Dataset Information

C16ORF70/Mytho promotes healthy ageing in C. elegans and prevents cellular senescence in mammals.

ABSTRACT: The identification of genes that confer either extension of lifespan or accelerate age-related decline was a step forward in understanding the mechanisms of ageing and revealed that it is partially controlled by genetics and transcriptional programs. Here we discovered that the human DNA sequence C16ORF70 encoded for a protein, named MYTHO (Macroautophagy and YouTH Optimizer), which controls life- and health-span. MYTHO protein is conserved from C. elegans to humans and its mRNA was upregulated in aged mice and elderly people. Deletion of the ortholog myt-1 gene in C. elegans dramatically shortened lifespan and decreased animal survival upon exposure to oxidative stress. Mechanistically, MYTHO is required for autophagy likely because it acts as a scaffold that binds WIPI2 and BCAS3 to recruit and assemble the conjugation system at the phagophore, the nascent autophagosome. We conclude that MYTHO is a transcriptionally regulated initiator of autophagy that is central in promoting stress resistance and healthy ageing.

SUBMITTER: Franco-Romero A

PROVIDER: S-EPMC11291266 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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Publications

C16ORF70/MYTHO promotes healthy aging in C.elegans and prevents cellular senescence in mammals.

Franco-Romero Anais A Morbidoni Valeria V Milan Giulia G Sartori Roberta R Wulff Jesper J Romanello Vanina V Armani Andrea A Salviati Leonardo L Conte Maria M Salvioli Stefano S Franceschi Claudio C Buonomo Viviana V Swoboda Casey O CO Grumati Paolo P Pannone Luca L Martinelli Simone S Jefferies Harold Bj HB Dikic Ivan I van der Laan Jennifer J Cabreiro Filipe F Millay Douglas P DP Tooze Sharon A SA Trevisson Eva E Sandri Marco M

The Journal of clinical investigation 20240613 15

The identification of genes that confer either extension of life span or accelerate age-related decline was a step forward in understanding the mechanisms of aging and revealed that it is partially controlled by genetics and transcriptional programs. Here, we discovered that the human DNA sequence C16ORF70 encodes a protein, named MYTHO (macroautophagy and youth optimizer), which controls life span and health span. MYTHO protein is conserved from Caenorhabditis elegans to humans and its mRNA was ...[more]

PMID: 38869949

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Project description:BackgroundNuclear factor-κB is a multi-subunit transcription factor that plays a central role in cellular senescence. We previously reported that an increase in the p52 subunit is seen in senescent cells and aged tissue. In the current work, we examined the mechanism by which p52 is activated and whether the increase in p52 promotes senescence.ResultsUsing both primary mouse embryonic fibroblasts (MEFs) and WI-38 human lung fibroblasts, we examined cells after serial passage and following prolonged culture. An increase in p52 was found in the nucleus relative to pre-senescent cells. The increase in p52 protein was not reflected by an increase in NFKB2 mRNA or by an increase in the abundance of upstream activating kinases, IKKα and NIK. To examine whether p52 promotes senescence, we over-expressed mature p52 in primary MEFs. Significantly more senescence was seen compared to control, a finding not seen with p52 mutated at critical DNA binding residues. In addition, blocking p52 nuclear translocation with the peptide inhibitor, SN52, decreased β-galactosidase (β-gal) formation. Subsequent filtration studies demonstrated that proteins in conditioned media (CM) were necessary for the increase in p52 and mass spectrometry identified S100A4 and cyclophilin A (CYPA) as potential factors in CM necessary for induction of p52. The requirement of these proteins in CM for induction of p52 was confirmed using depletion and supplementation studies. In addition, we found that activation of STAT3 signaling was required for the increase in p52. Finally, genome wide ChIP-sequencing analysis confirmed that there is an increase in p52 chromatin enrichment with senescence and identified several downstream factors whose expression is regulated by increased p52 binding.ConclusionsThese results demonstrate that p52 nuclear translocation is increased in senescent cells by factors in conditioned media and that mature p52 induces cellular senescence. The data are consistent with the prior observation that p52 is elevated in aged tissue and support the hypothesis that p52 contributes to organismal aging.

Dataset Information

C16ORF70/Mytho promotes healthy ageing in C. elegans and prevents cellular senescence in mammals.

Publications

C16ORF70/MYTHO promotes healthy aging in C.elegans and prevents cellular senescence in mammals.

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