SLP2/prohibitins aggregates and instability of the PHB complex are key elements in CHCHD10S59L-related disease

CHCHD10 is an ALS/FTD gene, also involved in a large clinical spectrum, that encodes a protein whose precise function within mitochondria is unclear. Here we show that CHCHD10 interacts with the Stomatin-Like Protein 2 (SLP2) to control the stability of the Prohibitin (PHB) complex in the inner mitochondrial membrane. In affected tissues, SLP2 forms aggregates with prohibitins and the instability of the PHB complex results in activation of OMA1 and accelerated OPA1 proteolysis leading to mitochondrial fragmentation, loss of mitochondrial cristae and apoptosis. Abnormal cristae morphogenesis depends on both the PHB complex destabilization leading to MICOS complex instability, via disruption of OPA1/Mitofilin interaction, and the activation of PINK1-mediated pathways. We also show that the increase of mitophagy found in both heart and hippocampus of Chchd10 S59L/+ mito -QC mice is PINK1/Parkin-dependent. Thus, SLP2/PHBs aggregates and destabilization of the PHB complex with PINK1 activation are critical in the sequence of events leading to CHCHD10 S59L -related disease.