Updated project metadata. A novel quantitative crosslinking mass spectrometry technique (qXL-MS) was applied to elucidate interactome changes in aged murine skeletal muscle mitochondria that contribute to age-related mitochondrial functional decline. Reported here are results from initial investigations of murine muscle mitochondrial interactomes that enable identification of statistically significant changes associated with aging. Newly developed isobaric quantitative protein interaction reporter (iqPIR) technologies15 enabled reproducible detection of age-related mitochondrial interactome changes. Muscle mitochondria from young and old mice were isolated, cross-linked with iqPIR molecules, young and old mitochondrial samples were paired, process and analyzed to quantify age-related mitochondrial interactome changes. In parallel, mitochondria were also subjected to additional measurements of mitochondrial protein yield, functional measurements including oxygen consumption rates on Complex I and Complex II substrates, and citrate synthase activity.