Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3‐dependent mechanism in male mice

Abstract

Nicotinamide adenine dinucleotide (NAD+) is a central signaling molecule and enzyme cofactor that is involved in a variety of fundamental biological processes. NAD+ levels decline with age, neurodegenerative conditions, acute brain injury, and in obesity or diabetes. Loss of NAD+ results in impaired mitochondrial and cellular functions. Administration of NAD+ precursor, nicotinamide mononucleotide (NMN), has shown to improve mitochondrial bioenergetics, reverse age‐associated physiological decline, and inhibit postischemic NAD+ degradation and cellular death. In this study, we identified a novel link between NAD+ metabolism and mitochondrial dynamics. A single dose (62.5 mg/kg) of NMN, administered to male mice, increases hippocampal mitochondria NAD+ pools for up to 24 hr posttreatment and drives a sirtuin 3 (SIRT3)‐mediated global decrease in mitochondrial protein acetylation. This results in a reduction of hippocampal reactive oxygen species levels via SIRT3‐driven deacetylation of mitochondrial manganese superoxide dismutase. Consequently, mitochondria in neurons become less fragmented due to lower interaction of phosphorylated fission protein, dynamin‐related protein 1 (pDrp1 [S616]), with mitochondria. In conclusion, manipulation of mitochondrial NAD+ levels by NMN results in metabolic changes that protect mitochondria against reactive oxygen species and excessive fragmentation, offering therapeutic approaches for pathophysiologic stress conditions.

SIRT3 Haploinsufficiency Aggravates Loss of GABAergic Interneurons and Neuronal Network Hyperexcitability in an Alzheimer's Disease Model

“…These findings reveal a mitochondria-mediated mechanism that may contribute to the previously reported beneficial effects of KE treatment on cognition and A␤ and pTau pathologies in 3xTgAD mice (Kashiwaya et al, 2013), as well as the ability of the combination of pyruvate and ␤-hydroxybutyrate to reduce hyperexcitability in AppPs1 mice (Zilberter et al, 2013). Bolstering mitochondrial NAD ϩ levels with the NAD ϩ precursors nicotinamide and nicotinamide riboside is another approach for enhancing SIRT3 activity and protecting neurons against A␤ and oxidative stress (Liu et al, 2013;Hou et al, 2018;Klimova et al, 2019). Interestingly, exercise and intermittent fasting protect against neuronal dysfunction and cognitive impairment in multiple mouse models of AD and other disorders that involve neuronal excitability (Wang et al, 2005;Halagappa et al, 2007;Nichol et al, 2007;Nigam et al, 2017, and also induce expression of SIRT3 in hippocampal and cortical neurons (Cheng et al, 2016;Liu et al, 2019).…”

Perindopril Improves Cardiac Function by Enhancing the Expression of SIRT3 and PGC-1α in a Rat Model of Isoproterenol-Induced Cardiomyopathy

“…Previous studies (Torrens-Mas et al, 2019) have shown that SIRT3 regulates mitochondrial biosynthesis by activating PGC-1a. NAD+ is necessary as a cofactor for SIRT3 deacetylation (Klimova et al, 2019); as a result, SIRT3 activity can be regulated by NAD+, NADH and some NAD+ metabolites. In this study, SIRT3 expression was downregulated in the myocardial tissues of the ISO group, which could be related to an altered NAD/NADH ratio as a result of AngII stimulation.…”

Role of NAD+—Modulated Mitochondrial Free Radical Generation in Mechanisms of Acute Brain Injury

“…Sirt3, Sirt4, and Sirt5 were identified as mitochondrial deacetylases [ 79 ]. However, only Sirt3 is considered to be the major mitochondrial deacetylase [ 84 , 85 , 86 ].…”

“…Apart from respiratory complexes and TCA cycle enzymes, enzymes of the mitochondrial antioxidative system, particularly MnSOD, are also hyperacetylated [ 56 ]. The increased acetylation of MnSOD inhibits the activity of this enzymes [ 88 ], and as a result, mitochondrial capacity to detoxify superoxide is compromised and mitochondria become a hot spot for ROS production ( Figure 3 ) [ 56 , 86 ].…”