Mitochondrial Regulator CRIF1 Plays a Critical Role in the Development and Homeostasis of Alveolar Macrophages via Maintaining Metabolic Fitness.

The importance of mitochondrial function in macrophages is well established. Alveolar macrophages (AMs), the tissue-resident macrophages (TRMs) of the lung, are particularly dependent on mitochondria-driven oxidative phosphorylation (OXPHOS) to support their functions and maintain homeostasis. However, the specific genes and pathways that regulate OXPHOS in AMs remain unclear. In this study, we investigated the role of CR6-interacting factor 1 (CRIF1), a mitochondrial regulator, as a key factor that specifically modulates the metabolic fitness and maintenance of AMs. Using single-cell RNA sequencing and transcriptomic analyses, we found CRIF1 to be highly expressed in AMs compared to TRMs from other tissues, correlating with enhanced OXPHOS activity. Genetic ablation of in macrophages resulted in a marked reduction in AM populations exclusively in the lung, while other TRM populations were unaffected. CRIF1-deficient AMs exhibited an altered metabolic profile, including impaired mitochondrial function, increased glycolysis, and aberrant lipid accumulation. These findings underscore the essential role of CRIF1 in regulating mitochondrial functions and metabolic fitness in AMs, distinguishing it from broader mitochondrial regulators like mitochondrial transcription factor A, which operates across multiple TRM populations. Our study provides critical insights into the tissue-specific regulation of macrophage metabolism and suggests potential therapeutic avenues for lung diseases associated with AM dysfunction.