Welcome all seeking refuge from low carb dogma!

“To kill an error is as good a service as, and sometimes even better than, the establishing of a new truth or fact”
~ Charles Darwin (it's evolutionary baybeee!)

Monday, September 6, 2010

Mitochondrial H2O2 Emission, Cellular Redox State and Insulin Resistance - Part I

Reader Ryan emailed me this link a while back and I've been remiss in getting around to it.  Better late than never!  Thanks for the link Ryan!

Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans
Mitochondrial dysfunction and oxidative stress have been implicated in the disease process, but the underlying mechanisms are still unknown. Here we show that in skeletal muscle of both rodents and humans, a diet high in fat increases the H2O2-emitting potential of mitochondria, shifts the cellular redox environment to a more oxidized state, and decreases the redox-buffering capacity in the absence of any change in mitochondrial respiratory function. Furthermore, we show that attenuating mitochondrial H2O2 emission, either by treating rats with a mitochondrial-targeted antioxidant or by genetically engineering the overexpression of catalase in mitochondria of muscle in mice, completely preserves insulin sensitivity despite a high-fat diet. These findings place the etiology of insulin resistance in the context of mitochondrial bioenergetics by demonstrating that mitochondrial H2O2 emission serves as both a gauge of energy balance and a regulator of cellular redox environment, linking intracellular metabolic balance to the control of insulin sensitivity.

The introduction is chock-full of background information (references) regarding the etiology of IR in skeletal muscle.

The accumulation of lipid in skeletal muscle has long been associated with the development of insulin resistance (1), a maladaptive response that is currently attributed to the generation and intracellular accumulation of proinflammatory lipid metabolites (e.g., fatty acyl-CoAs, diacylglycerols, and/or ceramides) and associated activation of stress-sensitive serine/threonine kinases that antagonize insulin signaling (24). Skeletal muscle of obese individuals is also characterized by profound reductions in mitochondrial function, as evidenced by decreased expression of metabolic genes (5, 6), reduced respiratory capacity (79), and mitochondria that are smaller and less abundant (9), leading to speculation that a decrease in the capacity to oxidize fat due to acquired or inherited mitochondrial insufficiency may be an underlying cause of the lipid accumulation and insulin resistance that develops in various metabolic states (10, 11).

H2O2 is hydrogen peroxide.  Dip your finger into even the dilute OTC prep, and we see what it can do.  Obviously we're not talking those concentrations in the cells or we'd all be dead.  But H2O2 is chemically unstable (which is why it is sold in brown opaque bottles with directions to store in a cool place).  H202 is a reactive species (RS) that can cause damage.

Here is a link to but one summary article on H2O2, and another on RS and antioxidants in general.

Back to the article and some more background:

In addition to providing energy for the cell, mitochondria are now recognized as an important site for the generation, dispensation, and removal of a number of intracellular signaling effectors, including hydrogen peroxide (H2O2), calcium, and nitric oxide. In fact, the emission rate of H2O2 from mitochondria, which reflects the balance between the rate of electron leak/superoxide formation from the respiratory system and scavenging of H2O2 in the matrix, varies over a remarkably consistent range across diverse forms of aerobic life (20). Once in the cytosol, H2O2 can alter the redox state of the cell by either reacting directly with thiol residues within redox-sensitive proteins or shifting the ratio of reduced glutathione to oxidized glutathione (GSH/GSSG), the main redox buffer of the cell. Thus, the rate at which H2O2 is emitted from mitochondria is considered an important barometer of mitochondrial function and modulator of the overall cellular redox environment (21).

For the non-chemists in the audience, oxidation involves the loss of electrons from a molecule, reduction involves a gain.  The term "redox" is a contraction of reduction and oxidation and, since electrons do not exist as separate particles (well, in the solution chemistry sense which is what our bodies are) these reactions occur in "redox" pairs -- where one molecule loses electrons picked up by the other -- a species is oxidized when another is reduced.  Which direction these reactions go depends on the relative oxidation potentials (a measure of reactivity) of the chemicals involved.  Rusting iron is a classic example everyone is familiar with.  Put an iron nail into water and come back in a week or so and the water will be brown and there will be rust plumes on the nail.  Add salt and it will go faster.  This is because dissolved oxygen in the water has a higher oxidation potential than the iron, therefore in the reaction, oxygen is reduced while iron is oxidized.  That orange stuff is the product of this reaction.  We can think of this as environmental oxidative damage b/c the result is to convert a bright shiny strong nail into a rusty nail that can eventually degrade to where the head falls off, etc.  In our bodies, O2 is an essential oxidizing agent, and metabolically it serves a key role so we don't consider it damaging.   Reactive Oxidative Species (ROS or sometimes just RS) are molecules with high oxidation potentials.  In our bodies, they can have the effect of "rusting" critical components of cell membranes, signalling proteins, DNA, etc.  Back to my Bill Nye the Science Guy experimentation.  Take two nails and put salt water in two glasses.  In one just put the plain steel nail.  In the other, wrap a similar nail with aluminum foil.  Report back in a week.  What you'll see is that the nail wrapped in foil is virtually free from rust but you might see a bit of white cloudiness around the foil.  Aluminum in this context acts as the antioxidant.  It essentially reacts preferentially with the oxygen (the white stuff is the less aesthetically offensive product) protecting the iron.  While not a perfect analogy (or, for that matter a perfect description of galvanic corrosion which is what the iron/aluminum scenario is), this is the role antioxidants play in our bodies.   Antioxidants "scavenge" ROS and take the hit (are oxidized) so that the ROS won't damage critical molecules.  The oxidized form of the antioxidant is usually harmless and either eventually excreted or "recycled" back to it's reduced form by some biochemical mechanism.

End of chemistry lesson ...

What this article is saying is that H2O2 is one such RS/ROS produced in the mitochondria (under perfectly normal conditions), but that in balance we produce natural antioxidants (glutathione, etc.) that serve to "remove"  these ROS before they can damage critical molecules.

Here's where obesity and high fat diet figure in.  (Summarized from:  Obesity/diet alter mitochondrial H2O2 emission in humans.)  The comparison was between lean insulin sensitive (I'll call these LIS) males and obese insulin resistant males (OIR) in skeletal muscle.

  • H2O2 emission was 4X greater in OIR vs. LIS at basal ("fat burning") rates
  • H2O2 emission was 2X greater in OIR vs. LIS in response to stimulation
  • The difference in H2O2 emission did not correlate with O2 utilization which was not different between the two groups.
  • Maximum stimulated O2 consumption was ~35% less in OIR vs. LIS indicating reduced respiratory capacity in the obese.
Figure 5 from the article:  Caption:  H2O2 emission elevated in obese men and lean men following a high fat meal.

Part II to follow as a separate post.



MM said...


Do you think this effect has anything to do with the phenomenon recently discovered that hair follicles that produce grey hair have a build-up of H2O2? If you google peroxide and grey hair you'll find lots of stories. Here's one.

CarbSane said...

This one has been on my back burner. Sure sounds plausible. If gray hairs are any indication, I have none to speak of yet. But I use a lot of peroxide ;)

Ilya said...

I can't find Part 2, can you give or mail me some directions, please?

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