Long Covid: Mitochondria, the Big Miss, and Hope

This week there was news on Long Covid in two very different directions—emergence of strong data to support mitochondrial dysfunction as the basis for the condition in some people—and learning how the $1.15 billion allocation to the NIH RECOVER initiative has largely been wasted. In this edition of Ground Truths, I’ll review this news and offer a plan to get clinical trials testing treatments into high gear.

Sick Mitochondria as a Root Cause

When we published our review of Long Covid earlier this year, we highlighted the key established underpinnings as shown in the Figure below. As you’ll note, mitochondria was not one of them. There was a body of data emerging to support the role of mitochondria, as we asserted: ”Long COVID research has found mitochondrial dysfunction including loss of mitochondrial membrane potential and possible dysfunctional mitochondrial metabolism, altered fatty acid metabolism…” and that this had also been seen in myalgic encephalomyelitis (ME/CFS).

A new paper In Science Translational Medicine by leaders in mitochondria biology has advanced the case for direct interactions between SARS-CoV-2 and critical mitochondrial proteins for the potential basis of Long Covid—at least in some people.

This was a systematic study in 2 different experimental models (hamsters and mice) and in people, both via 700 nasopharyngeal samples in patients, and in-depth assessment from 35 autopsy specimens. The Figure above summarizes the findings, and at the same time, portrays how ultra-complex this story is to convey.

My first thoughts about trying to explain the multiple pathways that are occurring in the mitochondria (as shown below) was “Oh no,” not the Krebs cycle again and all these other processes. Let’s not forget the main function of mitochondria is energy production via OXPHOS—oxidative phosphorylation—generating ATP, which is why mitochondria are the powerhouse of cells.

Here’s a more easily understandable, simplified summary of major mitochondrial functions.

So let’s review the new paper’s finding with respect to this principal mitochondrial function of energy production. It turns out the virus binds directly to essential mitochondrial proteins, suppressing mitochondrial gene expression (both nuclear-encoded and mitochondria-encoded), inducing mitochondrial energy production dysfunction and activation of the immune response (innate immunity, spelled wrong, top right, in their Figure below).

A more precise graphic to show how the virus induces inflammatory cytokines and activates the innate immunity [Type 1 interferon (IFN)] is shown here

Notably, the virus’s suppression of mitochondrial genes inhibited or inactivated the entire OXPHOS complex, forces an alternative pathway to energy production—essentially hijacking the cells to make more virus.

The autopsy samples provided evidence that this disruption of mitochondrial genes and function was occurring in many organs throughout the body, especially the heart, but also the liver, kidneys, and lymph nodes. Even after clearance of the virus, there was evidence of chronic OXPHOS inhibition. The authors point out: “The irreversible inhibition of visceral mitochondrial transcription could also contribute to the multisystem symptoms of Long Covid.”

Which brings us to potential therapies that would restore intact mitochondrial function, especially those that can be repurposed. There’s a long list of candidates, but the authors specifically mention the mTOR inhibitor rapamycin, which has been studied for improving mitochondrial function as seen below. Another drug that has already been shown to help prevent Long Covid, metformin, working in this same pathway, without the immune suppression of rapamycin, and very low cost, would also deserve attention for clinical trials.

The Big Miss

More than 3 years in, with tens of millions of people suffering Long Covid, this is the comprehensive list of validated treatments, as established via rigorous randomized trials.

That’s right. Zero. Nada. Which is incredible.

STAT news exposed what has happened with the $1.15 billion allocated to the NIH RECOVER Long Covid initiative, announced in December 2020. The funds are now almost totally accounted for and there very likely won’t be any new support via Congress to NIH.

The RECOVER investigators prioritized observational research, in this case re-doing what was already known, with respect to cataloging the symptoms of people with Long Covid. And studying the underlying biology, such as the immune response, to get clues as to what might be suitable treatments to test. We already knew quite a bit about the underlying biology (a cluster of data from 1 year ago I previously reviewed and this excellent review of the immunology of Long Covid by Danny Altman and colleagues), not to have to divert so much of these precious funds for repeating that work, too. Only 15% of all the funds were used for clinical trials, one of which is for Paxlovid (already with a negative small randomized trial at Stanford). We knew things were really wacko at RECOVER when the first clinical trial they were going to start was with exercise! Currently at clinicaltrials.gov, where all clinical trials are supposed to be registered, there are only 12 trials of drug therapies for Long Covid ongoing. That, beyond RECOVER’s big missed opportunity, is extraordinary, given the enormous, now longstanding, rampant public health burden—which is still growing each and every day from new or repeat infections.

When I spoke to leadership at the NIH, I was told that a significant part of the problem of getting clinical trials off the ground was their being held up by the FDA. But when I discussed this with FDA leadership, it was categorically and vehemently denied. A blame game isn’t going to get this mess on track. We desperately need clinical trials testing interventions, whether they be with solid candidate drugs or devices, to get into high velocity, as my colleague Julia Moore Vogel pointed out in a recent op-ed. Or its devastating chronic impact, as so well articulated by Madeline Miller in her op-ed last week.

Hope: The Road Ahead

We can do this, but it’s not going to get done by traditional means of having people with Long Covid show up to clinics and go through extensive baseline evaluations and endless surveys about their symptoms (the RECOVER approach). So many of the folks affected with Long Covid can barely get out of bed, no less trek to a clinic appointment. As was done with the successful metformin randomized trial shown to prevent Long Covid (I reviewed here and here), participants were recruited digitally and sent the medication (be it active or placebo) via the mail. This is the concept of the direct-to-participant digitized clinical trial (Figure below), at scale, through smartphone apps and websites, that my colleagues (especially Steven Steinhubl) and I introduced several years ago.

This enables a high-velocity approach to respond to the urgent need. With so many millions of people affected, it should not be difficult or costly to rapidly accrue tens of thousands, and well over one hundred thousand, participants. It is well suited for repurposed drugs or devices, and would not work as easily for investigational drugs (although possible in coordination with hub research centers). There is no shortage of very reasonable repurposed candidate drugs to test as reviewed here, here and in our review. Looking at all the many lists, there’s a notable absence (with rare exception) for those focused on restoration of mitochondrial function, particularly with drugs such as rapamycin—which offers a twofer for suppressing the immune response—and metformin. That’s why this week’s paper pinpointing mitochondrial dysfunction may provide a ray of hope. Altogether, the number of promising candidate interventions is remarkable. Since Long Covid is quite heterogeneous, with different mechanistic underpinnings in different people, we must anticipate that none of the drugs tested in the future will have a eureka effect across the board. But it’s well past time—like 3 years overdue—that we go after this with absolute maximum force and priority. There’s a path forward to do this that exploits our digital infrastructure in conjunction with the huge number of people suffering Long Covid who would be willing to become participants. We need to urgently find a suitable funding source and get this appropriately organized and off the ground ASAP. I remain optimistic this is still possible—that’s my hope. Never give up.

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