Reprinted with the kind permission of Cort Johnson and HealthRising.
“It’s the cellular equivalent of chronic fatigue.” Paul Fisher
One of the really nice things about the Emerge conference was the nice, big chunks of time they gave to some of their presenters. Paul Fisher, an Australian specialist in neurodegenerative diseases and the mitochondria, used that time to his advantage: he gave one of the most interesting chronic fatigue syndrome (ME/CFS) presentations I’ve seen in years.
Fisher said he’s been knocking on ME/CFS’s door, trying to get in for over ten years. Only recently did he get his opportunity – and he’s made the best of it. My guess is that more “Paul Fishers” are out there just waiting for their opportunity to get their Seahorse machines, their brain scans, their flow cytometers and mass spectrometers, etc. to work on this fascinating and difficult disease.
Fisher, well-published and funded for work into Parkinson’s disease by the Michael J. Fox Foundation, is definitely the kind of researcher we want to attract. His interest is encouraging. Researchers of his stature don’t take on diseases without good reason, without those diseases piquing their curiosity. Why would you use your precious time on something you don’t think will work out?
A Little Crisis – A Little Rant
Which brings up my underground legitimacy crisis – the fact that I’m still somewhat shocked when someone like Fisher is interested in studying this disease. I’m like: “Really? Us? Are you sure? Did you mistake us for someone else? If I pinch myself will you go away?”
I’m acting like someone who’s been beaten on a regular basis for twenty years. No self esteem left. It’s pitiful. Decades of poor funding and neglect have left their marks.
I declare that that’s over for me, though. Instead, I take the stand that this disease is an immense opportunity that’s waiting to happen for anyone smart enough and bold enough to take it on.
ME/CFS research is packed full of interesting findings, but that’s not where I draw this disease’s legitimacy from. I draw it from its ability to take my wonderfully athletic body and reduce it to this pitiful shadow of itself. I take it from its ability to push my incredibly smart and resourceful partner out of the workforce for the last 15 years! I take it from all our incredible, incredible stories.
This disease holds the keys to so much. It must! How could something that brings healthy, vital people in the prime of their lives down not hold within itself an immense opportunity?
We’re not a burden. We don’t need anyone’s pity. No! We are an immense opportunity. We’re offering a window into some of the fundamental processes that govern health. We offer researchers the opportunity to really break new ground – to be leaders. Don’t pass it up! These chances don’t come every day.
To those researchers who pass on us – too bad for you! The truth is we probably don’t want you, anyway. Small thinkers, people striving to fit in – people whose foremost goal is to make a career out of research – please stay away! You’ll just use up our precious resources.
Don’t forget who we are. We’re masters at slipping through the cracks! We’re paragons of paradox. We excel in breaking the mold. If that kind of thing doesn’t excite you, you should go elsewhere.
If you are excited, though, by a disease that requires you to stretch your mind, think differently, connect dots that haven’t been connected before and entertain possibilities that haven’t been entertained before – by all means, please apply. You’ll find a community that will support you like no other.
Fishing for Mitochondrial Problems in ME/CFS (And Finding Them)
Note that Fisher is studying the mitochondria outside of the plasma – where some sort of inhibiting factor may reside. If anything in the blood is interfering with mitochondrial production – as Ron Davis and Oystein Fluge have suggested – Fisher’s tests will not pick it up.
On the other hand, there’s a purity to Fisher’s examination of just the mitochondria. No outside influences allowed; that is, unless the mitochondria came into the experiment already damaged by something in the blood – a possibility.
Fisher immortalized ME/CFS lymphocytes so that he could grow them in vitro (in the lab) and test (i.e. torture) them again and again and again. Fisher put ME/CFS mitochondria through the wringer so many times that one almost ends up feeling sorry for them.
The first thing Fisher wanted to get across is that mitochondrial respiration – the act of producing energy – is VERY complex, involving numerous pathways. The act of measuring the mitochondria’s ability to produce energy, however, is actually quite simple. Since they run on oxygen, you simply need to measure the amount of oxygen they consume in order to determine how much energy they’re producing.
You might think that producing energy would be – should be – must be – a clean process. After all, you are dealing with something that could potentially go “boom”. (Look at Chernobyl.) Energy production, however, is inherently volatile, and like any volatile situation, it’s a bit hard to control.
Some of the electrons involved in the energy production process inevitably leak out of the mitochondria, create reactive oxygen species (ROS), and attempt to tear apart any cell they come into contact with. Energy production is essential, but it’s also the biggest producer of free radicals in our bodies.
Fisher was merciless in his efforts to torture, er test, the mitochondria of the immortalized ME/CFS white blood cells in every which way he could. He inhibited every complex (there are five of them) of the Krebs cycle possible; plus, he assessed how well glycolysis – the process of turning glucose into ATP for the mitochondria – was doing.
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As expected, the mitochondrial mass and the number of mitochondrial genome copies was normal: there was no drop in number or mass of mitochondria in ME/CFS. The surprise came in the glycolysis findings – all normal! Glycolytic rate, glycolytic production, capacity, reserve – all perfectly fine.
