Mitochondrial Pyruvate Import Promotes Long-Term Survival of Antibody-Secreting Plasma Cells

Abstract

Summary Durable antibody production after vaccination or infection is mediated by long-lived plasma cells (LLPCs). Pathways that specifically allow LLPCs to persist remain unknown. Through bioenergetic profiling, we found that human and mouse LLPCs could robustly engage pyruvate-dependent respiration whereas their short-lived counterparts could not. LLPCs took up more glucose than did short-lived plasma cells (SLPCs) in vivo, and this glucose was essential for the generation of pyruvate. Glucose was primarily used to glycosylate antibodies, but glycolysis could be promoted by stimuli such as low ATP levels and the resultant pyruvate used for respiration by LLPCs. Deletion of Mpc2, which encodes an essential component of the mitochondrial pyruvate carrier, led to a progressive loss of LLPCs and of vaccine-specific antibodies in vivo. Thus, glucose uptake and mitochondrial pyruvate import prevent bioenergetic crises and allow LLPCs to persist. Immunizations which maximize these plasma cell metabolic properties may thus provide enduring antibody-mediated immunity.

Metabolic abnormalities and oxidative stress in lupus

“…Interestingly, when the reduction of pyruvate to lactate was blocked in the same mice with dichloroacetate (DCA), a drug that enhances the import of pyruvate into the mitochondria for oxidation, no improvements were noted [31]. Additionally, the survival of long-lived plasma cells, which are associated with pathogenicity in SLE, was recently found to be dependent on pyruvate flux into the mitochondria [32]. These studies imply that targeting glucose oxidation [i.e., through the inhibition of the mitochondrial pyruvate complex (MCP)], rather than the reversal of the Warburg effect, could be a putative effective target in SLE patients.…”

Comparison of the effect of the aerobic glycolysis inhibitor dichloroacetate and of the Krebs cycle inhibitor LW6 on cellular and humoral alloimmunity

“…This may be attributed to the direct effect of DCA on B cells. Since plasma cells are mainly dependent on the Krebs cycle for covering their high energy requirements (12,(16)(17)(18), DCA-induced increased pyruvate entry into the mitochondria may enhance their ability to produce antibodies. However, an indirect effect cannot be excluded.…”

“…This may be the indirect result of the inhibition of T-cell clonal expansion by LW6, but it may also be the direct effect of the Krebs cycle inhibition on plasma cells. As already noted, plasma cells are dependent on the Krebs cycle for covering the high energy demands for the high protein synthesis (12,(16)(17)(18). The Krebs cycle and the consequent oxidative phosphorylation are more effective than aerobic glycolysis in ATP production.…”

“…During plasma cell differentiation the transcription factor XBP1 increases mitochondrial mass and function (16). Pyruvate entry into the Krebs cycle is required for the long-term survival of antibody-secreted plasma cells (17). Glutamine again serves as a major source of the Krebs cycle.…”

From Pipe Dream to Donor-Specific PC Elimination

“…In a more recent publication in Immunity , Lam and co-workers 8 characterized a potential vulnerability of LLPC compared to SLPC, wherein the enhanced survival capacity of LLPC was dependent on a higher rate of glucose import that was mediated, at least in part, via an increased expression of the glucose transporter, Glut1. LLPC primarily utilized glucose to glycosylate antibodies, but also for sustaining LLPC through glycolysis and pyruvate generation.…”