CCNA2 dually encodes a microprotein that regulates mitochondrial function and cell cycle via PMPCA-PMPCB complex

The mitochondrial processing peptidase PMPCA-PMPCB complex is responsible for cleaving the mitochondrial targeting sequence of preproteins, thereby sustaining mitochondrial proteome integrity and functionality. However, it is currently unclear how this complex is regulated in cells. Here, we show that the human CCNA2 gene dually encodes an unannotated microprotein MMOP (Microprotein modulator of PMPCA-PMPCB complex), which mainly localizes to the mitochondria and is cell-cycle regulated with a global high expression during G2/M phase. Loss of MMOP alters mitochondrial morphology and impairs mitochondrial function, leading to decreased ATP production. Loss of MMOP also prolongs the M phase and delays cell proliferation. Mechanistically, MMOP interacts with PMPCA-PMPCB complex, and loss of MMOP alters mitochondrial proteome, leading to an overall decrease in mitochondrial protein levels. Together, these results demonstrate that MMOP acts as a modulator of PMPCA-PMPCB complex, regulating mitochondrial proteome and function. In addition, the CCNA2 transcript encodes two sequence-independent proteins that co-regulate cell cycle through different molecular mechanisms, broadening our understanding of multicistronic human gene functions.