Post by Nadica (She/Her) on Oct 31, 2024 2:20:15 GMT
The Mitochondria in Long COVID Pt. I: Are Core Problems Being Uncovered? - published Oct 24, 2024
by Cort Johnson
(Listen to the gist and the full article at the link!)
The GIST
Recent studies suggest that a hypermetabolic state that damages the mitochondria results in a hypometabolic state in chronic fatigue syndrome (ME/CFS), long COVID, and fibromyalgia (FM). They also suggest that something in the blood, serum, or plasma is damaging the mitochondria in these diseases.
We’re not done with the mitochondria, though – far from it! Now we look at a bevy of recent long-COVID mitochondrial studies suggesting that mitochondrial dysfunction affects more than energy production and which illuminate what may have gone wrong in the mitochondria.
Muscle biopsies of 120 long-COVID patients who had ended up in the ICU found that a year later their muscles had higher levels of immune cells involved in tissue repair and reduced activity of the 2nd and fourth mitochondrial complexes. The authors concluded that there was “aberrant repair and altered mitochondrial activity in skeletal muscle.”
They couldn’t explain how a respiratory illness affected the muscles but a subsequent study did. A hamster model found that the coronavirus suppressed the genes associated with the muscle fibers, protein production, both sides of the mitochondrial energy production process (Krebs cycle and electron transport chain), and fat breakdown.
As it was doing that, it unleashed a barrage of inflammatory factors (IFN-α, IFN-γ, and TNF-α) which triggered a shift from relying mostly on aerobic energy production to the less effective process of anaerobic energy production (glycolysis).
The authors concluded that using treatments “that can boost mitochondrial functions, enhance protein synthesis, and inhibit protein degradation” may be useful for treating muscle fatigue in long COVID.
Next, a muscle study assessing “maximal fatty acid oxidation (MFO)” (i.e. energy produced by the breakdown of fats during exercise) found significantly reduced levels of fatty acid oxidation in long COVID and a “premature shift” from relying on fats to carbohydrates to powering their cells.
This was important because the body prefers to burn fats during exercise and because fats play key roles in both parts of the mitochondrial energy production process. The finding wasn’t so surprising, though. Problems with carnitine – which transports fatty acids into the mitochondria – have popped up in both long COVID and ME/CFS – suggesting that the fatty acids that power the mitochondria during exercise may not be getting into them.
A review paper asserted that increased free radical production (reactive oxygen species (ROS)) by the mitochondria both pushes the cell into a state of anaerobic energy production but also pushes the immune system to activate the inflammatory or innate immune response and away from the adaptive immune response that targets pathogens. This benefits the viruses by providing the substrates they need to grow and allows them to escape from the immune system.
Several researchers, including Avindra Nath, believe that the immune system tries to compensate for the impaired adaptive immune defense by ramping up the innate immune response. Nath believes this shift plays a central role in ME/CFS.
They proposed that treatments to boost mitochondrial functioning and reduce the production of mitochondrial reactive oxygen species (ROS) (free radicals) will be beneficial.
Lastly, a review asserted that the predominant view of the mitochondria as the main energy producers of the cell is misguided and incomplete. Harkening back to Naviaux’s characterization of the mitochondria as the primary threat-sensing part of the cell, the authors believe the mitochondria regulate the “physiological processes at the level of the cell, organ and organism”; i.e. the mitochondrial problems affect much more than low energy levels and fatigue.
A blog on red light/infrared light therapy – which could both boost mitochondrial health and antioxidant defenses – is coming up.
Health Rising recently reported on studies suggesting that a hypermetabolic state that damages the mitochondria results in a hypometabolic state in chronic fatigue syndrome (ME/CFS), long COVID, and fibromyalgia (FM). We also reported on studies suggesting that something in the blood, serum, or plasma is damaging the mitochondria.
We’re not done with the mitochondria yet, though – far from it! Now, we turn to a recent spate of mitochondrial studies in long COVID, ME/CFS, and FM.
First, long COVID. While there’s always been some interest in the mitochondria in long COVID, it’s picked up dramatically in the past year or so and it seems like we’re seeing movement in this issue.
