DAMPs May Link Age-Related Mitochondrial Dysfunction and Chronic Inflammation
Mitochondria-derived damage-associated molecular patterns (DAMPs) are a range of DNA and protein fragments that are thought to be generated as a result of mitochondrial damage, insufficient mitochondrial quality control, or some combination of the two. Mitochondria are the power plants of the cell, each cell having its own small herd of these descendants of ancient symbiotic bacteria. They have long since evolved into integrated cellular components, but retain a little of their original DNA. There is copious evidence to point to a sizable role for mitochondria in the harms caused by aging. In the SENS view, the most important problem is that mitochondrial DNA (mtDNA), less protected than the DNA in the cell nucleus, becomes damaged in ways that both cause dysfunction and make the broken mitochondria more resistant to removal by the machinery responsible for quality control.
The focus of this open access paper is on understanding how mitochondrial dysfunction can be linked to the characteristic chronic inflammation that occurs with age. There are many contributions to inflammation among the processes of aging. Obviously, issues internal to the immune system account for much of the problem, but any cell is, in principle, given the right circumstances, capable of generating signals that will induce local immune cells to adopt an inflammatory state. This is one of the ways in which senescent cells cause significant harm, for example, forcing the immune system into consistent overactivation, a state that disrupts the usual beneficial activities of immune cells. Do cells that are not senescent, but are suffering significant mitochondrial damage produce similar outcomes? Do they also rouse the immune system into constant activation, via different mechanisms? Possible so.
Due to the relevance of mitochondria to cell physiology and whole-body metabolism, a comprehensive set of adaptive quality control mechanisms is in place to ensure the preservation of mitochondrial structural and functional integrity. Mitochondrial quality control (MQC) mechanisms also allow for the dynamic modulation of organelle function and number to meet the heterogeneous energy demands of the various tissues. MQC is accomplished through a set of interrelated processes (i.e., protein folding and degradation, mitochondrial autophagy, mitochondrial fission and fusion, and mitochondrial biogenesis).
The regulation of mitochondrial content is achieved through the dynamic balance between mitochondrial biogenesis and degradation. Mitochondrial biogenesis is a multistage process finalized to producing new mitochondria upon the coordinated expression of nuclear and mtDNA-encoded genes. Mitochondrial fusion allows for mtDNA mixing within the network, thereby preventing focal accumulation of mutant mtDNA and preserving mtDNA integrity. Mitochondrial fission, instead, segregates defective or unnecessary organelles for their subsequent removal through mitophagy. The integration of mitochondrial dynamics with the selective removal of dysfunctional mitochondria, referred to as mitophagy, ensures an efficient MQC process and preserves metabolic cellular "fitness."
Derangements of the MQC axis have been described during aging and in the context of a number of disease conditions, including cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. Along with mitochondrial dysfunction, chronic inflammation is a hallmark of both aging and degenerative diseases. The two phenomena may be linked to one another. Indeed, emerging evidence indicates that circulating cell-free mtDNA, one of the damage-associated molecular patterns (DAMPs), may establish a functional relationship between mitochondrial damage and systemic inflammation. mtDNA can be released into the circulation in response to cell insults. Here, it is able to induce an inflammatory response through hypomethylated CpG motifs resembling those of bacterial DNA. These regions, indeed, bind and activate membrane or cytoplasmic pattern recognition receptors (PRRs), such as the Toll-like receptor (TLR), the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR), and cytosolic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) DNA sensing system-mediated pathways.
The possible contribution of mitochondrial DAMPs to the inflammatory milieu that characterizes muscle wasting disorders has not yet been explored. However, this hypothesis is worth being pursued as it could help identify novel biological targets for the management of muscle loss. Here, we summarize the current evidence on circulating mtDNA as a trigger for age-related systemic inflammation. We first describe two candidate mechanisms generating and releasing cell-free mtDNA: (1) dysregulation of TFAM binding to mtDNA, and (2) impairment of mitophagy. Subsequently, we illustrate the pathways linking mitochondrial dysfunction with systemic inflammation during aging. Finally, we propose a role for the triad "MQC failure/cell-free mtDNA/inflammation" in two major muscle wasting disorders, sarcopenia and cachexia.
Isn't the Sens view you linked *way* outdated and no longer the case? What about mitochondrial dynamics?
@Nathan: No. There are two separate things going on; one is the SENS-related mitochondrial damage and resulting major cellular dysfunction in a small number of cells that spreads bad things out into tissues via, e.g., oxidized lipids. The other is the general malaise of mitochondrial function and dynamics that is global in near all cells, and best studied in neurodegenerative conditions. That, I suspect, is secondary to SENS categories of damage, but there's no good model for how that happens at this point. See this post for a short summary of the two:
https://www.fightaging.org/archives/2017/12/reviewing-the-mitochondrial-contribution-to-aging-and-age-related-disease
@Reason thanks, I'm getting a lot of mixed messages about the SENS view lately. See the comment on the article you linked.
This is an interesting paper. Despite only being a review with no new results, I think we can see the writing is on the wall for the theory that mito mutations are that important in aging. There is more than enough evidence of declining mitophagy and rising inflammation and the link between them to explain a lot of the problems with things like sarcopenia without need for mitochondrial mutations.