© Springer-Verlag London Limited 2012. Mitochondrial dysfunction is frequently associated with neurodegenerative diseases and is thought to be a major contributor to the pathophysiology of Parkinson’s, Alzheimer’s, Huntington’s, and stroke. The mechanisms that lead to these defects have in common generation of reactive oxygen and nitrogen species and the covalent, and often irreversible, modification of proteins. Recently, it has become clear that the interplay between this protein modification and the cellular pathways that process damaged proteins is a key link between cellular bioenergetics and cell death. In this short overview, we will review the literature which supports the concept that protein aggregation, dysregulation of autophagy, and oxidative stress can result from and impact on mitochondrial dysfunction. Understanding the regulation of protein aggregation, autophagy, oxidative stress, and mitochondrial dysfunction may then offer new avenues for the development of mitochondrial-specific therapies in neurodegenerative diseases.