Misfolded proteins and neurodegeneration: role of non-native cytochrome c in cell death

Abstract

Intermediates play a relevant role in the protein-folding process, because the onset of diseases of genetic nature is usually coupled with protein misfolding and the formation of stable intermediate species. This article describes and briefly discusses the mechanisms considered responsible, at molecular level, for a number of neurodegenerative diseases. In particular, interest is focused on the newly discovered role of cytochrome c in programmed cell death (apoptosis), consisting of acquisition of powerful cardiolipin-specific peroxidase action. Cardiolipin oxidation induces cytochrome c detachment from the mitochondrial membrane and favors the accumulation of products releasing proapoptotic factors. Cytochrome c showing peroxidase activity has non-native structure, and shows enhanced access of the heme catalytic site to small molecules, such as H₂O₂. The strict correlation linking cytochrome c with the onset of neurodegenerative disorders is described and the therapeutic approach discussed.

Keywords::

• apoptosis
• cardiolipin
• cytochrome c
• minocycline
• misfolding
• neurodegenerative disease
• protein folding

Financial & competing interests disclosure

Research was funded in part by grants from the Italian MIUR (PRIN 2007KAWXCL). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.