Mitochondrial DNA and Inflammation: Mechanisms of Release and Signaling Pathways
Author(s): Anastasia V. Poznyak, Elizaveta Romanovna Korchagina, Fei Liu, Yanke Shan, Alexander N. Orekhov
Abstract
Mitochondria (Mt) play a crucial role in various cellular processes, including energy production and metabolism. Damage-Associated Molecular Patterns (DAMPs) released by mitochondria, such as mitochondrial DNA (mtDNA), cardiolipin, succinate, and ATP, can trigger inflammation signaling pathways. This review article delves into the evolutionary origins of mitochondria from bacterial ancestors and their role as regulators of inflammation through DAMPs release. The intricate mechanisms of mtDNA leakage into the cytoplasm and extracellular space are explored, focusing on pathways involving the Mitochondrial Permeability Transition Pore (mPTP), Cell-Free mtDNA, and Extracellular Vesicles (EVs). Additionally, the involvement of key immune signaling pathways such as the cyclic GMP-AMP Synthase (cGAS)-Stimulator of Interferon Genes (STING), Toll-like receptor-9, and inflammasomes in recognizing mtDNA as a danger signal and inducing inflammatory responses is discussed. The active and passive release of mtDNA by various cell types, including neutrophils and lymphocytes, and the implications of mtDNA in inflammatory diseases are examined. Understanding these mechanisms sheds light on the intricate interplay between mitochondria, inflammation, and immune responses, with potential implications for therapeutic interventions targeting mitochondria-related inflammatory pathways.