Mitochondrial calcium uptake regulates tumour progression in embryonal rhabdomyosarcoma

Abstract

Embryonal rhabdomyosarcoma (ERMS) is characterised by a failure of cells to complete skeletal muscle differentiation. Although ERMS cells are vulnerable to oxidative stress, the relevance of mitochondrial calcium homoeostasis in oncogenesis is unclear. Here, we show that ERMS cell lines as well as primary tumours exhibit elevated expression of the mitochondrial calcium uniporter (MCU). MCU knockdown resulted in impaired mitochondrial calcium uptake and a reduction in mitochondrial reactive oxygen species (mROS) levels. Phenotypically, MCU knockdown cells exhibited reduced cellular proliferation and motility, with an increased propensity to differentiate in vitro and in vivo. RNA-sequencing of MCU knockdown cells revealed a significant reduction in genes involved in TGFβ signalling that play prominent roles in oncogenesis and inhibition of myogenic differentiation. Interestingly, modulation of mROS production impacted TGFβ signalling. Our study elucidates mechanisms by which mitochondrial calcium dysregulation promotes tumour progression and suggests that targeting the MCU complex to restore mitochondrial calcium homoeostasis could be a therapeutic avenue in ERMS.

Role of mitochondria in the myopathy of juvenile dermatomyositis and implications for skeletal muscle calcinosis

“…To investigate mechanisms of calcification that may primarily rely on mitochondria, we used the rhabdomyosarcoma cell line RH30, which has metabolically functional mitochondria [ 21 , 30 ]. Given that calcium deposits of JDM calcinosis are primarily of HA in nature [ 4 , 5 ], we quantified calcium phosphate complexes in RH30 cells using Osteoimage ™ [ 31 ], a fluorescent staining reagent highly specific for HA as represented in the schematic ( Fig.…”

The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Role in Human Diseases

“…Finally, mtCa 2+ uptake was found to be critical in embryonal rhabdomyosarcoma (ERMS). Indeed, MCU expression is upregulated in ERMS, and its downregulation causes mROS level decreases and an increased propensity to differentiate, inhibiting the oncogenic phenotype [ 92 ].…”

Cell-specific modulation of mitochondrial respiration and metabolism by the pro-apoptotic Bcl-2 family members Bax and Bak

“…5 c,d). As mitochondrial calcium is known to modulate respiration [39], we also analysed whether Bax/Bak deficiency affects cellular and mitochondrial calcium levels, and found that calcium levels were, in contrast to parental cells, maintained in Bax/Bak-deficient U87 cells challenged with calcium-free cerebrospinal fluid (aCSF) (Suppl. Fig.…”