Researchers synthesized 38 peptides from ancient mitochondrial DNA and tested them against bacteria

Researchers synthesized 38 peptides from ancient mitochondrial DNA and tested them against bacteria

On 20 August, researchers at the University of Pennsylvania posted a preprint describing their search for peptides, which are short chains of amino acids, in 2 025 ancient human mitochondrial genomes. They synthesized 38 of the peptides they found.

Mitochondria evolved from bacteria and retain their own DNA. The authors tested whether sequences in this DNA could encode short fragments capable of inhibiting bacterial growth.

The group used a similar approach in a 2023 study. They searched ancient and modern proteins for hidden peptide fragments, synthesized candidate peptides, and tested them in the laboratory. This time, the compact mitochondrial genome served as the source material.

First, computational tools translated the DNA sequences into possible amino acid chains. Another program then predicted where cellular enzymes might cleave these chains, and a machine learning model selected 65 candidates from 741 575 fragments. The researchers synthesized 38 of these peptides and measured whether they inhibited the growth of 16 bacterial strains.

One candidate, mitochondrin-32, inhibited the growth of ten strains. Closely related sequences differed in their effects because replacing several amino acids changed their activity. Activity required a precise arrangement of hydrophobic and positively charged regions.

Two fluorescence changing dyes indicated whether the bacterium's outer envelope became permeable and whether its inner membrane lost its electrical potential. Some peptides produced strong signals in these assays, whereas others produced weak signals even though they also inhibited bacterial growth. The authors therefore propose that mitochondrins act against bacteria through several mechanisms.

For the next experiments, the authors propose searching for mitochondrins in cells and tissues, measuring their abundance during infection, and determining which enzymes might release them. These experiments would test the hypothesis that mitochondrial DNA contributes to antimicrobial defense by encoding short peptides.