Methods of Treating Mitochondrial Dysfunction

Abstract

The present invention provides methods of treating various disorders associated with mitochondrial dysfunction, including but not limited to metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, and diseases of aging.

1 . A method of treating a disorder associated with mitochondrial dysfunction comprising administering to subject suffering from or susceptible to developing a metabolic disorder one or more compounds that increases intracellular nicotinamide adenine dinucleotide (NAD + ) in an amount sufficient to activate SIRT1 or SIRT3. 
     
     
         2 . A method of promoting oxidative metabolism comprising administering to subject suffering from or susceptible to developing a metabolic disorder one or more compounds that increases intracellular nicotinamide adenine dinucleotide (NAD + ) in an amount sufficient to activate SIRT1 or SIRT3. 
     
     
         3 . The method of  claim 1 , wherein said disorder associated with mitochondrial dysfunction is a metabolic disorder, a neurodegenerative disease, an aging related disorder or a chronic inflammatory disease. 
     
     
         4 . The method of  claim 3 , wherein the metabolic disorder is obesity or type II diabetes. 
     
     
         5 . A method of treating cancer comprising administering to subject suffering from or susceptible to developing a cancer a PARP inhibitor and a NAD+ booster, a PARP inhibitor and an AMPK agonist, or an AMPK agonist and a NAD+ booster. 
     
     
         6 . The method according to  claim 1 , wherein the compound is a NAD booster, a PARP-1 inhibitor, an AMPK activator or combination thereof. 
     
     
         7 . The method of  claim 5 , wherein the PARP inhibitor is PJ34, TIQ, TES-500, TES-501, BSI-202, Iniparib, AZD2281, Olaparib, ABT-888, Veliparib, AG014699, CEP 9722, or MK 4827. 
     
     
         8 . The method of  claim 5 , wherein the PARP-1 inhibitor is a nucleic acid that inhibits PARP-1 expression or activity. 
     
     
         9 . The method of  claim 5 , wherein the NAD booster is tryptophan, nicotinamide riboside (NR), niacin, nicotinic acid (NA), nicotinamide (NAM), N-formylkynurenine, quinolinic acid, nictotinamide riboside kinase (NRK) or nicotinamide mononucleotide (NMN). 
     
     
         10 . The method of  claim 5 , wherein the AMPK agonist is 5-aminoimidazole-4-carboxamide-1-b-D-ribosicie, PT-1, A-769662 (Abbott), Adiponectin, Leptin, Ghrelin, Cannabinoids, alpha-lipoic acid, Interleukin-6 (IL-6), Resveratrol, Quercetin, Metformin, Berberine, Curcumine, Epigallocatechin-3-gallate (green tea), Thiazolidinediones, such as rosiglitazone and pioglitazone or Dinitrophenol (DNP). 
     
     
         11 . A method of increasing the concentration of NAD +  within the mitochondria comprising contacting mitrocondria with nicotinamide riboside (NR). 
     
     
         12 . A method of activating mitochondrial sirtuin comprising contacting mitochondria with nicotinamide riboside (NR). 
     
     
         13 . The method of  claim 12 , wherein the sirtuin is SIRT3, SIRT4 or SIRT5.