TLR4-mediated AKT activation is MyD88/TRIF dependent and critical for induction of oxidative phosphorylation and mitochondrial transcription factor A in murine macrophages.
Mitochondria play a critical role in cell survival and death. Mitochondrial recovery during inflammatory processes such as sepsis is associated with cell survival. Recovery of cellular respiration, mitochondrial biogenesis, and function requires coordinated expression of transcription factors encoded by nuclear and mitochondrial genes, including mitochondrial transcription factor A (T-fam) and cytochrome c oxidase (COX, complex IV). LPS elicits strong host defenses in mammals with pronounced inflammatory responses, but also triggers activation of survival pathways such as AKT pathway. AKT/PKB is a serine/threonine protein kinase that plays an important role in cell survival, protein synthesis, and controlled inflammation in response to TLRs. Hence we investigated the role of LPS-mediated AKT activation in mitochondrial bioenergetics and function in cultured murine macrophages (B6-MCL) and bone marrow-derived macrophages. We show that LPS challenge led to increased expression of T-fam and COX subunits I and IV in a time-dependent manner through early phosphorylation of the PI3K/AKT pathway. PI3K/AKT pathway inhibitors abrogated LPS-mediated T-fam and COX induction. Lack of induction was associated with decreased ATP production, increased proinflammatory cytokines (TNF-α), NO production, and cell death. The TLR4-mediated AKT activation and mitochondrial biogenesis required activation of adaptor protein MyD88 and Toll/IL-1R domain-containing adaptor-inducing IFN-β. Importantly, using a genetic approach, we show that the AKT1 isoform is pivotal in regulating mitochondrial biogenesis in response to TLR4 agonist.
Department of Pediatrics, St. John Hospital and Medical Center, Detroit, MI 48236, USA.
Christian P
CP
Bauerfeld
Ruchi
R
Rastogi
Gaila
G
Pirockinaite
Icksoo
I
Lee
Maik
M
Hüttemann
Bobby
B
Monks
Morris J
MJ
Birnbaum
Luigi
L
Franchi
Gabriel
G
Nuñez
Lobelia
L
Samavati
D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D006609:High Mobility Group Proteins / Q000276:immunology / Q000378:metabolism; D015151:Immunoblotting; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D010085:Oxidative Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D051057:Proto-Oncogene Proteins c-akt; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C081930:Tfam protein, mouse; C493487:Tlr4 protein, mouse