Whacked Skeletal Muscles, Oh My
The first study examined 120 long-COVID patients who had ended up in the ICU – not our typical group. A follow-up indicated that almost all of them suffered from post-viral fatigue and did poorly on a six-minute walk test (@45% of normal).
Muscle biopsies done almost a year later found a higher abundance of M2-like macrophages (which are involved in tissue repair) and satellite cells and lower activity of the 2nd and fourth mitochondrial complexes. The authors concluded that “aberrant repair and altered mitochondrial activity in skeletal muscle associates with long-term impairments in patients surviving an ICU admission for COVID-19.”
I was unable to get this study, but the obvious questions here are: how does a respiratory infection like COVID-19 end up damaging the skeletal muscles, and why are immune factors involved in tissue repair still apparently trying to repair the muscle fibers almost a year after the infection?
A recent US study, “Respiratory SARS-CoV-2 Infection Causes Skeletal Muscle Atrophy and Long-Lasting Energy Metabolism Suppression“, had an answer for this. This study used a hamster model to suss out what was happening in the skeletal muscles after a coronavirus infection.
The fact that the virus did not invade the muscles but still produced atrophy of the muscle fibers brings up the question of how it managed to do this.
It appears that the virus initiated two processes that allowed it to do this. For one, it suppressed the genes associated with the muscle fibers, the ribosomes (which produce proteins), with mitochondrial metabolism (energy production) as well as genes involved in fatty acid B-oxidation (a key source of energy for the mitochondria), the TCA or citric acid or Krebs cycle and all five of the complexes found in the electron transport chain. The gist is the virus turned off genes involved in energy production.
Note that there are two parts to aerobic energy production. First, the TCA, or Krebs cycle, produces electron carriers (NADH, FADH) and then provides them to the OXPHOS complex (electron transport chain). OXPHOS then produces the end result – ATP. Somehow, the virus downregulated genes associated with both these complexes!
As it was doing that, it unleashed a barrage of inflammatory factors (IFN-α, IFN-γ, and TNF-α) which triggered a shift from relying mostly on aerobic energy production to anaerobic energy production (glycolysis). Since it also downregulated genes associated with muscle fibers, it’s no wonder the hamsters’ muscles were in such poor shape.
The authors concluded – in what looks like the beginning of a nice treatment regimen – that targeting TNF-α during acute SARS-CoV-2 infection to tone down the inflammation that triggers the energy “shift”, and then using drugs “that can boost mitochondrial functions, enhance protein synthesis, and inhibit protein degradation”, may be useful for treating the muscle fatigue associated with long COVID.
The Muscles Pt. II
A muscle study, “Maximal oxidative capacity during exercise is associated with muscle power output in patients with long coronavirus disease 2019 (COVID-19) syndrome. A moderation analysis”, assessed “maximal fatty acid oxidation (MFO)”; i.e. energy produced by the breakdown of fats during exercise.
In fatty acid oxidation, fatty acids are transported into the mitochondria via carnitine where they are broken up and then enter both the TCA cycle (where the electron carriers are created) and the electron transport chain where ATP is finally produced; i.e., fats play key roles in both parts of the mitochondrial energy production process.
Fat breakdown is an important aspect of energy production during exercise because during “moderate exercise” (45-65% of VO2 max) the body mostly uses fats as its primary fuel source. This study found significantly reduced levels of fatty acid oxidation in the long-COVID patients and a “premature shift” from relying on fats to carbohydrates to power our cells.
This wasn’t so surprising. Problems with carnitine – which transports fatty acids into the mitochondria – have popped up in both long COVID and ME/CFS – suggesting that the fatty acids that power the mitochondria during exercise may not be getting into them. Rob Wust, in fact, recently found that muscle atrophy was associated with reduced fatty acid oxidation (energy production) in long COVID.
Importantly, the authors noted that in cases like this, dysfunctional mitochondria consume excess oxygen but produce less ATP (energy), resulting in an increased production of the same reactive oxygen species (ROS or free radicals) featured in the studies above.
A Core Breakdown Identified?
