Mitochondrial membrane alpha-tocopherol/homologues: super scavengers or peroxidase inhibitors?

I love research that alters established dogma with new technology (hence Nutritional Blogma), so I felt compelled to highlight this one.

Polyunsaturated fatty acids (PUFAs) are structurally important in cell and some organelle membranes.  For simplicity’s sake, we are often shown a representation like this:

Each of the heads with 2 tails represents a phospholipid, which is composed of the polar NH3 group, a phosophate group, glycerol, and 2 fatty acid tails.  In this representation, one of the fatty acids is unsaturated.

There are other components that make up membranes, but this research focuses on PUFAs.  There are thousands of lipid species in our bodies, but as the authors of a new paper state, there are thousands of PUFA species alone identified with mass spec.

Onto the dogma.  I was taught that PUFAs in the membrane, because of their double bonds, made the membranes especially susceptible to peroxidation (and thus oxidative damage), and the more double bonds, the more susceptible.  However, as the researchers describe, lipidomics and oxidative lipidomics (with asymmetric topography) has shown that peroxidation products of PUFAs have unique roles such as cellular signaling.  They also accumulate in specific classes of phospholipids.  The authors use the example of a phospholipid unique to mitochondria: cardiolipin (CL) that usually only appears in the inner mitochondrial membrane.  CL has 4 fatty acid tails, thus many possibilities for different combinations (species) (see this page for a good table).  The number of species is tissue dependent (despite cardio in its name, it appears in other tissues than the heart), from a few in some tissues to hundreds in others, and their roles in each need to be further studied.

CL is involved in apoptosis- it travels from the inner to the outer mitochondrial membrane with the help of at least 4 proteins.  It then interacts with a protein called cytochrome c (cyt c).  You may recognize this is you are up on your biochemistry- is it a part of the electron transport chain between complex III and IV.  When cyt c and CL bind, the complex unfolds and gives peroxidase activity to cyt c.  Further reactions and structural changes allow molecules such as hydrogen peroxide to react with it.  So this process catalyzes CL peroxidation, and the byproducts increase membrane permeability, release of pro-apoptotic factors, and cell death.  Keep in mind that CL is specific to mitochondria, so this doesn’t happen in all membranes, and random peroxidation of other PUFAs does not occur here, even if they contain more double bonds than CL.

Finally the other part of the dogma: I recall being taught that antioxidants like alpha-tocopherol (vitamin E), the major one of membranes and lipoproteins, were protective in membranes because they broke the reactivity chains; oxidation products reacting with other PUFAs because of their double bonds were stopped by vitamin E and this is why it is so important to not be deficient.  The authors discuss research showing its efficacy in vitro against random phospholipid peroxidation, that the different homologues of E inhibit peroxidation at differing effectiveness by side-chain length, etc.  E is “recharged” (reduced) by ubiquinol, ascorbate (vitamin C), and the electron transport chain thus maintaining its antioxidant potential.

The purpose of the study was to see what effect the different side-chain lengths of alpha-tocopherol and 2 homologues (PMC and C6) had on CL/cyt c peroxidation (by hydrogen peroxide).  The researchers found that all 3 were effective are preventing peroxidation of CL, and that the side-chain length influenced the effectiveness.  The 3 also inhibited the formation of 2 major peroxidation products of CL, and the rate of generation of these products was slowed, showing that the vitamin E homologues (especially PMC) compete with CL as substrates in the peroxidase reaction.

The authors note that previous research shows vitamin E homologues can be substrates and inhibitors for different peroxidases, and that suggests that, as they conclude: “inhibition of peroxidase activity of cyt c can significantly contribute to the protective effect of vitamin E and its homologues, against oxidative damage to mitochondria.”

Ok, so it isn’t a huge paradigm shift, only fine-tuning molecular details, but if you are still reading at this point, you must get excited about the little things like I do.  In any case, this area of research seems important, as argued in another paper by a couple of the authors and others that inhibiting CL peroxidation seems a very promising drug target for many diseases involving apoptosis.

Reference

Samhan-Arias AK, Tyurina YY, & Kagan VE (2011). Lipid antioxidants: free radical scavenging versus regulation of enzymatic lipid peroxidation. Journal of clinical biochemistry and nutrition, 48 (1), 91-5 PMID: 21297919