Phenotypic pharmacology of novel Complex I inhibitors eliciting tissue repair concurrent to control of inflammation

A key challenge of regenerative medicine is to provide a signal that can promote and regulate the repair and maintenance of tissues and organ systems to overcome progressive decline. Profiling of novel inhibitors of mitochondrial Complex I (NIC1s) showed differential effects on myeloid and fibroblast cells in vitro and revealed augmented and anatomically appropriate tissue repair in vivo. In a mouse model of collagen-induced arthritis, therapeutic treatment with NIC1s reduced inflammation and bone pathology and concurrently improved the production of anatomically appropriate osteoid, indicative of an osteoblastogenic repair response. In a bleomycin-induced lung fibrosis model, treatment with NIC1s reduced fibrosis and inflammation and mobilized a controlled and appropriate alveolar epithelial repair response that preceded overt antifibrotic and anti-inflammatory effects. We hypothesize that these findings are consistent with a hormetic model of mitochondrial stress transduction, which leads to constrained cell fate selection in myeloid and fibroblast cells. Our work characterizes a new class of Complex I inhibitors and suggests that Complex I may act as a signaling checkpoint to promote and regulate context-dependent repair responses in vivo. SIGNIFICANCE STATEMENT: A key challenge of regenerative medicine is to promote and regulate the repair and maintenance of tissues and organ systems to overcome progressive decline. Augmented and anatomically appropriate tissue repair was demonstrated in disease models of arthritis and lung injury concurrent to ongoing inflammation and/or fibrosis and elicited by a novel mechanistic transduction of mitochondrial stress. These findings provide proof-of-concept for the pharmacological induction of tissue repair using novel inhibitors of mitochondrial Complex I, with important therapeutic implications.

Complex I; Fibrosis; Inflammation; Integrated stress response; Regeneration; Tissue Repair.