Mitochondrial metabolites extend lifespan

Abstract

SummaryDisruption of mitochondrial respiration in the nematode Caenorhabditis elegans can extend lifespan. We previously showed that long‐lived respiratory mutants generate elevated amounts of α‐ketoacids. These compounds are structurally related to α‐ketoglutarate, suggesting they may be biologically relevant. Here, we show that provision of several such metabolites to wild‐type worms is sufficient to extend their life. At least one mode of action is through stabilization of hypoxia‐inducible factor‐1 (HIF‐1). We also find that an α‐ketoglutarate mimetic, 2,4‐pyridinedicarboxylic acid (2,4‐PDA), is alone sufficient to increase the lifespan of wild‐type worms and this effect is blocked by removal of HIF‐1. HIF‐1 is constitutively active in isp‐1(qm150) Mit mutants, and accordingly, 2,4‐PDA does not further increase their lifespan. Incubation of mouse 3T3‐L1 fibroblasts with life‐prolonging α‐ketoacids also results in HIF‐1α stabilization. We propose that metabolites that build up following mitochondrial respiratory dysfunction form a novel mode of cell signaling that acts to regulate lifespan.

Krebs Cycle Intermediates Protective against Oxidative Stress by Modulating the Level of Reactive Oxygen Species in Neuronal HT22 Cells

“…AKG at 1mM protected the cells against H 2 O 2 (Figure 1) without causing a significant reduction in ROS levels (Figure 3). Because AKG is reported to activate the degradation of HIF-1α subunit and reduce the expression of downstream enzymes [6,7], reduction of this pathway may have been involved in the protective effects of AKG. FA may be another exceptional KCI.…”

“…KCIs activate specific signaling transduction pathways and exert various biological actions, such as neuroprotection, anti-inflammation, osteogenesis, and anti-aging [3]. For example, external supplementation with pyruvate (PA), oxaloacetate (OAA), α-ketoglutarate (AKG), malic acid (MA) or fumarate (FA), but not lactic acid (LA), succinate (SA), citrate (CA) or iso-citrate (ICA) significantly extends the lifespan of Caenorhabditis elegans by activating various transcriptional factor(s)-dependent transcriptional pathways [4,5,6]. Although fragmental information about the physiological roles of KCIs in the brain is available, KCIs are also proposed as being cardioprotective agents against myocardical infarction [7].…”

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

“…On the basis of the similar property principle (Nigsch & Mitchell, 2008), which states that structural similar molecules are more likely to have similar properties and biological activities, we used 2D and 3D molecular fingerprints to disentangle whether biguanides functioned as KDM inhibitors by mimicking KDM crystallographic ligands and/or tricarboxylic acid cycle (TCA) intermediates that have been shown to interact with KDMs (Tarhonskaya et al., 2017) and extend lifespan (Mishur et al., 2016). When pairwise similarity calculations were measured using Dice and Tanimoto coefficients, we failed to observe a significant 2D structural resemblance between biguanides and KDM‐targeted metabolites (Figure 5, top panels).…”

“…Thus, the unique side chains that are known to determine the pharmacological differences of biguanides including mitochondrial accumulation and mCI inhibition (Boukalova et al., 2016; Bridges, Sirviö, Agip & Hirst, 2016; Bridges et al., 2014) might also influence the ability of the biguanides to interfere with KDM6A/UTX activity. Our discovery that biguanides do not exhibit either 2D structural‐topological analogies or 3D nonanalogous bioisosteric physicochemical relationships with KDM‐targeted metabolites (Mishur et al., 2016; Tarhonskaya et al., 2017) strongly suggest that different biguanides might be viewed as a new family of pharmacologically active KDM6A/UTX regulators.…”

The Krebs Cycle Enzyme Isocitrate Dehydrogenase 3A Couples Mitochondrial Metabolism to Synaptic Transmission

“…Although the TCA cycle is known to generate electron carriers for the ETC, mutations in different TCA cycle enzymes result in phenotypic heterogeneity (Rustin et al, 1997) indicating that each step affects specific functions that remain to be elucidated (Brière et al, 2006). Indeed, TCA metabolites have been implicated in numerous cellular pathways that control ageing, neurodegeneration and cancer (Brière et al, 2006; Mishur et al, 2016). One of the most prominent TCA metabolites, the product of the Isocitrate Dehydrogenase complex (IDH), alpha-ketoglutarate (αKG), affects stem cell proliferation (TeSlaa et al, 2016), ageing (Chin et al, 2014) and DNA methylation (Yang et al, 2016) emphasizing the pleiotropy governed by TCA metabolites.…”