PT - JOURNAL ARTICLE AU - Weigele, Jochen AU - Zhang, Lihong AU - Franco, Antonietta AU - Cartier, Etienne AU - Dorn, Gerald W. TI - <strong>Sensory-motor neuropathy in Mfn2 T105M knock-in mice and its reversal by a novel piperine-derived mitofusin activator</strong> AID - 10.1124/jpet.124.002258 DP - 2024 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - JPET-AR-2024-002258 4099 - http://jpet.aspetjournals.org/content/early/2024/09/16/jpet.124.002258.short 4100 - http://jpet.aspetjournals.org/content/early/2024/09/16/jpet.124.002258.full AB - Mitochondrial dysfunction is a hallmark of many genetic neurodegenerative diseases, but therapeutic options to reverse mitochondrial dysfunction are limited. While recent studies support the possibility of improving mitochondrial fusion/fission dynamics and motility to correct mitochondrial dysfunction and resulting neurodegeneration in Charcot-Marie-Tooth disease (CMT) and other neuropathies, the clinical utility of reported compounds and relevance of pre-clinical models are uncertain. Here, we describe motor and sensory neuron dysfunction characteristic of clinical CMT type 2A in a CRISPR/Casp-engineered Mfn2 Thr105Met (T105M) mutant knock-in mouse. We further demonstrate that daily oral treatment with a novel mitofusin activator derived from the natural product piperine can reverse these neurological phenotypes. Piperine derivative 8015 promoted mitochondrial fusion and motility in Mfn2-deficient cells in a mitofusin-dependent manner, and reversed mitochondrial dysfunction in cultured fibroblasts and reprogrammed motor neurons from a human CMT2A patient carrying the MFN2 T105M mutation. Like previous mitofusin activators, 8015 exhibited stereospecific functionality, but the more active stereoisomer, 8015-P2, is unique in that it has sub-nanomolar potency and undergoes entero-hepatic recirculation which extends its in vivo half-life. Daily administration of 8015-P2 to Mfn2 T105M knock-in mice for 6 weeks normalized neuromuscular and sensory dysfunction and corrected histological/ultrastructural neurodegeneration and neurogenic myoatrophy. These studies describe a more clinically relevant mouse model of CMT2A and an improved mitofusin activator derived from piperine. We posit that 8015-P2 and other piperine derivatives may benefit CMT2A or other neurodegenerative conditions wherein mitochondrial dysdynamism plays a contributory role. Significance Statement Mitochondrial dysfunction is widespread and broadly contributory in neurodegeneration, but difficult to target therapeutically. Here, we describe 8015-P2, a new small molecule mitofusin activator with ~10-fold greater potency and improved in vivo pharmacokinetics vs comparators, and demonstrate its rapid reversal of sensory and motor neuron dysfunction in an Mfn2 T105M knock-in mouse model of Charcot-Marie-Tooth disease type 2A. These findings further support the therapeutic approach of targeting mitochondrial dysdynamism in neurodegeneration.