Diagnosis of mitochondrial disease is based on multiple criteria, such as clinical scores (assessing muscle, central nervous system, and multisystem involvement), imaging results, biopsy histology, genome analyses and biochemical analyses of the electron transport chain complex activities. The complex activities vary strongly between healthy individuals and limits the use for diagnosis. In this project, we have evaluated posttranslational and genetic contributors to such variation in complex activities that -if corrected for- could improve diagnostic precision. We have used proteomic analyses of mitochondria to examine the degree that protein composition of the mitochondria correlates with biochemical activity of complexes as well as posttranslational and genetic factors.