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I see this claim in the (low carb) paleo community all the time but I've never seen any evidence of it. I've seen evidence that diabetes-induced hyperglycemia increases the generation of reactive oxygen species (ROS), but I've never seen anything that indicated that metabolizing lipids generates a different amount than metabolizing glucose. Since the actual mitochondrial oxidation of acetyl-CoA is the same for both, the difference must be during glycolysis that turns glucose into pyruvate or the step that turns pyruvate into acetyl-CoA.

So which is it? What part of the process generates more ROS? As far as I can tell, all the ROS that is generated during cellular respiration occurs during the electron transport chain, which would be the same for lipids or glucose. Is the claim actually that a fat-sourced acetyl-CoA molecule "burns cleaner" than a glucose-sourced one? If so, that's preposterous.

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 This might be interesting to you if you haven't seen it already: care.diabetesjournals.org/content/30/6/… – Edward J. Edmonds Nov 2 2011 at 23:50
Hadn't seen that...wow. – Travis Culp♦ Nov 2 2011 at 23:58
Safe starches aren't so safe.... – cliff Nov 3 2011 at 0:08
Cliff, I know you're a fan of orange juice, but how much of that can you really be drinking? Your carb target was in the stratosphere if I recall correctly, so what do you use? – Travis Culp♦ Nov 3 2011 at 0:20
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 I especially enjoyed the phrase "Equicaloric amounts of orange juice or water...". WTF? – Dave S. Nov 3 2011 at 17:08
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5 Answers

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You are correct, the generation of ROS is in the ETC. But it differs from electrons derived from glucose or fatty acids. Glucose generates more NADH+, which then transfer electrons to complex I (NADH dehydrogenase). Fatty acids produce almost an equal amount of NADH+ and FADH2, which utilizes preferentially complex II (succinate dehydrogenase).

1 molecule of glucose:

Ratio NADH+:FADH2 = 5:1

1 molecule of palmitate:

Ratio NADH+:FADH2 = 2:1

Complex I is the main producer of ROS in the ETC, along with complex III. See:

http://www.ncbi.nlm.nih.gov/pubmed/19398655?dopt=Abstract

http://www.ncbi.nlm.nih.gov/pubmed/15254374

Another complex which is utilized by catabolism of fatty acids is the electron-transferring flavoprotein.

A good, comprehensive review can be found here

And, the basics here.

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Oh man, now that's an answer. Thanks a lot. – Travis Culp♦ Nov 2 2011 at 23:32
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 We are so glad to have you here Lucas! – Bread-Eating Beelzebub Nov 3 2011 at 3:10
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 Nice answer Lucas. Good to see you here – Aravind Nov 3 2011 at 15:10
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 Thank you guys. Cliff, you are comparing apples with oranges. ROS production in the mitochondria is normal and necessary (mitohormesis). The studies you have cited measured ROS production by PBMCs, which is different than the process by which the mitochondria generates ROS. For example, compromised ROS production in macrophages is deleterious for the host defense. – Lucas Tafur Nov 3 2011 at 17:18
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 uric acid is the most potent mammalian antioxidant?? Doesn't excess uric acid cause terrible gout and other health issues? – Jack Kronk Nov 3 2011 at 18:06
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You might find this paper interesting: How mitochondria produce reactive oxygen species

While there may be something to the balance of ROS formed from NADH, this is at least somewhat balanced, if not outweighed, by the fact that glucose doesn't produce byproducts that can hang around with inefficient oxidation to become peroxidized. Lipids do. Indeed there's really no "incomplete" glucose oxidation at the point of the mitochondria since up to pyruvate occurs in the cytosol whereas beta-oxidation of fatty acids occurs within the mitochondria.

ROS formation is also not necessarily detrimental, it plays an important signalling role. See, for example: Hydrogen peroxide: a Jekyll and Hyde signalling molecule

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OK ... I'm just curious. Why would someone down-vote this reply? – Evelyn aka CarbSane Nov 6 2011 at 17:01
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 Lots of 'tards here. I'll up-vote you just for spite. – Edward J. Edmonds Nov 6 2011 at 17:05
Evelyn: You've written about incomplete FA oxidation before, right? Your blog is so jam-packed with info that I don't know where to start. – Travis Culp♦ Nov 6 2011 at 18:10
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 Thanks Edward :-) @Lucas: I've only recently been blogging on the mitos per se, but the FA "lipotoxicity" has been a topic I've blogged on quite a bit. Which reminds me that the following post is almost three months old, and I've got several half-baked posts sitting in the draft bin: carbsanity.blogspot.com/2011/08/… This post/study was a turning point in this thought process: carbsanity.blogspot.com/2010/11/… There can be no doubt that fats burn dirty, I would say dirtier, than carbs. – Evelyn aka CarbSane Nov 7 2011 at 13:26
I wonder, too, if ROS → dysfunction → metabolic mahem and accelerated aging, and carbs → more ROS than fats, then why does RQ decline with age, but is preserved in the longest living women in the study that was the subject of this blog post?: carbsanity.blogspot.com/2011/10/… – Evelyn aka CarbSane Nov 7 2011 at 13:30
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Nice Lucas. The paper you cited is in line with Rosedale:

Another implication of the hypothesis is that it may be possible to reverse age-related impairments by producing carefully controlled hypoglycemia at levels lower than can be produced by optimum dietary restriction.

