Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer

Yu, Meifang; Nguyen, Nathalie; Huang, Yanqing; Lin, Daniel; Fujimoto, Tara N.; Molkentine, Jessica M.; Deorukhkar, Amit; Kang, Ya’an; Lucas, F. Anthony San; Fernandes, Conrad; Koay, Eugene J.; Gupta, Sonal; Ying, Haoqiang; Koong, Albert C.; Herman, Joseph M.; Fleming, Jason B.; Maitra, Anirban; Taniguchi, Cullen M.

doi:10.1172/jci.insight.126915

Cited by 123 publications

(139 citation statements)

References 59 publications

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“…59 Similar to these findings, studies showed that mdivi-1 increased OCR in some cancer cells 60,61 but decreased OCR in other cancer cells. 25,62 To better understand the regulatory role of DRP1 in cancer metabolism, we used [U- 13 C] glucose tracing to directly reveal the intracellular glucose metabolism in DRP1-deficient H460 lung cancer cells and in multiple mdivi-1-treated cancer cell lines. Our data show that mdivi-1 treatment decreased oxidative metabolism in three cancer cell lines, and DRP1 deficiency did not alter glucose metabolism in H460 lung cancer cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial division inhibitor (mdivi-1) decreases oxidative metabolism in cancer

et al. 2020

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BACKGROUND: Previous studies suggested that mdivi-1 (mitochondrial division inhibitor), a putative inhibitor of dynamin-related protein (DRP1), decreased cancer cell proliferation through inducing mitochondrial fusion and altering oxygen consumption. However, the metabolic reprogramming underlying the DRP1 inhibition is still unclear in cancer cells. METHODS: To better understand the metabolic effect of DRP1 inhibition, [U-13 C]glucose isotope tracing was employed to assess mdivi-1 effects in several cancer cell lines, DRP1-WT (wild-type) and DRP1-KO (knockout) H460 lung cancer cells and mouse embryonic fibroblasts (MEFs). RESULTS: Mitochondrial staining confirmed that mdivi-1 treatment and DRP1 deficiency induced mitochondrial fusion. Surprisingly, metabolic isotope tracing found that mdivi-1 decreased mitochondrial oxidative metabolism in the lung cancer cell lines H460, A549 and the colon cancer cell line HCT116. [U-13 C]glucose tracing studies also showed that the TCA cycle intermediates had significantly lower enrichment in mdivi-1-treated cells. In comparison, DRP1-WT and DRP1-KO H460 cells had similar oxidative metabolism, which was decreased by mdivi-1 treatment. Furthermore, mdivi-1-mediated effects on oxidative metabolism were independent of mitochondrial fusion. CONCLUSIONS: Our data suggest that, in cancer cells, mdivi-1, a putative inhibitor of DRP1, decreases oxidative metabolism to impair cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial division inhibitor (mdivi-1) decreases oxidative metabolism in cancer

et al. 2020

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“…In cancer, an increasing body of literature links mitochondrial fusion/fission to cancer cell metabolism [24,25]. Apparently discordant results concerning functional impact of mitochondrial fusion/fission [2][3][4] suggest that disturbing mitochondrial dynamics is more important than specifically inhibiting fusion or fission [5].…”

Section: Discussionmentioning

confidence: 99%

“…This oscillation, referred as mitochondrial dynamics, was tightly linked to PDAC aggressiveness. Indeed, it was shown that increasing mitochondrial fusion suppressed oxidative phosphorylation (OXPHOS), promoted mitophagy, and improved median survival in PDAC mice models significantly [3]. Conversely, we previously showed in PDAC cell lines that a mitochondrial fission was associated with OXPHOS decrease, and enhanced autophagy [4].…”

Section: Introductionmentioning

confidence: 95%

Myoferlin Is a Yet Unknown Interactor of the Mitochondrial Dynamics’ Machinery in Pancreas Cancer Cells

Anania

Peiffer

Rademaker

et al. 2020

Cancers

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Pancreas ductal adenocarcinoma is one of the deadliest cancers where surgery remains the main survival factor. Mitochondria were described to be involved in tumor aggressiveness in several cancer types including pancreas cancer. We have previously reported that myoferlin controls mitochondrial structure and function, and demonstrated that myoferlin depletion disturbs the mitochondrial dynamics culminating in a mitochondrial fission. In order to unravel the mechanism underlying this observation, we explored the myoferlin localization in pancreatic cancer cells and showed a colocalization with the mitochondrial dynamic machinery element: mitofusin. This colocalization was confirmed in several pancreas cancer cell lines and in normal cell lines as well. Moreover, in pancreas cancer cell lines, it appeared that myoferlin interacted with mitofusin. These discoveries open-up new research avenues aiming at modulating mitofusin function in pancreas cancer.

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“…The relative extent of mitochondrial fusion is also consistent with differential cystathionine levels between D1-Bx and D1-Mia. Mitochondrial fusion has disputed implications in cellular survival roles, but in conjunction with other pro-survival factors appears to function as a promoter of cell survival in D1-Bx and D1-Mia (49,51).…”

Section: Confocal Microscopy Imaging Of Wt-and D1-cells Demonstrated mentioning

confidence: 99%

DNAJA1 dysregulates metabolism promoting an anti-apoptotic phenotype in pancreatic ductal adenocarcinoma

Roth

Bhinderwala

Franco

et al. 2020

Preprint

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BackgroundAt less than 7%, pancreatic ductal adenocarcinoma (PDAC) has one of the poorest 5-year cancer survival rates and is set to be the leading cause of cancer related deaths by 2030. The co-chaperone protein DNAJA1 (HSP40) is downregulated four-fold in pancreatic cancer cells, but its impact on pancreatic ductal adenocarcinoma (PDAC) progression remains unclear.MethodsDNAJA1 was overexpressed in pancreatic cancer cell lines, BxPC-3 and MIA PaCa-2, through retroviral transfection. The impact of overexpressing DNAJA1 was investigated using a combination of untargeted metabolomics, stable isotope resolved metabolomics (SIRM), confocal microscopy, flow-cytometry, and cell-based assays.ResultsPancreatic cancer cells overexpressing DNAJA1 exhibited a global metabolomic change. Specifically, differential output from Warburg glycolysis, an increase in redox currency, and an alteration in amino acid levels were observed in both overexpression cell lines. DNAJA1 overexpression also led to mitochondrial fusion, an increase in the expression of Bcl-2, a modest protection from redox induced cell death, a loss of structural integrity due to the loss of actin fibers, and an increase in cell invasiveness in BxPC-3. These differences were more pronounced in BxPC-3, which contains a loss-of-function mutation in the tumor suppressing gene SMAD4.ConclusionsThe overexpression of DNAJA1 promoted cellular proliferation, redox tolerance, invasiveness, and anti-apoptosis, which suggests DNAJA1 has numerous regulatory roles. Overall, our findings suggest a proto-oncogenic role of DNAJA1 in PDAC progression and suggests DNAJA1 may function synergistically with other proteins with altered activity in pancreatic cancer cell lines.

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Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer

Cited by 123 publications

References 59 publications

Mitochondrial division inhibitor (mdivi-1) decreases oxidative metabolism in cancer

Mitochondrial division inhibitor (mdivi-1) decreases oxidative metabolism in cancer

Myoferlin Is a Yet Unknown Interactor of the Mitochondrial Dynamics’ Machinery in Pancreas Cancer Cells

DNAJA1 dysregulates metabolism promoting an anti-apoptotic phenotype in pancreatic ductal adenocarcinoma

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