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Mitochondrial Ca²⁺ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.

ABSTRACT: Endoplasmic reticulum to mitochondria Ca²⁺ transfer is important for cancer cell survival, but the role of mitochondrial Ca²⁺ uptake through the mitochondrial Ca²⁺ uniporter (MCU) in pancreatic adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in PDAC patients. In isogenic murine PDAC models, Mcu deletion (Mcu ^KO) ablated mitochondrial Ca²⁺ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to-mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca²⁺ uptake reduced expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGFβ. Snail re-expression and TGFβ treatment rescued deficits in Mcu ^KO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.

SUBMITTER: Weissenrieder JS

PROVIDER: S-EPMC11326289 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.

Weissenrieder Jillian S JS Peura Jessica J Paudel Usha U Bhalerao Nikita N Weinmann Natalie N Johnson Calvin C Wengyn Maximilian M Drager Rebecca R Furth Emma Elizabeth EE Simin Karl K Ruscetti Marcus M Stanger Ben Z BZ Rustgi Anil K AK Pitarresi Jason R JR Foskett J Kevin JK

bioRxiv : the preprint server for biology 20240809

Endoplasmic reticulum to mitochondria Ca2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) in pancreatic adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in PDAC patients. In isogenic murine PDAC models, Mcu deletion (Mcu KO) ablated mitochondrial Ca2+ ...[more]

PMID: 39149344

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Project description:ObjectiveHepatic Ca2+ signaling has been identified as a crucial key factor in driving gluconeogenesis. The involvement of mitochondria in hormone-induced Ca2+ signaling and their contribution to metabolic activity remain, however, poorly understood. Moreover, the molecular mechanism governing the mitochondrial Ca2+ efflux signaling remains unresolved. This study investigates the role of the Na+/Ca2+ exchanger, NCLX, in modulating hepatic mitochondrial Ca2+ efflux, and examines its physiological significance in hormonal hepatic Ca2+ signaling, gluconeogenesis, and mitochondrial bioenergetics.MethodsPrimary mouse hepatocytes from both an AAV-mediated conditional hepatic-specific and a total mitochondrial Na+/Ca2+ exchanger, NCLX, knockout (KO) mouse models were employed for fluorescent monitoring of purinergic and glucagon/vasopressin-dependent mitochondrial and cytosolic hepatic Ca2+ responses in cultured hepatocytes. Isolated liver mitochondria and permeabilized primary hepatocytes were used to analyze the ion-dependence of Ca2+ efflux. Utilizing the conditional hepatic-specific NCLX KO model, the rate of gluconeogenesis was assessed by first monitoring glucose levels in fasted mice, and subsequently subjecting the mice to a pyruvate tolerance test while monitoring their blood glucose. Additionally, cultured primary hepatocytes from both genotypes were assessed in vitro for glucagon-dependent glucose production and cellular bioenergetics through glucose oxidase assay and Seahorse respirometry, respectively.ResultsAnalysis of Ca2+ responses in isolated liver mitochondria and cultured primary hepatocytes from NCLX KO versus WT mice showed that NCLX serves as the principal mechanism for mitochondrial calcium extrusion in hepatocytes. We then determined the role of NCLX in glucagon and vasopressin-induced Ca2+ oscillations. Consistent with previous studies, glucagon and vasopressin triggered Ca2+ oscillations in WT hepatocytes, however, the deletion of NCLX resulted in selective elimination of mitochondrial, but not cytosolic, Ca2+ oscillations, underscoring NCLX's pivotal role in mitochondrial Ca2+ regulation. Subsequent in vivo investigation for hepatic NCLX role in gluconeogenesis revealed that, as opposed to WT mice which maintained normoglycemic blood glucose levels when fasted, conditional hepatic-specific NCLX KO mice exhibited a faster drop in glucose levels, becoming hypoglycemic. Furthermore, KO mice showed deficient conversion of pyruvate to glucose when challenged under fasting conditions. Concurrent in vitro assessments showed impaired glucagon-dependent glucose production and compromised bioenergetics in KO hepatocytes, thereby underscoring NCLX's significant contribution to hepatic glucose metabolism.ConclusionsThe study findings demonstrate that NCLX acts as the primary Ca2+ efflux mechanism in hepatocytes. NCLX is indispensable for regulating hormone-induced mitochondrial Ca2+ oscillations, mitochondrial metabolism, and sustenance of hepatic gluconeogenesis.

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Mitochondrial Ca²⁺ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.

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Mitochondrial Ca<sup>2+</sup> controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.

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Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.

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Mitochondrial Ca&lt;sup&gt;2+&lt;/sup&gt; controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.

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OmicsDI is part of the ELIXIR infrastructure

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Mitochondrial Ca²⁺ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.

Mitochondrial Ca<sup>2+</sup> controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.