A Reminder that Mitochondrial Biochemistry is Complex

Cells are very dynamic entities. They don't sit still, and they and their components are constantly in a state of flux. A cell is a sack of things that can be listed, understood and counted, sure, but at any given moment in time numerous parts are being dismantled and new parts created from raw materials. Levels of proteins ebb and flow as they are formed and destroyed.

All of this dynamism places an interesting spin on attempts to understand and then repair aspects of aging that depend on malfunctioning cellular components. Within cells there exist a range of important structures called organelles, some of which number in the hundreds or thousands, such as mitochondria. These are themselves very dynamic entities, busy with the process of dividing, fusing, and exchanging proteins between one another. Damage in mitochondria is not a static thing, as those damaged proteins can be shared around, and damaged and undamaged mitochondria can fuse to create an organelle that works. The only forms of damage that can last are those that provide some survival advantage to a mitochondrion, such as the ability to evade cellular quality control mechanisms, or wherein the particular form of damage can overwhelm undamaged variants.

Most interesting of all cells can even pass around mitochondria, which is a great way for potentially harmful forms of persistent or replicating damage to spread and thus have a greater detrimental effect than would otherwise be the case. The present view of mitochondria in aging is that there are indeed forms of damage to mitochondrial DNA that cause dysfunction in mitochondrial function that is both harmful and leads to the spread of damaged mitochondria because they evade quality control mechanisms. Thus the damaged forms can divide and multiply to take over a cell - and if exported elsewhere they will take over that cell as well. This doesn't actually appear to happen to more than a small fraction of cells over a human life span, but that small fraction is enough to cause great harm to tissues, blood vessels, and more.

The research linked below is another reminder that mitochondrial biochemistry is complicated, delving further into how mitochondrial pass around between cells. In this case it definitely looks like a vector by which bad mitochondria of the sort we care about could spread more than they otherwise would. Any approach to repairing mitochondria in aged tissue must thus be sufficiently comprehensive to ensure that all these tricks have no effect: it cannot matter how dynamic or widely traveled a mitochondrion is, the treatment must either repair it along with all of its peers or destroy it, leaving none of the damage behind to spread once more.

Getting Rid of Old Mitochondria

It's broadly assumed that cells degrade and recycle their own old or damaged organelles, but [researchers] have discovered that some neurons transfer unwanted mitochondria - the tiny power plants inside cells - to supporting glial cells called astrocytes for disposal. The [findings] suggest some basic biology may need revising, but they also have potential implications for improving the understanding and treatment of many neurodegenerative and metabolic disorders.

"It does call into question the conventional assumption that cells necessarily degrade their own organelles. We don't yet know how generalized this process is throughout the brain, but our work suggests it's probably widespread. The discovery of a standard process for transfer of trash from neuron to glia will most likely be very important to understanding age-related declines in function of the brain and neurodegenerative or metabolic disorders. We expect the impact to be significant in other areas of biomedicine as well."

Transcellular degradation of axonal mitochondria

Mitochondria are organelles that perform many essential functions, including providing the energy to cells. Cells remove damaged mitochondria through a process called mitophagy. Mitophagy is considered a subset of a process called autophagy, by which damaged organelles are enwrapped and delivered to lysosomes for degradation. Implicit in the categorization of mitophagy as a subset of autophagy, which means "self-eating," is the assumption that a cell degrades its own mitochondria. However, we show here that in a location called the optic nerve head, large numbers of mitochondria are shed from neurons to be degraded by the lysosomes of adjoining glial cells. This finding calls into question the assumption that a cell necessarily degrades its own organelles.

Any news on the MitoSENS project? I wonder what the holdup is given that Aubrey talks about mitochondrial import of nuclear encoded proteins being demonstrated by in 2007? What are they working on right now?

Posted by: Jim at June 26th, 2014 12:53 AM

It proceeds at the slow and uncertain pace reserved for poorly funded research. Much of the outside help comes from groups who only want to manage allotopic expression for one or two genes associated with LHON or similar conditions. They are making progress in solidifying their methods, but not in any way now that helps the larger project.

The goals now are to take the methods pioneered for use with LHON and similar and apply them to the other mitochondrial genes, which is more or less a matter of recreating a process from scratch for each one as each is completely different with regard to how you get the protein from the nucleus back into the mitochondria.

