The

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clinical implications of basic research

The Mitochondrion A Trojan Horse That Kicks Off

Inflammation?
Angelo A. Manfredi, M.D., and Patrizia Rovere-Querini, M.D., Ph.D.
Threats to the integrity of an organism cause
inflammation. The response is highly conserved
and essential: defective or deregulated inflammation is usually incompatible with survival. However, inflammation is risky. Leukocytes recruited
to fight microbes cause collateral damage that is
often more severe than that originally triggered
by the pathogen. Moreover, inflammation takes
place even in patients with sterile tissue injuries
such as trauma and ischemiareperfusion.
The price that patients pay for inflammation
in these conditions is often high. A recent study
by Zhang and colleagues1 reveals details of this
exchange. In short, the immune system recognizes mitochondria released from dying tissues
as the bacteria they (the mitochondria) once were,
and it mobilizes its destructive potential to limit
their proliferation and arrest an unlikely invasion. This tragic misunderstanding could have
a role in several human diseases, leading to inflammation in conditions as clinically diverse as
post-traumatic systemic inflammatory response
syndrome, myocardial infarction, cerebral ischemia, and systemic and organ autoimmunity.
The innate immune system is very effective
at recognizing pathogens. This recognition is
achieved through the identification of molecular
tags, referred to as pathogen-associated molecular patterns, that label microbes and not
host cells. Given the enormous evolutionary pressure, it seems likely that these patterns are critical to the ability of the microbe to survive or to
infect.2 Examples of pathogen-associated molecular patterns are formyl methionine and
formylated bacterial proteins, which are synthesized by bacteria and are potent stimuli for leukocyte attraction and activation. Similarly, unmethylated cytosinephosphateguanine (CpG)
dinucleotides are common in microbial DNA

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and elicit inflammatory and immunostimulatory

responses.
Dedicated pattern-recognition receptors endow
immune cells neutrophils, macrophages, dendritic cells, and mast cells with the ability to
recognize microbes; the intracellular toll-like receptor 9 (TLR9), for example, identifies microbial DNA in the endosomal compartment. Germlineencoded pattern-recognition receptors are
not clonally distributed. All cells that express
them immediately identify pathogen-associated
molecular patternexpressing microbes as a potential threat. They initiate inflammation, secreting cytokines and chemokines, which alert
and attract other leukocytes, thus focusing their
destructive potential at the site of infection.
Mitochondria are membrane-bound organelles
that produce energy in virtually all eukaryotic
cells. They have evolved from an endosymbiont
alpha-proteobacterium (a relative of brucella and
rickettsia). Mitochondria have their own DNA,
enriched in hypomethylated CpG-containing sequences, which is duplicated when mitochondria divide. The origin of the eukaryotic cell is
still controversial, and transitional forms between prokaryotes and eukaryotes have not been
persuasively documented.3 The amalgamation of
two prokaryotes or the amalgamation of a pro
karyote with an eukaryotic precursor cell are
possible scenarios. Regardless, the merger would
have occurred long before the existence of an
immune system, which by definition is a feature
that is unique to multicellular organisms.
Zhang et al. reason that, by virtue of their
evolutionary origin, mitochondria might be recognized by pattern-recognition receptors and thus
might initiate inflammation. This event seems
unlikely to occur in healthy tissues, in which
membrane-bound mitochondria are contained

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clinical implications of basic research

Extensive tissue
damage

Mitochondrial
DAMPs

Bacterial
PAMPs

Infection

Mitochondrial
DAMPs
PMN
activation
PRR
PRR

PMN
extravasation

Peripheral vein

Normal lung

Acute lung injury

TNF-
Interleukin-6

Figure 1. Mitochondrial Danger Signals.

Mitochondrial molecules share several characteristics with microbial molecules. For example, mitochondrial proteins, like bacterial proteins, are formylated at their amino termini. Zhang et al.1 recently observed that intravenously injecting mitochondrial formylated proteins into mice activates neutrophils in the blood, prompting them to extravasate and migrate into peripheral organs. Sequelae include
key features of acute lung injury, such as the release of proteases and other toxic moieties that damage the vessel endothelium, with loss
of barrier function and edema. DAMP denotes damage-associated molecular pattern, PAMP pathogen-associated molecular pattern,
PMN polymorphonuclear cell, PRR pattern-recognition receptor, and TNF- tumor necrosis factor .

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clinical implications of basic research

within cells. Zhang et al. detected mitochondrial

DNA in the blood of patients with systemic inflammatory response syndrome after major trauma, at concentrations sufficient to activate TLR9
and to phosphorylate the p38 mitogen-activated
protein kinase (a signaling molecule that is downstream of TLR9). Moreover, Zhang et al. observed
that mitochondrial proteins from human tissues
activated the receptor of formyl peptide receptor-1 on neutrophils, resulting in the production
of a collagenase that sustains leukocyte migration in peripheral tissues. Intravenous injection
of mitochondrial proteins into mice resulted in
activation of circulating neutrophils, with random extravasation in peripheral organs such as
the liver and lung. Acute lung injury developed
in these mice, with the production of tumor necrosis factor and interleukin-6 and accumulation of proteins and fluids in the alveolar space
(Fig. 1). Conversely, neutrophils lost the ability
to respond to chemoattractants; this could limit
their ability to reach sites of infection, which
could contribute to the immune depression associated with systemic inflammatory response
syndrome.
The study by Zhang et al. provides new clues
about systemic inflammatory response syndrome
in patients with major trauma, a condition that
to a large extent has hitherto been unexplained.
Key questions remain. Molecular mechanisms
other than those described by Zhang et al. may
be involved in the inflammatory action of mitochondrial molecules. For example, mitochondrial
constituents selectively activate an inflammasome4

that regulates the processing and secretion of

interleukin-1 and interleukin-18. This observation suggests a possible link with other sterile
inflammatory conditions such autoinflammatory
diseases. Moreover, other signals (or damageassociated molecular patterns) provided by dying
cells have inflammatory potential.5 Mitochondrial structures released by injured cells possibly
prompt inflammation during heart, kidney, or
brain ischemiareperfusion injuries, in which
local neutrophil activation and further tissue
damage occur when the blood flow is restored.
Finally, mitochondria are probably released in
patients with infectious disease in whom
substantial cell death takes place possibly
contributing to the molecular pathology of sepsis. Altogether, the identification of mitochondria as instigators of inflammation may lead to
a new, intriguing candidate for drug discovery.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From the Istituto Scientifico San Raffaele and Universit VitaSalute San Raffaele, Milan, Italy.
1. Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial

DAMPs cause inflammatory responses to injury. Nature 2010;

464:104-7.
2. Janeway CA Jr. Approaching the asymptote? Evolution and
revolution in immunology. Cold Spring Harb Symp Quant Biol
1989;54:1-13.
3. Davidov Y, Jurkevitch E. Predation between prokaryotes and
the origin of eukaryotes. Bioessays 2009;31:748-57.
4. Iyer SS, Pulskens WP, Sadler JJ, et al. Necrotic cells trigger a
sterile inflammatory response through the Nlrp3 inflamma
some. Proc Natl Acad Sci U S A 2009;106:20388-93.
5. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to
know about danger. J Leukoc Biol 2007;81:1-5.
Copyright 2010 Massachusetts Medical Society.

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