Chemical genetic screen in fission yeast reveals roles for vacuolar acidification, mitochondrial fission, and cellular GMP levels in lifespan extension

Abstract

The discovery that genetic mutations in several cellular pathways can increase lifespan has lent support to the notion that pharmacological inhibition of aging pathways can be used to extend lifespan and to slow the onset of age-related diseases. However, so far, only few compounds with such activities have been described. Here, we have conducted a chemical genetic screen for compounds that cause the extension of chronological lifespan of Schizosaccharomyces pombe. We have characterized eight natural products with such activities, which has allowed us to uncover so far unknown anti-aging pathways in S. pombe. The ionophores monensin and nigericin extended lifespan by affecting vacuolar acidification, and this effect depended on the presence of the vacuolar ATPase (V-ATPase) subunits Vma1 and Vma3. Furthermore, prostaglandin J₂ displayed anti-aging properties due to the inhibition of mitochondrial fission, and its effect on longevity required the mitochondrial fission protein Dnm1 as well as the G-protein-coupled glucose receptor Git3. Also, two compounds that inhibit guanosine monophosphate (GMP) synthesis, mycophenolic acid (MPA) and acivicin, caused lifespan extension, indicating that an imbalance in guanine nucleotide levels impinges upon longevity. We furthermore have identified diindolylmethane (DIM), tschimganine, and the compound mixture mangosteen as inhibiting aging. Taken together, these results reveal unanticipated anti-aging activities for several phytochemicals and open up opportunities for the development of novel anti-aging therapies.

The yeast protein kinase Sch9 adjusts V-ATPase assembly/disassembly to control pH homeostasis and longevity in response to glucose availability

“…Although V-ATPase activity has been implicated in regulating yeast ageing [25, 29], not much is known about the effect on CLS when the V-ATPase function is abrogated in S . cerevisiae .…”

“…Besides fermentable sugars, additional signals, such as osmotic stress and high extracellular pH, also influence V 0 -V 1 assembly levels [22–24]. Interestingly, increasing evidence suggests that V-ATPase activity is required for regulating cell survival in both yeast and higher eukaryotes [25–29]. …”

Recent Insights into the Structure, Regulation, and Function of the V-ATPases

“…The latter function accounts for the increased assembly of the V-ATPase observed on exposure of yeast cells to high salt. A particularly intriguing observation is the link between vacuolar acidification and lifespan, where enhanced vacuolar acidity helps preserve mitochondrial function [113,114]. …”

Gold nanoparticles enhance TRAIL sensitivity through Drp1-mediated apoptotic and autophagic mitochondrial fission in NSCLC cells

“…25,26 Mitochondrial dynamics is known to be involved in various fundamental biological processes, such as mitochondrial biogenesis, maintenance of mitochondrial DNA, cell metabolism, calcium buffering, and cell survival and death, 27 and abnormal mitochondrial dynamics has been linked to neurodegenerative diseases, diabetes, aging, and cancer. 28,29 Mitochondrial fission is a critical event leading to mitochondrial outer membrane permeabilization, resulting in the release of cytochrome c that ultimately activates the intrinsic apoptotic pathway, while fusion confers resistance to apoptosis. 30 Recent evidence highlighted the importance of mitochondrial fission in quality control and autophagic clearance of damaged mitochondria, the process referring to mitophagy.…”

“…30 Recent evidence highlighted the importance of mitochondrial fission in quality control and autophagic clearance of damaged mitochondria, the process referring to mitophagy. 29 Since the efficiency of the mitochondria-mediated cell death can be greatly influenced by mitochondrial fission, extensive effort has been devoted to developing therapeutic approaches to reverse chemoresistance focusing on the regulation of mitochondrial dynamics. 31,32 Indeed, several studies suggested that chemoresistant cancer cells show a higher mitochondrial fusion rate than their chemosensitive counterparts.…”