Kastor and Polluks polypeptides encoded by a single gene locus cooperatively regulate VDAC and spermatogenesis

Abstract

Although several long noncoding RNAs (lncRNAs) have recently been shown to encode small polypeptides, those in testis remain largely uncharacterized. Here we identify two sperm-specific polypeptides, Kastor and Polluks, encoded by a single mouse locus (Gm9999) previously annotated as encoding a lncRNA. Both Kastor and Polluks are inserted in the outer mitochondrial membrane and directly interact with voltage-dependent anion channel (VDAC), despite their different amino acid sequences. Male VDAC3-deficient mice are infertile as a result of reduced sperm motility due to an abnormal mitochondrial sheath in spermatozoa, and deficiency of both Kastor and Polluks also severely impaired male fertility in association with formation of a similarly abnormal mitochondrial sheath. Spermatozoa lacking either Kastor or Polluks partially recapitulate the phenotype of those lacking both. Cooperative function of Kastor and Polluks in regulation of VDAC3 may thus be essential for mitochondrial sheath formation in spermatozoa and for male fertility.

New Roles for EVs, miRNA and lncRNA in Bovine Embryo Implantation

“…Mice without both Kastor and Polluks expression exhibit severely impaired male fertility due to abnormal mitochondrial sheath formation. These authors conclude that cooperative function of these polypeptides in the regulation of VDAC3 may be essential for mitochondrial sheath formation in spermatozoa (72). Moreover, the relationship between lncRNA and spermatogenesis in association with the extracellular matrix and spermatogenesis (73) and in varicoceleinduced spermatogenic dysfunction has also been demonstrated (74).…”

MORN2 regulates the morphology and energy metabolism of mitochondria and is required for male fertility in mice

“…The ultrastructure and formation of the mitochondrial sheath have been described in previous studies, and knockout of several genes ( e.g. , ARMC12 [ 3 ], SPATA33 [ 24 ], and VDAC3 [ 25 , 26 ]) is known to cause abnormal mitochondrial sheath formation and subsequent infertility [ 27 ]. These studies have also shown that the integrated formation of the mitochondrial sheath is closely related to sperm motility [ 3 , 25 ], thus these observations of morphological and structural abnormalities in the mitochondrial sheaths of Morn2 –/– spermatozoa are likely to contribute to the observed sperm motility defects and male infertility.…”

Re-evaluating the impact of alternative RNA splicing on proteomic diversity

“…Genome-wide translation profiling has recently revealed that small ORFs identified in lncRNA genes can code for micropeptides, polypeptides with a length of less than 100 amino acids essential for cellular growth (Chen et al, 2020). Other small peptides produced from lncRNAs have also been reported in functional studies (Odermatt et al, 1997;MacLennan and Kranias 2003;Slavoff et al, 2013;Ruiz-Orera et al, 2014;Pang, Mao, and Liu 2018;Hartford Corrine and Lal, 2020;Nita et al, 2021;Mise et al, 2022). Eukaryotic lncRNA genes are usually composed of multiple exons with an average of 2.49 exons per human lncRNA gene (Khan, Wellinger, and Laurent 2021).…”