Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. Infections in MtD patients more frequently progress to sepsis, pneumonia, and other detrimental inflammatory endpoints. However, the underlying immune alterations that enhance immunopathology in MtD remain unclear, constituting a key gap in knowledge that complicates treatment and increases mortality in this vulnerable population. This data set utilizes an in vitro assay using Pseudomonas aeruginosa (PA) infection of bone marrow derived macrophages (BMDMs) to clarify the molecular and cellular basis for innate immune hyperactivity in a mouse model of polymerase gamma (Polg)-related MtD. This dataset reports the proteome signatures of WT and Polg D257A mutant BMDMs at rest and 2-8 hours post infection with PA.