Mitochondria-Derived Damage-Associated Molecular Patterns in Aging

Mitochondria-derived damage-associated molecular patterns (DAMPs) are a proposed link between age-related mitochondrial damage and age-related inflammation, and this open access paper outlines present thinking on the topic. Mitochondria, the power plants of the cell, are strongly implicated in the progression of aging in a number of ways, the SENS view of damage to mitochondrial DNA producing dysfunctional cells being one, and a more general decline in mitochondrial energy generation for other reasons, yet to be fully mapped, being another. DAMPs are more in line with the first view rather than the second, in which broken cells and their mitochondria generate signals and other molecules that are either directly or indirectly causing further damage. Increased chronic inflammation might be considered a form of damage; it drives faster progression of all of the common age-related conditions, and any dysfunction that produces chronic inflammation is in effect a contributing cause of aging.

Aging is a complex and multi-factorial process characterized by increased risk of adverse health outcomes. Understanding the intimate mechanisms of aging is therefore instrumental for contrasting its negative correlates. As initially proposed in the "mitochondrial theory of aging", mitochondria are deeply involved in the aging process mainly through respiratory dysfunction and oxidant generation. Although unique as fueling systems within the cell, mitochondria participate in other essential functions, including heme metabolism, regulation of intracellular calcium homeostasis, modulation of cell proliferation, and integration of apoptotic signaling. It is therefore crucial that a pool of healthy and well-functioning organelles is maintained within the cell. To this aim, a comprehensive set of adaptive quality control processes operates via interrelated systems, including pathways pertaining to protein folding and degradation, mitochondrial biogenesis, dynamics, and autophagy (mitophagy). The activation of individual mitochondrial quality control (MQC) pathways depends on the degree of mitochondrial damage. Due to these vital responsibilities, disruption of the MQC axis is invoked as a major pathogenic mechanism in a number of disease conditions.

Together with mitochondrial dysfunction, chronic inflammation is another hallmark of both aging and degenerative diseases. Interestingly, emerging evidence suggests that the two phenomena are related to one another. In particular, circulating cell-free mitochondrial DNA (mtDNA), one of the cell damage-associated molecular patterns (DAMPs), has been proposed as a functional link between mitochondrial damage and systemic inflammation. Indeed, mtDNA, which is released as a result of cellular stress, contains hypomethylated CpG motifs resembling those of bacterial DNA and is therefore able to induce an inflammatory response. These regions 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 the cytosolic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) DNA sensing system-mediated pathways. The mechanisms responsible for the generation of mitochondrial DAMPs as well as their contribution to the inflammatory milieu that characterizes aging and its associated conditions are not completely understood.

Population aging poses a tremendous burden on the society. This has instigated intense research on the mechanisms that make the elderly more susceptible to diseases and disability. Several processes have been identified. Among these, inflamm-aging, a condition of chronic inflammation that develops independent of infections, has gained special attention. The cellular mechanisms responsible for inflamm-aging are not fully understood. However, recent studies suggest that a danger cellular-driven response may represent a relevant player. The coexistence of oxidative stress resulting from mitochondrial dysfunction and sterile inflammation has been summarized in the concept of oxy-inflamm-aging that merges the role of inflammation and oxidative stress in the aging process. Specific "danger molecules" generated in an oxidative milieu have been proposed to contribute to inflamm-aging. From this perspective, aging may be envisioned as the result of an "autoimmune-like" process. Given the role played by mitochondrial DAMPs in the activation of sterile inflammation, the mechanisms favoring organelle damage, in particular failing MQC processes, represent a relevant matter to be addressed by future investigations.


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