That, of course, bucks with Neil McGregor’s recent findings and hypothesis that ME/CFS begins and ends with glycolytic issues. I asked McGregor what was up with this? He believes that Fisher’s inability to use plasma (the Seahorse will not accept it) could account for the different results.
Fisher also found that the rate of ATP synthesis and production and ROS production were within normal limits. The cells appeared to be producing normal amounts of ATP and were not being slammed, as has been suspected, by reactive oxygen species or free radicals.
Major Mitochondrial Complex Hit Hard
However, then the results began playing a familiar tune.
ATP production was normal, but once Fisher began stressing the energy production systems strange things began happening. In particular, Fisher found that Complex V – the last of the five complexes and arguably the most important – responded poorly. Complex V transfers protons through the inner mitochondrial membranes to the mitochondria. That process, which involves ATP synthase, releases the energy used to drive ATP synthesis.
The complex looked fine at baseline, but when put under stress it pooped out – suffering a 25% drop in production compared to healthy mitochondria.
That drop caused the other four complexes to spring into action. ME/CFS patients’ mitochondrial membranes became packed with extra copies of the mitochondrial complexes. Complex I – the main electron gradient producing complex that provides electrons to Complex V – went gangbusters in an attempt to provide Complex V with as many electrons as possible. ME/CFS patients’ proton pumps worked overtime to pump protons out of the mitochondria en masse in order to increase the membrane potential and get more electrons into the cell. Enzymes that consumed O2 were jacked up as well.
The NIH reports that Complex V Deficiency can produce a wide variety of symptoms including extreme fatigue, low muscle tone (hypotonia), increased levels of lactic acid, rapid breathing, cognitive issues, etc.
The Complex I upregulation detected by the Seahorse was validated when a proteomic analysis demonstrated that a huge increase in Complex I proteins had taken place.
The end result was that the ME/CFS mitochondria were working harder than ever. They were able to get the cells’ ATP production up to normal – at rest – but this was not enough to handle stressful conditions. Fisher cleverly noted that he had uncovered important aspects of mitochondrial function with ME/CFS.
The fact that mitochondrial measures generally correlated significantly with disease severity in ME/CFS (i.e. were worse in the patients with the most severe disease) was encouraging.
While Fisher did not find problems with glycolysis, he did find that the energy stressed ME/CFS patients’ cells had moved from breaking down glucose to breaking down the more ATP-rich fatty acids in order to squeeze out as much energy as possible. That fatty acid switch – which was similar to what McGregor found (but which McGregor extended to proteins) – was demonstrated by an increase in levels of the six enzymes that break down the fatty acids, as well as the proteins that import fatty acids into the cells.
Ten years ago, Fisher’s intuition was correct. ME/CFS patients’ mitochondria are having problems producing energy. Something that’s gone wrong in one mitochondrial complex is throwing off the rest of the complex. The good news is that the problem is not subtle: Fisher appears to be seeing major problems across the mitochondrial pathways.
The bad news is how complex the mitochondria are. Fisher doesn’t think he’s going to find a single cause that responds to a single, simple fix. He also left open the possibility that the Complex V problems could be a consequence of another as yet unknown problem.
Mitochondrial Results Starting to Add Up
We haven’t had a lot of mitochondrial studies, but the results are beginning to add up. Tomas’s 2018 results could have been taken word for word from Fisher’s presentation. Using a Seahorse machine, the U.K. group found that the mitochondria pooped out when put under stress as well. Tate recently reported getting similar results in his New Zealand cohort as well.
“Maximal respiration was determined to be the key parameter in mitochondrial function to differ between CFS and control PBMCs….The lower maximal respiration in CFS PBMCs suggests that when the cells experience physiological stress they are less able to elevate their respiration rate to compensate for the increase in stress and are unable to fulfill cellular energy demands.”
We need more and larger studies, but three studies thousands of miles apart getting similar results using the same machine is pretty darn good. It should be noted that Myhill also found mitochondrial dysfunction in every patient tested.
A 2016 Stanford study, which did not use the Seahorse machine, might seem to be an outlier, but maybe not. It found increased ATP respiration – but from non-mitochondrial sources – and increased mitochondrial membrane area and increased number of cristae in ME/CFS, two findings which might be compensatory mechanisms as well.
Plus, in 2015 an in-silico model of ME/CFS showed how problems with mitochondrial functioning could potentially explain the post-exertional problems and long recovery periods needed. The authors suggested a number of issues, including mitochondrial deletions, Epstein-Barr virus-induced alterations of mitochondrial gene transcription, pro-inflammatory cytokines and increased levels of oxidative stress, that could result in an inability to ramp energy levels up in ME/CFS.
With Solve ME’s Ramsay award and other studies underway that are measuring energy production in immune cells, expect more results soon.
Meanwhile, Fisher is engaged and on the hunt. His next step – which he stated he is taking now – is to manipulate one thing at a time in an attempt to identify the core problem in the mitochondria. His first ME/CFS paper should be published soon.
About the Author: ProHealth is pleased to share information from Cort Johnson. Cort has had myalgic encephalomyelitis /chronic fatigue syndrome for over 30 years. The founder of Phoenix Rising and Health Rising, he has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort’s and other bloggers’ work at Health Rising.