Transcriptional control of mitochondrial biogenesis and its interface with inflammatory processes.
Cells avoid major mitochondrial damage and energy failure during systemic inflammatory states, such as severe acute infections, by specific targeting of the inflammatory response and by inducing anti-inflammatory and anti-oxidant defenses. Recent evidence indicates that these cell defenses also include mitochondrial biogenesis and the clearance of damaged mitochondria through autophagy.This review addresses a group of transcriptional signaling mechanisms that engage mitochondrial biogenesis, including energy-sensing and redox-regulated transcription factors and co-activators, after major inflammatory events.Stimulation of the innate immune system by activation of toll-like receptors (TLR) generates pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α)and interleukin-1β (IL-1β), necessary for optimal host defense, but which also contribute to mitochondrial damage through oxidative stress and other mechanisms. To protect its energy supply, host cells sense mitochondrial damage and initiate mitochondrial biogenesis under the control of an inducible transcriptional program that also activates anti-oxidant and anti-inflammatory gene expression. This multifunctional network not only increases cellular resistance to metabolic failure, oxidative stress, and cell death, but promotes immune tolerance as shown in the graphical abstract.The post-inflammatory induction of mitochondrial biogenesis supports metabolic function and cell viability while helping to control inflammation. In clinical settings, patients recovering from severe systemic infections may develop transient immune suppression, placing them at risk for recurrent infection, but there may be therapeutic opportunities to enhance mitochondrial quality control that would improve the resolution of life-threatening host responses to such infections.
Piantadosi, CA; Suliman, HB
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