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.

We claim: 
     
         1 . A method of treating a disorder associated with mitochondrial dysfunction comprising administering to a subject suffering from or susceptible to developing a metabolic disorder a PARP inhibitor and one or more compounds that increases intracellular and mitochondrial nicotinamide adenine dinucleotide (NAD + ) in an amount sufficient to induce SIRT1 or SIRT3 protein expression. 
     
     
         2 . A method of promoting oxidative metabolism comprising administering to a subject suffering from or susceptible to developing a metabolic disorder a PARP inhibitor and one or more compounds that increases intracellular nicotinamide adenine dinucleotide (NAD + ) in an amount sufficient to induce SIRT1 or SIRT3 protein expression. 
     
     
         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 . The method according to  claim 1 , wherein the one or more compounds is a NAD booster, a PARP inhibitor, or an AMPK activator, or a combination thereof. 
     
     
         6 . The method of  claim 5 , wherein the NAD booster is tryptophan, nicotinamide riboside (NR), niacin, nicotinic acid (NA), nicotinamide (NAM), N-formylkynurenine, quinolinic acid, nicotinamide riboside kinase (NRK), or nicotinamide mononucleotide (NMN). 
     
     
         7 . The method of  claim 5 , wherein the AMPK agonist is 5-aminoimidazole-4-carboxamide-1-b-D-riboside, 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). 
     
     
         8 . 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. 
     
     
         9 . The method of  claim 5 , wherein the PARP inhibitor is a nucleic acid that inhibits PARP-1 expression or activity. 
     
     
         10 . The method of  claim 2 , wherein said disorder associated with mitochondrial dysfunction is a metabolic disorder, a neurodegenerative disease, an aging related disorder, or a chronic inflammatory disease. 
     
     
         11 . The method of  claim 10 , wherein the metabolic disorder is obesity or type II diabetes. 
     
     
         12 . The method according to  claim 2 , wherein the one or more compounds is a NAD booster, a PARP inhibitor, or an AMPK activator, or a combination thereof. 
     
     
         13 . 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. 
     
     
         14 . The method of  claim 13 , 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. 
     
     
         15 . The method of  claim 13 , wherein the PARP inhibitor is a nucleic acid that inhibits PARP-1 expression or activity. 
     
     
         16 . The method of  claim 13 , wherein the NAD booster is tryptophan, nicotinamide riboside (NR), niacin, nicotinic acid (NA), nicotinamide (NAM), N-formylkynurenine, quinolinic acid, nicotinamide riboside kinase (NRK), or nicotinamide mononucleotide (NMN). 
     
     
         17 . The method of  claim 13 , wherein the AMPK agonist is 5-aminoimidazole-4-carboxamide-1-b-D-riboside, 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). 
     
     
         18 . A method of increasing the concentration of NAD +  within the mitochondria comprising contacting mitrocondria with a PARP inhibitor and a NAD +  precursor selected from the group consisting of nicotinamide riboside (NR), nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN), and tryptophan. 
     
     
         19 . A method of activating mitochondrial sirtuin comprising contacting mitochondria with a PARP inhibitor and a NAD +  precursor selected from the group consisting of nicotinamide riboside (NR), nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN), and tryptophan 
     
     
         20 . The method of  claim 19 , wherein the sirtuin is SIRT3, SIRT4 or SIRT5.