PCSK9 is well-known for its role in cholesterol homeostasis, and most are aware that PCSK9 targets the LDL receptor for lysosomal degradation. Given that the LDL receptor in the liver is what clears the majority of ApoB cholesterol-laden particles from circulation, it isn’t a good thing for your Lipid Neighborhood when there is too much PCSK9 around. Essentially, the LDL receptor is like that claw grabber at the arcade that wins your kiddo the ApoB(ear), and if PCSK9 isn’t around, the claw grabber stays in working order. The LDL receptor typically recirculates hundreds of times to the surface of the liver. Conversely, if the LDL receptor claw grabber is put out of commission by PCSK9, kids aren’t winning the ApoB(ear) and, in their impatience, may start creating mischief in your arterial wall.
People who lack PCSK9 genetically don’t seem to have any issues, and they have a reduced risk of having cardiovascular events. Additionally, medications that inhibit PCSK9 have been wildly successful, and there are even plans to use CRISPR Cas9 gene editing to make PCSK9 an anatomical afterthought! One injection and you never have to worry about heart disease again, right? Whether or not this is a good idea, a quixotically epic miscalculation, or somewhere in between remains to be seen!
But although the majority of PCSK9 is produced by the liver, there are other sites in the body where PCSK9 is produced intracellularly. One of these sites is the cardiac myocyte, and although PCSK9 in the heart muscle cell is only present at 0.2% of the levels seen in the liver, it appears to play an important role in mitigating cardiomyopathy.
This study featured mice that lacked PCSK9 in the cardiomyocyte…and they quickly developed Big Bad Hearts and died prematurely. We call this the Reverse Grinch Effect (well, maybe we should), and it was determined that the mice lacking cardiomyocyte PCSK9 had impaired mitochondrial function. The Powerhouses of the Cell typically have folds called cristae, which enable the electron transport chain to rev up your cellular batteries and drive ATP Synthase. (This is easy to remember for me, since my wife’s name is Christa, she is a Powerhouse, and I am useless without her).
However, in these PCSK9-deficient mice, the cristae were shaped like onions, and they weren’t able to generate ATP. This also makes sense, because if you only ate onions, you probably wouldn’t have any energy and your life would stink.
The specific reason for this energy crisis was that PCSK9 interacts with a chaperone protein called GRP78. When PCSK9 is around, it prevents GRP78 from activating another transport protein called TSPO…and TSPO transports cholesterol into the mitochondria. So if there is no PCSK9 to regulate the activity of GRP78 and TSPO, the cardiac muscle mitochondria become overloaded with a toxic level of cholesterol due to excessive TSPO activity. This leads to heart failure, and interestingly, we also see elevated TSPO levels in people with dilated and ischemic cardiomyopathies.
Now remember, currently available therapeutic agents affecting PCSK9 do not impact local intracellular PCSK9 production. PCSK9 inhibitor monoclonal antibodies “mop up” the extracellular PCSK9, and PCSK9 inhibitor siRNA agents “turn off the faucet” of PCSK9 production in the liver. This should be reassuring, and the litany of safety data accumulated over the past decade for folks on these medications is similarly comforting.
In summary, PCSK9 seems to be a Pretty Crazy Sick K9 (credit to Dr. Susan Dimick for that mnemonic) when unleashed extracellularly. But if that canine is kept in its intracellular cage, perhaps it may be a useful watchdog for important cellular processes in the realm of mitochondrial bioenergetics and autophagy. As always, there is much more to learn!
