CHCHD10 and SLP2 control the stability of the PHB complex: a key factor for motor neuron viability.

Abstract

CHCHD10 is an amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) gene that encodes a mitochondrial protein whose precise function is unclear. Here we show that CHCHD10 interacts with the Stomatin-Like Protein 2 (SLP2) and participates to the stability of the Prohibitin (PHB) complex in the inner mitochondrial membrane. By using patient fibroblasts and mouse models expressing the same CHCHD10 variant (p.Ser59Leu), we show that SLP2 forms aggregates with prohibitins, found in vivo in the hippocampus and as aggresome-like inclusions in spinal motor neurons of Chchd10S59L/+ mice. Affected cells and tissues display instability of the PHB complex which participates at least in part to the activation of the OMA1 cascade with OPA1 processing leading to mitochondrial fragmentation, abnormal mitochondrial cristae morphogenesis and neuronal death found in spinal cord and the hippocampus of Chchd10S59L/+ animals. Destabilization of the PHB complex leads to the instability of the mitochondrial contact site and cristae organizing system (MICOS) complex, likely via the disruption of OPA1/Mitofilin interaction. Thus, SLP2/PHB aggregates and destabilization of the PHB complex are critical in the sequence of events leading to motor neuron death in CHCHD10S59L-related disease.