This is also what T.Ely claims, vitamin C researcher, independently from Rosedale.

There are more things to consider.

http://ncbi.nlm.nih.gov/pmc/articles/PMC2605959

Two modes of operation by isolated mitochondria result in significant O2•− production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Δp (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix.

... and eating fat provides more CoQ10. But ROS might be good also, via mitohormesis
http://ncbi.nlm.nih.gov/pubmed/16242247

"Reactive oxygen species, derived from the mitochondrial electron transport system, may be necessary triggering elements for a sequence of events that result in benefits ranging from the transiently cytoprotective to organismal-level longevity"

but not if you are old enough http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.2011.206623/full

The causes of this increased oxidative damage are uncertain, but substantial data now indicate that the ability of skeletal muscle from aged organisms to respond to an increase in ROS generation by increased expression of cytoprotective proteins through activation of redox-sensitive transcription factors is severely attenuated

So there are other things to consider, obviously, apart from glucose and fat

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 Immune system will adapt to higher fat levels. Vitamin C prevents that too. See Endotoxins and vit C vitaminc.co.nz/pdf/ENDOTOXIN-AND-VITAMIN-C.pdf. Carbs block C. – majkinetor Nov 3 2011 at 13:45
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 .. and vitamin C helps A LOT with that. Thats why I always say that C + HF paleo is win win combination. – majkinetor Nov 3 2011 at 13:59
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 @cliff, I think there are two separate issues here: 1) The ROS produced as a byproduct of metabolizing macronutrients in your mitochondria. 2) The postprandial ROS producing effects of macronutrients while they are floating around in your blood after eating. – Matt Nov 3 2011 at 14:18
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 @cliff: You don't read carefully. Ely said "excesses of protein and fat with respect to intakes of pyridoxine (vitamin B6) and Mg". If you have those two right, no problem. i eat very little pure glucose how did you convince your tongue to produce less salivary amylase ? – majkinetor Nov 3 2011 at 14:23
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 @cliff These OJ papers demonstrate context, that's it. They show that a single molecule can have a certain effect in one context and a completely different effect in another context. Some of the other observations of the paper are interesting for mental masturbation but far from proving drinking 1.5 liters a day of OJ as a OPTIMAL energy source. That's why you perceive maj picking on you, he's not, you're trying to make a point that is not supported by this particular paper, you're picking on yourself because of your own doubts. – Edward J. Edmonds Nov 3 2011 at 14:58
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Beta-oxidation of fatty acids doesn't only occur in the mitochondria, thus it isn't the only place where ROS generation can occur with fatty acid metabolism. Peroxisomes another cellular organelle is involved in beta-oxidation as well. The organelle handles long chain fatty acids breaks them down with an enzyme(s) and shuttles them off to the mitochondria . During the FA breakdown ROS is generated. If you’ve ever had a really fatty meal it’s my opinion the warming effect is a consequence of this reaction.

Peroxisomes have another use especially in leukocytes where they can produce hydrogen peroxide to kill pathogens. They play a role in the liver as well. And their malfunction is speculated to be involved in many different inflammatory diseases.

I think they are a double edge sword, on one hand they generate ROS on the other hand they play a role against pathogens and can scavenge ROS, etc. However, things can go wrong. The circumstances in which things go wrong from what I’ve seen aren’t yet completely clear.

Peroxisomes is one place you won't find glucose metabolism :)

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Actually it's incorrect to say FA metabolism (in the sense of metabolism meaning usefull energy is being produced) happens in Peroxisomes, it doesn't, the long chains just get broken down there. – Edward J. Edmonds Nov 6 2011 at 23:38
For a brief overview of Peroxisomes see ncbi.nlm.nih.gov/pubmed/15241609 – Edward J. Edmonds Nov 8 2011 at 17:30
If you can't access the paper e-mail me. – Edward J. Edmonds Nov 8 2011 at 17:30
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Good question. I always thought it was happening in the chain to get to the final product (Acetyl-COA) vs the final product. But I never looked into it.

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