Mitochondrial proteomics--a tool for the study of metabolic disorders.

Mitochondria are important for a number of life and death processes, such as energy production, creation of reactive oxygen species, and elicitation of stress responses. These responses range from induction of protein quality control and antioxidant systems to mitochondria elimination and cell death. Mitochondrial dysfunctions are involved in pathologies associated with many diseases, for example metabolic disorders, diabetes, cancers, cardiovascular and neurodegenerative diseases as well as obesity and aging. Mitochondrial proteomics can be a powerful tool in the study of these diseases, especially since it can cover mitochondrial proteins from several metabolic pathways, such as the citric acid cycle, fatty acid oxidation, and respiratory chain, as well as protein networks involved in stress responses. The mitochondrial proteome can consist of more than 1,000 different proteins. However, it is difficult to define the precise number, since mitochondria are dynamic and difficult to purify, and because an unknown number of proteins possess dual or multiple localization, depending on cell type and physiological conditions. This review describes several quantitative studies of proteins from mitochondria isolated by centrifugation, separated by various methods (e.g., electrophoresis and nanoLC), and analyzed by advanced mass spectrometry. We illustrate the methods by showing that multiple pathways and networks are affected in cells from patients carrying gene variations affecting a mitochondrial protein. The study of cultured skin fibroblasts from patients with ethylmalonic aciduria associated with variations in the genes coding for short-chain acyl-CoA dehydrogenase (SCAD) or ETHE1 are two of the examples. The possibility of obtaining mitochondrial proteomics data from whole cell proteomics studies is also exemplified by the involvement of liver mitochondria in metabolic syndrome.