NAD+ precursors prolong survival and improve cardiac phenotypes in a mouse model of Friedreich's Ataxia.

• DOI: 10.1172/jci.insight.177152
• Publication Date: 2024-07-18
• Authors: Caroline E Perry; Sarah Halawani; Sarmistha Mukherjee; Lucie Ngaba; Melissa Lieu; Won Dong Lee; James G. Davis; Gabriel Komla Adzika; Alyssa N Bebenek; Daniel D Bazianos; Beishan Chen; Elizabeth Mercado...; Liam Flatley; Arjun P Suryawanshi; Isabelle Ho; Joshua D. Rabinowitz; Suraj D. Serai; David M. Biko; Jaclyn Tamaroff; Anna Dedio; Kristin Wade; Kimberly Y. Lin; David J. Livingston; Shana E. McCormack; David R. Lynch; Joseph A. Baur

Friedreich's ataxia (FRDA) is a progressive disorder caused by insufficient expression of frataxin, which plays critical role in assembly iron-sulfur centers mitochondria. Individuals are cognitively normal but display loss motor coordination and cardiac abnormalities. Many ultimately develop heart failure. Administration nicotinamide adenine dinucleotide-positive (NAD+) precursors has shown promise human mitochondrial myopathy rodent models failure, including mice lacking frataxin cardiomyocytes. We studied with systemic knockdown (shFxn), deficits early mortality hypertrophy. Hearts these do not "fail" per se become hyperdynamic small chamber sizes. Data from an ongoing natural history study indicate that hearts observed young individuals FRDA, suggesting the mouse model could reflect pathology. Administering mononucleotide or riboside to shFxn increases survival, modestly improves hypertrophy, limits ejection fraction. Mechanistically, most transcriptional metabolic changes induced insensitive NAD+ precursor administration, glutathione levels increased, improved antioxidant capacity. Overall, our findings cardioprotective this FRDA warrant further investigation.