PTEN is an important tumour suppressor gene located on chromosome 10q23.3 and was first cloned in 1997 (Li et al., 1997; Steck et al., 1997). Mutations or deletions of PTEN are associated with many types of cancer (Hollander et al., 2011). Heterozygous deletion of Pten results in spontaneous tumours in mice, while homozygous Pten-deficient mice die in the embryonic period (Di Cristofano et al., 1998; Suzuki et al., 1998). Loss of PTEN also leads to metabolic disorders, neurological abnormities, and immune system defects (Horie et al., 2004; Garcia-Cao et al., 2012; Knafo et al., 2016; Chen and Guo, 2017). PTEN functions in a phosphatase-dependent or phosphatase-independent manner. In the cytoplasm, PTEN dephosphorylates PIP3 and antagonizes the PI3K/AKT signalling pathway (Stambolic et al., 1998); while in the nucleus, PTEN is a guardian of the genome, physically associating with CENP-C and regulating the expression of RAD51 (Shen et al., 2007). Recently, our laboratory and other scientists reported a series of N-terminally extended forms of PTEN (PTENα/PTEN-L, PTENβ, and PTENε), which are translated from non-AUG codons upstream of canonical PTEN (Hopkins et al., 2013; Liang et al., 2014; Liang et al., 2017; Zhang et al., 2021). The identification of PTEN isoforms expands the knowledge of linear mRNA transcripts encoded by PTEN.

CircRNAs are formed by back-splicing under the regulation of cis-acting elements and trans-acting factors (Chen and Yang, 2015; Li et al., 2018). In contrast to linear RNAs, circRNAs are covalently closed loop structures without 5′ caps or 3′ poly(A) tail (Chen, 2020), and the loop structure of a circRNA enables it to resist the degradative action of exonucleases (Kristensen et al., 2019). CircRNAs are expressed in a tissue-specific pattern and play vital roles in cell proliferation, senescence, and differentiation (Cai et al., 2019; Mester-Tonczar et al., 2020). In addition, circRNAs were confirmed to be widely involved in the occurrence and development of cancer, neurodegenerative diseases, autoimmunity, and many other diseases (Ghasemi et al., 2019; Zhou et al., 2019; Mehta et al., 2020; Goodall and Wickramasinghe, 2021). Moreover, the characteristic resistance to exonuclease degradation endows circRNAs with the potential to be molecular markers (Kristensen et al., 2018; Verduci et al., 2019). Although great progress has been made in the study of the function of circRNAs, the mechanisms by which circRNAs participate in most cellular processes remain unknown.

Despite extensive studies have aimed to elucidate the PTEN protein and PTEN isoforms derived from linear mRNA transcripts. Recent studies have also focused on the function of circRNAs generated from PTEN in tumor progression. CircPTEN1 (hsa_circ_0002232) prevents colorectal cancer (CRC) metastasis by inhibiting the interaction between Smad2/3 (Zheng et al., 2022). CircPTEN (hsa_circ_0094343) acts as a sponge for microRNA-4470 to elevate PTEN expression, which further suppresses CRC progression (Li and Li, 2021).

Here, we reported that hsa_circ_0002934, a circRNA generated from PTEN, is located in mitochondria, named circPTEN-MT. CircPTEN-MT regulates the expression of mitochondrial complex I subunits by interacting with the mitochondrial leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), participating in the regulation of mitochondrial function.