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

Abstract

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.

AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD + elevation

“…Reduced cellular NAD + level is a feature of aging (Gomes et al ., 2013), and a link between NAD + synthesis and AMPK has been suggested (Brandauer et al ., 2013). For these reasons, we next examined the relationships among AMPK, NAD + synthesis and senescence.…”

“…Given that NAD + is a coenzyme of Sirt family deacetylases that positively regulates autophagy (Lee et al ., 2008), and restrain aging (Gomes et al ., 2013), the activity of Sirt1 was monitored. As the findings, the activity of Sirt1 was increased by AMPK activation in senescent cells (Fig.…”

“…A decline in the nicotinamide adenine dinucleotide (NAD + ) in cells is another feature of aged organisms (Yoshino et al ., 2011; Gomes et al ., 2013). Supplementation with NAD + precursors was shown to ameliorate or reverse the effects of aging in old worms or mice (Gomes et al ., 2013; Mouchiroud et al ., 2013).…”

“…Supplementation with NAD + precursors was shown to ameliorate or reverse the effects of aging in old worms or mice (Gomes et al ., 2013; Mouchiroud et al ., 2013). However, the reasons why the NAD + decreases with age are not fully understood.…”

Age modifies respiratory complex I and protein homeostasis in a muscle type‐specific manner

“…However, neither abundance nor turnover of ND‐1 changed with age in either muscle. The nonuniform effects of age on complex I subunit abundance reported here are consistent with the loss of coordination between nuclear and mitochondrial‐encoded subunits of the respiratory chain recently described in aging muscle (Gomes et al ., 2013; Miwa et al ., 2014), although the change reported here (increased nuclear‐encoded and ND5 subunits) was dissimilar to that reported by Gomes et al . (decreased mitochondrial‐encoded subunits).…”