Ovarian cancer is a heterogeneous disease that includes several types of tumors with distinct clinicopathological and molecular features and prognosis. The majority of cases of ovarian cancer are of epithelial origin, which has been classified into 5 histological subtypes: serous, the most common; endometrioid; mucinous; clear cells and Brenner tumors. Besides, undifferentiated carcinomas or mixture type are present in some cases (3). The standard treatment is surgery followed by platinum-taxane chemotherapy but still with poor long-term survival rate. Regarding to the fact that ovarian cancer is among the deadliest of gynecological malignancies, there has been a surge to explore more effective targeted therapies are required to boost survival rates for women with ovarian cancer (18-20).
The main physiological function of mitochondria is to provide energy for cell proliferation and cell growth through oxidative phosphorylation. In addition, mitochondria are responsible for cell metabolism, differentiation and apoptosis by regulating redox reactions, amino acid and lipid metabolism, reactive oxygen species (ROS) production, calcium homeostasis and mitochondrial permeability transition pore (mPTP) (21, 22). Mitochondrial dysfunction is closely related to tumorigenesis, growth, invasion and metastasis (23). Mitochondria are capable of performing a series of biologically precise functions with specialized molecular partners, the mitochondrial unfolded protein response (mtUPR) and processing peptidases that facilitate proper protein folding and complex assembly. A set of endogenous mechanisms maintains the dynamic balance of mitochondrial protein homeostasis (24).
Inner membrane is the mainly location where mitochondrial process of oxidative phosphorylation and generate ROS with abundant protein studded on it. Two forms of mitochondrial AAA proteases, m-AAA and i-AAA protease, are considered as quality control enzymes in the inner membrane. i-AAA proteases is composed of homologous YME1L1 subunits, which form cylinder-shaped hexameric complexes, exposes its catalytic domains to the intermembrane space. In contrast to i-AAA, m-AAA protease faces its catalytic domains to the matrix side with a composed of a homo-oligomeric AFG3L2 or a hetero-oligomeric form of AFG3L2 and paraplegin (25-29).
Cristae are invaginations protruding into the mitochondrial matrix and studded with respiratory complexes and ATP synthase. The folding structure increase surface area for oxidative phosphorylation. The dynamin-like GTPase OPA1 is one of protein complexes that maintain the shape of cristae, which responsible for inner membrane fusion and maintenance of cristae structure by bridging apposing membranes in the cristae fold (30). It was also identified as a substrate of YME1L1. The membrane-anchored OPA1 is cleaved by proteases OMA1 and YME1LI at S1 and S2 respectively to generate short variant OPA1 (S-OPA1), which lacks the membrane-anchoring domain. The uncleaved OPA1 is considered as OPA1 long form (L-OPA1), the form required for inner-membrane fusion (31, 32). However, the optimal fusion depends on the balance of fusion-active L-OPA1 and fusion-inactive S-OPA1 isoforms. Thus, YME1L may mediate mitochondrial fusion, respiration, and cristae morphology maintenance through processing OPA1(32, 33).
The YME1L1 gene is also believed to be related to the mechanism of NUMT insertion. The transfer of DNA fragments from mitochondrial to the nuclear DNA (NUMTs) is a natural biological phenomenon in eukaryotes and plays an important role in genomic variability (34). In the process, different insertion loci may have completely different effects on cells. The insertion of NUMTs is non-random, the inferred insertion points of NUMTs have a strong associated with specific chromatin regions and with retrotransposons(35). In some cases, NUMT is related to aging, mutations and oncogenesis (31, 36). For yeast Saccharomyces cerevisiae, it is well known that inactivation Yme1p causes an increased frequency of mtDNA escape from mitochondria to the nucleus (37-39). In a recent study, human YME1L1 reduces the escape of mtDNA into the nucleus when expressed in an inactive Yme1 yeast strain. The finding indicated that YME1LI may be a NUMT suppressor gene in humans, whose inactivation results in increased numtogenesis (39).
So far, the correlations between YME1L1 and clinicopathological data and patient survival had not yet been investigated in ovarian cancers. Our study demonstrated that the expression levels of YME1L1 were elevated in ovarian cancer tissues compared with other tumor tissues, and YME1L1 mRNA levels were significantly higher in ovarian carcinoma tissues compared to normal tissues. In general, the mutational load of ovarian cancer is within the range of variation, while the most mutant sites are in residues 400-700 of the YME1L1-encoded protein. The survival analysis indicated that overexpression of YME1L1 was associated with lower survival rate in women with ovarian cancer, the result was in line with the significantly increased of YME1L1 expression in advanced cancer stage patients. Overall, our findings emphasized the upregulation of YME1L1 is highly associated with ovarian cancer and tumor progression.
Only few research have been investigated the relationship between YME1L1 and cancer, relatively, which is a topic worthy of further exploration. YME1L1 was identified as one of the seven gliomas landscape genes, which cooperatively promote gliomagenesis and contribute to poor overall survival and prognosis (40). Reprogramming of mitochondria enables cells to respond to environmental variations and challenges such as hypoxic conditions during tumorigenesis. Through the axis of mTORC1–LIPIN1–YME1L, cells perform mitochondrial proteostasis between mitochondrial dynamics and cell metabolism. YME1L downgrades lipid transfer proteins and mitochondrial protein translocases to manipulate dynamics of mitochondria and support cell development. YME1L-mediated mitochondrial reshaping helps the cell growth of pancreatic ductal adenocarcinoma (PDAC). When cells are present in hypoxic conditions, as in the environment of solid tumors like PDACs (41), YME1L may be regulated by a HIF1α-dependent reaction, and rewiring of glutamine metabolism was observed. YME1L-mediated proteolysis with of stabilization of HIF1α may help tumor growths and adjust mitochondrial function in harsh environments (42).
It is established that ovarian cancers are highly hypoxia-dependent solid tumor. Under hypoxia condition, highly expression of HIF-1α in epithelial ovarian cancer helps tumor cells to endure hypoxia increased tumor tumor growth and metastasis (43, 44). mTOR also play an important role in ovarian cancer progression, especially mTORC1 activity is required for cell proliferation (45). To the present, there are still further studies and evidences needed to demonstrate whether the modulating mechanism to promote the growth of PDAC of YME1L1 gene can be repeated on ovary cancer cells