Meanwhile, in “SARS-CoV-2 mitochondrial metabolic and epigenomic reprogramming in COVID-19“, the Center for Mitochondrial and Epigenomic Medicine reported that an exhaustive search” revealed that the coronavirus not only “strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) (aerobic energy production)” but also increases mitochondrial reactive oxygen species (mROS); i.e. free radical production.
This paper, like the review below, proposed that mitochondrial breakdown does more than impact energy production: it also radically alters immune system functioning.
Note that authors believe that increased free radical production (reactive oxygen species (ROS)) pushes the cell into anaerobic energy production. A similar idea was proposed by Stanford researcher Vishnu Shankar, whose ME/CFS T-cell study found that higher ROS levels resulted in increased T-cell proliferation – not necessarily a good thing. Shankar believes that all that T-cell proliferation puts a greater strain on ME/CFS patients’ probably-already-damaged mitochondria – resulting in the production of even more reactive oxygen species (ROS) – and more damage to the mitochondria.
The immune shift engineered by viruses (through the production of “DAMPS”) is an intentional one to distract the immune system and get cells to provide the substrates the viruses need to grow. High levels of reactive oxygen species ROS (free radicals) levels release mitochondrial DNA (mtDNA), which then triggers the activation of the innate, or early, immune side of the immune system.
That’s not a good thing, as the innate immune system is responsible for much of the inflammation produced by the immune system but is not designed to combat pathogens. The part of the immune system that is – the adaptive immune side – is sidelined, resulted in impaired pathogen defenses and increased inflammation.
Several researchers including Avindra Nath believe that the immune system tries to compensate for the impaired adaptive immune defense by ramping up the innate immune response. Nath believes this impaired adaptive immune response is the key driver in ME/CFS.
The authors believe this process triggers epigenetic alterations that suppress aerobic energy production long after the virus has been vanquished. They noted that all the common symptoms of long COVID (and thus of ME/CFS as well) (post-exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, heart palpitations, hormonal alterations, thirst (blood sugar alterations), chronic cough (inflammation), chest pain, and abnormal movements (cerebellar effects)) have been found in mitochondrial diseases.
Given that, they proposed that the most effective therapies will include treatments to boost mitochondrial functioning and reduce the production of mitochondrial reactive oxygen species (ROS) (free radicals). Shankar found antioxidant treatments like NAC, metformin, and liprostatin-1 reduced the problematic T-cell proliferation he found in culture.
The Core Breakdown – Take II
Three other review papers over the past year have explicated how a coronavirus infection may be impacting energy metabolism and the mitochondria in long COVID. One asserted that the predominant view of the mitochondria as the main energy producers of the cell is misguided and incomplete.
Harkening back to Naviaux’s characterization of the mitochondria as the primary threat-sensing part of the cell, the authors think of the mitochondria as central cellular processors that integrate signals from inside and outside the cell and then send out signals that regulate “physiological processes at the level of the cell, organ and organism”. In their conception, the leaky electron transport chains in the mitochondria of long-COVID patients even have something to do with their leaky guts; i.e. the mitochondrial problems affect much more than low energy levels and fatigue.
Conclusion
Poorly functioning mitochondria may be doing a lot more than simply impacting energy levels: they could be causing an immune shift that impairs our ability to fight off pathogens and pushes our immune systems more toward allergic (and mast cell) responses. Plus, as Naviaux pointed out some time ago, they may have a broad impact on physiological processes across the body. Indeed, Dr. Martin Lerner was fond of saying that increased energy levels took care of virtually all his ME/CFS patients’ symptoms.
We may also be getting closer to understanding why the mitochondria have gone wrong. Problems with fatty oxidation, for instance, may be preventing fatty acids from getting to the mitochondria. Infections may be shifting the mitochondria into a hypermetabolic state which exhausts them. Why that would happen in ME/CFS and long COVID we don’t know, but the production of increased reactive oxygen species (free radicals) could be pushing our cells to rely on anaerobic energy production. Whether that is a secondary phenomenon caused by mitochondrial breakdown, or whether a breakdown in our antioxidant defenses is to blame, or both, is unclear.
