The Role of Bacteria-Mitochondria Communication in the Activation of Neuronal Innate Immunity: Implications to Parkinson's Disease

Mitochondria play a key role in regulating host metabolism, immunity and cellular homeostasis. Remarkably, these organelles are proposed to have evolved from an endosymbiotic association between an alphaproteobacterium and a primitive eukaryotic host cell or an archaeon. This crucial event determined that human cell mitochondria share some features with bacteria, namely cardiolipin, N-formyl peptides, mtDNA and transcription factor A, that can act as mitochondrial-derived damage-associated molecular patterns (DAMPs). The impact of extracellular bacteria on the host act largely through the modulation of mitochondrial activities, and often mitochondria are themselves immunogenic organelles that can trigger protective mechanisms through DAMPs mobilization. In this work, we demonstrate that mesencephalic neurons exposed to an environmental alphaproteobacterium activate innate immunity through toll-like receptor 4 and Nod-like receptor 3. Moreover, we show that mesencephalic neurons increase the expression and aggregation of alpha-synuclein that interacts with mitochondria, leading to their dysfunction. Mitochondrial dynamic alterations also affect mitophagy which favors a positive feedback loop on innate immunity signaling. Our results help to elucidate how bacteria and neuronal mitochondria interact and trigger neuronal damage and neuroinflammation and allow us to discuss the role of bacterial-derived pathogen-associated molecular patterns (PAMPs) in Parkinson's disease etiology.

Automated summary

Mitochondria, which evolved from an endosymbiotic association, play a crucial role in regulating host metabolism, immunity, and cellular homeostasis. They share certain features with bacteria, known as mitochondrial-derived damage-associated molecular patterns (DAMPs), and their activities can be modulated by extracellular bacteria. In this study, it was found that mesencephalic neurons exposed to an environmental alphaproteobacterium activate innate immunity and show increased expression and aggregation of alpha-synuclein, which interacts with mitochondria, leading to dysfunction. These findings provide insights into the interaction between bacteria and neuronal mitochondria in triggering neuronal damage and neuroinflammation, and the role of bacterial-derived pathogen-associated molecular patterns (PAMPs) in Parkinson's disease.