Parkin deficiency in mice leads to mitochondrial dysfunction and oxidative stress without nigral degeneration. Loss-of-function mutations in parkin are the primary cause of familial Parkinson's disease. Parkin functions as an E3 ubiquitin ligase, and its loss is hypothesized to cause nigral degeneration through the accumulation of its substrates. Using proteomic analysis, researchers found decreased abundance of proteins involved in mitochondrial function and oxidative stress in parkin-deficient mice. Functional assays showed reduced respiratory capacity of striatal mitochondria, while electron microscopy revealed no gross morphological abnormalities. Parkin-deficient mice also exhibited delayed weight gain, suggesting broader metabolic issues. These mice showed reduced levels of proteins involved in oxidative stress protection, along with decreased serum antioxidant capacity and increased protein and lipid peroxidation. The study highlights parkin's essential role in regulating mitochondrial function and provides the first direct evidence of mitochondrial dysfunction and oxidative damage in a genetic mouse model of Parkinson's disease without nigral degeneration. The findings suggest that mitochondrial dysfunction and oxidative stress are key factors in the pathogenesis of Parkinson's disease.Parkin deficiency in mice leads to mitochondrial dysfunction and oxidative stress without nigral degeneration. Loss-of-function mutations in parkin are the primary cause of familial Parkinson's disease. Parkin functions as an E3 ubiquitin ligase, and its loss is hypothesized to cause nigral degeneration through the accumulation of its substrates. Using proteomic analysis, researchers found decreased abundance of proteins involved in mitochondrial function and oxidative stress in parkin-deficient mice. Functional assays showed reduced respiratory capacity of striatal mitochondria, while electron microscopy revealed no gross morphological abnormalities. Parkin-deficient mice also exhibited delayed weight gain, suggesting broader metabolic issues. These mice showed reduced levels of proteins involved in oxidative stress protection, along with decreased serum antioxidant capacity and increased protein and lipid peroxidation. The study highlights parkin's essential role in regulating mitochondrial function and provides the first direct evidence of mitochondrial dysfunction and oxidative damage in a genetic mouse model of Parkinson's disease without nigral degeneration. The findings suggest that mitochondrial dysfunction and oxidative stress are key factors in the pathogenesis of Parkinson's disease.