Abstract:
Elevated levels of reactive oxygen species can damage proteins. Sulfur-containing amino acid
residues, cysteine and methionine, are particularly susceptible to such damage. Various enzymes evolved to
protect proteins or repair oxidized residues, including methionine sulfoxide reductases MsrA and MsrB,
which reduce methionine (S)-sulfoxide (Met-SO) and methionine (R)-sulfoxide (Met-RO) residues, respectively,
back to methionine. Here, we show that MsrA and MsrB are involved in the regulation of
mitochondrial function. Saccharomyces cerevisiae mutant cells lacking MsrA, MsrB, or both proteins had
normal levels of mitochondria but lower levels of cytochrome c and fewer respiration-competent mitochondria.
The growth of single MsrA or MsrB mutants on respiratory carbon sources was inhibited, and that of the
double mutant was severely compromised, indicating impairment of mitochondrial function. Although MsrA
and MsrB are thought to have similar roles in oxidative protein repair each targeting a diastereomer of
methionine sulfoxide, their deletion resulted in different phenotypes. GFP fusions of MsrA and MsrB showed
different localization patterns and primarily localized to cytoplasm and mitochondria, respectively. This
finding agreed with compartment-specific enrichment of MsrA and MsrB activities. These results show that
oxidative stress contributes to mitochondrial dysfunction through oxidation of methionine residues in
proteins located in different cellular compartments.
