mitochondrial fusion proteins Opa1 and Marf (Dubal et al, 2022;Sessions et al, 2022).…”

Section: Drp1 Depleted Pfcs Are Present In Multiple Layers In the End...mentioning

confidence: 99%

Mitochondrial morphology dynamics and ROS regulate apical polarity and differentiation inDrosophilafollicle cells

Uttekar

Tomer

Rikhy

2023

Preprint

View full text Add to dashboard Cite

Mitochondrial morphology dynamics regulate signaling pathways during epithelial cell formation and differentiation. The mitochondrial fission protein Drp1 affects the appropriate activation of EGFR and Notch signaling-driven differentiation of posterior follicle cells inDrosophilaoogenesis. The mechanisms by which Drp1 regulates epithelial polarity during differentiation are not known. In this study, we show that Drp1 depleted follicle cells are constricted in early stages and present in multiple layers at later stages with decreased levels of apical polarity protein aPKC. This defect is suppressed by additional depletion of mitochondrial fusion protein Opa1. Opa1 depletion leads to mitochondrial fragmentation and increased reactive oxygen species (ROS) in follicle cells. We find that increasing ROS by depleting the ROS scavengers, mitochondrial SOD2, and catalase also leads to mitochondrial fragmentation. Further, the loss of Opa1, SOD2, and catalase partially restores the defects in epithelial polarity and aPKC along with EGFR and Notch signaling in Drp1 depleted follicle cells. Our results show a crucial interaction between mitochondrial morphology, ROS generation, and epithelial cell polarity formation during the differentiation of follicle epithelial cells inDrosophilaoogenesis.

show abstract

Opa1 and Drp1 reciprocally regulate cristae morphology, ETC function, and NAD+ regeneration in KRas-mutant lung adenocarcinoma

Cited by 21 publications

References 64 publications

Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations

Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations

Inhibition of the mitochondria-shaping protein Opa1 restores sensitivity to Gefitinib in a lung adenocarcinomaresistant cell line

Mitochondrial morphology dynamics and ROS regulate apical polarity and differentiation inDrosophilafollicle cells

Contact Info

Product

Resources

About