This study investigates tissue-specific changes in fatty acid metabolism in a mouse model of isolated complex I deficiency (ICD). Using mass spectrometry-based proteomics, the study examines protein expression changes in the brainstem, cerebellum, olfactory bulb, heart, kidney, and liver of Ndufs4 KO mice. The findings reveal that metabolic adaptations in fatty acid metabolism in response to ICD are tissue-specific and often opposing, indicating a complex compensatory response to mitochondrial dysfunction. Understanding these differential adaptations could inform future treatment targets for mitochondrial disorder