Is cholesterol bad for mitochondria?

Redoxoma Highlights by Sayuri Miyamoto

Cholesterol is an important component of cell membranes and plays essential structural and signaling roles. It is synthesized in the endoplasmic reticulum and distributed to other cell membranes/compartments through a tightly regulated trafficking system involving vesicular and non-vesicular processes [1]. Cholesterol distribution among intra-cellular membranes is not homogeneous. Mitochondria are cholesterol-poor organelles (less than 5 %). However, mitochondrial cholesterol is increased in cancer cell lines and treatment of these cells with statins (cholesterol lowering drugs) increases their susceptibility to chemotherapy [2].

How mitochondrial cholesterol could influence cell death mechanisms? Cholesterol is easily oxidized by reactive oxygen species, giving rise to oxidized products, especially hydroperoxides and aldehydes. The study by Genaro-Mattos et al., 2015 [3] showed that cholesterol hydroperoxides react with cytochrome c, inducing a fast decomposition of the heme group of this protein (heme bleaching) and also the production of protein radicals. During this process, cytochrome-c underwent oligomerization, producting dimeric and trimeric species. These findings demonstrate that cytochrome c is seriously damaged in the presence of cholesterol hydroperoxides and this could inhibit its ability to induce apoptosis. Similarly, in a previous work [4] our group showed that cholesterol derived aldehydes are able to attach covalently on Lys residues (Lys 22 and Lys 8) located at the surface of cytochrome c, creating a hydrophobic tail in the protein. This modification caused a reduction in cytochrome c detachment from a model membrane in vitro. Overall, these studies indicate that cytochrome c can be modified by cholesterol oxidation products and it is tempting to speculate that these effects could have potential implications on cell death mechanisms.

1. E. Ikonen. Cellular cholesterol trafficking and compartmentalization. Nature Reviews Molecular Cell Biology, 9 (2): 125-38, 2008. | dx.doi.org/10.1038/nrm2336
2. J. Montero, M. Mari, A. Colell, A. Morales, G. Basañez, C. Garcia-Ruiz, J. C. Fernández-Checa. Cholesterol and peroxidized cardiolipin in mitochondrial membrane properties, permeabilization and cell death. Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1797 (6-7): 1217-24, 2010. | dx.doi.org/10.1016/j.bbabio.2010.02.010
3. T. C. Genaro-Mattos, R. F. Queiroz, D. Cunha, P. P. Appolinario, P. Di Mascio, I. L. Nantes, O. Augusto, S. Miyamoto. Cytochrome c reacts with cholesterol hydroperoxides to produce lipid- and protein-derived radicals. Biochemistry, 54 (18): 2841-50, 2015. | dx.doi.org/10.1021/bi501409d
4. T. C. Genaro-Mattos, R. F. Queiroz, D. Cunha, P. P. Appolinario, P. Di Mascio, I. L. Nantes, O. Augusto, S. Miyamoto. Covalent binding and anchoring of cytochrome c to mitochondrial mimetic membranes promoted by cholesterol carboxyaldehyde. Chemical Research in Toxicology, 26: 1536-44, 2013. | dx.doi.org/10.1021/tx4002385

Sayuri Miyamoto, PhD. Assistant Professor at Department of Biochemistry, Institute of Chemistry, University of São Paulo, Brazil