Mitochondrial Escape Provokes Cytokine Storms That Doom the Heart
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Mitochondrial DNA that Escapes from Autophagy Causes
Inflammation and Heart Failure
Oka et al
Nature. 2012; 485:251–255.
Mitochondria are derived from primordial bacterial endosymbionts and retain partial genomes. In mammalian cells, damaged or dysfunctional mitochondria are recognized, targeted for elimination, then neatly packaged and eliminated via mitophagy. A recent paper from Oka et al describes how interrupting normal mitophagic mitochondrial DNA degradation after pressure overload can activate Toll-like receptor-9 mediated innate immunity, causing myocardial inflammation that contributes to cardiomyopathic decompensation.
The revelation that bacterial DNA potently stimulates the immune system anticipated by a handful of years the discovery of innate immunity mediated by pattern recognition receptors (PRR), including the Toll-like receptors (TLR).1 TLR-9 is the prototypical TLR,2 but a total of 10 human TLR are known (12 in the mouse). Recognizing foreign DNA and RNA is the specific function of the subfamily of nucleic acid-sensing TLR (TLR-3, -7, -8, and -9), which are further distinguished by subcellular localization to endosomes, enabling their specific surveillance for internalized foreign nucleic acids. Innate immune responses mediated by nucleic acid-sensing TLRs thus establishes an initial barrier to microbial and viral invasion; DNA or RNA released from captured and degraded microbes is sensed by TLR-rich cells and triggers cytokine release (Figure). The endosomal TLR system acts in parallel with a more broadly expressed cytosolic PRR system that recognizes foreign nucleic acids of infecting microbes and responds by transcriptionally inducing interferon production,3 and with the inflammasome complex that activates caspase 1/interleukin converting enzyme.4
In a recent issue of Nature, Oka and colleagues uncover a potent role for TLR-9 mediated inflammation in pressure overload hypertrophy decompensation.5 The heart responds to hemodynamic overload through genetic reprogramming and tissue/chamber remodeling that is initially compensatory. These measures fail over …