Distinct Essentiality of the Mitochondrial Respiratory Chain in Proliferating Cells in Vivo

Mitochondrial respiratory chain (RC) activity is essential for in vivo cell proliferation, particularly in cancer, CD4⁺ and CD8⁺ T cells, and endothelial cells involving ATP production and biosynthesis. The RC is essential for the oxidative tricarboxylic acid (TCA) cycle to produce intermediates that funnel into anabolic pathways to synthesize lipids, proteins, and nucleotides. By contrast, mitochondrial respiration has a distinct role in other proliferating cells including regulatory T cells (Tregs) and stem cells whereby mitochondria are dispensable for in vivo cell proliferation but determine cell fate and function through several signaling mechanisms. In this review, we discuss how the mitochondrial RC is an anabolic engine that supports the proliferation of cancer cells, CD4⁺ and CD8⁺ T cells, and endothelial cells while mitochondria serve as central hubs that integrate metabolic signals to control Treg and stem cell fate and function in vivo.