New quantitative approach reveals heterogeneity in mitochondrial structure–function relations in tumor-initiating cells

Spurlock, Brian; Gupta, Priyanka; Basu, Malay Kumar; Mukherjee, A. K.; Hjelmeland, Anita B.; Darley‐Usmar, Victor; Parker, Danitra; Foxall, McKenzie E.; Mitra, Kasturi

doi:10.1242/jcs.230755

Cited by 16 publications

(33 citation statements)

References 38 publications

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“…In our earlier study, we showed that elevated Hipk increases glucose uptake and glycolytic flux ( Wong et al, 2019 ). Given that mitochondrial metabolism can be influenced by alterations in energy demand and nutrient supply ( Liesa and Shirihai, 2013 ; Spurlock et al, 2019 ), we were motivated to examine whether elevated Hipk leads to any changes in mitochondrial dynamics, abundance and energetics. We first examined mitochondrial morphology using mito-GFP ( Pilling et al, 2006 ).…”

Section: Resultsmentioning

confidence: 99%

“…1 D,D′). Several image analysis tools such as MitoGraph ( Viana et al, 2015 ), MiNA ( Valente et al, 2017 ) and Mito-SinCe 2 ( Spurlock et al, 2019 ) have been developed for quantifying mitochondrial dynamics. In this study, we used the MiNA (Mitochondrial Network Analysis) toolset to generate skeleton images for quantitative analyses of mitochondrial morphology ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Hyperpolarized mitochondria accumulate in Drosophila Hipk-overexpressing cells to drive tumor-like growth

Wong

Liao

Shih

et al. 2020

Journal of Cell Science

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Both functional and dysfunctional mitochondria are known to underlie tumor progression. Here, we establish use of the proto-oncogene Drosophila Homeodomain-interacting protein kinase (Hipk) as a new tool to address this paradox. We find that, in Hipk-overexpressing tumor-like cells, mitochondria accumulate and switch from fragmented to highly fused interconnected morphologies. Moreover, elevated Hipk promotes mitochondrial membrane hyperpolarization. These mitochondrial changes are at least in part driven by the upregulation of Myc. Furthermore, we show that the altered mitochondrial energetics, but not morphology, is required for Hipk tumor-like growth as knockdown of pdsw (NDUFB10 in mammals; a Complex I subunit) abrogates the growth. Knockdown of ATPsynβ (a Complex V subunit), which produces higher levels of reactive oxygen species (ROS) than pdsw knockdown, instead synergizes with Hipk to potentiate JNK activation and the downstream induction of Matrix metalloproteinases. Accordingly, ATPsynβ knockdown suppresses Hipk tumor-like growth only when ROS scavengers are co-expressed. Altogether, our work presents an in vivo tumor model featuring the accumulation of hyperfused and hyperpolarized mitochondria, and reveals respiratory Complex subunit-dependent, opposing effects on tumorigenic outcomes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Hyperpolarized mitochondria accumulate in Drosophila Hipk-overexpressing cells to drive tumor-like growth

Wong

Liao

Shih

et al. 2020

Journal of Cell Science

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“…Metabolic remodeling such as decreased oxidative phosphorylation in mitochondria and increased glycolysis in the cytoplasm (Warburg effect), is a hallmark of cancer [ 53 , 105 , 106 , 107 ]. Breast cancer cells can compensate energy deficits during impaired oxidative phosphorylation by upregulating genes involved in glycolysis [ 108 ].…”

