Passive transfer of IgG immune complex from ME/CFS patients alters mitochondrial architecture and function

Autoimmunity is an established clinical feature in both Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) and Post-Acute Sequelae of COVID (PASC). Passive transfer of immunoglobulins from patients' sera into mice induces some clinical features of PASC. IgG-induced transfer of disease phenotypes has long been appreciated, yet the exact mechanism of disease development remains largely elusive. Here, we show that IgG isolated from ME/CFS patients selectively induces mitochondrial fragmentation in primary human endothelial cells and alters mitochondrial energetics. Blocking IgG entry into cells using an Fc blocker inhibits the mitochondrial fragmentation phenotype. Both the digested Fab and Fc regions of IgG separately entered the endothelial cells. However, only the Fab fragment alone was able to alter the mitochondrial energetics, similar to native IgG. Proteomics analysis of IgG-bound immune complex revealed significant and specific changes within the immune complex of ME/CFS and PASC patients compared to healthy controls and other disease controls. We demonstrate that IgGs from ME/CFS patients carry a chronic protective response signal that promotes mitochondrial adaptation to stress through mitochondrial fragmentation, without altering mitochondrial ATP generation capacity in endothelial cells. Our results suggest that chronic and pathogenic IgG-induced mitophagy and metabolic alterations to stress-dependent ATP production may lead to cellular saturation, ultimately affecting mitochondrial health. These results provide an opportunity to develop alternative therapeutic intervention strategies.