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

Emmanuelle C Genin (1) , Sylvie Bannwarth (1) , Baptiste Ropert (1) , Françoise Lespinasse (1) , Alessandra Mauri-Crouzet (1) , Gaelle Augé (1) , Konstantina Fragaki (1) , Charlotte Cochaud (1) , Erminia Donnarumma (2) , Sandra Lacas-Gervais (3) , Timothy Wai (2) , Véronique Paquis-Flucklinger (1)

1 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
2 Biologie mitochondriale – Mitochondrial biology
3 CCMA - Centre Commun de Microscopie Appliquée

CHCHD10 is an amyotrophic lateral sclerosis/frontotemporal dementia gene that encodes a mitochondrial protein whose precise function is unclear. Here we show that Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing protein 10 interacts with the Stomatin-Like Protein 2 and participates in the stability of the prohibitin complex in the inner mitochondrial membrane. By using patient fibroblasts and mouse models expressing the same CHCHD10 variant (p.Ser59Leu), we show that Stomatin-Like Protein 2 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 prohibitin complex, which participates at least in part in 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 prohibitin complex leads to the instability of the mitochondrial contact site and cristae organizing the system complex, probably by the disruption of OPA1–mitofilin interaction. Thus, Stomatin-Like Protein 2/prohibitin aggregates and destabilization of the prohibitin complex are critical in the sequence of events leading to motor neuron death in CHCHD10S59L-related disease.

Keywords: amyotrophic lateral sclerosis; frontotemporal dementia; motor neuron disease; mitochondrion; ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia; IMM = inner mitochondrial membrane; MICOS = mitochondrial contact site and cristae organizing system; MN = motor neuron; PHB = prohibitin; PLA = proximity ligation assay; RC = respiratory chain

Domains: Santé publique et épidémiologie

Emmanuelle C Genin, Sylvie Bannwarth, Baptiste Ropert, Françoise Lespinasse, Alessandra Mauri-Crouzet, et al.. CHCHD10 and SLP2 control the stability of the PHB complex: a key factor for motor neuron viability. Brain - A Journal of Neurology , 2022, 145 (10), pp.3415-3430. ⟨10.1093/brain/awac197⟩. ⟨pasteur-03853884⟩