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ATP synthase subunit a ATP synthase subunit beta, mitochondrial ADP/ATP translocase 1 HMG-CoA reductase Mevalonate kinase Phosphomevalonate kinase Farnesyl pyrophosphate synthase Farnesyl pyrophosphate synthase Squalene synthase Diphosphomevalonate decarboxylase Geranylgeranyl pyrophosphate synthase Hydroxymethylglutaryl- CoA synthase, cytoplasmic Acetyl-CoA acetyltransferase, mitochondrial ATP synthase lipid-binding protein, mitochondrial ATP synthase subunit alpha, mitochondrial ATP synthase subunit b, mitochondrial ATP synthase subunit delta, mitochondrial ATP synthase subunit epsilon, mitochondrial ATP synthase subunit gamma, mitochondrial Clodronic Acid Clodronic Acid Clodronic Acid Clodronic Acid ADP ADP ATP ATP ADP ATP Clodronic Acid Clodronic Acid 3-Hydroxy-3-methylglutaryl-CoA NADPH H+ NADP CoA Mevalonate ATP Mevalonate-5P ADP ATP Mevalonate-5PP ADP Isopentenyl-PP Dimethylallylpyrophosphate PPi Geranyl-PP Isopentenyl pyrophosphate Farnesyl pyrophosphate PPi H+ NADPH PPi NADP Squalene Cholesterol ATP ADP Pi CO2 Isopentenyl pyrophosphate Geranylgeranyl-PP PPi Acetyl-CoA H2O Acetoacetyl-CoA CoA CoA H+ H+ Magnesium Magnesium Magnesium Magnesium Osteoclast Cytosol Mevalonate Pathway Clodronic acid enters the cell through endocytosis. The endocytic vesicles are acidified and the clodronic acid is released into the cytosol. Inner Membrane Outer Membrane Mitochondrial Matrix Clodronic acid travels to the mitochondrial matrix inhibiting ADP/ATP translocase. Without ATP the osteoclast cannot function and dies. Clodronic acid structure allows it to become an ATP analogue that is nonfunctional disrupting osteoclast survival Bone Loss Clodronic Acid is administered orally and travels to the bone Clodronic Acid acts to counteract osteoclast activity and reduce bone degradation
Mitochondria MT-ATP6 ATP5B SLC25A4 HMGCLL1 MVK PMVK FDPS FDPS FDFT1 MVD GGPS1 HMGCS1 ACAT1 ATP5G2 ATP5A1 ATP5F1 ATP5D ATP5E ATP5C1 Clodronic Acid Clodronic Acid Clodronic Acid Clodronic Acid Adenosine diphosphate Adenosine diphosphate Adenosine triphosphate Adenosine triphosphate Adenosine diphosphate Adenosine triphosphate Clodronic Acid Clodronic Acid 3-Hydroxy-3- methylglutaryl- CoA NADPH Hydrogen Ion NADP Coenzyme A Mevalonate Adenosine triphosphate Mevalonate-5P Adenosine diphosphate Adenosine triphosphate Mevalonate-5PP Adenosine diphosphate Isopentenyl-PP Dimethylallylpyrophosphate Pyrophosphate Geranyl-PP Isopentenyl pyrophosphate Farnesyl pyrophosphate Pyrophosphate Hydrogen Ion NADPH Pyrophosphate NADP Squalene Cholesterol Adenosine triphosphate Adenosine diphosphate Phosphate Carbon dioxide Isopentenyl pyrophosphate Geranylgeranyl- PP Pyrophosphate Acetyl-CoA Water Acetoacetyl-CoA Coenzyme A Coenzyme A Hydrogen Ion Hydrogen Ion
MT-ATP6 ATP5B SLC25A4 HMGCLL1 MVK PMVK FDPS FDPS FDFT1 MVD GGPS1 HMGCS1 ACAT1 ATP5G2 ATP5A1 ATP5F1 ATP5D ATP5E ATP5C1 Clo Aci Clo Aci Clo Aci Clo Aci ADP ADP ATP ATP ADP ATP Clo Aci Clo Aci HMG-CoA NADPH H+ NADP CoA Meval ATP Meva-5P ADP ATP Mev-5PP ADP Isop-PP Ipe PPi Gryl-PP IsopPyr FarPP PPi H+ NADPH PPi NADP Squalen Lanol ATP ADP Pi CO2 IsopPyr GGDP PPi Ac-CoA H2O ActaCoA CoA CoA H+ H+ Mg2+ Mg2+ Mg2+ Mg2+ Osteoclast Cytosol Mevalonate Pathway Clodronic acid enters the cell through endocytosis. The endocytic vesicles are acidified and the clodronic acid is released into the cytosol. Inner Membrane Outer Membrane Mitochondrial Matrix Clodronic acid travels to the mitochondrial matrix inhibiting ADP/ATP translocase. Without ATP the osteoclast cannot function and dies. Clodronic acid structure allows it to become an ATP analogue that is nonfunctional disrupting osteoclast survival Bone Loss Clodronic Acid is administered orally and travels to the bone Clodronic Acid acts to counteract osteoclast activity and reduce bone degradation
Mitochondria MT-ATP6 ATP5B SLC25A4 HMGCLL1 MVK PMVK FDPS FDPS FDFT1 MVD GGPS1 HMGCS1 ACAT1 ATP5G2 ATP5A1 ATP5F1 ATP5D ATP5E ATP5C1 Clo Aci Clo Aci Clo Aci Clo Aci ADP ADP ATP ATP ADP ATP Clo Aci Clo Aci HMG-CoA NADPH H+ NADP CoA Meval ATP Meva-5P ADP ATP Mev-5PP ADP Isop-PP Ipe Ppi Gryl-PP IsopPyr FarPP Ppi H+ NADPH Ppi NADP Squalen Lanol ATP ADP Pi CO2 IsopPyr GGDP Ppi Ac-CoA H2O ActaCoA CoA CoA H+ H+