Ketone and Fat "Burning" are Not the Same Thing to Your Mitochondria

This notion of being a "sugar burner" vs. a "fat burner" -- with the latter being touted as preferable based on nothing I've seen in the scientific literature -- is getting really out of hand.  This is not a new idea, but it certainly seems to be being pushed more lately, particularly in the area of athletic performance.  There were a smattering of posts about the diets of Olympians about the net and I just have to shake my head at the one that goes something like "just imagine how much better fill in the blank would do if (s)he didn't eat grains" or "ate LCHF" or "went paleo".  C'mon already ... Michael Phelps is a prime offender of all laws and gods nutritional, but will someone please remind me how many medals he's earned and records he's held/broken in his career?  Gawd forbid any of these elite athletes set a bad example by having their face put on a box of Wheaties!  I dunno ... it all seems so silly when Phelps sports one of the leanest torsos on the planet burning sugar.  But I digress ...

But with ketomania in full-blown fad form, there's a new twist on the fat burning meme which is to confuse fat burning with ketone burning.  It is not.  Yes, ketones are produced mostly from the breakdown of fatty acids (they are also produced from some amino acids), so you "burn fat" in your liver to produce them.  If you are in caloric deficit, the source of the fatty acids will be body fat.  However, if you're fueling the other cells of your body with ketones, this is not the same as the mitochondria in those cells "burning fat".  

Below is a schematic of a brain cell mitochondria and the metabolic pathways showing where ketones feed into Krebs (aka the TCA), from:  D-β-Hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease (thus it shows the points of issue for these two diseases) 

See there just above and to the right of this sentence?  That's the major ketone that enters the mitochondria and produces an NADH if converted to acetoacetate which is then converted to acetoacetyl-CoA and finally to two acetyl-CoA's.  Acetyl-CoA feeds into Krebs generating the NADH that is put through -- yikes! -- Complex I of the ETC.  Glycolysis to produce pyruvate takes place outside the mitochondria, so if one wants to nit pick, the mitochondria are directly fueled by pyruvate primarily, and alternately by ketones.  It would appear that ketones may work by feeding the TCA intermediates from a point in the cycle other than where the defect occurs glucose metabolism ... but that's not the subject of this post.  

direct image link

Unlike glucose, fatty acid burning, aka beta oxidation in what is commonly referred to as the fatty acid spiral, occurs entirely within the mitochondrial matrix.  First the fatty acids must be activated and transported through the double membrane of the mitochondria into the matrix as shown at right.  The entire mitochondrial transport/metabolism scheme is shown below.  Notice anything?  In addition to ROS which are formed in not the common TCA, and common ETC (though yes, different ratios of ROS from different protein complexes used), we have metabolic byproducts that can build up inside the mitochondria.  When one wants to talk about a "clean burning fuel" it is one that is "burnt" completely.  This is the case for glucose/pyruvate and ketones.  But not fats.  I will go into this in more depth in another post or few with citations, but incomplete oxidation of fatty acids and the buildup leads to lipid peroxidation and so forth.  This particular schematic comes from this paper (I do not currently have the full text, if anyone is so inclined, I'd appreciate a copy carbsane at gmail dot com).  

image link 

Caption from article:   Lipotoxicity evokes mitochondrial dysfunction by affecting organelle-associated protein phosphorylation. Illustration of the proposed consequences of lipotoxicity on mitochondrial protein phosphorylation: (i) fatty acid overload exceeds the oxidative capacity of the mitochondria, resulting in enhanced radical production that is accompanied by generation of lipotoxic derivates. ROS can affect constitutive matrix kinases and/or phosphatases, yielding deleterious changes in the mitochondrial phosphoproteome. (ii) Upon excess substrate flow, various enzymes and/or kinases are activated (e.g. Nox, JNK and/or PKCβ), leading to phosphorylation of protein mediators, such as p66Shc, that translocate to the mitochondria and trigger organelle dysfunction. (iii) During the onset of lipotoxic responses, cytoplasmic kinases are activated and associate with the inner mitochondrial membrane to affect ion-transporter activity by reversible phosphorylation, causing mitochondrial dysfunction because of an ionic imbalance. Abbreviations: I, II, III, IV, complexes of the respiratory chain; Cyt c, cytochrome C; acyl-CoA, acyl-Coenzyme A; GPDH, glycerol-3-phosphate dehydrogenase; IMM, inner mitochondrial membrane; JNK, c-Jun N-terminal kinase; mtHsp70, mitochondrial heat-shock protein 70; NADH/H⁺, reduced nicotinamide adenine dinucleotide; Nox, (plasma) membrane-bound NADPH oxidases; OMM, outer mitochondrial membrane; p66Shc, Src-homology-2-domain-containing transforming protein 1; PKCβ, protein kinase C-β; PTP, permeability transition pore; Q, uniquinone; ROS, reactive oxygen species.

Missing from the schematic is UCP3 - uncoupling protein 3.  I have a lot of information on UCP3 and it's role in preventing fatty acid overload.  Much of the current literature makes a case that UCP3 is misnamed as it appears to be less of a true uncoupling protein and more of a transport protein facilitating fatty acid transport out of the mitochondria.  Mitochondrial dysfunction in diabetes is linked to defects in the genes encoding UCP3 -- a deficiency in the ability of mitochondria to essentially expel the "dirty" byproducts of burning fatty acids as fuel.  More details to come ...

Bottom line, certain cells of the "fat burning beast" may be operating more efficiently -- those that normally burn glucose and there's evidence that ketones can improve cardiac muscle efficiency (as does insulin!).  But the cells being forced to burn more actual fat for fuel?  If you've got dysfunctional mitochondria, this isn't going to make the situation better.  I don't know that it will make it worse, probably not in caloric deficit/weight loss, but nobody really knows in caloric balance, especially in the obese or overweight state.