TG2 deficiency in sebaceous glands leads to lipid accumulation and reduced autophagy, prompting investigation into mitochondrial dysfunction. Using CRISPR/Cas9, WT and TG2 KO sebocyte cell lines were compared, revealing differential expression of mitochondria-associated genes and decreased levels of oxidative phosphorylation complexes in TG2 KO cells. Elevated ROS levels further confirmed mitochondrial impairment, suggesting defective energy production pathways in TG2-deficient cells, warranting further research into disease implications and therapeutic strategies.