Thread by @ZdenekVrozina

COVID-19 is not just a story of inflammation. This review argues that it is also a story about what SARS2 does to mitochondria - and how that can turn infection into energy failure, cell injury, and worse oxygenation. This is an important mechanistic review🧵

Mitochondria are not framed here as passive bystanders damaged late in severe illness. In this model, they are active participants in disease - they shape ATP production, ROS, apoptosis, and oxygen sensing.

The review describes two main routes of damage -
very early changes in expression of mito-related genes (hours)
direct interactions between viral proteins and host mito proteins.
So not just the cell is stressed, but a more specific viral rewiring of core cell machinery.

One of the most interesting points is timing. The authors summarize data suggesting mitochondria relevant gene changes appear within hours of infection. That shifts mitochondria from being a late casualty of inflammation to being an early target of the infection process itself.

The first major pathway is energetic.
SARS2 is proposed to suppress parts of the respiratory chain, especially complex I, and disrupt ATP synthesis. The result would be weaker oxidative metabolism and a more energy vulnerable cell, especially in airway epithelium.

The second pathway is structural-functional.
The virus appears to push mitochondria toward fragmentation! Instead of a connected mitochondrial network, cells show smaller broken up fragments - a pattern linked to stress, poorer function, and greater susceptibility to death.

The third pathway is apoptotic.
Viral proteins are described as interacting with the mitochondrial permeability transition pore (mPTP)!, helping keep it open and promoting release of cytochrome c, AIF, and ROS into the cytosol. That shifts the cell toward programmed death!

Think of it this way. Mitochondria are not just batteries. They also contain signals that can tell a damaged cell to shut itself down. If viral proteins keep that mitochondrial pore open, those signals leak out - and the cell can tip from stress into programmed death.

Put simply, the paper is not just saying mitochondria are damaged. It is proposing a sequence
hit energy production + fragment the network + open mPTP + trigger apoptosis = more injury to cells during infection.

A key strength of the review is that it goes down to the level of individual viral proteins. The authors try to map which proteins may be doing which kinds of cellular damage.

Nsp7 is linked to complex I dysfunction and lower ATP.
Nsp7 and Nsp9 are linked to mitochondrial fragmentation.
Nsp6 and M are linked to mPTP opening and apoptotic signaling.
M is also tied to cell cycle arrest.

That is especially important because some of these effects did not require a whole virus. Individual viral proteins were enough here to reproduce parts of the mitochondrial dysfunction! That strengthens the idea of direct protein-mediated injury.

So in simole language, what does that mean?
The virus is proposed to rework mitochondrial behavior in three steps.
Weaken energy production,
disrupt the normal mitochondrial network,
open the door to apoptosis.
The end result is a cell that functions worse and dies more easily.

The review is mainly about the lungs - but this logic may not end in the lungs. The authors also describe mitochondrial injury in pulmonary vascular cells, immune cells, and cardiomyocytes! So the lungs are the main frame here, not necessarily the only organ system affected.

The heart is especially interesting in this context. The review cites work linking SARS2 proteins to components of mPTP in cardiomyocytes, with consequences for bioenergetics and cell survival. It may be a direct mitochondrial hit in cardiac tissue too.

In the lungs, this mito story has consequence. Mitochondria are also part of oxygen sensing. If the virus disrupts that system, it may impair hypoxic pulmonary vasoconstriction that normally redirects blood away from poorly ventilated parts of the lung toward better ventilated regions.

If that mechanism fails, blood keeps flowing through areas that are not exchanging oxygen well. That increases intrapulmonary shunting, can worsen hypoxemia. Authors connect mitochondrial injury to the clinical picture of severe COVID-19 pneumonia.

And the long COVID section is especially important. The review points that during acute infection SARS2 suppresses transcription of nuclear-encoded OXPHOS genes, shifts metabolism toward HIF-1α-driven glycolysis, and activates stress and innate immune pathways. So - it looks like deeper metabolic reprogramming.

The paper also notes that infection may induce miR-2392, further lowering expression of mitochondrial genes. And there is an important organ specific nuance - after viral clearance, mito function in the lungs often recovered, but in the kidney and liver there was still marked downregulation of OXPHOS genes.

So recovery may be incomplete and uneven across organs!

The review adds more possible reasons why problems could persist. Residual viral proteins, especially spike, may continue to drive oxidative stress and disrupt energy metabolism, viral proteins may trigger autoantibodies against mito proteins, and in nervous tissue, disrupted ER mitochondrial calcium signaling, ROS, and mito dynamics may contribute to cognitive and energy related long COVID symptoms.

In this important review, long COVID does not look like a simple after effect of infection, but like a possible state in which part of the virus triggered mito and metabolic reprogramming persists even after viral clearance.

Wu at al., SARS-CoV-2 targets mitochondria, exacerbating COVID-19 pneumonia. @szupraha @ZdravkoOnline @adamvojtech86 physoc.onlinelibrary.wiley.com/doi/full/10.11…