MitomiRs in human inflamm-aging: a hypothesis involving miR-181a, miR-34a and miR-146a

Abstract

Mitochondria are intimately involved in the aging process. The decline of autophagic clearance during aging affects the equilibrium between mitochondrial fusion and fission, leading to a build-up of dysfunctional mitochondria, oxidative stress, chronic low-grade inflammation, and increased apoptosis rates, the main hallmarks of aging. Current research suggests that a large number of microRNAs (miRs or miRNAs) are differentially expressed during cell aging. Other lines of evidence indicate that several miRs likely share in "inflamm-aging", an aging-related state characterized by systemic chronic inflammation that in turn provides a biological background favoring susceptibility to age-related diseases and disabilities. Interestingly, miRs can modulate mitochondrial activity, and a discrete miR set has recently been identified in mitochondria of different species and cell types (mitomiRs). Here we show that some mitomiRs (let7b, mir-146a, -133b, -106a, -19b, -20a, -34a, -181a and -221) are also among the miRs primarily involved in cell aging and in inflamm-aging. Of note, Ingenuity Pathway Analysis (IPA) of aging-related mitomiR targets has disclosed a number of resident mitochondrial proteins playing large roles in energy metabolism, mitochondrial transport and apoptosis. Among these, Bcl-2 family members--which are critically involved in maintaining mitochondrial integrity--may play a role in controlling mitochondrial function and dysfunction during cellular aging, also considering that Bcl-2, the master member of the family, is an anti-oxidant and anti-apoptotic factor and regulates mitochondrial fission/fusion and autophagy. This intriguing hypothesis is supported by several observations: i) in endothelial cells undergoing replicative senescence (HUVECs), a well-established model of cell senescence, miR-146a, miR-34a, and miR-181a are over-expressed whereas their target Bcl-2 is down-regulated; ii) IPA of the miR-146a, miR-34a and miR-181a network shows that they are closely linked to each other, to Bcl-2 and to mitochondria; and iii) miR-146a, miR-34a, and miR-181a are involved in important cell functions (growth, proliferation, death, survival, maintenance) and age-related diseases (cancer, skeletal and muscle disorders, neurological, cardiovascular and metabolic diseases). In conclusion several aging-related mitomiRs may play a direct role in controlling mitochondrial function by regulating mitochondrial protein expression. Their modulation could thus mediate the loss of mitochondrial integrity and function in aging cells, inducing or contributing to the inflammatory response and to age-related diseases.

Keywords: Aging; Bcl-2 family; Inflamm-aging; MicroRNA; Mitochondria; MitomiR.