Section: Alteration Of Mitochondrial Energy Metabolismmentioning

confidence: 99%

Cellular Mechanisms of Circulating Tumor Cells During Breast Cancer Metastasis

Park

Brown

Kim

2020

IJMS

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Circulating tumor cells (CTCs) are cancer cells that detach from the primary site and travel in the blood stream. A higher number of CTCs increases the risk of breast cancer metastasis, and it is inversely associated with the survival rates of patients with breast cancer. Although the numbers of CTCs are generally low and the majority of CTCs die in circulation, the survival of a few CTCs can seed the development of a tumor at a secondary location. An increasing number of studies demonstrate that CTCs undergo modification in response to the dynamic biophysical environment in the blood due in part to fluid shear stress. Fluid shear stress generates reactive oxygen species (ROS), triggers redox-sensitive cell signaling, and alters the function of intracellular organelles. In particular, the mitochondrion is an important target organelle in determining the metastatic phenotype of CTCs. In healthy cells, mitochondria produce adenosine triphosphate (ATP) via oxidative phosphorylation in the electron transport chain, and during oxidative phosphorylation, they produce physiological levels of ROS. Mitochondria also govern death mechanisms such as apoptosis and mitochondrial permeability transition pore opening to, in order eliminate unwanted or damaged cells. However, in cancer cells, mitochondria are dysregulated, causing aberrant energy metabolism, redox homeostasis, and cell death pathways that may favor cancer invasiveness. In this review, we discuss the influence of fluid shear stress on CTCs with an emphasis on breast cancer pathology, then discuss alterations of cellular mechanisms that may increase the metastatic potentials of CTCs.

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“…Mitochondrial activity is a critical determinant of primary HSCs with LT-hematopoietic reconstituting potential (Vannini et al, 2016;Anso et al, 2017;Spurlock et al, 2019;Liang et al, 2020). We previously demonstrated that VPA-expanded HSCs exhibited a remodeled primitive mitochondrial network characterized by low mitochondrial ROS, mass and MMP (Papa et al, 2018).…”

Section: Vpa-generated Hscs That Are Characterized By Increased Exprementioning

confidence: 99%

“…This LT-repopulating capacity is due to the HSC's ability to balance self-renewal with commitment decisions (Orkin and Zon, 2008;Seita and Weissman, 2010). Such balance is controlled by complex mechanisms that rely on both the transcriptomic and metabolic properties of LT-HSCs (Jang and Sharkis, 2007;Schieke et al, 2008;Takubo et al, 2013;Warr and Passegue, 2013;Kohli and Passegue, 2014;Maryanovich et al, 2015;Mohrin et al, 2015;Vannini et al, 2016;Anso et al, 2017;Papa et al, 2019b;Spurlock et al, 2019). The transcriptome and metabolism of LT-HSCs are intrinsically coupled to their mitochondrial activity, which is profoundly altered during HSC commitment and maturation.…”

Section: Introductionmentioning

confidence: 99%

Limited Mitochondrial Activity Coupled With Strong Expression of CD34, CD90 and EPCR Determines the Functional Fitness of ex vivo Expanded Human Hematopoietic Stem Cells

Papa

Djedaini

Martin

et al. 2020

Front. Cell Dev. Biol.

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Ex vivo expansion strategies of human hematopoietic stem cell (HSC) grafts with suboptimal stem cell dose have emerged as promising strategies for improving outcomes of HSC transplantation in patients with hematological malignancies. While exposure of HSCs to ex vivo cultures expands the number of phenotypically identifiable HSCs, it frequently alters the transcriptomic and metabolic profiles, therefore, compromising their long-term (LT) hematopoietic reconstitution capacity. Within the heterogeneous pool of expanded HSCs, the precise phenotypic, transcriptomic and metabolic profile and thus, the identity of HSCs that confer LT repopulation potential remains poorly described. Utilizing valproic acid (VPA) in ex vivo cultures of umbilical cord blood (UCB)-CD34+ cells, we demonstrate that expanded HSCs phenotypically marked by expression of the stem cell markers CD34, CD90 and EPCR (CD201) are highly enriched for LT-HSCs. Furthermore, we report that low mitochondrial membrane potential, and, hence, mitochondrial activity distinguishes LT-HSCs within the expanded pool of phenotypically defined HSCs. Remarkably, such reduced mitochondrial activity is restricted to cells with the highest expression levels of CD34, CD90 and EPCR phenotypic markers. Together, our findings reveal that high expression of CD34, CD90 and EPCR in conjunction with low mitochondrial activity is critical for identification of functional LT-HSCs generated within ex vivo expansion cultures.

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New quantitative approach reveals heterogeneity in mitochondrial structure–function relations in tumor-initiating cells

Cited by 16 publications

References 38 publications

Hyperpolarized mitochondria accumulate in Drosophila Hipk-overexpressing cells to drive tumor-like growth

Hyperpolarized mitochondria accumulate in Drosophila Hipk-overexpressing cells to drive tumor-like growth

Cellular Mechanisms of Circulating Tumor Cells During Breast Cancer Metastasis

Limited Mitochondrial Activity Coupled With Strong Expression of CD34, CD90 and EPCR Determines the Functional Fitness of ex vivo Expanded Human Hematopoietic Stem Cells

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