Red light / infrared therapy is an intriguing possibility since it could boost both mitochondrial and antioxidant production. While no one expects it to be a fix for these diseases, it could help. A blog is coming up on that.
by Cort Johnson
(Listen to the gist and the full article at the link!)
The GIST
Recent studies suggest that a hypermetabolic state that damages the mitochondria results in a hypometabolic state in chronic fatigue syndrome (ME/CFS), long COVID, and fibromyalgia (FM). They also suggest that something in the blood, serum, or plasma is damaging the mitochondria in these diseases.
We’re not done with the mitochondria, though – far from it! Now we look at a bevy of recent long-COVID mitochondrial studies suggesting that mitochondrial dysfunction affects more than energy production and which illuminate what may have gone wrong in the mitochondria.
Muscle biopsies of 120 long-COVID patients who had ended up in the ICU found that a year later their muscles had higher levels of immune cells involved in tissue repair and reduced activity of the 2nd and fourth mitochondrial complexes. The authors concluded that there was “aberrant repair and altered mitochondrial activity in skeletal muscle.”
They couldn’t explain how a respiratory illness affected the muscles but a subsequent study did. A hamster model found that the coronavirus suppressed the genes associated with the muscle fibers, protein production, both sides of the mitochondrial energy production process (Krebs cycle and electron transport chain), and fat breakdown.
As it was doing that, it unleashed a barrage of inflammatory factors (IFN-α, IFN-γ, and TNF-α) which triggered a shift from relying mostly on aerobic energy production to the less effective process of anaerobic energy production (glycolysis).
The authors concluded that using treatments “that can boost mitochondrial functions, enhance protein synthesis, and inhibit protein degradation” may be useful for treating muscle fatigue in long COVID.
Next, a muscle study assessing “maximal fatty acid oxidation (MFO)” (i.e. energy produced by the breakdown of fats during exercise) found significantly reduced levels of fatty acid oxidation in long COVID and a “premature shift” from relying on fats to carbohydrates to powering their cells.
This was important because the body prefers to burn fats during exercise and because fats play key roles in both parts of the mitochondrial energy production process. The finding wasn’t so surprising, though. Problems with carnitine – which transports fatty acids into the mitochondria – have popped up in both long COVID and ME/CFS – suggesting that the fatty acids that power the mitochondria during exercise may not be getting into them.
A review paper asserted that increased free radical production (reactive oxygen species (ROS)) by the mitochondria both pushes the cell into a state of anaerobic energy production but also pushes the immune system to activate the inflammatory or innate immune response and away from the adaptive immune response that targets pathogens. This benefits the viruses by providing the substrates they need to grow and allows them to escape from the immune system.
Several researchers, including Avindra Nath, believe that the immune system tries to compensate for the impaired adaptive immune defense by ramping up the innate immune response. Nath believes this shift plays a central role in ME/CFS.
They proposed that treatments to boost mitochondrial functioning and reduce the production of mitochondrial reactive oxygen species (ROS) (free radicals) will be beneficial.
Lastly, a review asserted that the predominant view of the mitochondria as the main energy producers of the cell is misguided and incomplete. Harkening back to Naviaux’s characterization of the mitochondria as the primary threat-sensing part of the cell, the authors believe the mitochondria regulate the “physiological processes at the level of the cell, organ and organism”; i.e. the mitochondrial problems affect much more than low energy levels and fatigue.
A blog on red light/infrared light therapy – which could both boost mitochondrial health and antioxidant defenses – is coming up.
Health Rising recently reported on studies suggesting that a hypermetabolic state that damages the mitochondria results in a hypometabolic state in chronic fatigue syndrome (ME/CFS), long COVID, and fibromyalgia (FM). We also reported on studies suggesting that something in the blood, serum, or plasma is damaging the mitochondria.
We’re not done with the mitochondria yet, though – far from it! Now, we turn to a recent spate of mitochondrial studies in long COVID, ME/CFS, and FM.
First, long COVID. While there’s always been some interest in the mitochondria in long COVID, it’s picked up dramatically in the past year or so and it seems like we’re seeing movement in this issue.
