Mitochondrial intermediate peptidase is an enzyme that in humans is encoded by the MIPEPgene.[1] This protein is a critical component of human mitochondrial protein import machinery involved in the maturing process of nuclear coded mitochondrial proteins that with a mitochondrial translocation peptide, especially those OXPHOS-related proteins.[2]
The gene MIPEP encodes one metalloprotease that hydrolyzes peptide fragment of eight amino acids in lengths to process mitochondria-targeted proteins. a.[1] The human gene MIPEP has 21 Exons and locates at chromosome band13q12. Evidences showed that the human gene MIPEP is highly expressed in the heart, skeletal muscle, and pancreas, three organ systems that are frequently reported with OXPHOS disorders.
Protein
The human protein Mitochondrial intermediate peptidase is 80.6 kDa in size and composed of 713 amino acids. It contains a mitonchondria targeting peptide (Amino acid 1-35 of the peptide sequence). The mature protein has a theoretical pI of 6.03.[3]
Function
Working in concert with general mitochondrial processing peptidase (MPP), MIPEP plays critical role in the maturation of a specific class of nuclear-encoded precursor proteins characterized by the motif, XRX(f)(F/L/I)XX(T/S/G)XXXX(f).[4] Initially, peptidase MPP cleaves the precursors at positions two peptide bonds from the R residue, leaving a typical octapeptide at the protein N- terminus; subsequently, MIP cleaves the octapeptide, completing the final maturation of processed protein.[5][6] A recent study showed that mitochondrial intermediate peptidase can degrade the transmembrane receptor Notch at its S5 site and assist Notch protein maturation.[7]
Clinical significance
Since MIPEP plays critical roles in mitochondrial protein maturation, it has been linked to many diseases associated with mitochondrial dysfunctions. In a GWAS study of Chinese population, a significant association between high myopia and a variant at chromosome band region 13q12.12. Gene MIPEP locates in the same locus and appears to expressed in the retina and retinal pigment epithelium (RPE) and are more likely associated with high myopia.[8]
Biallelic pathogenic variants in MIPEP cause the autosomal recessive disorder Eldomery-Sutton syndrome. This typically presents in infancy or early childhood with hypotonia (low muscle tone) and a rare type of cardiomyopathy, called left ventricular non-compaction. Cataracts may also be seen. In the limited number of cases reported to date, the cardiomyopathy is progressive and results in death in the first few years of life.[9]