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.

The role of SIRT1 in skeletal muscle function and repair of older mice

“…As SIRT1 has a role in regulating oxidative metabolism and connecting global metabolism to longevity and regeneration, we also examined mitochondrial subpopulations to identify potential differences in these subpopulations resulting from variant SIRT1 expression. Mitochondrial dysfunction may be a fundamental component that regulates aging responses along several pathways . Previous work has suggested that IFM and SSM subpopulations are affected differently in cardiac muscle by diabetes .…”

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

“…Mitochondria are double membrane‐bound organelles responsible for energy production. Mitochondrial integrity is maintained through the coordination of several processes such as biogenesis and mitophagy, which have been collectively referred to as mitochondrial quality control (MQC) . Dysfunctional MQC and inflammation are key signatures of ageing and several ageing‐related diseases.…”

“…Mitochondrial integrity is maintained through the coordination of several processes such as biogenesis and mitophagy, which have been collectively referred to as mitochondrial quality control (MQC). 17 Dysfunctional MQC and inflammation are key signatures of ageing and several ageing-related diseases. As part of the mitochondrial energy generating process involving the electron transport chain (ETC), high-energy electrons leak and generate reactive oxygen species (ROS).…”

Cachexia and advanced dementia

“…Moreover, dysfunctional mitochondrial quality control and neuroinflammation have been considered to be at the crossroads of ageing and muscle wasting disorders. In particular, mitochondria‐derived damage‐associated molecular patterns have been specifically implicated in experimental sarcopenia and cachexia models …”

“…In particular, mitochondriaderived damage-associated molecular patterns have been specifically implicated in experimental sarcopenia and cachexia models. 63 However, our comprehensive literature search found that the current body of evidence mainly concerns cachexia associated with cancer, end-stage pulmonary disease, heart failure, and renal failure. Therefore, there is a knowledge gap in regarding cachexia and dementia, and our understanding of the pathophysiological background is currently based on mere extrapolation from these other findings.…”