MFI8 is a small-molecule inhibitor of mitochondrial fusion[1]. By binding to the HR2 domain of the mitofusins MFN1/MFN2, MFI8 inhibits mitochondrial fusion and promotes fission, thereby affecting mitochondrial function[2]. MFI8 is commonly used in studies on mitochondrial dynamics, apoptotic signaling pathways, and Parkinson's disease animal models associated with mitochondrial dysfunction[3,4].
In vitro, treatment of U2OS cells expressing CytoGFP/MitoCherry with MFI8 (20μM) for 6h induced minority mitochondrial outer membrane permeabilization (MOMP). Treatment of WT MEF cells with MFI8 (10, 15, 20μM) for 6h concentration-dependently increased caspase-3/7 activity[5]. Treatment of PANC-1 cells under low-glucose (0.2g/L) conditions with MFI8 (5μM) for 48h caused pronounced mitochondrial fragmentation[6].
In vivo, intrathecal injection of MFI8 (0.5µg/5µL) into postherpetic neuralgia (PHN) model mice (Gcn5l1-deficient) reversed the suppressive effect of Gcn5l1 deficiency on the inflammatory cytokines TNF-α, IL-1β, and IL-6[7].
References:[1] Song Y, Ren S, Chen X, et al. Inhibition of MFN1 restores tamoxifen-induced apoptosis in resistant cells by disrupting aberrant mitochondrial fusion dynamics[J]. Cancer letters, 2024, 590: 216847.
[2] Hernandez-Resendiz S, Prakash A, Loo S J, et al. Targeting mitochondrial shape: at the heart of cardioprotection[J]. Basic Research in Cardiology, 2023, 118(1): 49.
[3] Zacharioudakis E, Gavathiotis E. Mitochondrial dynamics proteins as emerging drug targets[J]. Trends in pharmacological sciences, 2023, 44(2): 112-127.
[4] Zacharioudakis E, Agianian B, Kumar MV V, et al. Modulating mitofusins to control mitochondrial function and signaling[J]. Nature communications, 2022, 13(1): 3775.
[5] Zhang Y, Tian S, Niu M, et al. Activin A protects against lipopolysaccharide/TNF-α induced damage of dopaminergic neurons both in vivo and in vitro by regulating mitochondrial fusion[J]. Neuroscience, 2025.
[6] Zhang Z, Fang L, Furukawa H, et al. Maladaptive role of peridroplet mitochondria during lipophagy disruption in pancreatic cancer[J]. Biochemical and Biophysical Research Communications, 2025: 152609.
[7] Li W, Cao X, Wang S, et al. GCN5L1 Aggravates Postherpetic Neuralgia Through Regulating Microglial Mitochondrial Fission–Fusion Homeostasis[J]. Journal of Cellular and Molecular Medicine, 2025, 29(18): e70861.