Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging

By A. P. Gomes, Nathan L. Price, A. Ling, J. Moslehi, M. Montgomery, Luis A. Rajman, James P. White, J. Teodoro, C. Wrann, Basil P. Hubbard and 7 more. Cell, 2013

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SUMMARY Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD+ and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.

Subfields: Geriatrics and Gerontology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/3bd14d3d4b7de2b5f83cf0658de769cdf311b95a

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Citations in the corpus

Sirt1 and the Mitochondria (2016, background): “That Sirt1 may act upstream of AMPK has support in a previous report, which showed that Sirt1 could potentially deacetylate and activate the major AMPK activating kinase, Serine/threonine kinase 11 (STK11) (or liver kinase B1, LKB1) (Lan et al., 2008).”
CD38 dictates age-related NAD decline and mitochondrial dysfunction through a SIRT3-dependent mechanism (2016, neutral): “1134 Cell Metabolism 23, 1127–1139, June 14, 2016 CD38Degrades NAD Precursors: Implications for NAD Replacement Therapy NAD precursors such as NMN and NR (nicotinamide riboside) have been proposed as NAD-replacement therapy for ageand diet-induced metabolic dysfunction (Cantó et al., 2012; Gomes et ”
Metabolic Control of Longevity. (2016, background): “Part of this deterioration is caused by the abovementioned decrease in NAD+ availability and consequent functional impairment of the deacetylase SIRT1 (Gomes et al., 2013).”
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “Combining the evidence that mitochondrial dysfunction is a hallmark of aging and NAD plays a crucial role in the maintenance of mitochondrial function.(341,345), we can hypothesize that aging-related NAD decline might be the cause of mitochondria dysfunction.”
Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype (2015, background): “Notably, NAD+ declines with age in several tissues (Braidy et al., 2011; Gomes et al., 2013; Stein and Imai, 2014; Yoshino et al., 2011), linking NAD to both senescence and aging.”
NAD+ metabolism and the control of energy homeostasis - a balancing act between mitochondria and the nucleus (2015, background): “Furthermore, as NMNAT1 is located in the nucleus, the nuclear NAD+ pool may play a more dominant role for the induction of mitochondrial-encoded OXPHOS transcripts, potentially through alterations in SIRT1-directed HIF1a destabilization, leading to c-Myc activation of the nuclear-encoded mitochondri”
Therapeutic potential of NAD-boosting molecules: the in vivo evidence (2018, neutral): “for 7 days) reverses detrimental age-associated changes in muscle by increasing mitochondrial function, increasing ATP production, reducing inflammation, and switching glycolytic type II muscle to a more oxidative fiber type (Gomes et al., 2013).”
NAD+ intermediates: The biology and therapeutic potential of NMN and NR (2017, neutral): “NMN improves high-fat-diet-induced glucose intolerance and dyslipidemia (Yoshino et al., 2011), skeletal muscle mitochondrial oxidative metabolism (Gomes et al., 2013), and endothelial function (de Picciotto et al., 2016) better in aged mice than young mice.”