Mitochondrial NUDIX hydrolases: A metabolic link between NAD catabolism, GTP and mitochondrial dynamics. (October 2017)

• Record Type: Journal Article
• Authors: Long, Aaron; Klimova, Nina; Kristian, Tibor
• Is Part Of: Neurochemistry international. Volume 109(2017)
• Page Start: 193
• Page End: 201
• Publication Date: 2017-10
• Subjects: NAD+ -- PARP1 -- NUDIX -- AMP -- GTP -- Mitochondrial dynamics; ADPr ADP- ribose -- ADPrP ADPr-phosphate -- AIF apoptosis inducing factor -- AK3 adenylate kinase 3 -- AMP adenosine monophosphate -- AMPK AMP-activated protein kinase -- ANT adenine nucleotide translocase -- ARH3 ADP-ribosyl hydrolase-3 -- ARTD1 ADP-ribosyltransferase diphtheria toxin-like one -- ARTs ADP-ribosyl transferases -- cADPr cyclic ADP-ribose -- CaMKKβ calmodulin-dependent protein kinase kinase-β -- CD38 / CD157 ADP-ribosyl cyclases or cyclic ADP-ribose synthases -- Drp1 Dynamin-related protein 1 -- GAPDH glyceraldehyde 3-phosphate dehydrogenase -- HDACs histone deacetylases -- HK1 hexokinase 1 -- IM inner membrane -- IMS intermembrane space -- LKB1 liver kinase B1 -- macroD Macro domain -- MARylation mono-ADP-ribosylation -- MFF mitochondria fission factor -- MFN mitofusin -- mtPARP1 intramitochondrial localized PARP1 -- Nam nicotinamide -- NAADP nicotinamide acid ADP -- NDPK nucleoside diphosphate kinase -- NMN nicotinamide mononucleotide -- NMNATs NMN adenyl transferases -- NR nicotinamide riboside -- NUDIX nucleoside diphosphate linked to another moiety x -- OAADPr O-acetyl-ADP-ribose -- OM outer membrane -- OPA1 optic atrophy protein -- PARG poly(ADP-ribose) glycohydrolase -- PARP1 Poly(ADP-ribose) polymerase 1 -- PARylation poly-ADP-ribosylation -- Polγ DNA polymerase gamma -- ROS reactive oxygen species -- SCS succinyl-CoA synthetase (ligase) -- TCA tricarboxylic acid cycle -- TRPM2 Transient receptor potential melastatin 2; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2017.03.009
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: NAD + catabolism and mitochondrial dynamics are important parts of normal mitochondrial function and are both reported to be disrupted in aging, neurodegenerative diseases, and acute brain injury. While both processes have been extensively studied there has been little reported on how the mechanisms of these two processes are linked. This review focuses on how downstream NAD + catabolism via NUDIX hydrolases affects mitochondrial dynamics under pathologic conditions. Additionally, several potential targets in mitochondrial dysfunction and fragmentation are discussed, including the roles of mitochondrial poly(ADP-ribose) polymerase 1(mtPARP1), AMPK, AMP, and intra-mitochondrial GTP metabolism. Mitochondrial and cytosolic NUDIX hydrolases (NUDT9α and NUDT9β) can affect mitochondrial and cellular AMP levels by hydrolyzing ADP- ribose (ADPr) and subsequently altering the levels of GTP and ATP. Poly (ADP-ribose) polymerase 1 (PARP1) is activated after DNA damage, which depletes NAD + pools and results in the PARylation of nuclear and mitochondrial proteins. In the mitochondria, ADP-ribosyl hydrolase-3 (ARH3) hydrolyzes PAR to ADPr, while NUDT9α metabolizes ADPr to AMP. Elevated AMP levels have been reported to reduce mitochondrial ATP production by inhibiting the adenine nucleotide translocase (ANT), allosterically activating AMPK by altering the cellular AMP: ATP ratio, and by depleting mitochondrial GTP pools by being phosphorylated by adenylate kinase 3 (AK3), which uses GTP as a phosphate donor. Recently, activated AMPK was reported to phosphorylate mitochondria fission factor (MFF), which increases Drp1 localization to the mitochondria and promotes mitochondrial fission. Moreover, the increased AK3 activity could deplete mitochondrial GTP pools and possibly inhibit normal activity of GTP-dependent fusion enzymes, thus altering mitochondrial dynamics. Highlights: A link between NAD + catabolism and mitochondrial dynamics is proposed. The mechanism is centered around elevated AMP due to NUDIX enzymes activity. The mechanism also supports the idea of an intra-mitochondrial PARP1. Phosphorylation of mitochondrial AMP depletes GTP levels, inhibiting fusion. Elevated AMP also activates AMPK, leading to Drp1 induced fission.