Lactate-mediated mitoribosomal defects impair mitochondrial oxidative phosphorylation and promote hepatoma cell invasiveness

Abstract

Impaired mitochondrial oxidative phosphorylation (OXPHOS) capacity, accompanied by enhanced glycolysis, is a key metabolic feature of cancer cells, but its underlying mechanism remains unclear. Previously, we reported that human hepatoma cells that harbor OXPHOS defects exhibit high tumor cell invasiveness via elevated claudin-1 (CLN1). In the present study, we show that OXPHOS-defective hepatoma cells (SNU354 and SNU423 cell lines) exhibit reduced expression of mitochondrial ribosomal protein L13 (MRPL13), a mitochondrial ribosome (mitoribosome) subunit, suggesting a ribosomal defect. Specific inhibition of mitoribosomal translation by doxycycline, chloramphenicol, or siRNA-mediated MRPL13 knockdown decreased mitochondrial protein expression, reduced oxygen consumption rate, and increased CLN1-mediated tumor cell invasiveness in SNU387 cells, which have active mitochondria. Interestingly, we also found that exogenous lactate treatment suppressed MRPL13 expression and oxygen consumption rate and induced CLN1 expression. A bioinformatic analysis of the open RNA-Seq database from The Cancer Genome Atlas (TCGA) liver hepatocellular carcinoma (LIHC) cohort revealed a significant negative correlation between MRPL13 and CLN1 expression. Moreover, in patients with low MRPL13 expression, two oxidative metabolic indicators, pyruvate dehydrogenase B expression and the ratio of lactate dehydrogenase type B to type A, significantly and negatively correlated with CLN1 expression, indicating that the combination of elevated glycolysis and deficient MRPL13 activity was closely linked to CLN1-mediated tumor activity in LIHC. These results suggest that OXPHOS defects may be initiated and propagated by lactate-mediated mitoribosomal deficiencies and that these deficiencies are critically involved in LIHC development.

Lactic acidosis caused by repressed lactate dehydrogenase subunit B expression down-regulates mitochondrial oxidative phosphorylation via the pyruvate dehydrogenase (PDH)–PDH kinase axis

“…Moreover, exposure of oxidative hepatoma cells (Ch-L and SNU387) to lactate decreased OXPHOS activity in a rapid response via PDH phosphorylation. Recently, we reported that lactate also induced mitoribo-somal defect in a delayed response via suppressing MRPL13 expression, eventually contributing to the endogenous OXPHOS defect of SNU354 and SNU423 cells (46). Together, these results indicate that lactate may play a key role in the maintenance and propagation of mitochondrial OXPHOS dysfunction in the tumoral context, even under normoxic conditions.…”

Integrated Analysis of the Functions and Prognostic Values of RNA Binding Proteins in Lung Squamous Cell Carcinoma

“…These hub RBPs are mitochondrial ribosomal proteins that are essential for maintaining mitochondrial functions. Impaired mitochondrial functions such as apoptosis and oxidative phosphorylation are found in most cancers, however, their mechanisms are unclear (Koc et al, 2015;Lee et al, 2017;Lin et al, 2019). Lee et al (2017) found that suppressed MRPL13 expression increased hepatoma cell invasiveness.…”

“…Impaired mitochondrial functions such as apoptosis and oxidative phosphorylation are found in most cancers, however, their mechanisms are unclear (Koc et al, 2015;Lee et al, 2017;Lin et al, 2019). Lee et al (2017) found that suppressed MRPL13 expression increased hepatoma cell invasiveness. Koc et al (2015) proposed that defects in mitochondrial function in head and neck squamous cell carcinoma might be caused by a decrease in MRPL11 expression.…”

Inhibition of NF-κB Signaling Alters Acute Myelogenous Leukemia Cell Transcriptomics

“…The second network of genes encoding several mitochondrial ribosomal protein large (MRPL) was also identified by this analysis of downregulated genes. Seven of the eight genes encoded proteins involved in mitochondrial protein synthesis/ribosomes, and mitochondrial markers, including different MRPLs, which have recently been linked to carcinogenesis [ 35 , 36 ]. The last gene encoded a mitochondrial protein involved in energy metabolism.…”

“…Compensatory upregulation of this gene in response to NF-κB inhibition is probably consistent with this. Our network analysis also identified a network associated with NF-κB inhibition as well as altered expression of MRRPL , SNRP , and IFIT genes that possibly are involved in malignant cell transformation [ 35 , 36 , 37 , 38 ]. Of particular interest in the setting of AML is SNRP that is crucial for the spliceosome [ 37 ]; this effect may be relevant, especially for patients with mutations in spliceosome genes [ 4 ].…”