Methods of treating mitochondrial dysfunction

1. A method of treating a disorder associated with mitochondrial dysfunction, the method comprising administering to a subject in need thereof:

(a) a poly(ADP-ribose) polymerase (PARP) inhibitor; and

(b) one or more compounds that increases intracellular and mitochondrial nicotinamide adenine dinucleotide (NAD + ) in an amount sufficient to induce Sirtuin 1 (SIRT1) or Sirtuin 3 (SIRT3) protein expression,

wherein the PARP inhibitor is N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acetamide hydrochloride (PJ34), Thieno[2,3-c]isoquinolin-5-one (TIQ), 4-iodo-3-nitrobenzamide (Iniparib or BSI-201), 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one (Olaparib or AXD2281), 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (Veliparib or ABT-888), 6-fluoro-2-[4-(methylaminomethyl)phenyl]-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraen-9-one (Rucaparib or AG014699), 11-methoxy-2-((4-methylpiperazin-1-yl)methyl)-4,5,6,7-tetrahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione (CEP-9722), or 2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide (Niraparib or MK 4827), and wherein said disorder associated with mitochondrial dysfunction is a neurodegenerative disease.

2. The method according to claim 1 , wherein the one or more compounds is a NAD booster.

3. The method of claim 2 , 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).

4. The method of claim 1 , wherein the neurodegenerative disease is Dementia, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

5. A method of increasing the concentration of NAD + within the mitochondria, the method 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, wherein the PARP inhibitor is N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acetamide hydrochloride (PJ34), Thieno[2,3-c]isoquinolin-5-one (TIQ), 4-iodo-3-nitrobenzamide (Iniparib or BSI-201), 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one (Olaparib or AXD2281), 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (Veliparib or ABT-888), 6-fluoro-2-[4-(methylaminomethyl)phenyl]-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraen-9-one (Rucaparib or AGO 14699), 11-methoxy-2-((4-methylpiperazin-1-yl)methyl)-4,5,6,7-tetrahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione (CEP-9722), or 2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide (Niraparib or MK 4827).

6. A method of activating mitochondrial sirtuin, the method 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, wherein the PARP inhibitor is N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acetamide hydrochloride (PJ34), Thieno[2,3-c]isoquinolin-5-one (TIQ), 4-iodo-3-nitrobenzamide (Iniparib or BSI-201), 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one (Olaparib or AXD2281), 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (Veliparib or ABT-888), 6-fluoro-2-[4-(methylaminomethyl)phenyl]-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraen-9-one (Rucaparib or AG014699), 11-methoxy-2-((4-methylpiperazin-1-yl)methyl)-4,5,6,7-tetrahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione (CEP-9722), or 2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide (Niraparib or MK 4827).

7. The method of claim 6 , wherein the sirtuin is SIRT3, SIRT4 or SIRT5.