Perry 2024 JCI Insight

From Bioblast
Publications in the MiPMap
Perry CE, Halawani SM, Mukherjee S, Ngaba LV, Lieu M, Lee WD, Davis JG, Adzika GK, Bebenek AN, Bazianos DD, Chen B, Mercado-Ayon E, Flatley LP, Suryawanshi AP, Ho I, Rabinowitz JD, Serai SD, Biko DM, Tamaroff J, DeDio A, Wade K, Lin KY, Livingston DJ, McCormack SE, Lynch DR, Baur JA (2024) NAD+ precursors prolong survival and improve cardiac phenotypes in a mouse model of Friedreich's Ataxia. JCI Insight 9:e177152. https://doi.org/10.1172/jci.insight.177152

Β» PMID: 39171530 Open Access

Perry Caroline E, Halawani Sarah M, Mukherjee Sarmistha, Ngaba Lucie V, Lieu Melissa, Lee Won Dong, Davis James G, Adzika Gabriel K, Bebenek Alyssa N, Bazianos Daniel D, Chen Beishan, Mercado-Ayon Elizabeth, Flatley Liam P, Suryawanshi Arjun P, Ho Isabelle, Rabinowitz Joshua D, Serai Surja D, Biko David M, Tamaroff Jaclyn, DeDio Anna, Wade Kristin, Lin Kimberly Y, Livingston David J, McCormack Shana E, Lynch David R, Baur Joseph A (2024) JCI Insight

Abstract: Friedreich's ataxia (FRDA) is a progressive disorder caused by insufficient expression of frataxin, which plays a critical role in assembly of iron-sulfur centers in mitochondria. Individuals are cognitively normal but display a loss of motor coordination and cardiac abnormalities. Many ultimately develop heart failure. Administration of nicotinamide adenine dinucleotide-positive (NAD+) precursors has shown promise in human mitochondrial myopathy and rodent models of heart failure, including mice lacking frataxin in cardiomyocytes. We studied mice with systemic knockdown of frataxin (shFxn), which display motor deficits and early mortality with cardiac hypertrophy. Hearts in these mice do not "fail" per se but become hyperdynamic with small chamber sizes. Data from an ongoing natural history study indicate that hyperdynamic hearts are observed in young individuals with FRDA, suggesting that the mouse model could reflect early pathology. Administering nicotinamide mononucleotide or riboside to shFxn mice increases survival, modestly improves cardiac hypertrophy, and limits increases in ejection fraction. Mechanistically, most of the transcriptional and metabolic changes induced by frataxin knockdown are insensitive to NAD+ precursor administration, but glutathione levels are increased, suggesting improved antioxidant capacity. Overall, our findings indicate that NAD+ precursors are modestly cardioprotective in this model of FRDA and warrant further investigation. β€’ Keywords: Cardiology, Metabolism, Mitochondria, Neurological disorders β€’ Bioblast editor: Plangger M β€’ O2k-Network Lab: US PA Philadelphia Wallace DC, US PA Philadelphia Baur JA


Labels: MiParea: Gender, Respiration, Genetic knockout;overexpression  Pathology: Cardiovascular 

Organism: Mouse  Tissue;cell: Heart  Preparation: Isolated mitochondria 


Coupling state: LEAK, OXPHOS  Pathway: F, N, S, CIV  HRR: Oxygraph-2k 

2024-09 

Cookies help us deliver our services. By using our services, you agree to our use of cookies.