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Cited by 559Genetics, Aging, and Longevity in Model OrganismsAutophagy in Disease and TherapyMitochondrial Function and Pathology

An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast

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Hughes, Adam L., Gottschling, Daniel E.·2012·Nature
DOI 10.1038/nature11654PMC PMC3521838
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Abstract

Mitochondria have a central role in ageing. They are considered to be both a target of the ageing process and a contributor to it. Alterations in mitochondrial structure and function are evident during ageing in most eukaryotes, but how this occurs is poorly understood. Here we identify a functional link between the lysosome-like vacuole and mitochondria in Saccharomyces cerevisiae, and show that mitochondrial dysfunction in replicatively aged yeast arises from altered vacuolar pH. We found that vacuolar acidity declines during the early asymmetric divisions of a mother cell, and that preventing this decline suppresses mitochondrial dysfunction and extends lifespan. Surprisingly, changes in vacuolar pH do not limit mitochondrial function by disrupting vacuolar protein degradation, but rather by reducing pH-dependent amino acid storage in the vacuolar lumen. We also found that calorie restriction promotes lifespan extension at least in part by increasing vacuolar acidity via conserved nutrient-sensing pathways. Interestingly, although vacuolar acidity is reduced in aged mother cells, acidic vacuoles are regenerated in newborn daughters, coinciding with daughter cells having a renewed lifespan potential. Overall, our results identify vacuolar pH as a critical regulator of ageing and mitochondrial function, and outline a potentially conserved mechanism by which calorie restriction delays the ageing process. Because the functions of the vacuole are highly conserved throughout evolution, we propose that lysosomal pH may modulate mitochondrial function and lifespan in other eukaryotic cells.

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  • Dementia with Lewy Bodies presents with frontal executive dysfunction and cognitive fluctuations associated with Lewy body inclusions in the amygdala and cortex.

    “In contrast to PD, dementia with Lewy Bodies (DLB) presents with frontal executive dysfunction and cognitive fluctuations associated with Lewy body inclusions in the amygdala and cortex.76”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [76]

    The paper’s ageing and mitochondrial-function passages concern yeast cells, not dementia with Lewy bodies. Searches for the claimed cognitive symptoms and Lewy body inclusions found no passage addressing them; the cited source therefore does not verify this claim. (LLM, conf=0.76)

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Authors
Hughes, A. L., & Gottschling, D. E.
Affiliations
Fred Hutch Cancer Center (US)
Corresponding author
Gottschling, Daniel E.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2012-11-21
Volume
492
Issue
7428
Pages
261-265
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature11654
PMC
PMC3521838
OpenAlex
W2154164675
Cited by
559
References
5
Citations by year
2026: 32 · 2025: 43 · 2024: 42 · 2023: 39 · 2022: 49 · 2021: 47 · 2020: 41 · 2019: 39 · 2018: 32 · 2017: 35 · 2016: 42 · 2015: 45 · 2014: 44 · 2013: 25 · 2012: 3
FWCI
12.16
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Helen Hay Whitney Foundation
  • National Institutes of Health
  • National Institute on Aging (T32AG000057, P01AG001751, R01AG037512, R01AG023779, R37AG023779, AG023779, AG037512)
  • National Cancer Institute (P30CA015704)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
vacuolar pH, mitochondrial dysfunction, lifespan extension, aging, Saccharomyces cerevisiae, caloric restriction, nutrient sensing, amino acid storage, lysosomes, asymmetric cell division, glucose limitation
MeSH terms
Amino Acids, Proton-Translocating ATPases, Homeostasis, Hydrogen-Ion Concentration, Lysosomes, Mitochondria, Saccharomyces cerevisiae, Vacuoles, Gene Expression, Saccharomyces cerevisiae Proteins, Microbial Viability

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