Differential Expression of Lonp1 Isoforms in Cancer Cells

Abstract

Lonp1 is a mitochondrial protease that degrades oxidized and damaged proteins, assists protein folding, and contributes to the maintenance of mitochondrial DNA. A higher expression of LonP1 has been associated with higher tumour aggressiveness. Besides the full-length isoform (ISO1), we identified two other isoforms of Lonp1 in humans, resulting from alternative splicing: Isoform-2 (ISO2) lacking aa 42-105 and isoform-3 (ISO3) lacking aa 1-196. An inspection of the public database TSVdb showed that ISO1 was upregulated in lung, bladder, prostate, and breast cancer, ISO2 in all the cancers analysed (including rectum, colon, cervical, bladder, prostate, breast, head, and neck), ISO3 did not show significant changes between cancer and normal tissue. We overexpressed ISO1, ISO2, and ISO3 in SW620 cells and found that the ISO1 isoform was exclusively mitochondrial, ISO2 was present in the organelle and in the cytoplasm, and ISO3 was exclusively cytoplasmatic. The overexpression of ISO1 and, at a letter extent, of ISO2 enhanced basal, ATP-linked, and maximal respiration without altering the mitochondria number or network, mtDNA amount. or mitochondrial dynamics. A higher extracellular acidification rate was observed in ISO1 and ISO2, overexpressing cells, suggesting an increase in glycolysis. Cells overexpressing the different isoforms did not show a difference in the proliferation rate but showed a great increase in anchorage-independent growth. ISO1 and ISO2, but not ISO3, determined an upregulation of EMT-related proteins, which appeared unrelated to higher mitochondrial ROS production, nor due to the activation of the MEK ERK pathway, but rather to global metabolic reprogramming of cells.

Mitochondria Deregulations in Cancer Offer Several Potential Targets of Therapeutic Interventions

“…Moreover, it regulates the Krebs cycle, oxidative phosphorylation, steroid and heme biosynthesis, and glutamine production. LonP1 is upregulated in many cancers, such as lung, breast, colon, prostate, stomach, glioma, pancreatic, endometrial, melanoma cancer and leukemia [ 115 , 116 ]. Gibellini et al demonstrated that LonP1 inhibition increases mitochondrial ROS accumulation, and triggers oxidative stress and apoptosis in cancer cells, while LonP1 overexpression reduces cell death [ 117 ].…”

The Role of Lonp1 on Mitochondrial Functions during Cardiovascular and Muscular Diseases

“…Thus, Lonp1 contributes to the solubilization of mitochondrial proteins [ 28 ]. Lonp1 overexpression has been observed in several cancers and has been shown to promote cell proliferation, apoptotic resistance to stresses, and the transformation of tumor cells [ 25 , 29 , 30 ].…”

“…Interestingly, this observation appears to be in opposition to what is seen in other cell types and models, particularly in tumour cells. For example, Lonp1 overexpression in cancer cells, such as colorectal cancer [ 14 , 21 , 30 ], Oral Squamous Cell Carcinoma, and Non-Small Lung Cancer, promotes cell proliferation, apoptotic resistance to stress, and neoplastic transformation [ 29 ]. This apparent contradiction between cancer cells and cardiomyocytes may be due to their different tolerance to ROS levels.…”

Alternative splicing analysis of lignocellulose-degrading enzyme genes and enzyme variants in Aspergillus niger

“…Alternative splicing (AS) allows eukaryotic organisms to produce multiple different transcripts from a limited set of genes, generating diverse protein variants and significantly expanding the proteome’s diversity. AS also diversifies the function of enzymes, which has been identified in numerous organisms (Zanini et al 2022 ; Yung et al 2022 ; Noda et al 2022 ). For instance, Tan et al ( 2023 ) identified an AS variant of the tumor suppressor liver kinase B1 (LKB1), noted as mitochondria-localized LKB1, which exhibited distinct tissue distribution, specific expression patterns, and biological functions compared to the normal splicing product LKB1.…”