Circulating Mitochondrial DNA at the Crossroads of Mitochondrial Dysfunction and Inflammation During Aging and Muscle Wasting Disorders

Abstract

Mitochondrial structural and functional integrity is maintained through the coordination of several processes (e.g., biogenesis, dynamics, mitophagy), collectively referred to as mitochondrial quality control (MQC). Dysfunctional MQC and inflammation are hallmarks of aging and are involved in the pathogenesis of muscle wasting disorders, including sarcopenia and cachexia. One of the consequences of failing MQC is the release of mitochondria-derived damage-associated molecular patterns (DAMPs). By virtue of their bacterial ancestry, these molecules can trigger an inflammatory response by interacting with receptors similar to those involved in pathogen-associated responses. Mitochondria-derived DAMPs, especially cell-free mitochondrial DNA, have recently been associated with conditions characterized by chronic inflammation, such as aging and degenerative diseases. Yet, their actual implication in the aging process and muscle wasting disorders is at an early stage of investigation. Here, we review the contribution of mitochondria-derived DAMPs to age-related systemic inflammation. We also provide arguments in support of the exploitation of such signaling pathways for the management of muscle wasting conditions.

Keywords: DAMPs; autophagy; cachexia; mitochondrial biogenesis; mitochondrial quality control; sarcopenia.

FIG. 1.

Damaged mtDNA can trigger inflammation through three distinct signaling pathways by interacting with (1) TLRs, (2) NLRP3 inflammasome, and (3) cytosolic cGAS-STING DNA sensing system. cGAS, cyclic GMP-AMP synthase; IFN, interferon; IL, interleukin; IRF-1, interferon regulatory factor 1; mtDNA, mitochondrial DNA; NF-κB, nuclear factor κB; NLRP3, NLR family pyrin domain containing 3; NOD, nucleotide-binding oligomerization domain; ROS, reactive oxygen species; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1; TLRs, Toll-like receptors; TNF-α, tumor necrosis factor alpha.

FIG. 2.

Proposed crosstalk between mitochondrial dysfunction and “sterile” inflammation during muscle wasting. The impairment of mitochondrial quality control in myocytes may lead to the release of mitochondrial damaged-associated molecular patterns, such as mtDNA and ATP, and subsequent recruitment of local macrophages. A persistent inflammatory trigger may also alert circulating immune cells, which, in turn, may mount a systemic response through the activation of mtDNA-induced inflammatory pathways. Cytokines, chemokines, NO, and ROS, released in the circulation by inflammatory cells, can induce further mitochondrial damage, thereby establishing a vicious circle and eventually contributing to muscle wasting. ATP, adenosine triphosphate; ETC, electron transport chain; NO, nitric oxide; TFAM, mitochondrial transcription factor A.