Mitochondrial ATP-sensitive K⁺ channels (MitoK_ATP) regulate brown adipocyte differentiation and metabolism

Brown adipose tissue (BAT) plays a central role in mammalian nonshivering thermogenesis, dissipating mitochondrial membrane potentials through the activity of uncoupling protein UCP1 to release heat. Inner membranes of mitochondria are known to be permeable to potassium ions (K⁺), which enter the matrix either through ATP-sensitive channels (MitoK_ATP) or leakage across the bilayer driven by inner membrane potentials. Mitochondrial K⁺ influx is associated with increased osmotic pressure, promoting water influx and increasing matrix volume. Since BAT mitochondria have lower inner membrane potentials due to uncoupling protein 1 (UCP1) activity, we hypothesized this could involve compensatory changes in MitoK_ATP activity and thus tested MitoK_ATP involvement in brown adipocyte activities under basal and stimulated conditions. We find that cold exposure and adrenergic stimulation in mice modulate BAT MitoK levels, the channel portion of MitoK_ATP. Genetic ablation of the gene that codes for the pore-forming subunit of MitoK_ATP in human preadipocytes decreased cellular respiration and proliferation, compromising differentiation into mature adipocytes. In mouse cell lines, the absence of the protein limited cellular oxygen consumption in the precursor stage but not in mature adipocytes. Interestingly, inhibition of MitoK_ATP in mature adipocytes increased adrenergic-stimulated oxygen consumption, indicating that shutdown of this pathway is important for full BAT thermogenesis. Similarly, MitoK_ATP inhibition increased oxygen consumption in BAT mitochondria isolated from mice treated with the β3 adrenergic receptor agonist CL316,243. Overall, our results suggest that the activity of MitoK_ATP regulates differentiation and metabolism of brown adipocytes, impacting thermogenesis.NEW & NOTEWORTHY Brown fat cells are important to maintain a healthy body weight by promoting mitochondrial uncoupling. Here, we demonstrate that mitochondrial ATP-sensitive potassium channels (MitoK_ATP) have important roles both in the differentiation of brown fat cells and in the activation of energy-dissipating uncoupling in this tissue.