Fine-tuned repression of Drp1-driven mitochondrial fission primes a ‘stem/progenitor-like state’ to support neoplastic transformation

Spurlock, Brian; Parker, Danitra; Basu, Malay Kumar; Hjelmeland, Anita B.; Gc, Sajina; Liu, Shanrun; Siegal, Gene P.; Gunter, Alan; Moran, Aida; Mitra, Kasturi

doi:10.7554/elife.68394

Cited by 10 publications

(13 citation statements)

References 84 publications

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“…DRP1 inhibition and mitochondrial fusion inhibit apoptosis induced by a variety of stress situations ( 38, 39, 48, 49 ). Moreover, fine tuning of DRP1 activity to increase mitochondrial fusion and OXPHOS has further been associated with increased oncogenic transformation ( 50, 51 ). LENOX may therefore optimize OXPHOS and survival to favor oncogenic transformation and subsequent progression in stressful cellular environments encountered during primary tumor growth and metastatic dissemination ( 52 ).…”

Section: Discussionmentioning

confidence: 99%

The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma

et al. 2022

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Tumor heterogeneity is a key feature of melanomas that hinders development of effective treatments. Aiming to overcome this, we identified LINC00518 (LENOX; LincRNA-ENhancer of OXidative phosphorylation) as a melanoma-specific lncRNA expressed in all known melanoma cell states and essential for melanoma survival in vitro and in vivo. Mechanistically, LENOX promoted association of the RAP2C GTPase with mitochondrial fission regulator DRP1, increasing DRP1 S637 phosphorylation, mitochondrial fusion, and oxidative phosphorylation. LENOX expression was upregulated following treatment with MAPK inhibitors, facilitating a metabolic switch from glycolysis to oxidative phosphorylation and conferring resistance to MAPK inhibition. Consequently, combined silencing of LENOX and RAP2C synergized with MAPK inhibitors to eradicate melanoma cells. Melanomas are thus addicted to the lncRNA LENOX, which acts to optimize mitochondrial function during melanoma development and progression.

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Section: Discussionmentioning

confidence: 99%

The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma

et al. 2022

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“…On one hand, Drp1-mediated fission is crucial for mitosis in cancer cells 14, 15 , while on the other hand, fragmented mitochondria hinder the G1-S transition in cells, which is linked to the accumulation of cyclin E and a hyperfused mitochondria 63 . Similarly, elevated mitochondrial fusion has been identified as a feature of ovarian cancer neoplastic stem cells, priming them for self-renewal and proliferation 64 . We predict these conflicting reports related to Drp1 expression and cell proliferation might be partially resolved by considering Drp1 variant expression.…”

Section: Discussionmentioning

confidence: 99%

“…Yet it is known that during G1-S transition, mitochondrial networks fuse, which aids in cyclin E mediated G1-S transition, and inhibition of Drp1-mediated fission can induce the proliferation of quiescent cells 63 . Similarly, elevated mitochondrial fusion has been identified as a feature of ovarian cancer neoplastic stem cells, priming them for self-renewal and proliferation 64 . Our present work suggests distinct impacts of Drp1 alternative splice variants on cell proliferation, and one might speculate that their variable abundance could be associated with changes in cell cycle progression.…”

Section: Discussionmentioning

confidence: 99%

Alternative splice variants of the mitochondrial fission proteinDNM1L/Drp1 regulate mitochondrial dynamics and tumor progression in ovarian cancer

Javed,

Shin,

Pan

et al. 2023

Preprint

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Aberrant mitochondrial fission/fusion dynamics have previously been reported in cancer cells. While post translational modifications are known regulators of GTPases of the mitochondrial fission/fusion machinery, we show for the first time that alternate splice variants of the fission protein Drp1 (DNM1L) have specific and unique roles in ovarian cancer, adding to the complexity of mitochondrial fission/fusion regulation in tumor cells. We find that ovarian cancer specimens express a Drp1 alternate splice transcript variant lacking exon 16 of the variable domain. High expression of Drp1 lacking exon 16 relative to other transcripts is associated with poor patient outcome. Unlike the unspliced variant, expression of Drp1 lacking exon 16 leads to decreased association of Drp1 to mitochondrial fission sites, more fused mitochondrial networks, enhanced respiration and TCA cycle metabolites, and is associated with a more tumorigenic phenotype. These effects can also be reversed by specific siRNA-mediated inhibition of the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the significance of the pathophysiological consequences of Drp1 alternate splicing and divergent functions of Drp1 splice variants, and strongly warrant consideration of Drp1 splicing in future studies.

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“…14: 230279 royalsocietypublishing.org/journal/rsob Open Biol. 14: 230279 smaller network size (comprising of ≤ 40% of the total mitochondrial network size) supports stem cell gene expression profile in keratinocyte lineage, while almost complete fusion of mitochondrial network (hyperfusion) prevents it [128]. The smaller mitochondrial network size is reminiscent of the theoretical conceptualization of a quantitively defined 'meso-fused' royalsocietypublishing.org/journal/rsob Open Biol.…”

Section: Quantitative Aspects Of Heterogeneity Of Mitochondrial Shape...mentioning

confidence: 96%

“…The majority of such studies investigated the impact of mitochondrial shape at the extremes of the morphometric spectrum, largely leaving out the shapes in between the extremes. Precise quantification of mitochondrial network length revealed that maintenance of smaller network size (comprising of ≤ 40% of the total mitochondrial network size) supports stem cell gene expression profile in keratinocyte lineage, while almost complete fusion of mitochondrial network (hyperfusion) prevents it [ 128 ]. The smaller mitochondrial network size is reminiscent of the theoretical conceptualization of a quantitively defined ‘meso-fused’ mitochondrial structure, where the active fission rate dominates to maintain smaller mitochondrial network size [ 141 ].…”

Section: Quantitative Aspects Of Heterogeneity Of Mitochondrial Shape...mentioning

confidence: 99%

Significance of quantitative analyses of the impact of heterogeneity in mitochondrial content and shape on cell differentiation

Agarwala,

Dhabal,

Mitra

2024

Open Biol.

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Mitochondria, classically known as the powerhouse of cells, are unique double membrane-bound multifaceted organelles carrying a genome. Mitochondrial content varies between cell types and precisely doubles within cells during each proliferating cycle. Mitochondrial content also increases to a variable degree during cell differentiation triggered after exit from the proliferating cycle. The mitochondrial content is primarily maintained by the regulation of mitochondrial biogenesis, while damaged mitochondria are eliminated from the cells by mitophagy. In any cell with a given mitochondrial content, the steady-state mitochondrial number and shape are determined by a balance between mitochondrial fission and fusion processes. The increase in mitochondrial content and alteration in mitochondrial fission and fusion are causatively linked with the process of differentiation. Here, we critically review the quantitative aspects in the detection methods of mitochondrial content and shape. Thereafter, we quantitatively link these mitochondrial properties in differentiating cells and highlight the implications of such quantitative link on stem cell functionality. Finally, we discuss an example of cell size regulation predicted from quantitative analysis of mitochondrial shape and content. To highlight the significance of quantitative analyses of these mitochondrial properties, we propose three independent rationale based hypotheses and the relevant experimental designs to test them.

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Fine-tuned repression of Drp1-driven mitochondrial fission primes a ‘stem/progenitor-like state’ to support neoplastic transformation

Cited by 10 publications

References 84 publications

The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma

The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma

Alternative splice variants of the mitochondrial fission proteinDNM1L/Drp1 regulate mitochondrial dynamics and tumor progression in ovarian cancer

Significance of quantitative analyses of the impact of heterogeneity in mitochondrial content and shape on cell differentiation

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