I think we can say that ketogenic diets are pretty rubbish for managing mitochondrial illnesses.
By chance there is also a twitter discussion on-going relating to omega 6 based ketogenic diets.
First, nutritionists LOVE omega 6 PUFA and HATE saturated fats. In case anyone hadn't noticed. This tweet came from laura cooper, this time picked up via Raphi and Tucker.
Supported by this
It seems very likely that we can combine these two concepts and come up with some sort of an explanation.
I think we can accept that the ketone induced metabolic changes noted by Veech in isolated working rat hearts, resulting in increased energy yield per ATP molecule, still apply even with poorly functional mitochondria, because there is comparable improvement in the control of abnormal mitochondria induced intractable epilepsy vs ordinary intractable epilepsy. The ketogenic diet is clearly doing something...
That's good.
Everything else is bad.
If there is a significant problem with the structure/function of complex I ketones will not be directly helpful. They deliver acetyl-CoA to the TCA and essentially nothing else. There will be a small FADH2 input from succinate dehydrogenase but all other electrons will be presented as NADH, which needs a functional complex I to do anything much.
To bypass a poorly functional complex I we really need input as FADH2 directly to the CoQ couple without having to turn the TCA. That means beta oxidation of fatty acids, in particular it needs those fatty acids to be fully saturated because electron transporting flavoprotein only receives electrons to form FADH2 from the first desaturation step at the start of beta oxidation. Any double bonds skip this step.
Using PUFA immediately reduces energy sourced via this route.
The next thing we need to realise that modern nutritionist derived ketogenic diets cause, amongst other things, pancreatitis. I posted about pancreatitis, Intralipid and propofol here. It should come as no surprise that the side effects (from here) of PUFA based ketogenic diets in children can be severe, they're probably a lot higher in PUFA than even F3666 rodent chow...
"Other early-onset complications, in order of frequency, were hypertriglyceridemia, transient hyperuricemia, hypercholesterolemia, various infectious diseases, symptomatic hypoglycemia, hypoproteinemia, hypomagnesemia, repetitive hyponatremia, low concentrations of high-density lipoprotein, lipoid pneumonia due to aspiration, hepatitis, acute pancreatitis, and persistent metabolic acidosis. Late-onset complications also included osteopenia, renal stones, cardiomyopathy, secondary hypocarnitinemia, and iron-deficiency anemia".
Then there are cardiolipins. Each cytochrome C molecule is anchored to the outer surface of the inner mitochondrial membrane by four lipid anchors. Their nature is largely controlled by the dietary lipid supply. Modern PUFA based ketogenic diets will result in highly unsaturated cardiolipin anchors. Damaged mitochondria produce an excess of ROS. ROS break PUFA based cardiolipins giving apoptosis or, if ATP levels are too low for this, necrosis. Not going to do your ragged red muscle fibres any good. Or you cardiomyopathic cardiomyocytes.
I could go on, but you get the flavour.
Is there any end to the damage done by the lipid hypothesis?
Probably not.
Peter
