The word “immunity” conjures up an image of our body fighting against infections. We picture our immune cells heroically battling against foreign, unwanted substances – viruses and bacteria – that have breached our barriers and invaded our anatomical space. Most of us love the classic tale of “good” versus “bad”. But what about the more twisted, exciting tale of “good-turned-bad”? Some systems designed to ensure our body’s survival can become dysfunctional and trigger an unnecessary immune response against the body’s own cells.
One of such essential systems are the mitochondria – organelles or structures inside each cell that generate chemical energy required to fuel cellular processes. The mitochondria use the tricarboxylic acid (TCA) cycle and electron transport chain to convert nutrients into adenosine triphosphate (ATP) molecules. Energy or ATP production is undeniably their most well-known function; however, the mitochondria carry out multiple other tasks to maintain cell survival. Mitochondrial products are used to make amino acids, nucleotides, and lipids – the building blocks of proteins, DNA, and cell membranes, respectively. For example, citrate and alpha ketoglutarate are both TCA cycle metabolites produced by the mitochondria. In addition to participating in the TCA cycle, citrate is involved in synthesizing fatty acids and cholesterol while alpha ketoglutarate is converted to glutamate – the precursor to amino acids glutamine, alanine, and aspartate.
The responsibilities of mitochondria extend far beyond energy production or the synthesis of essential molecules. Mitochondria can indirectly induce inflammation, alerting the immune system of infections and setting it to “attack” mode. Upon infection, a cell usually dies and bursts open, releasing its contents for adjacent cells to recognize and receive danger signals. The most common danger signal is the mitochondrial product, ATP. Once released from the host cell, it binds to corresponding proteins on the surface of nearby immune cells and activates their inflammatory programming.
However, inflammatory responses that occur in absence of infections are far from benign as these “attacks” are directed against our own cells. Unwarranted and self-harming inflammatory responses can be initiated by mitochondria-gone-rogue. For instance, dysfunctional mitochondria can release high levels of reactive oxygen species (ROS), the natural by-product of ATP production. Excessive ROS is toxic to cells as it damages DNA, proteins, and lipids. It can also trigger the formation of inflammasomes, large multi-protein structures that signals an inflammatory cellular program.
Additionally, dysfunctional mitochondria release their DNA. Mitochondrial DNA (mtDNA) is different from DNA found in the nucleus and it is normally contained within the organelle to produce necessary mitochondrial proteins. However, once released out of its designated environment, mtDNA can trigger a pathway called “cGAS-STING”. The cGAS-STING pathway is designed to sense foreign (usually viral) DNA that enters cells. Thus, mtDNA is inappropriately recognized as “foreign” by the cGAS-STING pathway, which again activates immune responses.
Ultimately, mitochondria-induced inflammation can have detrimental effects on our overall health. For example, mitochondrial dysfunction has been associated with systemic lupus erythematosus (SLE). SLE is an autoimmune disease that results in fever, joint pains, skin rashes, and damage to internal organs including brain, lungs, and kidneys. Studies have shown that patients with SLE have increased amounts of mtDNA in circulation, which activate the cGAS-STING pathway and promote an inflammatory attack against the body’s own tissues. Similarly, chronic bronchitis – an inflammatory lung disease that restricts air flow – is also associated with high levels of mtDNA, ROS, and general mitochondrial dysfunction in the lungs.
How can the mitochondria – an essential part of our cellular system – become so dangerous? In other words, what causes these mitochondria to become inflammatory? Naturally, there are mechanisms in place to prevent mitochondria-induced inflammation. For instance, dysfunctional or damaged mitochondria are eliminated from cells by a process called “mitophagy”. A similar process called “autophagy” can remove inflammasomes induced by mitochondrial ROS. Alternatively, cells that contain dysfunctional mitochondria undergo programmed cell death or apoptosis. This process involves permeabilization of the outer mitochondrial membrane, which releases mitochondrial molecules called cytochrome c. The rapid accumulation of cytochrome c in the cytoplasm initiates a cascade of events that lead to the death of a cell with inflammatory potential.
As soon as these safeguarding mechanisms are out of order, the mitochondria can easily trigger unwanted inflammation. In fact, patients with SLE have an excess of circulating mtDNA due to defects in mitophagy. Similarly, patients with Crohn’s disease – a chronic inflammatory disease of the digestive tract – have mutations in genes that regulate autophagy. These mutations result in faulty autophagy machineries, leading to the accumulation of dysfunctional mitochondria and mitochondria-induced inflammation.
Mitochondria are indeed necessary for the proper functioning of our cells. They supply not only energy but also materials to build fundamental cellular components. Yet, when rendered dysfunctional or mechanisms that remove defunct organelles go awry, the mitochondria can be a source of disease-causing inflammation. These complex and contradictory features, the good and the bad, make this organelle so much more than a “powerhouse of a cell”.
Marchi, S., Guilbaud, E., Tait, S.W.G. et al. Mitochondrial control of inflammation. Nat Rev Immunol 23, 159–173 (2023). doi:10.1038/s41577-022-00760-x
Spinelli JB, Haigis MC. The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol 20, 745-754 (2018). doi:10.1038/s41556-018-0124-1
Martínez-Reyes, I., Chandel, N.S. Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun 11, 102 (2020). doi:10.1038/s41467-019-13668-3
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