UPRmt

N-Propargylglycine is a brain-penetrant and orally active PRODH inhibitor. N-Propargylglycine covalently modifies enzyme-bound FAD and active site lysine, causing enzyme structural distortion, protein decay, and irreversible inhibition of proline and 4-hydroxyproline catabolism. N-Propargylglycine induces UPRmt, upregulates mitochondrial chaperones and YME1L1, enhances mitochondrial proteostasis, blocks astrocytic L-proline consumption, and abolishes L-proline’s ATP-maintaining and viability-protective effects. N-Propargylglycine stimulates neural processes, increases brain proline, hydroxyproline, and sarcosine levels, partially normalizes Huntington’s disease whole brain transcriptomes. N-Propargylglycine reduces hyperoxaluria, prevents calcium oxalate stone formation, reduces kidney tubular damage, and restores weight and survival in Grhpr knockout mice. N-Propargylglycine can be used for the research of breast cancer, neurodegenerative disorders, Huntington’s disease, and primary hyperoxaluria type 2 .

Tigilanol tiglate (EBC-46) is a protein kinase C (PKC)/C1 domain activator. Tigilanol tiglate is associated with mitochondrial/endoplasmic reticulum (ER) dysfunction, leading to activation of the unfolded protein response (UPRmt/ER) and subsequent induction of ATP depletion, organelles expansion, Caspase activation, gasdermin E cleavage, and terminal necrosis. Tigilanol tiglate, as a small anti-tumor molecule with immunomodulatory effects, can be used in the study of head and neck squamous cell carcinoma and soft tissue sarcoma .

Mitochondrial respiration-IN-1 is a mitochondrial respiratory inhibitor. Mitochondrial respiration-IN-1 reduces platelet aggregation, adhesion, and platelet-induced coagulation responses. Mitochondrial respiration-IN-1 induces adaptive glycolysis, decreases mitochondrial membrane potential, selectively reduces ATP production derived from oxidative phosphorylation, and exerts bidirectional regulatory effects on cell proliferation. Mitochondrial respiration-IN-1 activates UPRmt and upregulates the expression of SDHA-1 and MT-CO1. Mitochondrial respiration-IN-1 restores metabolic homeostasis in type 2 diabetic mice. Mitochondrial respiration-IN-1 can be used to investigate diseases mediated by inappropriate platelet activation/aggregation and type 2 diabetes .