Mdivi-1 affects neuronal activity by inhibition of Complex I and respiratory supercomplex assembly

Several human diseases, including cancer and neurodegeneration, are associated with excessive mitochondrial fragmentation. In this context, mitochondrial division inhibitor (Mdivi-1) has been tested as a therapeutic to block the fission-related protein dynamin-like protein-1 (Drp1). Recent studies suggest that Mdivi-1 interferes with mitochondrial bioenergetics. Here we show that the molecular mechanism of Mdivi-1 is based on inhibition of complex I at the IQ site. This leads to the destabilization of complex I, impairs the assembly of N- and Q-respirasomes and is associated with increased ROS production. The result is a reduced efficiency of ATP generation. Second, the calcium homeostasis of cells is impaired, which severely affects the electrical activity of neurons. Given the results presented here, a potential therapeutic application of Mdivi-1 is challenging because of its impact on synaptic activity. Similar to the Complex I inhibitor rotenone, Mdivi-1 may lead to neurodegenerative effects in the long term. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/577160v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1bffc82org.highwire.dtl.DTLVardef@15ae3b5org.highwire.dtl.DTLVardef@1ba3a5org.highwire.dtl.DTLVardef@94cfc0_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIMdivi-1 inhibits respiratory complex I at the IQ-site C_LIO_LIInhibition destabilizes complex I and reduces supercomplex formation C_LIO_LIMitochondrial ATP levels decrease C_LIO_LICa2+ metabolism is affected C_LIO_LINeuronal activity is compromised C_LI