Whacked Skeletal Muscles, Oh My
The first study examined 120 long-COVID patients who had ended up in the ICU – not our typical group. A follow-up indicated that almost all of them suffered from post-viral fatigue and did poorly on a six-minute walk test (@45% of normal).
Muscle biopsies done almost a year later found a higher abundance of M2-like macrophages (which are involved in tissue repair) and satellite cells and lower activity of the 2nd and fourth mitochondrial complexes. The authors concluded that “aberrant repair and altered mitochondrial activity in skeletal muscle associates with long-term impairments in patients surviving an ICU admission for COVID-19.”
I was unable to get this study, but the obvious questions here are: how does a respiratory infection like COVID-19 end up damaging the skeletal muscles, and why are immune factors involved in tissue repair still apparently trying to repair the muscle fibers almost a year after the infection?
A recent US study, “Respiratory SARS-CoV-2 Infection Causes Skeletal Muscle Atrophy and Long-Lasting Energy Metabolism Suppression“, had an answer for this. This study used a hamster model to suss out what was happening in the skeletal muscles after a coronavirus infection.
The fact that the virus did not invade the muscles but still produced atrophy of the muscle fibers brings up the question of how it managed to do this.
It appears that the virus initiated two processes that allowed it to do this. For one, it suppressed the genes associated with the muscle fibers, the ribosomes (which produce proteins), with mitochondrial metabolism (energy production) as well as genes involved in fatty acid B-oxidation (a key source of energy for the mitochondria), the TCA or citric acid or Krebs cycle and all five of the complexes found in the electron transport chain. The gist is the virus turned off genes involved in energy production.
Note that there are two parts to aerobic energy production. First, the TCA, or Krebs cycle, produces electron carriers (NADH, FADH) and then provides them to the OXPHOS complex (electron transport chain). OXPHOS then produces the end result – ATP. Somehow, the virus downregulated genes associated with both these complexes!
As it was doing that, it unleashed a barrage of inflammatory factors (IFN-α, IFN-γ, and TNF-α) which triggered a shift from relying mostly on aerobic energy production to anaerobic energy production (glycolysis). Since it also downregulated genes associated with muscle fibers, it’s no wonder the hamsters’ muscles were in such poor shape.
The authors concluded – in what looks like the beginning of a nice treatment regimen – that targeting TNF-α during acute SARS-CoV-2 infection to tone down the inflammation that triggers the energy “shift”, and then using drugs “that can boost mitochondrial functions, enhance protein synthesis, and inhibit protein degradation”, may be useful for treating the muscle fatigue associated with long COVID.
The Muscles Pt. II
A muscle study, “Maximal oxidative capacity during exercise is associated with muscle power output in patients with long coronavirus disease 2019 (COVID-19) syndrome. A moderation analysis”, assessed “maximal fatty acid oxidation (MFO)”; i.e. energy produced by the breakdown of fats during exercise.
In fatty acid oxidation, fatty acids are transported into the mitochondria via carnitine where they are broken up and then enter both the TCA cycle (where the electron carriers are created) and the electron transport chain where ATP is finally produced; i.e., fats play key roles in both parts of the mitochondrial energy production process.
Fat breakdown is an important aspect of energy production during exercise because during “moderate exercise” (45-65% of VO2 max) the body mostly uses fats as its primary fuel source. This study found significantly reduced levels of fatty acid oxidation in the long-COVID patients and a “premature shift” from relying on fats to carbohydrates to power our cells.
This wasn’t so surprising. Problems with carnitine – which transports fatty acids into the mitochondria – have popped up in both long COVID and ME/CFS – suggesting that the fatty acids that power the mitochondria during exercise may not be getting into them. Rob Wust, in fact, recently found that muscle atrophy was associated with reduced fatty acid oxidation (energy production) in long COVID.
Importantly, the authors noted that in cases like this, dysfunctional mitochondria consume excess oxygen but produce less ATP (energy), resulting in an increased production of the same reactive oxygen species (ROS or free radicals) featured in the studies above.
A Core Breakdown Identified?