Meanwhile there are some other early stage methods that might be better or worse if pursued.

As to what they are working on right now - send an email to the SENS Research Foundation. They'll give you an overview.

Posted by: Reason at June 26th, 2014 5:12 AM

Yeah, I think I'll just wait for some news from the upcoming August conference. They are not really that much into the business of explaining what they are up to for laypersons on the internet.

It would be nice to know if the donation I made did end up helping them to buy a cell counter or not though. I guess I'm spoiled in this age of Kickstarter projects where detailed weekly progress reports are almost mandated.

Posted by: Jim at June 26th, 2014 8:52 AM

Hi folks,

The MitoSENS team is making good and ongoing progress. Some of this is summarized in our last Research Report; yes, this was quite a few months ago, but most of the progress has been so far into the weeds that it's hard to summarize it or its significance to anyone but mitochondrial specialists. Our MitoSENS lab chief, Dr. Matthew ("Oki") O'Connor, did present a then up-to-date presentation on progress in mitoSENS at SENS6, and also responded to questions from supporters over at Longecity and did a podcast interview with Longecity officer "Mind".

Hope that's useful. If anyone has more specific additional questions, I'd suggest adding on to the Longecity Q&A (especially if you donated to the Longecity research fundraiser :) ).

Posted by: Michael at June 26th, 2014 10:56 AM

Thanks for the reply Michael. I feel like I am discussing Manchester United's prospects on a website then Alex Ferguson weights in...

Posted by: Jim at June 26th, 2014 6:58 PM

Many thanks Jim for your comments - and your donation! Yes, we got the cell counter! The work on LHON that Reason mentions was arguably the first really robust demonstration of mitochondrial protein import, and it was only a year later than my estimate :-) - but as Michael says, there is still a long way to go to get it working comprehensively, and the main reason for that is indeed because funding has been so far from adequate. However, just in the past couple of months our own work on this (headed by Dr. O'Connor) has seen a burst of progress, including advances that no one else had previously reported, so you'll be seeing much more on this pretty soon (though it's not for me to jump the gun and talk about details until the researchers are ready).

Posted by: Aubrey de Grey at June 27th, 2014 9:50 AM

Not to disagree to vociferously with our Chief Science Officer ;) , but I think that "soon" should be qualified. Even if all of the technical issues were resolved tomorrow leading to smashing success next week, the normal care and attention of preparing a scientific manuscript and the unbearable bureaucracy of scientific publication would likely mean that nothing would be seen beyond a hint that something good had happened for 6 months, unless one were attending a scientific conference with its convention of confidentiality.

Posted by: Michael at June 27th, 2014 10:08 AM

Any idea what the effect of moving the mito genes to the nucleus would have on other, less well known, products of mtDNA such as humanin?

Posted by: Dan at June 30th, 2014 2:37 PM

Dan: several things. First, it's not yet clear whether humanin really does serve a physiological function or is just a byproduct of mt RNA's unusual processing (the fact that adding it to cells has beneficial effects in disease models doesn't prove anything one way or another, since adding a range of drugs benefits these cells too).

Second, if indeed it's a genuinely physiologically functional peptide, the sequence encoding it it may be much less likely to be mutated with age than the proteins of the electron transport chain, because it's located by the minor arc of the mtDNA loop, which is rarely affected by deletions in aging.

Third, if it is physiologic and sufficiently susceptible to mutations as to be problematic for the cell in which it occurs, that isn't necessarily all that big a deal. Remember, only a very small number of cells accumulate large deletions of mtDNA with age; the reason why we worry so much about them is because they seem likely to spread metabolically harmful effects across the body, because of the abnormal metabolic state that such cells must adopt when deletions knock out their ability to perform oxidative phosphorylation. Even if we find that a small number of cells do lose the ability to synthesize humanin with age, and even if those cells in isolation might be harmed by its absence, still the dysfunction or death of so small a number of cells is not going to cause the dysfunction of an entire tissue or the body generally the way that a rising burden of OXPHOS-disabled cells probably does. And cells hypothetically rendered dead or dysfunctional for lack of humanin could be periodically replaced with cell therapy.

And finally: if there turns out to be some really compelling reason why it's important to prevent cells from losing humanin expression with age, we do have the option of developing an allotopic backup in case of shutdown of translation by large deletions.

Posted by: Michael at June 30th, 2014 8:54 PM

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