NQO1 Binds and Supports SIRT1 Function

Silent information regulator 2-related enzyme 1 (SIRT1) is an NAD+-dependent class III deacetylase and a key component of the cellular metabolic sensing pathway. The requirement of NAD+ for SIRT1 activity led us to assume that NQO1, an NADH oxidoreductase producing NAD+, regulates SIRT1 activity. We show here that SIRT1 is capable of increasing NQO1 (NAD(P)H Dehydrogenase Quinone 1) transcription and protein levels. NQO1 physically interacts with SIRT1 but not with an enzymatically dead SIRT1 H363Y mutant. The interaction of NQO1 with SIRT1 is markedly increased under mitochondrial inhibition. Interestingly, under this condition the nuclear pool of NQO1 is elevated. Depletion of NQO1 compromises the role of SIRT1 in inducing transcription of several target genes and eliminates the protective role of SIRT1 following mitochondrial inhibition. Our results suggest that SIRT1 and NQO1 form a regulatory loop where SIRT1 regulates NQO1 expression and NQO1 binds and mediates the protective role of SIRT1 during mitochondrial stress. The interplay between an NADH oxidoreductase enzyme and an NAD+ dependent deacetylase may act as a rheostat in sensing mitochondrial stress.

NQO1 binds and supports SIRT1 function

Silent information regulator 2-related enzyme 1 (SIRT1) is an NAD+-dependent class III deacetylase and a key component of the cellular metabolic sensing pathway. The requirement of NAD+ for SIRT1 activity led us to assume that NQO1, an NADH oxidoreductase producing NAD+, regulates SIRT1 activity. We show here that SIRT1 is capable of increasing NQO1 (NAD(P)H Dehydrogenase Quinone 1) transcription and protein levels. NQO1 physically interacts with SIRT1 but not with an enzymatically dead SIRT1 H363Y mutant. The interaction of NQO1 with SIRT1 is markedly increased under mitochondrial inhibition. Interestingly, under this condition the nuclear pool of NQO1 is elevated. Depletion of NQO1 compromises the role of SIRT1 in inducing transcription of several target genes and eliminates the protective role of SIRT1 following mitochondrial inhibition. Our results suggest that SIRT1 and NQO1 form a regulatory loop where SIRT1 regulates NQO1 expression and NQO1 binds and mediates the protective role of SIRT1 during mitochondrial stress. The interplay between an NADH oxidoreductase enzyme and an NAD+ dependent deacetylase may act as a rheostat in sensing mitochondrial stress.

Charnoly body as a novel biomarker of nutritional stress in Alzheimer’s Disease

Background: Charnoly body (CB) was discovered as universal biomarker of cell injury in the developing undernourished rat cerebellar Purkinje neurons and in the intrauterine Domoic acid and Kainic acid-exposed mice hippocampus and hypothalamic neurons. The incidence of CB increased with the severity of nutritional and environmental neurotoxic insult. Purpose: We proposed that stress (nutritional/environmental)-induced cortisol release augments, whereas metallothioneins (MTs), insulin-like growth factor (IGF-1), and brain-derived neurotropic factor (BDNF inhibit CB formation to prevent progressive neurodegeneration, early morbidity, and mortality in Alzheimer’s disease (AD).Results: CB is a pre-apoptotic biomarker of compromised mitochondrial bioenergetics and is formed in the most vulnerable cell in response to nutritional stress, intrauterine infection, environmental toxins, and/or drugs of abuse due to free radical overproduction and mitochondrial genome down-regulation. It appears as a pleomorphic, electron-dense multi-lamellar, quasi-crystalline stack of degenerated mitochondrial membranes in highly susceptible neurons and may be induced by microbial infection. CB formation was accompanied with stunted neuritogenesis in the aging mitochondrial genome knock out (RhOmgko) human dopaminergic (SK-N-SH, SHS-Y-5Y) neurons due to down-regulation of ubiquinone NADH oxidoreductase (complex-1). Transfection of RhOmgko neurons with ubiquinone NADH oxidoreductase (complex-1) gene and CoQ10, inhibited CB formation and augmented neuritogenesis, as confirmed in α-synuclein-metallothioneins triple knock out and weaver mutant mice. CB formation was attenuated in MTs-over-expressing weaver mutant mice.Findings: Accumulation of CB at the junction of axon hillock impairs axoplasmic transport of enzymes, neurotransmitters, hormones, neurotropic factors (NGF, BDNF), and mitochondria at the synaptic terminals to cause cognitive impairment, early morbidity, and mortality. Nonspecific induction of CB causes alopecia, myelosuppression, and GIT symptoms in multi-drug-resistant malignancies. Antioxidants and MTs inhibit CB formation as free radical scavengers by zinc-mediated transcriptional regulation of genes involved in growth, proliferation, differentiation, and development. Hence drugs may be developed to prevent CB formation and/or enhance charnolophagy as a basic molecular mechanism of intracellular detoxification to avert cognitive impairments in AD.Conclusion: Brain regional monoamine oxidase-specific CBs can be detected by 11C or 18F-labeled MAO-A or MAO-B inhibitors in vivo in addition to 18FdG-PET neuroimaging to quantitatively assess and improve the mitochondrial bioenergetics in AD. Key Words: Charnoly Body, Nutrition, Metallothioneins, Mitochondrial DNA, RhOmgko Neurons, Cortisol, IGF-1, BDNF, Alzheimer’s Disease