Meanwhile, in “SARS-CoV-2 mitochondrial metabolic and epigenomic reprogramming in COVID-19“, the Center for Mitochondrial and Epigenomic Medicine reported that an exhaustive search” revealed that the coronavirus not only “strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) (aerobic energy production)” but also increases mitochondrial reactive oxygen species (mROS); i.e. free radical production.
This paper, like the review below, proposed that mitochondrial breakdown does more than impact energy production: it also radically alters immune system functioning.
Note that authors believe that increased free radical production (reactive oxygen species (ROS)) pushes the cell into anaerobic energy production. A similar idea was proposed by Stanford researcher Vishnu Shankar, whose ME/CFS T-cell study found that higher ROS levels resulted in increased T-cell proliferation – not necessarily a good thing. Shankar believes that all that T-cell proliferation puts a greater strain on ME/CFS patients’ probably-already-damaged mitochondria – resulting in the production of even more reactive oxygen species (ROS) – and more damage to the mitochondria.
The immune shift engineered by viruses (through the production of “DAMPS”) is an intentional one to distract the immune system and get cells to provide the substrates the viruses need to grow. High levels of reactive oxygen species ROS (free radicals) levels release mitochondrial DNA (mtDNA), which then triggers the activation of the innate, or early, immune side of the immune system.
That’s not a good thing, as the innate immune system is responsible for much of the inflammation produced by the immune system but is not designed to combat pathogens. The part of the immune system that is – the adaptive immune side – is sidelined, resulted in impaired pathogen defenses and increased inflammation.
Several researchers including Avindra Nath believe that the immune system tries to compensate for the impaired adaptive immune defense by ramping up the innate immune response. Nath believes this impaired adaptive immune response is the key driver in ME/CFS.
The authors believe this process triggers epigenetic alterations that suppress aerobic energy production long after the virus has been vanquished. They noted that all the common symptoms of long COVID (and thus of ME/CFS as well) (post-exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, heart palpitations, hormonal alterations, thirst (blood sugar alterations), chronic cough (inflammation), chest pain, and abnormal movements (cerebellar effects)) have been found in mitochondrial diseases.
Given that, they proposed that the most effective therapies will include treatments to boost mitochondrial functioning and reduce the production of mitochondrial reactive oxygen species (ROS) (free radicals). Shankar found antioxidant treatments like NAC, metformin, and liprostatin-1 reduced the problematic T-cell proliferation he found in culture.
The Core Breakdown – Take II
Three other review papers over the past year have explicated how a coronavirus infection may be impacting energy metabolism and the mitochondria in long COVID. One asserted that the predominant view of the mitochondria as the main energy producers of the cell is misguided and incomplete.
Harkening back to Naviaux’s characterization of the mitochondria as the primary threat-sensing part of the cell, the authors think of the mitochondria as central cellular processors that integrate signals from inside and outside the cell and then send out signals that regulate “physiological processes at the level of the cell, organ and organism”. In their conception, the leaky electron transport chains in the mitochondria of long-COVID patients even have something to do with their leaky guts; i.e. the mitochondrial problems affect much more than low energy levels and fatigue.
Conclusion
Poorly functioning mitochondria may be doing a lot more than simply impacting energy levels: they could be causing an immune shift that impairs our ability to fight off pathogens and pushes our immune systems more toward allergic (and mast cell) responses. Plus, as Naviaux pointed out some time ago, they may have a broad impact on physiological processes across the body. Indeed, Dr. Martin Lerner was fond of saying that increased energy levels took care of virtually all his ME/CFS patients’ symptoms.
We may also be getting closer to understanding why the mitochondria have gone wrong. Problems with fatty oxidation, for instance, may be preventing fatty acids from getting to the mitochondria. Infections may be shifting the mitochondria into a hypermetabolic state which exhausts them. Why that would happen in ME/CFS and long COVID we don’t know, but the production of increased reactive oxygen species (free radicals) could be pushing our cells to rely on anaerobic energy production. Whether that is a secondary phenomenon caused by mitochondrial breakdown, or whether a breakdown in our antioxidant defenses is to blame, or both, is unclear.
Red light / infrared therapy is an intriguing possibility since it could boost both mitochondrial and antioxidant production. While no one expects it to be a fix for these diseases, it could help. A blog is coming up on that.