Marine-Derived N-Terminal Mitochondrial-Targeting Sequences Exhibit Antimicrobial and Anticancer Activities

The potential of N-terminal mitochondrial-targeting sequences (MTSs) as potent antimicrobial peptides (AMPs) has been previously reported. Building on this, 3923 mitochondrial proteins were identified from various marine organisms, among which 470 MTSs were predicted using MitoFates. Of these, 25 MTSs were synthesized and assessed for antimicrobial activity. All MTSs exhibited antifungal activity against <i>Candida albicans</i>, while 22 and 20 MTSs demonstrated activity against <i>Escherichia coli</i> and <i>Staphylococcus aureus</i>, respectively. Notably, the MTS of methylcrotonyl-CoA carboxylase subunit 1 (MCCC1-MTS) derived from swimming crab (<i>Portunus trituberculatus</i>) and the MTS of dihydrolipoamide branched-chain transacylase E2 (DBT-MTS) derived from herring (<i>Oncorhynchus keta</i>) showed strong antimicrobial activity against both Gram-positive and Gram-negative bacteria, as well as fungi. In addition, MCCC1-MTS markedly reduced the viability of multiple cancer cell lines with minimal cytotoxicity toward HaCaT cells and effectively suppressed the growth of A549-xenografted tumors in BALB/c nude mice without inducing weight loss. These findings demonstrate that MTSs derived from marine organisms function as potent AMPs with selective cytotoxicity toward cancer cells, further supporting previous evidence that protozoan MTSs represent novel AMP candidates.