From the previous article:
“the rate of substrate oxidation in resting muscle is not determined/limited by mitochondrial oxidative capacity, but by the rate of ATP breakdown/ADP formation, which is regulated by the cells’ need for energy”
The mitochondria can only make ATP if there is ADP and a phosphate present. The complex V in the electron transport chain, also called ATP synthase, adds a phosphate to ADP, forming ATP. ATP is then transported out of the cell through the ADP/ATP carrier (ANT), which imports ADP into the cell in exchange for ATP.
Without proper ANT functioning there won’t be much ADP to convert to ATP. ANT is stabilized by cardiolipins (CL). CL, a phospholipid of the inner mitochondrial membrane, plays a pivotal role in several mitochondrial bio-energetic processes, as well as in mitochondrial-dependent steps of apoptosis, and in mitochondrial membrane stability and dynamics.
Next, you have to understand reactive oxygen species and oxidative stress before we can continue.
Reactive oxygen species (ROS) are mostly created in the mitochondria by the electron transport chain (ETC). Complex I and III are the major contributes, however electron leak can happen at any point along the chain. ROS generated by the ETC is superoxide. Superoxide is highly reactive and attacks mitochondrial constituents, including proteins, lipids, and mitochondrial DNA (mtDNA). ROS-induced cumulative damage to mtDNA may lead to DNA strand breaks, as well as to the occurrence of somatic mtDNA mutations; which in turn may lead to impairment of the respiratory chain complexes activity with increased ROS production and additional mitochondrial DNA mutations.
As you can see on the picture, the O2·− is the superoxide. The black circles around ANT are the cardiolipin. This picture is good, but not perfect, as it doesn’t show the additional NADH input from glycerol-3-phosphate dehydrogenase (G3Pdh), or the electron transfer flavoprotein dehydrogenase (ETFdh) to the Q couple above CII.
Nitric oxide can also increase ROS production and creates its own toxic radicals, called reactive nitrogen species (RNS); which is similar to ROS, and can actually combine with superoxide to generate the toxic peroxynitrite (ONOO¯ ). But that is for another article.
Cardiolipin stabilizes all the proteins, transporters and complexes in the mitochondria membranes (not indicated in the picture), and this includes complex I and III where most of the ROS are generated.
When someone is eating a normal diet with moderate amounts of polyunsaturated fats, the CL will mainly consist of PUFAs as well. In fact, CL molecules are rich in unsaturated fatty acyl chains, notably linoleic acid in heart and liver (usually around 90%), or docosahexaenoic (DHA) and arachidonic acids in brain tissue mitochondria. The PUFAs in CL are susceptible to oxidative stress, and when it’s damaged by a ROS, it becomes oxidized, detaches from the complex and the complex then loses stability and function. Recent studies have shown that 4-hydroxy-2-nonenal (HNE) is one of the major products of CL oxidation (formed via lipid peroxidation).
HNE is known to affect the structural integrity and several parameters of mitochondrial function, such as protein transportation, respiratory metabolism (for ATP generation), mitochondrial dynamics and mitophagy quality control through fission and fusion of mitochondria. Oxidation and depletion of CL is associated with mitochondrial dysfunction in several metabolic and degenerative diseases; HNE plays a major part.
When the CL that stabilizes the ANT gets oxidized by ROS, ANT loses stability and function. Lower ANT efficiency allows for less ATP and ADP exchange, lowering the ATP production of the cell.
It’s been found that when CL gets oxidized, it increases the activity of mitochondrial permeability transition pore (MPTP), which allows calcium to flood into the cell, causing more ROS production and CL oxidation, which in turn leads to cell death. And it can be seen in this study, where one group of hamsters were fed saturated fat and the other group PUFAs, the PUFA fed group had increased sensitivity to MPTP, and suffered sudden death from heart failure, whereas the saturated fat group didn’t. (2)
Loss of mitochondrial stability and function occurs when cardiolipin gets oxidized, leading to an increase in intramitochondrial calcium, which causes cell death.
This can all be avoided by consuming as little PUFA as possible, in order to keep CL as saturated as possible. It’s been found that feeding old rats hydrogenated peanut oil (consisting of 31% saturated fat, 62% monounsaturated fat and less than 0.5% polyunsaturated fat), restored the complex I by 80% and complex IV by 100%. This indicates that saturated fats are able to restore defective mitochondrial complexes and cardiolipin almost completely after just 6 weeks. (1)
The study shows:
“The complete restoration of the activity of complex IV in the animals obtaining hydrogenated peanut oil is likely to be due to the fact that this oil contains mostly resistant to oxidation fatty acids (Table 1). It has been found that 90% of the fatty acid chains of triglycerides efficiently maintaining the subunit composition of cytochrome c oxidase are resistant to oxidation palmitic (17%), stearic (12%), and oleic (61%) acids”
So even if there is a demand for ATP, but CL is oxidized, the mitochondria cannot produce ATP, no matter how much glucose or fats you throw at it.
Now you might think, just use lots of anti-oxidants to clean up all the ROS, but the constant use of antioxidants for the defense of tissue is impossible, since ROS normally plays an important role in both cellular and intramitochondrial signaling. But of course, anti-oxidants would still help reduce excess ROS production.