The role of mitochondrial sirtuins in health and disease

Tarragó

Molecular and Cellular Endocrinology

2017

155

179

Life as we know it cannot exist without the nucleotide nicotinamide adenine dinucleotide (NAD). From the simplest organism, such as bacteria, to the most complex multicellular organisms, NAD is a key cellular component. NAD is extremely abundant in most living cells and has traditionally been described to be a cofactor in electron transfer during oxidation-reduction reactions. In addition to participating in these reactions, NAD has also been shown to play a key role in cell signaling, regulating several pathways from intracellular calcium transients to the epigenetic status of chromatin. Thus, NAD is a molecule that provides an important link between signaling and metabolism, and serves as a key molecule in cellular metabolic sensoring pathways. Importantly, it has now been clearly demonstrated that cellular NAD levels decline during chronological aging. This decline appears to play a crucial role in the development of metabolic dysfunction and age-related diseases. In this review we will discuss the molecular mechanisms responsible for the decrease in NAD levels during aging. Since other reviews on this subject have been recently published, we will concentrate on presenting a critical appraisal of the current status of the literature and will highlight some controversial topics in the field. In particular, we will discuss the potential role of the NADase CD38 as a driver of age-related NAD decline.

Section: What Causes the Nad Decline Observed During The Aging Process?mentioning

confidence: 99%

Section: What Causes the Nad Decline Observed During The Aging Process?mentioning

confidence: 99%

NAD and the aging process: Role in life, death and everything in between

Tarragó

Molecular and Cellular Endocrinology

2017

155

179

“…7 In addition to their traditional HDAC activity, it has also been found that many sirtuins target non-histone proteins throughout the cell, and are capable of catalyzing several additional post-translational modification reactions. 8,9 Given the diversity of the biological processes they modulate, it comes as no surprise that this class of enzymes has been found to be involved in many different diseases in humans, including cancer (reviewed in 10).…”

Section: Introductionmentioning

confidence: 99%

Expression profile of SIRT2 in human melanoma and implications for sirtuin-based chemotherapy

et al. 2017

Melanoma is cancer of melanin-containing melanocyte cells. This neoplasm is one of the most deadly forms of skin cancer, and currently available therapeutic options are insufficient in significantly improve outcomes for many patients. Therefore, novel targets are required to effectively manage this neoplasm. Several sirtuins have previously been found to be upregulated in melanoma, so in this study, the expression profile of SIRT2 was determined. Employing a tissue microarray containing benign nevi, primary melanomas, and lymph node metastases, we have found that the tissue from lymph node metastases appears to have a significant upregulation of SIRT2 relative to primary tumors across the nuclear, cytoplasmic, and whole cell data. Additionally, SIRT2 staining was found to be higher in the nucleus of metastatic melanomas compared to cytoplasmic staining. As SIRT2 is considered to be a predominantly cytoplasmic protein, this is a novel and very interesting finding. This, combined with previous studies that show other sirtuins are increased in melanoma and involved in cellular proliferation and survival, leads to the suggestion that exploring pan-sirtuin inhibitors may be the best target for the next iteration of melanoma chemotherapeutics.

Free Radical Biology and Medicine

“…NAD + content appears to be unevenly distributed throughout the cell with the lowest concentrations observed in the nucleus in comparison to the mitochondria and cytosol [151, 152]. NAD + is a substrate for two families of enzymes that serve critical roles in the DNA repair response: the PARP family and the sirtuin family of NAD + -dependent deacetylases (SIRTs) [7, 153–155]. Three of the 17-membered PARP family of enzymes (PARPs1–3) have known roles in DNA repair where PARP1 and PARP2 play a role in BER, while PARP3 senses DSBs and is involved in DSBR [81, 156–159].…”

Section: Mitochondrial Dna Genome Maintenancementioning

confidence: 99%

DNA damage related crosstalk between the nucleus and mitochondria

Saki

Prakash

2017

119

102

The electron transport chain is the primary pathway by which a cell generates energy in the form of ATP. Byproducts of this process produce reactive oxygen species that can cause damage to mitochondrial DNA. If not properly repaired, the accumulation of DNA damage can lead to mitochondrial dysfunction linked to several human disorders including neurodegenerative diseases and cancer. Mitochondria are able to combat oxidative DNA damage via repair mechanisms that are analogous to those found in the nucleus. Of the repair pathways currently reported in the mitochondria, the base excision repair pathway is the most comprehensively described. Proteins that are involved with the maintenance of mtDNA are encoded by nuclear genes and translocate to the mitochondria making signaling between the nucleus and mitochondria imperative. In this review, we discuss the current understanding of mitochondrial DNA repair mechanisms and also highlight the sensors and signaling pathways that mediate crosstalk between the nucleus and mitochondria in the event of mitochondrial stress.